Phase Separation Enhanced PROTAC for Highly Efficient Protein Degradation.

Biomacromolecular condensates formed via phase separation establish compartments for the enrichment of specific compositions, which is also used as a biological tool to enhance molecule condensation, thereby increasing the efficiency of biological processes. Proteolysis-targeting chimeras (PROTACs) have been developed as powerful tools for targeted protein degradation in cells, offering a promising approach for therapies for different diseases. Herein, we introduce an intrinsically disordered region in the PROTAC (denoted PSETAC), which led to the formation of droplets of target proteins in the cells and increased degradation efficiency compared with PROTAC without phase separation. Further, using a nucleus targeting intrinsically disordered domain, the PSETAC was able to target and degrade nuclear-located proteins. Finally, we demonstrated intracellular delivery of PSETAC using lipid nanoparticle-encapsulated mRNA (mRNA-LNP) for the degradation of the endogenous target protein. This study established the PSETAC mRNA-LNP method as a potentially translatable, safe therapeutic strategy for the development of clinical applications based on PROTAC.

Efficacy and risk of donor-derived CAR-T treatment of relapsed B-cell acute lymphoblastic leukemia after hematopoietic stem cell transplantation.

The one-year survival rate for patients experiencing a relapse of B-cell acute lymphocytic leukemia (B-ALL) following hematopoietic stem cell transplantation (HSCT) is approximately 30%. Patients experiencing a relapse after allogeneic HSCT frequently encounter difficulties in obtaining autologous CAR-T products. We conducted a study involving 14 patients who received donor-derived CAR-T therapy for relapsed B-ALL following HSCT between August 2019 and May 2023 in our center. The results revealed a CR/CRi rate of 78.6% (11/14), a GVHD rate of 21.4% (3/14), and a 1-year overall survival (OS) rate of 56%. Decreased bone marrow donor cell chimerism in 9 patients recovered after CAR-T therapy. The main causes of death were disease progression and infection. Further analysis showed that GVHD (HR 7.224, 95% CI 1.42-36.82, P = 0.017) and platelet recovery at 30 days (HR 6.807, 95% CI 1.61-28.83, P = 0.009) are significantly associated with OS after CAR-T therapy. Based on the findings, we conclude that donor-derived CAR-T cells are effective in treating relapsed B-ALL patients following HSCT. Additionally, GVHD and poor platelet recovery impact OS, but further verification with a larger sample size is needed.

Mouse serum albumin induces neuronal apoptosis and tauopathies.

The elderly frequently present impaired blood-brain barrier which is closely associated with various neurodegenerative diseases. However, how the albumin, the most abundant protein in the plasma, leaking through the disrupted BBB, contributes to the neuropathology remains poorly understood. We here demonstrated that mouse serum albumin-activated microglia induced astrocytes to A1 phenotype to remarkably increase levels of Elovl1, an astrocytic synthase for very long-chain saturated fatty acids, significantly promoting VLSFAs secretion and causing neuronal lippoapoptosis through endoplasmic reticulum stress response pathway. Moreover, MSA-activated microglia triggered remarkable tau phosphorylation at multiple sites through NLRP3 inflammasome pathway. Intracerebroventricular injection of MSA into the brains of C57BL/6J mice to a similar concentration as in patient brains induced neuronal apoptosis, neuroinflammation, increased tau phosphorylation, and decreased the spatial learning and memory abilities, while Elovl1 knockdown significantly prevented the deleterious effect of MSA. Overall, our study here revealed that MSA induced tau phosphorylation and neuron apoptosis based on MSA-activated microglia and astrocytes, respectively, showing the critical roles of MSA in initiating the occurrence of tauopathies and cognitive decline, and providing potential therapeutic targets for MSA-induced neuropathology in multiple neurodegenerative disorders.

Molecular Epidemiological Study of a Human Brucellosis Outbreak - Weihai City, Shandong Province, China, 2022.

