Isolation and identification of uric acid-dependent Aciduricibacillus chroicocephali gen. nov., sp. nov. from seagull feces and implications for hyperuricemia treatment.

Hyperuricemia has become the second most prevalent metabolic disease after diabetes, but the limitations of urate-lowering treatment (ULT) drugs and patient nonadherence make ULT far less successful. Thus, more ULT approaches urgently need to be explored. Uric acid-degrading bacteria have potential application value in ULT. In this study, we isolated 44XBT, a uric acid-degrading bacterium, from black-headed gull (Chroicocephalus ridibundus) feces. Using a polyphasic taxonomic approach, strain 44XBT was identified as a novel genus within the family Bacillaceae; subsequently, the name Aciduricibacillus chroicocephali was proposed. Strain 44XBT had a unique uric acid-dependent phenotype and utilized uric acid and allantoin as the sole carbon and nitrogen sources, but not common carbon sources or complex media. In the genome, multiple copies of genes involved in uric acid metabolic pathway (pucL, pucM, uraD, and allB) were found. Six copies of pucL (encoding urate oxidase) were detected. Of these, five pucL copies were in a tandem arrangement and shared 70.42%-99.70% amino acid identity. In vivo experiments revealed that 44XBT reduced serum uric acid levels and attenuated kidney damage in hyperuricemic mice through uric acid catalysis in the gut and gut microbiota remodeling. In conclusion, our findings discover a strain for studying bacterial uric acid metabolism and may provide valuable insights into ULT. IMPORTANCE: The increasing disease burden of hyperuricemia highlights the need for new therapeutic drugs and treatment strategies. Our study describes the developmental and application values of natural uric acid-degrading bacteria found in the gut of birds and broadened the source of bacteria with potential therapeutic value. Furthermore, the special physiology characteristics and genomic features of strain 44XBT are valuable for further study.

IRF7 overexpression alleviates CFA-induced inflammatory pain by inhibiting nuclear factor-κB activation and pro-inflammatory cytokines expression in rats.

BACKGROUND: It is known that nerve signals arising from sites of inflammation lead to persistent changes in the spinal cord and contribute to the amplification and persistence of pain. Nevertheless, the underlying mechanisms have not yet been completely elucidated. We identified differentially expressed genes in the lumbar (L4-L6) segment of the spinal cord from complete Freund's adjuvant (CFA) rats compared to control animals via high throughput sequencing. Based on differential gene expression analysis, we selected interferon regulatory factor 7 (IRF7) for follow-up experiments to explore its antinociceptive potential. METHODS: An animal model of inflammatory pain was induced by intraplantar injection of CFA. We evaluated the effects of adeno-associated viral (AAV)-mediated overexpression of IRF7 in the spinal cord on pain-related behavior after CFA injection. Moreover, the activation of the nuclear factor-κB (NF-κB) and the expression of inflammatory cytokines were investigated to understand the underlying mechanisms related to the contribution of IRF7 to inflammatory pain. RESULTS: CFA intraplantar injection caused a significant decrease in the level of spinal IRF7, which is mainly expressed in the dorsal horn neurons and astrocytes. Moreover, IRF7 overexpression significantly attenuated pain-related behaviors, as well as the activity of NF-κB/p65 and the production of interleukin-1ß (IL-1ß), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) in the spinal cord of CFA rats. CONCLUSIONS: Our data indicated that spinal IRF7 plays an important role in the regulation of inflammatory pain. Thus, IRF7 overexpression at the spinal cord level might represent a potential target for the treatment of inflammatory pain.

Newcastle disease virus suppresses antigen presentation via inhibiting IL-12 expression in dendritic cells. / æ–°åŸŽç–«ç— æ¯’é€šè¿‡æŠ‘åˆ¶æ ‘çªçŠ¶ç»†èƒžç™½ä»‹ç´ 12的表达抑制抗原递呈.

As a potential vectored vaccine, Newcastle disease virus (NDV) has been subject to various studies for vaccine development, while relatively little research has outlined the immunomodulatory effect of the virus in antigen presentation. To elucidate the key inhibitory factor in regulating the interaction of infected dendritic cells (DCs) and T cells, DCs were pretreated with the NDV vaccine strain LaSota as an inhibitor and stimulated with lipopolysaccharide (LPS) for further detection by enzyme-linked immunosorbent assay (ELISA), flow cytometry, immunoblotting, and quantitative real-time polymerase chain reaction (qRT-PCR). The results revealed that NDV infection resulted in the inhibition of interleukin (IL)-12p40 in DCs through a p38 mitogen-activated protein kinase (MAPK)|-dependent manner, thus inhibiting the synthesis of IL-12p70, leading to the reduction in T cell proliferation and the secretion of interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), and IL-6 induced by DCs. Consequently, downregulated cytokines accelerated the infection and viral transmission from DCs to T cells. Furthermore, several other strains of NDV also exhibited inhibitory activity. The current study reveals that NDV can modulate the intensity of the innate|‒|adaptive immune cell crosstalk critically toward viral invasion improvement, highlighting a novel mechanism of virus-induced immunosuppression and providing new perspectives on the improvement of NDV-vectored vaccine.

