Updated systematic review and meta­analysis for risk predictors of 30­day unplanned readmission following gastric cancer surgery.

Readmission to hospital is a common occurrence due to adverse post-operative events. The primary objective of the present study was to examine the possible risk predictors for 30-day unplanned readmissions after the surgical treatment of gastric cancer. The secondary aim was to determine the clinical characteristics that are associated with readmission. Studies that reported the risk factors and clinical characteristics of patients with gastric cancer who had an unplanned 30-day post-operative readmission were identified systematically from PubMed, Cochrane Central Register of Controlled Trials, Web of Science and Embase databases, with a final search date of March 30, 2024. A systematic review and meta-analysis were then performed to estimate the risk predictors and relevant clinical characteristics for readmission. A total of 16,154 patients from 12 studies were included in the present study, with 1,736 patients who were readmitted and 14,418 patients who were not readmitted. A higher proportion of patients with an age ≥70 years, cardiovascular comorbidity, Nutritional Risk Screening (NRS) 2002 score ≥3, respiratory diseases, male sex, American Society of Anesthesiologists score ≥3, combined multi-organ resection, greater depth of invasion (T3-4/T1-2), discharge to home with provision of care services, neoadjuvant therapy, post-operative complications or a blood transfusion were found in the readmission group compared with that in the non-readmission group. A meta-analysis was also performed to calculate risk predictors using the results of multivariate regression analyses from the original literature. This identified cardiovascular comorbidity, NRS 2002 score ≥3, pancreatectomy and post-operative complications as risk predictors for 30-day unplanned readmission following surgery for gastric cancer. Therefore, it is recommended that extra attention and support should be given to patients with these high-risk predictors during the perioperative period.

Correlation between the C-reactive protein (CRP)-albumin-lymphocyte (CALLY) index and the prognosis of gastric cancer patients after gastrectomy: a systematic review and meta-analysis.

The C-Reactive Protein (CRP)-Albumin-Lymphocyte (CALLY) index is an established immuno-nutritional scoring system. We screened relevant literature from the major databases up until May, 2024, and extracted the data for analysis. A total of 2829 gastric cancer (GC) patients from six studies were included in this meta-analysis, the results of which revealed that the CALLY index was an independent prognostic factor for OS and RFS in both univariate analyses and multivariate analyses, and that a high CALLY index was a favorable prognostic factor. Moreover, GC patients in the high CALLY index group seemed to have better 5-year OS and 5-year RFS than those in the low CALLY index group. There was a higher proportion of patients with T1 status in the high CALLY index group than in the low CALLY index group. However, the opposite results were found in the analyses of lymph node metastasis positivity, lymph-vascular invasion positivity, postoperative complications, differentiated histological type, anastomotic leakage, and adjuvant chemotherapy. The present meta-analysis concluded that the CALLY index was a simple and useful independent prognostic biomarker for GC patients after gastrectomy.

Efficacy and side effects of pembrolizumab plus chemotherapy vs. chemotherapy alone in patients with advanced gastric or gastroesophageal junction adenocarcinoma: A meta­analysis.