What is already known about this topic?: Brucellosis, mainly caused by Brucella melitensis (B. melitensis), is regarded as a significant zoonotic disease in China. In Weihai, located at the eastern end of the Shandong Peninsula, brucellosis has been in a low epidemic phase for the past five years. What is added by this report?: This was the initial report of a brucellosis outbreak in the last five years. Strains of B. melitensis bv. 3 from Weihai and other cities showed a close genetic relationship, suggesting a potential common ancestry. What are the implications for public health practice?: Epidemiological investigations depend on standardized and effective molecular typing methods and analysis tools for public health laboratories to identify and trace outbreaks. Understanding the circulation patterns of livestock in free-range households in heavily affected areas is essential for controlling the spread of brucellosis.

Effects of temperature anomaly on sperm quality: A multi-center study of 33,234 men.

Backgrounds: Global fertility rates continue to decline and sperm quality is a prime factor affecting male fertility. Both extreme cold and heat have been demonstrated to be associated with decreased sperm quality, but no epidemiological studies have considered human adaptation to long-term temperature. Our aim was to conduct a multi-center retrospective cohort study to investigate exposure-response relationship between temperature anomaly (TA) that deviate from long-term climate patterns and sperm quality. Methods: A total of 78,952 semen samples measured in 33,234 donors from 6 provincial human sperm banks in China were collected. This study considered heat and cold acclimatization to prolonged exposure in humans and explored the exposure-response relationship between TAs and sperm quality parameters (sperm concentrations, sperm count, progressive motility, progressive sperm count, total motility and total motile sperm count) during the hot and cold seasons, respectively. Linear mixed models and generalized linear models were built separately for specific centers to pool in a meta-analysis to obtain the pooled effect of TA on sperm quality, considering repeated measurements data structure and spatial heterogeneity. Results: We identified an inverted U-shaped exposure-response relationship between TA and sperm quality during the hot season. Significant negative effect of anomalous cold on sperm quality during the hot season was found after additional adjustment for Body mass index, marital status and childbearing history. The heat-related TA in hot season was significantly negatively associated with sperm concentration, progressive sperm count and total motile sperm count (all P-values<0.05). After adjusting the relative humidity, the cold-related TA in cold season was negatively associated with the sperm total motility (P-values<0.05). Conclusions: Our results suggest both heat-related and cold-related TAs are associated with decreased sperm quality. The findings highlight the importance of reducing exposure to anomalous temperatures to protect male fertility.

Calcitonin gene-related peptide-modulated macrophage phenotypic alteration regulates angiogenesis in early bone healing.

OBJECTIVES: This study aimed to investigate the effect of calcitonin gene-related peptide (CGRP) on the temporal alteration of macrophage phenotypes and macrophage-regulated angiogenesis duringearlybonehealing and preliminarily elucidate the mechanism. METHODS: In vivo, the rat mandibular defect models were established with inferior alveolar nerve transection (IANT) or CGRP receptor antagonist injection. Radiographicandhistologic assessments for osteogenesis, angiogenesis, and macrophage phenotypic alteration within bone defects were performed. In vitro, the effect and mechanism of CGRP on macrophage polarization and phenotypic alteration were analyzed. Then the conditioned medium (CM) from CGRP-treated M1 or M2 macrophages was used to culture human umbilical vein endothelial cells (HUVECs), and the CGRP's effect on macrophage-regulated angiogenesis was detected. RESULTS: Comparable changes following IANT and CGRP blockade within bone defects were observed, including the suppression of early osteogenesis and angiogenesis, the prolonged M1 macrophage infiltration and the prohibited transition toward M2 macrophages around vascular endothelium. In vitro experiments showed that CGRP promoted M2 macrophage polarization while upregulating the expression of interleukin 6 (IL-6), a major cytokine that facilitates the transition from M1 to M2-dominant stage, in M1 macrophages via the activation of Yes-associated protein 1. Moreover, CGRP-treated macrophage-CM showed an anabolic effect on HUVECs angiogenesis compared with macrophage-CM and might prevail over the direct effect of CGRP on HUVECs. CONCLUSIONS: Collectively, our results reveal the effect of CGRP on M1 to M2 macrophage phenotypic alteration possibly via upregulating IL-6 in M1 macrophages, and demonstrate the macrophage-regulated pro-angiogenic potential of CGRP in early bone healing.

Ensemble learning-assisted prediction of prolonged hospital length of stay after spine correction surgery: a multi-center cohort study.