Development of a prognostic model based on different disulfidptosis related genes typing for kidney renal clear cell carcinoma.

Background: Kidney renal clear cell carcinoma (KIRC) is a common and clinically significant subtype of kidney cancer. A potential therapeutic target in KIRC is disulfidptosis, a novel mode of cell death induced by disulfide stress. The aim of this study was to develop a prognostic model to explore the clinical significance of different disulfidptosis gene typings from KIRC. Methods: A comprehensive analysis of the chromosomal localization, expression patterns, mutational landscape, copy number variations, and prognostic significance of 10 disulfide death genes was conducted. Patients were categorized into distinct subtypes using the Non-negative Matrix Factorization (NMF) typing method based on disulfidptosis gene expression patterns. Weighted Gene Co-expression Network Analysis (WGCNA) was used on the KIRC dataset to identify differentially expressed genes between subtype clusters. A risk signature was created using LASSO-Cox regression and validated by survival analysis. An interaction between risk score and immune cell infiltration, tumor microenvironment characteristics and pathway enrichment analysis were investigated. Results: Initial findings highlight the differential expression of specific DRGs in KIRC, with genomic instability and somatic mutation analysis revealing key insights into their role in cancer progression. NMF clustering differentiates KIRC patients into subgroups with distinct survival outcomes and immune profiles, and hierarchical clustering identifies gene modules associated with key biological and clinical parameters, leading to the development of a risk stratification model (LRP8, RNASE2, CLIP4, HAS2, SLC22A11, and KCTD12) validated by survival analysis and predictive of immune infiltration and drug sensitivity. Pathway enrichment analysis further delineates the differential molecular pathways between high-risk and low-risk patients, offering potential targets for personalized treatment. Lastly, differential expression analysis of model genes between normal and KIRC cells provides insights into the molecular mechanisms underlying KIRC, highlighting potential biomarkers and therapeutic targets. Conclusion: This study contributes to the understanding of KIRC and provides a potential prognostic model using disulfidptosis gene for personalized management in KIRC patients. The risk signature shows clinical applicability and sheds light on the biological mechanisms associated with disulfide-induced cell death.

Self-supporting noncovalent Choline Alginate/Tannic acid/Ag antibacterial films for strawberry preservation.

Packaging materials with peculiar antibacterial properties can shield off and inhibit microorganism proliferation, thus achieving packaging goals such as fresh-keeping, good hygiene, and biosafety. Especially, antibacterial films made of biocompatible substances have received wide attentions, which could effectively extend the shelf life, enhance food security, and guarantee economic benefits. Herein, a self-supporting hybrid antibacterial film was prepared based on non-covalently linked choline hydroxide (ChOH) and alginic acid (HAlg). Then tannic acid (TA) and silver ions were added to improve the mechanical and antimicrobial properties of this hybrid film. The rich hydroxyl groups from TA not only form multiple hydrogen bonds with ChAlg, but can also in situ reduce silver ions to silver nanoparticles, which were confirmed with various characterizations. In addition, the quantitative antibacterial test proved that the antibacterial rate was significantly improved after adding silver ions, reaching >60 %. In an actual storage test, we found that choline cation (Ch+) captured in antibacterial film by electrostatic interaction could achieve sustained release, i.e. sustainable bacteriostasis, and keep strawberries fresh for 48 h at room temperature. This work offers a new strategy for preparing antibacterial films via non-covalent weak interactions, explored an alternative antibacterial film for food packaging applications.

Heavy Metal Scavenger Metallothionein Rescues Against Cold Stress-Evoked Myocardial Contractile Anomalies Through Regulation of Mitophagy.