Recently, the treatment plan of pembrolizumab plus chemotherapy was regarded as a promising treatment for patients with advanced gastric cancer or gastroesophageal junction adenocarcinoma (GC/GEJC). However, the efficacy and side effects of pembrolizumab plus chemotherapy still lack evidence-based medical evidence to support. Therefore, a meta-analysis was conducted to evaluate the hot issue. By searching PubMed, EMBASE, Cochrane Library, Web of Science, any randomized clinical studies of pembrolizumab plus chemotherapy versus chemotherapy in patients with advanced GC/GEJC met the inclusion criteria were included. The quality of the literature was evaluated and the data was extracted. A correlative software was also used to analyze the data and to draw a conclusion. After screening 14,015 studies, four studies were eligible for the meta-analysis. Compared with chemotherapy alone group, the overall survival (OS) rate was significantly longer. In programmed cell death ligand 1 (PD-L1) combined positive score (CPS) ≥1 subgroup and PD-L1 CPS ≥10 subgroup analyses, the results showed that the response rate (RR) and complete response rate (CR) were both higher in pembrolizumab plus chemotherapy group compared with chemotherapy alone group. There were not significant differences in the CR, the treatment-related adverse events, succumbed to drug-related events and succumbed to immune-mediated events between the two groups. However, the effect events such as the treatment-related adverse events led to discontinuation, the 3-5 treatment-related adverse events and the immune-mediated adverse events and infusion reactions were more common in pembrolizumab plus chemotherapy group. In conclusion, the current meta-analysis revealed that, in treating advanced GC/GEJC, pembrolizumab plus chemotherapy had improved therapeutic efficacies than chemotherapy alone, as evidenced by the significantly longer OS. Furthermore, the patients in PD-L1 CPS ≥1 subgroup and PD-L1 CPS ≥10 subgroup appeared to benefit from pembrolizumab plus chemotherapy treatment because of higher RR and CR. However, side effects such as the treatment-related adverse events leading to discontinuation, the 3-5 treatment-related adverse events, and immune-mediated adverse events and infusion reactions deserved more attention.

Characterization of NMCR-3, NMCR-4 and NMCR-5, three novel non-mobile colistin resistance determinants: Implications for MCR-3, MCR-7, and MCR-5 progenitors, respectively.

In this study, the progenitors of MCR-3, MCR-7 and MCR-5, namely NMCR-3, NMCR-4 and NMCR-5, were firstly discovered and indicating Aeromonas was a natural reservoir for MCR-3 and MCR-7. Furthermore, different evolutionary models for MCR-3, MCR-7 and MCR-5 were proposed.

A review and new perspective on oral bacteriophages: manifestations in the ecology of oral diseases.

Objective: To explore the manifestations of bacteriophages in different oral disease ecologies, including periodontal diseases, dental caries, endodontic infections, and oral cancer, as well as to propel phage therapy for safer and more effective clinical application in the field of dentistry. Methods: In this literature review, we outlined interactions between bacteriophages, bacteria and even oral cells in the oral ecosystem, especially in disease states. We also analyzed the current status and future prospects of phage therapy in the perspective of different oral diseases. Results: Various oral bacteriophages targeting at periodontal pathogens as Porphyromonas gingivalis, Fusobacterium nucleatum, Treponema denticola and Aggregatibacter actinomycetemcomitans, cariogenic pathogen Streptococcus mutans, endodontic pathogen Enterococcus faecalis were predicted or isolated, providing promising options for phage therapy. In the realm of oral cancer, aside from displaying tumor antigens or participating in tumor-targeted therapies, phage-like particle vaccines demonstrated the potential to prevent oral infections caused by human papillomaviruses (HPVs) associated with head-and-neck cancers. Conclusion: Due to their intricate interactions with bacteria and oral cells, bacteriophages are closely linked to the progression and regression of diverse oral diseases. And there is an urgent need for research to explore additional possibilities of bacteriophages in the management of oral diseases.

Neuroinvasive virus facilitates viral replication by employing lipid droplets to reduce arachidonic acid-induced ferroptosis.

Lipids have been previously implicated in the lifecycle of neuroinvasive viruses. However, the role of lipids in programmed cell death and the relationship between programmed cell death and lipid droplets (LDs) in neuroinvasive virus infection remains unclear. Here, we found that the infection of neuroinvasive virus, such as rabies virus and encephalomyocarditis virus could enhance the LD formation in N2a cells, and decreasing LDs production by targeting diacylglycerol acyltransferase could suppress viral replication. The lipidomics analysis revealed that arachidonic acid (AA) was significantly increased after reducing LD formation by restricting diacylglycerol acyltransferase, and AA was further demonstrated to induce ferroptosis to inhibit neuroinvasive virus replication. Moreover, lipid peroxidation and viral replication inhibition could be significantly alleviated by a ferroptosis inhibitor, ferrostatin-1, indicating that AA affected neuroinvasive virus replication mainly through inducing ferroptosis. Furthermore, AA was demonstrated to activate the acyl-CoA synthetase long-chain family member 4-lysophosphatidylcholine acyltransferase 3-cytochrome P450 oxidoreductase axis to induce ferroptosis. Our findings highlight novel cross-talks among viral infection, LDs, and ferroptosis for the first time, providing a potential target for antiviral drug development.