PURPOSE: This research aimed to develop a machine learning model to predict the potential risk of prolonged length of stay in hospital before operation, which can be used to strengthen patient management. METHODS: Patients who underwent posterior spinal deformity surgery (PSDS) from eleven medical institutions in China between 2015 and 2022 were included. Detailed preoperative patient data, including demographics, medical history, comorbidities, preoperative laboratory results, and surgery details, were collected from their electronic medical records. The cohort was randomly divided into a training dataset and a validation dataset with a ratio of 70:30. Based on Boruta algorithm, nine different machine learning algorithms and a stack ensemble model were trained after hyperparameters tuning visualization and evaluated on the area under the receiver operating characteristic curve (AUROC), precision-recall curve, calibration, and decision curve analysis. Visualization of Shapley Additive exPlanations method finally contributed to explaining model prediction. RESULTS: Of the 162 included patients, the K Nearest Neighbors algorithm performed the best in the validation group compared with other machine learning models (yielding an AUROC of 0.8191 and PRAUC of 0.6175). The top five contributing variables were the preoperative hemoglobin, height, body mass index, age, and preoperative white blood cells. A web-based calculator was further developed to improve the predictive model's clinical operability. CONCLUSIONS: Our study established and validated a clinical predictive model for prolonged postoperative hospitalization duration in patients who underwent PSDS, which offered valuable prognostic information for preoperative planning and postoperative care for clinicians. Trial registration ClinicalTrials.gov identifier NCT05867732, retrospectively registered May 22, 2023, https://classic. CLINICALTRIALS: gov/ct2/show/NCT05867732 .

Multiresponsive luminescent metal-organic framework for cooking oil adulteration detection and gallium(III) sensing.

A new 3D metal-organic framework {[Cd16(tr2btd)10(dcdps)16(H2O)3(EtOH)]∙15DMF}n (MOF 1, tr2btd = 4,7-di(1,2,4-triazol-1-yl)benzo-2,1,3-thiadiazole, H2dcdps = 4,4'-sulfonyldibenzoic acid) was obtained and its luminescent properties were studied. MOF 1 exhibited bright blue-green luminescence with a high quantum yield of 74 % and luminescence quenching response to a toxic natural polyphenol gossypol and luminescence enhancement response to some trivalent metal cations (Fe3+, Cr3+, Al3+ and Ga3+). The limit of gossypol detection was 0.20 µM and the determination was not interfered by the components of the cottonseed oil. The limit of detection of gallium(III) was 1.1 µM. It was demonstrated that MOF 1 may be used for distinguishing between the genuine sunflower oil and oil adulterated by crude cottonseed oil through qualitative luminescent and quantitative visual gossypol determination.

Ln-MOF-Based Hydrogel Films with Tunable Luminescence and Afterglow Behavior for Visual Detection of Ofloxacin and Anti-Counterfeiting Applications.

Highly selective and sensitive quantitative detection of ofloxacin (OFX) at ultralow concentrations in aqueous media and development of new afterglow materials remains a challenge. Herein, a new 2D water-stable lanthanide metal-organic framework (NIIC-2-Tb) is proposed, which exhibits high selectivity towards OFX through the luminescence quenching with the lowest detection limit (1.1 × 10-9 M) reported to date and a fast response within 6 s. In addition, the luminescent detection of OFX by NIIC-2-Tb is not affected by typical components of blood plasma and urine. The excellent sensing effect of NIIC-2-Tb is further utilized to prepare a composite functional sensing carrageenan hydrogel material for the rapid detection of OFX in meat in real time and the first discovery of impressive afterglow in MOF-based hydrogels. This study not only presents novel Ln-MOF materials and Ln-MOF-based hydrogel films for luminescent sensing of OFX, but also demonstrates color-tunable luminescent films with afterglow, which expands the application of composite luminescent materials for detection and anti-counterfeiting.

Astrocytes Excessively Engulf Synapses in a Mouse Model of Alzheimer's Disease.