Cold stress prompts an increased prevalence of cardiovascular morbidity yet the underneath machinery remains unclear. Oxidative stress and autophagy appear to contribute to cold stress-induced cardiac anomalies. Our present study evaluated the effect of heavy metal antioxidant metallothionein on cold stress (4 °C)-induced in cardiac remodeling and contractile anomalies and cell signaling involved including regulation of autophagy and mitophagy. Cold stress (3 weeks) prompted interstitial fibrosis, mitochondrial damage (mitochondrial membrane potential and TEM ultrastructure), oxidative stress (glutathione, reactive oxygen species and superoxide), lipid peroxidation, protein injury, elevated left ventricular (LV) end systolic and diastolic diameters, decreased fractional shortening, ejection fraction, Langendorff heart function, cardiomyocyte shortening, maximal velocities of shortening/relengthening, and electrically stimulated intracellular Ca2+ rise along with elongated relaxation duration and intracellular Ca2+ clearance, the responses of which were overtly attenuated or mitigated by metallothionein. Levels of apoptosis, cell death (Bax and loss of Bcl2, IL-18), and autophagy (LC3BII-to-LC3BI ratio, Atg7 and Beclin-1) were overtly upregulated with comparable p62 under cold stress. Cold stress also evoked elevated mitophagy (decreased TOM20, increased Parkin and FUNDC1 with unaltered BNIP3). Cold stress overtly dampened phosphorylation of autophagy/mitophagy inhibitory molecules Akt and mTOR, stimulated and suppressed phosphorylation of ULK1 and eNOS, respectively, in the absence of altered pan protein levels. Cold stress-evoked responses in cell death, autophagy, mitophagy and their regulatory domains were overtly attenuated or ablated by metallothionein. Suppression of autophagy and mitophagy with 3-methyladenine, bafilomycin A1, cyclosporine A, and liensinine rescued hypothermia-instigated cardiomyocyte LC3B puncta formation and mechanical anomalies. Our findings support a protective nature for metallothionein in deep hypothermia-evoked cardiac abnormalities associated with regulation of autophagy and mitophagy.

Ag85B-ENO146-82 therapeutic vaccines enhance anti-tumor immunity by inducing CD8+ T cells and remodeling tumor microenvironment.

Lung cancer is the leading cause of cancer-related morbidity and mortality in China. However, the effect of traditional cancer treatment is limited. Herein, we designed a therapeutic cancer vaccine based on the tumor-associated antigen mENO1, which can prevent lung cancer growth in vivo, and explored the underlying mechanism of Ag85B-ENO146-82 therapy. Lewis lung carcinoma (LLC) tumor-bearing immunocompetent C57BL/6 mice that received Ag85B-ENO146-82 treatment showed antitumor effect. Further, we detected CD8+ T, CD4+ T in LLC-bearing C57BL/6 mice to understand the impact of Ag85B-ENO146-82 therapy on antitumor capacity. The Ag85B-ENO146-82 therapy induced intensive infiltration of CD4+ and CD8+ T cells in tumors, increased tumor-specific IFN-γ and TNF-α secretion by CD8+ T cells and promoted macrophage polarization toward M1 phenotype. Flow cytometric analysis revealed that CD8+ T effector memory (TEM) cells and central memory (TCM) cells were upregulated. qPCR and ELISA analysis showed that the expression of IFN-γ and TNF-α were upregulated, whereas of IL1ß, IL6 and IL10 were downregulated. This study demonstrated that Ag85B-ENO146-82 vaccine augmented antitumor efficacy, which was CD8+ T cells dependent. Our findings paved the way for therapeutic tumor-associated antigen peptide vaccines to enhance anti-tumor immunotherapy for treatment of cancer.

Diagnosis of SPECT/CT bone imaging combined with two serum examinations in patients with bone metastases from pulmonary cancer

Purpose To study the clinical diagnostic value of SPECT/CT bone imaging combined with two serum examinations in patients with bone metastases from pulmonary cancer. Methods The clinical data of 120 patients consistent with pulmonary cancer admitted to the First Affiliated Hospital of Hebei North University from March 2019 to December 2019 were selected for retrospective analysis, and they were divided into the bone metastasis group (n = 58) and non-bone metastasis group (n = 62) according to comprehensive evaluation result of X-ray, CT, MRI and clinical follow-up. The CT values of patients were obtained by SPECT/CT bone imaging to compare serum levels of ALP (alkaline phosphatase belongs to phosphoric monoester hydrolases, as a specific phosphatase, mainly in body tissues and body fluid) and BAP (bone alkaline phosphatase is formed by different modification and processing of alkaline phosphatase, and is mainly released by osteoblasts) and CT values of patients in both groups, using receiver operating characteristic (ROC) curve to evaluate the diagnostic efficacy of single detection and combined detection. Results SPECT/CT bone imaging in patients with bone metastasis from pulmonary cancer showed abnormal radioactive accumulation in spine, pelvis and bilateral ribs. Serum ALP, BAP and CT values in bone metastasis group were overtly higher than the non-bone metastasis group (P < 0.001). Logistic regression analysis showed that serum ALP, BAP and CT value were independent risk factors for bone metastasis from pulmonary cancer. The AUC value and Youden index of combined diagnosis were higher than those of single diagnosis. Conclusion SPECT/CT bone imaging combined with serum detection of ALP and BAP in patients with pulmonary cancer is helpful for early diagnosis of bone metastasis, which provides more basis for the formulation and selection of clinical treatment options (AU)

The Role of Zuo Jin Wan in Modulating the Tumor Microenvironment of Colorectal Cancer.