Identification and validation of cuproptosis-related genes for diagnosis and therapy in nonalcoholic fatty liver disease.

In recent years, nonalcoholic fatty liver disease (NAFLD) has become a more serious public health issue worldwide. This study strived to investigate the molecular mechanism of pathogenesis of NAFLD and explore promising diagnostic and therapeutic targets for NAFLD. Raw data from GSE130970 were downloaded from the Gene Expression Omnibus database. We used the dataset to analyze the expression levels of cuproptosis-related genes in NAFLD patients and healthy controls to identify the differentially expressed cuproptosis-related genes (DECRGs). The relationship and potential mechanism between DECRGs and clinicopathological factors were examined by enrichment analysis and two consensus clustering methods. We screened key DECRGs based on Random Forest (RF), and then verified the key DECRGs in NAFLD patients, high-fat diet (HFD)-fed mice, and palmitic acid-induced AML12 cells. ROC analysis showed good diagnostic function of DECRGs in normal and NAFLD liver tissue. Two consensus clusters indicated the important role of cuproptosis in the development of NAFLD. We screened for key DECRGs (DLD, DLAT) based on RF and found a close relationship between the DECRGs and clinicopathological factors. We collected clinical blood samples to verify the differences in gene expression levels by qPCR. In addition, we further verified the expression levels of DLD and DLAT in HFD mice and AML12 cells, which showed the same results. This study provides a novel perspective on the pathogenesis of NAFLD. We identified two cuproptosis-related genes that are closely related to NAFLD. These genes may play a significant role in the molecular pathogenesis of NAFLD, which may be useful to make progress in the diagnosis and treatment of NAFLD.

Polystyrene nanoplastics-induced lung apoptosis and ferroptosis via ROS-dependent endoplasmic reticulum stress.

It has been shown that exposure to nanoplastics (MNPs) through inhalation can induce pulmonary toxicity, but the toxicological mechanism of MNPs on the respiratory system remains unclear. Therefore, we explored the toxicological mechanism of exposure to polystyrene nanoplastics (PS-NPs) (0.05, 0.15, 0.2 mg/mL) on BEAS-2B cells. Results revealed that PS-NPs induce oxidative stress, increased apoptosis rate measured by flow cytometry, the key ferroptosis protein (GPX4 and FTH1) reduction, increased iron content, mitochondrial alterations, and increased malondialdehyde (MDA) level. Besides, consistent results were observed in mice exposed to PS-NPs (5 mg/kg/2d, 10 mg/kg/2d). Thus, we proved that PS-NPs induced cell death and lung damage through apoptosis and ferroptosis. In terms of mechanism, the elevation of the endoplasmic reticulum (ER) stress protein expression (IRE1α, PERK, XBP1S, and CHOP) revealed that PS-NPs induce lung damage by activating the two main ER stress pathways. Furthermore, the toxicological effects of PS-NPs observed in this study are attenuated by the ROS inhibitor N-acetylcysteine (NAC). Collectively, NPs-induced apoptosis and ferroptosis are attenuated by NAC via inhibiting the ROS-dependent ER stress in vitro and in vivo. This improves our understanding of the mechanism by which PS-NPs exposure leads to pulmonary injury and the potential protective effects of NAC.

A Method for the Synthesis of Thioindoles through Copper-Catalyzed C-S Bond Coupling Reaction.