Synapse loss is one of the most critical features in Alzheimer's disease (AD) and correlates with cognitive decline. Astrocytes mediate synapse elimination through multiple EGF-like domains 10 (MEGF10) pathways in the developing and adult brain to build the precise neural connectivity. However, whether and how astrocytes mediate synapse loss in AD remains unknown. We here find that the phagocytic receptor MEGF10 of astrocytes is significantly increased in vivo and in vitro, which results in excessive engulfment of synapses by astrocytes in APP/PS1 mice. We also observe that the astrocytic lysosomal-associated membrane protein 1 (LAMP1) is significantly elevated, colocalized with the engulfed synaptic puncta in APP/PS1 mice, and astrocytic lysosomes contain more engulfed synaptic puncta in APP/PS1 mice relative to wild type mice. Together, our data provide evidence that astrocytes excessively engulf synapses in APP/PS1 mice, which is mediated by increased MEGF10 and activated lysosomes. The approach targeting synapse engulfment pathway in astrocytes would be a potent therapy for AD.

Highly sensitive sensing of DPA by lanthanide metal-organic frameworks and detection of fiber membranes.

The detection of 2,6-pyridinecarboxylic acid (DPA), as a biomarker of Bacillus anthracis, has attracted wide attention. In previous reports of DPA detection, fluorescent probes may not have high specificity. Therefore, the rational design and development of fluorescent sensors with excellent performance is of great significance for the detection of DPA. In this study, two novel lanthanide metal-organic frameworks (Ln-MOFs) were synthesized by hydrothermal method using 3-polyfluorobiphenyl-3 ', 4,5 ' -tricarboxylic acid (H2FPTA) as ligand. Studies have shown that Ln-MOFs can detect DPA in real time, with detection limits of 0.54 µM and 0.67 µM, respectively, and have a high recovery rate (95 % -108 %) in fetal bovine serum. As a self-calibration sensor, other substances in the blood can be clearly distinguished by a two-dimensional fluorescence code diagram. After the Ln-MOFs were spun into nanofiber membranes, they responded quickly to DPA. This increases practicability and provides a promising idea for the development of simple and efficient ratio sensors.

Portable and Recyclable Luminescent Lanthanide Coordination Polymer Film Sensors for Adenosine Triphosphate in Urine.

Adenosine triphosphate (ATP) is a small molecule that is released to the urine from bladder urothelial cells and the bladder mucosal band of the human body. In certain cases, ATP can serve as a biomarker in bladder disease. For the practical applicability of luminescent sensors for ATP in urine, it is significant to find a new strategy for making the detection progress simple and available for in-field urine analysis. Here, a novel luminescent lanthanide coordination polymer (Tb-BPA) was designed and synthesized for quick and sensitive detection of ATP through luminescence quenching with a quenching constant of 4.90 × 103 M-1 and a detection limit of 0.55 × 10-6 M. Besides, Tb-BPA has excellent anti-interference ability and can detect ATP in simulated urine with a small relative standard deviation (<4%). Moreover, the luminescent polyacrylonitrile nanofiber films modified by Tb-BPA were prepared by electrospinning and were used for ATP visual detection. Notably, this film is easy to recover and reuse, and maintains good detection performance after at least 7 cycles.

Mettl3­mediated m6A RNA methylation regulates osteolysis induced by titanium particles.

Peri­prosthetic osteolysis (PPO) induced by wear particles is considered the primary cause of titanium prosthesis failure and revision surgery. The specific molecular mechanisms involve titanium particles inducing multiple intracellular pathways, which impact disease prevention and the targeted therapy of PPO. Notably, N6­methyladenosine (m6A) serves critical roles in epigenetic regulation, particularly in bone metabolism and inflammatory responses. Thus, the present study aimed to determine the role of RNA methylation in titanium particle­induced osteolysis. Results of reverse transcription­quantitative PCR (RT­qPCR), western blotting, ELISA and RNA dot blot assays revealed that titanium particles induced osteogenic inhibition and proinflammatory responses, accompanied by the reduced expression of methyltransferase­like (Mettl) 3, a key component of m6A methyltransferase. Specific lentiviruses vectors were employed for Mettl3 knockdown and overexpression experiments. RT­qPCR, western blotting and ELISA revealed that the knockdown of Mettl3 induced osteogenic inhibition and proinflammatory responses comparable with that induced by titanium particle, while Mettl3 overexpression attenuated titanium particle­induced cellular reactions. Methylated RNA immunoprecipitation­qPCR results revealed that titanium particles mediated the methylation of two inhibitory molecules, namely Smad7 and SMAD specific E3 ubiquitin protein ligase 1, via Mettl3 in bone morphogenetic protein signaling, leading to osteogenic inhibition. Furthermore, titanium particles induced activation of the nucleotide binding oligomerization domain 1 signaling pathway through methylation regulation, and the subsequent activation of the MAPK and NF­κB pathways. Collectively, the results of the present study indicated that titanium particles utilized Mettl3 as an upstream regulatory molecule to induce osteogenic inhibition and inflammatory responses. Thus, the present study may provide novel insights into potential therapeutic targets for aseptic loosening in titanium prostheses.

Neuronal conversion from glia to replenish the lost neurons.

ABSTRACT: Neuronal injury, aging, and cerebrovascular and neurodegenerative diseases such as cerebral infarction, Alzheimer's disease, Parkinson's disease, frontotemporal dementia, amyotrophic lateral sclerosis, and Huntington's disease are characterized by significant neuronal loss. Unfortunately, the neurons of most mammals including humans do not possess the ability to self-regenerate. Replenishment of lost neurons becomes an appealing therapeutic strategy to reverse the disease phenotype. Transplantation of pluripotent neural stem cells can supplement the missing neurons in the brain, but it carries the risk of causing gene mutation, tumorigenesis, severe inflammation, and obstructive hydrocephalus induced by brain edema. Conversion of neural or non-neural lineage cells into functional neurons is a promising strategy for the diseases involving neuron loss, which may overcome the above-mentioned disadvantages of neural stem cell therapy. Thus far, many strategies to transform astrocytes, fibroblasts, microglia, Müller glia, NG2 cells, and other glial cells to mature and functional neurons, or for the conversion between neuronal subtypes have been developed through the regulation of transcription factors, polypyrimidine tract binding protein 1 (PTBP1), and small chemical molecules or are based on a combination of several factors and the location in the central nervous system. However, some recent papers did not obtain expected results, and discrepancies exist. Therefore, in this review, we discuss the history of neuronal transdifferentiation, summarize the strategies for neuronal replenishment and conversion from glia, especially astrocytes, and point out that biosafety, new strategies, and the accurate origin of the truly converted neurons in vivo should be focused upon in future studies. It also arises the attention of replenishing the lost neurons from glia by gene therapies such as up-regulation of some transcription factors or down-regulation of PTBP1 or drug interference therapies.

How rumination influences meaning in life among Chinese high school students: the mediating effects of perceived chronic social adversity and coping style.

Meaning in life can be affected by many factors during adolescence. This study explored the relationship between rumination and meaning in life among high school students, as well as the mediating effect of perceived chronic social adversity and coping style. A sample of 1,275 Chinese high school students were surveyed using four questionnaires. Data analysis was conducted using Harman's single-factor test, Pearson's correlation coefficient with confidence intervals (CI), and a structural equation model. We found that rumination significantly negatively affected meaning in life among high school students (ß = -0.28, 95% CI = -0.33-0.23). Perceived chronic social adversity (ß = -0.14, 95% CI = -0.29-0.02) and negative coping style (ß = -0.09, 95% CI = -0.16-0.04) each had mediating effects between rumination and meaning in life. Further, perceived chronic social adversity and coping style had chain-mediating effects between rumination and meaning in life, with both positive (ß = -0.11, 95% CI = -0.17-0.07) and negative (ß = -0.08, 95% CI = -0.13-0.04) coping styles showing significant effects. To enhance the meaning in life among high school students, appropriate strategies to reduce the levels of rumination and perceived chronic social adversity are needed, while also fostering appropriate coping styles.

A single site ruthenium catalyst for robust soot oxidation without platinum or palladium.