We herein report the copper-catalyzed C-S bond coupling reaction of indoles with N-thiosuccinimides, resulting in moderate to excellent yields of mono- and bis-sulfenylated compounds such as arylthioindoles, alkylthioindoles, selenylated indoles, and cysteine-substituted indoles. Thioarylation and thioglycosylation at the C2 position of indole alkaloids in the Radix Isatidis were achieved via structural modification. The first total syntheses of isatindigotindolosides III and IV have been successfully carried out. The electrophilic sulfenyl bromides generated in situ can play an important role in the catalytic cycle.

Cadmium-induced pyroptosis is mediated by PERK/TXNIP/NLRP3 signaling in SH-SY5Y cells.

Cadmium (Cd) is a hypertoxic heavy metal that may be exposed to environmental pollutants by humans and animals. It can lead to cognitive disfunction, and is linked to neurodegenerative diseases. Cadmium reportedly can induce endoplasmic reticulum (ER) stress, but few studies have concentrated on it in nerve cells, and the connection between ER stress and neuroinflammation. In this study, in vitro experiments on SH-SY5Y neuroblastoma cells were carried out. We aimed at exploring whether Cd attributed to the cell pyroptosis and the role of PERK in promoting this form of cell damage which can induce strong inflammatory responses. Our results demonstrated that CdCl2 treatment induced excess reactive oxygen species (ROS) production, caused significant modifications in the expression of PERK and increased TXNIP, NLRP3, IL-1ß, IL-18, and caspase1 in SH-SY5Y cells. In addition, scavenging ROS with N-acetylcysteine or inhibiting the expression of PERK by using GSK2606414, rescued the SH-SY5Y cells from cadmium-induced pyroptosis. In conclusion, the results suggest that Cd induces pyroptotic death of SH-SY5Y cells through ER stress, and this may be the potential mechanism of Cd incurring neurological diseases.

Metabolomic analysis of seminal plasma to identify goat semen freezability markers.

Factors affecting sperm freezability in goat seminal plasma were investigated. Based on the total motility of thawed sperm, goats were divided into a high-freezability (HF) group with >60% total motility (n = 8) and a low-freezability (LF) group with <45% total motility (n = 8). Sperm and seminal plasma from the HF and LF groups were separated, HF seminal plasma was mixed with LF spermatozoa, LF seminal plasma was mixed with HF sperm, and the products were subjected to a freeze-thaw procedure. Semen from individual goats exhibited differences in freezability. HF semen had higher sperm motility parameters and plasma membrane and acrosome integrity after thawing; this difference could be related to the composition of seminal plasma. Seminal plasma from the HF and LF groups was evaluated using metabolomic analysis, and multivariate statistical analysis revealed a clear separation of metabolic patterns in the seminal plasma of goats with different freezability classifications. Forty-one differential metabolites were identified using the following screening conditions: variable importance in the projection > 1 and 0.05 < P-value < 0.1. Kyoto Encyclopedia of Genes and Genomes pathway analysis revealed significant enrichment of central carbon metabolism in cancer, protein digestion and absorption, aminoacyl-tRNA, and other pathways and significant differences in the abundance of seven differential metabolites, including L-glutamine, L-aspartate, L-arginine, phenylpyruvate, benzoic acid, ketoisocaproic acid, and choline between seminal plasma from the HF and LF groups (P-value < 0.05). These significantly differentially-expressed metabolites may be potential biomarkers for sperm freezability. L-glutamine, L-aspartate, and L-arginine may directly affect sperm freezability. Benzoic acid, ketoisocaproic acid, and choline may regulate sperm freezability by participating in anabolic processes involving phenylalanine, leucine, and phosphatidylcholine in sperm.

Mesenchymal stromal cells ameliorate diabetes-induced muscle atrophy through exosomes by enhancing AMPK/ULK1-mediated autophagy.

BACKGROUND: Diabetes and obesity are associated with muscle atrophy that reduces life quality and lacks effective treatment. Mesenchymal stromal cell (MSC)-based therapy can ameliorate high fat-diet (HFD) and immobilization (IM)-induced muscle atrophy in mice. However, the effect of MSCs on muscle atrophy in type 2 diabetes mellitus (T2DM) and the potential mechanism is unclear. Here, we evaluated the efficacy and explored molecular mechanisms of human umbilical cord MSCs (hucMSCs) and hucMSC-derived exosomes (MSC-EXO) on diabetes- and obesity-induced muscle atrophy. METHODS: Diabetic db/db mice, mice fed with high-fat diet (HFD), mice with hindlimb immobilization (IM), and C2C12 myotubes were used to explore the effect of hucMSCs or MSC-EXO in alleviating muscle atrophy. Grip strength test and treadmill running were used to measure skeletal muscle strength and performance. Body composition, muscle weight, and muscle fibre cross-sectional area (CSA) was used to evaluate muscle mass. RNA-seq analysis of tibialis anterior (TA) muscle and Western blot analysis of muscle atrophy signalling, including MuRF1 and Atrogin 1, were performed to investigate the underlying mechanisms. RESULTS: hucMSCs increased grip strength (P = 0.0256 in db/db mice, P = 0.012 in HFD mice, P = 0.0097 in IM mice), running endurance (P = 0.0154 in HFD mice, P = 0.0006 in IM mice), and muscle mass (P = 0.0004 in db/db mice, P = 0.0076 in HFD mice, P = 0.0144 in IM mice) in all models tested, with elevated CSA of muscle fibres (P < 0.0001 in db/db mice and HFD mice, P = 0.0088 in IM mice) and reduced Atrogin1 (P = 0.0459 in db/db mice, P = 0.0088 in HFD mice, P = 0.0016 in IM mice) and MuRF1 expression (P = 0.0004 in db/db mice, P = 0.0077 in HFD mice, P = 0.0451 in IM mice). MSC-EXO replicated all these hucMSC-mediated changes (P = 0.0103 for grip strength, P = 0.013 for muscle mass, P < 0.0001 for CSA of muscle fibres, P = 0.0171 for Atrogin1 expression, and P = 0.006 for MuRF1 expression). RNA-seq revealed that hucMSCs activated the AMPK/ULK1 signalling and enhanced autophagy. Knockdown of AMPK or inhibition of autophagy with 3-methyladenine (3-MA) diminished the beneficial anti-atrophy effects of hucMSCs or MSC-EXO. CONCLUSIONS: Our results suggest that human umbilical cord mesenchymal stromal cells mitigate diabetes- and obesity-induced muscle atrophy via enhancing AMPK/ULK1-mediated autophagy through exosomes, with implications of applying hucMSCs or hucMSC-derived exosomes to treat muscle atrophy.

Carbon dots as light-responsive oxidase-like nanozyme for colorimetric detection of total antioxidant capacity in fruits.

Evaluation of total antioxidant capacity (TAC) in fruits is essential for dietary guidance and health monitoring. Here, we have exploited light-response carbon dots (CDs) as oxidase-like nanozyme to determine the TAC of fruits. The CDs possess excellent oxidase-like activity with light stimulation due to the accelerated intramolecular charge transfer caused by abundant electron donating/drawing groups in precursors. The scavenger experiment reveals that the catalytic intermediate could be hydroxyl radical, which can oxidize the colorimetric substrate. With the introduction of antioxidants, the oxidization of colorimetric substrate will be alleviated due to the scavenging of this intermediate by antioxidants. Based on this, we have successfully detected three antioxidants and obtained TAC of fruits with desirable results. This work affords a rapid, cost-effective and convenient analysis tool for TAC, as well as building a strong bridge between CDs and the development of photo-responsive oxidase-like nanozymes.

[Advances of long non-coding RNA encoded micro-peptides].