The quest for efficient non-Pt/Pd catalysts has proved to be a formidable challenge for auto-exhaust purification. Herein, we present an approach to construct a robust catalyst by embedding single-atom Ru sites onto the surface of CeO2 through a gas bubbling-assisted membrane deposition method. The formed single-atom Ru sites, which occupy surface lattice sites of CeO2, can improve activation efficiency for NO and O2. Remarkably, the Ru1/CeO2 catalyst exhibits exceptional catalytic performance and stability during auto-exhaust carbon particle oxidation (soot), rivaling commercial Pt-based catalysts. The turnover frequency (0.218 h-1) is a nine-fold increase relative to the Ru nanoparticle catalyst. We further show that the strong interfacial charge transfer within the atomically dispersed Ru active site greatly enhances the rate-determining step of NO oxidation, resulting in a substantial reduction of the apparent activation energy during soot oxidation. The single-atom Ru catalyst represents a step toward reducing dependence on Pt/Pd-based catalysts.

Epidemiological characteristics and spatio-temporal analysis of brucellosis in Shandong province, 2015-2021.

BACKGROUND: Brucellosis is one of the major public health problems in China, it not only causes huge economic losses to the society, but also threatens the human's physical and mental health. The reported cases of brucellosis in Shandong province were at a high level, therefore, it is necessary for us to understand the epidemic characteristics and distribution trend of Brucellosis in Shandong province. This study aims to describe the epidemiological characteristics and spatial clustering characteristics of brucellosis in Shandong Province, provide a reference for the scientific prevention and control. METHODS: Human brucellosis data in Shandong province from 2015 to 2021 were obtained from the China Information System for Disease Control and Prevention, the data were analyzed by descriptive epidemiological methods, spatial autocorrelation analysis and spatial-temporal cluster analysis methods use ArcGIS and SaTScan software, the results were presented in ArcMap. RESULTS: A total of 22,251 human cases of brucellosis were reported, the annual incidence ranged between 2.41/100,000 and 4.07/100,000 from 2015 to 2021 in Shandong province, incidence has been decreasing year by year, while there was a significant increase in 2021. The distribution of brucellosis was of a seasonal trend, mainly concentrating during March to August. The age of the cases was mainly concentrated in the 30-74 age ranges, the average annual incidence rate was significantly higher in males than in females. The spatial analysis showed that the epidemics were mainly concentrated in the north and southwest. For the spatial autocorrelation analysis, a high global autocorrelation was observed at the county level, and the high-high clusters mainly distributed in the north and southwest region. For the spatio-temporal scanning, the most likely cluster areas mainly distributed in the north area, and then gradually moved southward, and the radius of clustered narrowed. CONCLUSIONS: Human brucellosis remains a common challenge, particularly in northern region in spring and summer. More disease prevention and control measures should be taken in high-risk populations, and such higher-risk susceptible areas to reduce the incidence of brucellosis and ensure the health of the people.

Exposure to Fine Particulate Matter Constituents and Human Semen Quality Decline: A Multicenter Study.

Exposure to fine particulate matter (PM < 2.5 µm in diameter [PM2.5]) may accelerate human sperm quality decline, although research on this association is limited. Our objective was to investigate the relationship between exposure to the chemical constituents of PM2.5 air pollution and decreased sperm quality and to further explore the exposure-response relationship. We conducted a multicenter population-based cohort study including 78,952 semen samples from 33,234 donors at 6 provincial human sperm banks (covering central, northern, southern, eastern, and southwestern parts of China) between 2014 and 2020. Daily exposure to PM2.5 chemical composition was estimated using a deep learning model integrating a density ground-based measure network at a 1 km resolution. Linear mixed models with subject- and center-specific intercepts were used to quantify the harmful impacts of PM2.5 constituents on semen quality and explore their exposure-response relationships. Per interquartile range (IQR) increase in PM2.5 exposure levels during spermatogenesis was significantly associated with decreased sperm concentration, progressive motility, and total motility. For PM2.5 constituents, per IQR increment in Cl- (ß: -0.02, 95% CI: [-0.03, -0.00]) and NO3- (ß: -0.05, 95% CI: [-0.08, -0.02]) exposure was negatively associated with sperm count, while NH4+ (ß: -0.03, 95% CI: [-0.06, -0.00]) was significantly linked to decreased progressive motility. These results suggest that exposure to PM2.5 chemical constituents may adversely affect human sperm quality, highlighting the urgent need to reduce PM2.5 exposure.

5-Hydroxymethylfurfural Ameliorates Allergic Inflammation in HMC-1 Cells by Inactivating NF-κB and MAPK Signaling Pathways.