Long non-coding RNA (lncRNA) refers to non-coding RNA longer than 200 nt, with one or more short open reading frames (sORF), which encode functional micro-peptides. These functional micro-peptides often play key roles in various biological processes, such as Ca2+ transport, mitochondrial metabolism, myocyte fusion, cellular senescence and others. At the same time, these biological processes play a key role in the regulation of body homeostasis, diseases and cancers development and progression, embryonic development and other important physiological processes. Therefore, studying the potential regulatory mechanisms of micro-peptides encoded by lncRNA in organisms will help to further elucidate the potential regulatory processes in organisms. Furthermore, it will provide a new theoretical basis for the subsequent targeted treatment of diseases and improvement of animal growth performance. This review summarizes the latest research progress in the field of lncRNA-encoded micro-peptides, as well as the progress in the fields of muscle physiological regulation, inflammation and immunity, common human cancers, and embryonic development. Finally, the challenges of lncRNA-encoded micro-peptides are briefly described, with the aim to facilitate subsequent in-depth research on micro-peptides.

The regulation mechanism of different hair types in inner Mongolia cashmere goat based on PI3K-AKT pathway and FGF21.

There is genetic diversity of hair types in the Inner Mongolia cashmere goat population. Previous studies have found that fibroblast growth factor 21 (FGF21) and PI3K-AKT signal pathways may be related to different hair types in Inner Mongolia cashmere goats. Therefore, the purpose of this study was to explore the effects of the PI3K-AKT signal pathway on different hair types, the expression of mRNA and protein expression sites of FGF21 in the hair follicles of cashmere goats with different hair types, so as to lay a foundation for understanding the molecular mechanism of different hair types and the role of skin hair follicle development. In this experiment, the skin tissues of long hair type (LHG) and short hair type (SHG) of Inner Mongolia cashmere goat were collected in three key periods of secondary hair follicle growth, namely, anagen (September), catagen (December), and telogen (March). The relative expression of FGF21 and PI3K-AKT signal pathway candidate gene mRNA in different periods and different hair types was detected by real-time fluorescence quantitative technique (qRT-PCR), and the expression site of FGF21 protein was located by immunohistochemical technique. Through qRT-PCR, it was found that the relative expression of FGF21, FGFR1, AKT3, BRCA1, PKN3, SPP1, and GNG4 was significantly different between LHG and SHG. The expression of FGF21 in the skin of LHG was significantly higher than that of SHG in the three periods. Through immunohistochemical test, it was found that FGF21 protein was mainly expressed in primary hair follicle connective tissue sheath, primary hair follicle outer root sheath, secondary hair follicle outer root sheath, and sebaceous glands. It was also found that the expression of LHG skin tissue in the outer root sheath of primary hair follicles was higher than that of SHG in three periods. In summary, it is suggested that the PI3K-AKT signal pathway may play an important role in the formation of different hair types in Inner Mongolia cashmere goats.

There is genetic diversity of hair types in Inner Mongolia cashmere goat population. The purpose of this study was to explore the effects of the PI3K-AKT signal pathway on different hair types, the expression of mRNA and protein expression sites of FGF21 in the hair follicles of cashmere goats with different hair types, so as to lay a foundation for understanding the molecular mechanism of different hair types. It was found that the relative expression of FGF21, FGFR1, AKT3, BRCA1, PKN3, SPP1, and GNG4 was significantly different between LHG and SHG. It was found that FGF21 protein was mainly expressed in primary hair follicle connective tissue sheath, primary hair follicle outer root sheath, secondary hair follicle outer root sheath, and sebaceous glands. It was also found that the expression of LHG skin tissue in the outer root sheath of primary hair follicles was higher than that of SHG in three periods. So, it is suggested that the PI3K-AKT signal pathway and FGF21 may play an important role in the formation of different hair types in Inner Mongolia cashmere goats.

High expression of ZFP36L2 correlates with the prognosis and immune infiltration in lower-grade glioma.

Background: The ZFP36 Ring Finger Protein Like 2 (ZFP36L2) is an RNA-binding protein that regulates gene expression at post-transcriptional level. However, the clinical significance and prognostic value of ZFP36L2 in lower-grade glioma (LGG) remain unclear. Method: ZFP36L2 expression was investigated using public datasets and the prognostic merit of ZFP36L2 with LGG patients was further evaluated. The correlation between the genetic alteration of ZFP36L2 and its mRNA expression was accessed via cBioPortal. Additionally, the prognostic value of the ZFP36L2 methylation levels in LGG was evaluated by MethSurv. The potential biological role of ZFP36L2 in LGG was identified by performing functional analyses. We also examined the correlation between ZFP36L2 expression and the immune infiltration. Finally, the predictive value of ZFP36L2 to immunotherapy was assessed. Result: ZFP36L2 was highly expressed in LGG patients and overexpressed ZFP36L2 predicted poor clinical outcomes. We further identified ZFP36L2 as an independent prognostic factor. The methylation level of ZFP36L2 negatively correlated with the ZFP36L2 expression, and patients with low ZFP36L2 methylation had worse overall survival. The results of functional analysis indicated that ZFP36L2 was involved in multiple immune response-related pathways in LGG. Furthermore, high expression of ZFP36L2 was significantly and positively correlated with immune infiltration. Finally, we found that ZFP36L2 expression was positively correlated with the immune checkpoint PD-L1, and ZFP36L2 low expression cohort gained better benefit from immunotherapy. Conclusion: Our findings demonstrate that ZFP36L2 is a potential biomarker for LGG, highlighting its potential as a therapeutic target in immunotherapy.

Ambient ozone, and urban PM2.5 co-exposure, aggravate allergic asthma via transient receptor potential vanilloid 1-mediated neurogenic inflammation.

Allergic asthma is the most common pulmonary inflammatory disease, and epidemiological studies have revealed that PM2.5 or ambient ozone (O3) exposure contribute to the higher prevalence of allergic asthma. Current experimental evidence focus principally on the pathogenic effect of exposure to a single air pollutant, ignoring the possible synergistic effect of combined exposure to a mix of these pollutants, which is a more realistic scenario. In this study, allergic mice and a nociceptor antagonist were used to explore the mechanisms of co-exposure to these two important air pollutants. Compared with exposure to either PM2.5 or O3, combined exposure to both greatly aggravated allergic asthma in a dose dependent manner, including increased airway hyperresponsiveness, goblet cell metaplasia, more severe airway inflammation and higher oxidative stress levels. In addition, co-exposure in the allergic mice resulted in elevation of the expression of transient receptor potential vanilloid 1 (TRPV1), and of the production of substance P (SP), which exacerbated lung inflammation by neurogenic inflammation. TRPV1 antagonist (capsazepine, CPZ) treatment for the co-exposed allergic mice, markedly attenuated TRPV1 expression and SP release, and reduced airway inflammation and oxidative damage, further alleviating airway hyperresponsiveness. We conclude that neuro-immune interactions might be involved in PM2.5 and O3 co-exposure aggravated allergic asthma.

Comparison of porcine milk microRNA expression in milk exosomes versus whole swine milk and prediction of target genes.

Milk exosomal microRNAs (miRNAs) are important for postnatal growth and immune system maturation in newborn mammals. The functional hypothesis of milk exosomal miRNAs and their potential bioavailability in milk to newborn mammals were investigated. Briefly, 37 exosomal miRNAs were upregulated compared to miRNAs found outside the exosomes. Among these miRNAs, ssc-miR-193a-3p expression was upregulated 1467.35 times, while ssc-miR-423-5p, ssc-miR-551a, ssc-miR-138, ssc-miR-1 and ssc-miR-124a were highly concentrated and upregulated 13.58-30.06 times. Moreover, these miRNAs appeared to be relevant for cell development and basic physiological processes of the immune system. Following the analysis of target gene prediction and related signalling pathways, 9262 target genes were mainly concentrated in three signalling pathways: metabolic pathways, pathways in cancer, and phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) signalling pathways. Among 9262 target genes, more than 20 miRNAs were enriched in exosomes, such as methyl CpG binding protein 2 (MECP2) and glycogen synthase 1 (GYS1). After determining the miRNA localization-, distribution- and function-related metabolism, we found that these exosomes were specifically concentrated miRNA target genes and they were interrelated with cell development and basic cell functions, such as metabolism and immunity. It is speculated that miRNAs in milk can influence offspring via milk exosomes.