Allergic inflammation is the foundation of multiple allergic disorders, such as allergic rhinitis and asthma. Mast cells are effector cells that initiate inflammatory response. 5-hydroxymethylfurfural (5-HMF), a furfural compound, is the heat-processed product of various fruit, foods, drinks, as well as some Chinese herbal medicines. 5-HMF was previously reported to inhibit mast cell activation. Our study aimed to explore the functions of 5-HMF in both phorbol 12-mystate 13-acetate (PMA) plus calcium ionophore (A23187)-induced allergic inflammation in human mast cell line HMC-1 and ovalbumin (OVA)-induced asthma mouse models. HMC-1 cells were pretreated with 5-HMF and then stimulated by PMA+A23187. The cytotoxicity of 5-HMF on HMC-1 cells was evaluated by MTT assay. Histamine content in cell supernatants was measured by the o-phthaldialdehyde spectrofluorometric procedure. Intracellular calcium was determined using the fluorescent dye Fura-2AM. The production and expression of pro-inflammatory cytokines were detected by ELISA and RT-qPCR. Caspase-1 colorimetric assay was employed to examine the enzymatic activity of caspase-1. Asthma mouse models were induced by OVA sensitization. The bronchoalveolar lavage fluid (BALF) and blood samples were collected for the detection of total and differential cell count as well as aspartate aminotransferase (AST), alanine aminotransferase (ALT), OVA-immunoglobulin E (OVA-IgE), OVA-immunoglobulin G1 (OVA-IgG1), and pro-inflammatory cytokine levels. The left lung of mouse was dissected for histopathological examination by hematoxylin and eosin (H&E) staining. The protein expression of pro-caspase-1 and the phosphorylation of NF-κB and MAPK pathway-associated molecules were assessed by Western blotting. Our findings revealed that 5-HMF efficiently suppressed the PMA+A23187-induced enhancement in histamine production and intracellular calcium in HMC-1 cells. Pro-inflammatory cytokine production and expression in HMC-1 cells were elevated after PMA plus A23187 stimulation, which, however, were inhibited by pretreatment of 5-HMF. Additionally, 5-HMF suppressed the activity of caspase-1 and the phosphorylation of NF-κB and MAPK-associated molecules including p65 NF-κB, p38 MAPK, ERK, and JNK in HMC-1 cells. In vivo experiments demonstrated that 5-HMF treatment reduced the lung/body weight index and total and differential (macrophages, neutrophils, lymphocytes, and eosinophils) cell counts in BALF of asthmatic mice, but exerted no influence on serum AST and ALT levels. Besides, 5-HMF reduced serum OVA-IgE and OVA-IgG1 levels, mitigated lung inflammation, and inhibited the NF-κB and MAPK signaling pathways in asthma mouse models. 5-HMF mitigates allergic inflammation in asthma by inactivating caspase-1 and NF-κB and MAPK signaling pathways.

Sperm quality decline associated with gaseous pollutant exposure: Evidence from a large cohort multicenter study.

BACKGROUND: Poor sperm quality is a prevalent cause of male infertility, and the association between gaseous ambient air pollutants exposure and semen quality remains unclear. OBJECTIVES: To examine the relationship between gaseous air pollution exposure with semen quality in a large-scale and multi-center study. METHODS: We analyzed 78,952 samples corresponding to 33,234 study subjects from 2014 to 2020. The high-resolution grid pollution dataset was used to estimate personal exposures to CO, SO2, NO2 and O3 across entire stage of semen formation and three crucial stages. The linear mixed models were performed to evaluate the relationships. RESULTS: The results showed that sperm count was inversely related to SO2 exposure (-0.0070, -0.0128 to -0.0011). Decreased sperm concentration was associated with SO2 (-0.0083, -0.0142 to -0.0024), NO2 (-0.0162, -0.0320 to -0.0005) and O3 (-0.0306, -0.0480 to -0.0133) during 0-90 lag days, respectively. Additionally, we observed significant decline of PR and total motility with SO2 exposure. Similar trends were observed for SO2 and CO exposure during 3 key periods. CONCLUSIONS: Our findings suggest that exposure to gaseous air pollutants may have negative impacts on sperm quality. These findings highlight the importance that critical periods of sperm development should be considered when implementing protective measures.