Polyadenylation of Histone H3.1 mRNA Promotes Cell Transformation by Displacing H3.3 from Gene Regulatory Elements.

Replication-dependent canonical histone messenger RNAs (mRNAs) do not terminate with a poly(A) tail at the 3' end. We previously demonstrated that exposure to arsenic, an environmental carcinogen, induces polyadenylation of canonical histone H3.1 mRNA, causing transformation of human cells in vitro. Here we report that polyadenylation of H3.1 mRNA increases H3.1 protein, resulting in displacement of histone variant H3.3 at active promoters, enhancers, and insulator regions, leading to transcriptional deregulation, G2/M cell-cycle arrest, chromosome aneuploidy, and aberrations. In support of these observations, knocking down the expression of H3.3 induced cell transformation, whereas ectopic expression of H3.3 attenuated arsenic-induced cell transformation. Notably, arsenic exposure also resulted in displacement of H3.3 from active promoters, enhancers, and insulator regions. These data suggest that H3.3 displacement might be central to carcinogenesis caused by polyadenylation of H3.1 mRNA upon arsenic exposure. Our findings illustrate the importance of proper histone stoichiometry in maintaining genome integrity.

Integrin α5ß1, as a Receptor of Fibronectin, Binds the FbaA Protein of Group A Streptococcus To Initiate Autophagy during Infection.

Group A Streptococcus (GAS), one of the most common extracellular pathogens, has been reported to invade epithelial and endothelial cells. Our results reveal that M1 GAS strain SF370 can be effectively eliminated by respiratory epithelial cells. Emerging evidence indicates that autophagy is an important strategy for nonphagocytes to eliminate intracellular bacteria. Upon pathogen recognition, cell surface receptors can directly trigger autophagy, which is a critical step in controlling infection. However, the mechanisms of how cells sense invading bacteria and use this information specifically to trigger autophagy remain unclear. In this study, we stimulated cells and infected mice with M and FbaA mutants of M1 GAS strain SF370 or with purified M and FbaA proteins (two critical surface structural proteins of GAS), and found that only FbaA protein was involved in autophagy induction. Furthermore, the FbaA protein induced autophagy independent of common pattern recognition receptors (such as Toll-like receptors); rather, it relies on binding to integrin α5ß1 expressed on the cell surface, which is mediated by extracellular matrix protein fibronectin (Fn). The FbaA-Fn-integrin α5ß1 complex activates Beclin-1 through the mTOR-ULK1-Beclin-1 pathway, which enables the Beclin-1/Vps34 complex to recruit Rab7 and, ultimately, to promote the formation of autophagosomes. By knocking down integrin α5ß1, Fn, Atg5, Beclin-1, and ULK1 in Hep2 cells and deleting Atg5 or integrin α5ß1 in mice, we reveal a novel role for integrin α5ß1 in inducing autophagy. Our study demonstrates that integrin α5ß1, through interacting with pathogen components, initiates effective host innate immunity against invading intracellular pathogens.IMPORTANCE Autophagy is generally considered a strategy used by the innate immune system to eliminate invasive pathogens through capturing and transferring them to lysosomes. Currently, researchers pay more attention to how virulence factors secreted by GAS regulate the autophagic process. Here, we provide the first evidence that the structural protein FbaA of M1 GAS strain SF370 is a potent inducer of autophagy in epithelial cells. Furthermore, we demonstrate that integrin α5ß1 in epithelial cells in vitro and in vivo acts as a receptor to initiate the signaling for inducing autophagy by binding to FbaA of M1 GAS strain SF370 via Fn. Our study reveals the underlying mechanisms by which pathogens induce Fn-integrin α5ß1 to trigger autophagy in a conserved pattern in epithelial cells.