INTRODUCTION: Traditional Chinese medicine (TCM) can modulate the immune function of tumor patients in various ways. Zuojin Wan (ZJW, a 6:1 ratio of Huanglian and Wuzhuyu) can modulate the microenvironment of ulcerative colitis, but its role in regulating the CRC microenvironment remains unclear. Exploring the role of ZJW in CRC immunomodulation may improve the antitumor effect of existing immunotherapeutic strategies. MATERIAL AND METHODS: The active compounds of each herb in ZJW were obtained from the HIT2.0 database with literature evidence. Single-cell RNA sequencing data of CRC were obtained from published studies (PMID: 32451460, 32103181, and 32561858). Pathway enrichment was analyzed using the reactome database, and intergenic correlation analysis was performed using the corrplot R software package. ZJW-regulated gene expression was verified by RT-qPCR. RESULTS: Huanglian and Wuzhu contain 19 and 4 compounds, respectively. Huang Lian targets 146 proteins, and Wu Zhu Yu targets 28 proteins based on evidence from the literature. ZJW regulates a range of biological processes associated with immune function, including cytokine signaling and Toll-Like Receptor 4 (TLR4) cascade. ZJW regulates malignant CRC cells, immune cells (including T-cells, B-cells, mast cells, NK/NKT cells, and myeloid cells), and other non-immune cells (including endothelial cells, enteric glial cells, and pericytes). We confirmed that ZJW significantly downregulated the expression of TIMP1 and MTDH. CONCLUSIONS: ZJW regulates a range of cells in the CRC microenvironment, including malignant CRC, immune cells, and stromal cells. In CRC cell lines, downregulation of TIMP1 and MTDH by ZJW may play an important role in the immunomodulation in CRC.

HCMV IE1/IE1mut Therapeutic Vaccine Induces Tumor Regression via Intratumoral Tertiary Lymphoid Structure Formation and Peripheral Immunity Activation in Glioblastoma Multiforme.

Glioblastoma multiforme (GBM), a highly malignant invasive brain tumor, is associated with poor prognosis and survival and lacks an effective cure. High expression of the human cytomegalovirus (HCMV) immediate early protein 1 (IE1) in GBM tissues is strongly associated with their malignant progression, presenting a novel target for therapeutic strategies. Here, the bioluminescence imaging technology revealed remarkable tumor shrinkage and improved survival rates in a mouse glioma model treated with HCMV IE1/IE1mut vaccine. In addition, immunofluorescence data demonstrated that the treated group exhibited significantly more and larger tertiary lymphoid structures (TLSs) than the untreated group. The presence of TLS was associated with enhanced T cell infiltration, and a large number of proliferating T cells were found in the treated group. Furthermore, the flow cytometry results showed that in the treatment group, cytotoxic T lymphocytes exhibited partial polarization toward effector memory T cells and were activated to play a lethal role in the peripheral immunological organs. Furthermore, a substantial proportion of B cells in the draining lymph nodes expressed CD40 and CD86. Surprisingly, quantitative polymerase chain reaction indicated that a high expression of cytokines, including chemokines in brain tumors and immune tissues, induced the differentiation, development, and chemokine migration of immune cells in the treated group. Our study data demonstrate that IE1 or IE1mut vaccination has a favorable effect in glioma mice models. This study holds substantial implications for identifying new and effective therapeutic targets within GBM.

Single-Cell RNA Sequencing Transcriptomics Revealed HCMV IE2-Related Microglia Responses in Alzheimer's-Like Disease in Transgenic Mice.

    Although multiple factors are known to concur with Alzheimer's disease (AD), the relationship between human cytomegalovirus (HCMV) and AD-like disease is unclear. Here, we propose a hypothesis that HCMV immediate-early 2 (IE2) protein promotes microglia activation and thus leads to AD-like disease. We successfully constructed IE2 transgenic mice expressing IE2 in the hippocampus. Single-cell sequencing analysis revealed that IE2 promoted the activation of microglia and upregulated the expression of disease-associated microglia genes. Differentially expressed gene analysis and pathway enrichment revealed that IE2 upregulated immune and nervous system disease-related genes. Immunohistochemical analysis showed that the expressions of both amyloid precursor protein (APP) and p-Tau were significantly upregulated in the brains of IE2 mice and were markers of AD. Taken together, these findings provide useful insights into AD-like disease activated by HCMV IE2.

Diagnosis of SPECT/CT bone imaging combined with two serum examinations in patients with bone metastases from pulmonary cancer.

PURPOSE: To study the clinical diagnostic value of SPECT/CT bone imaging combined with two serum examinations in patients with bone metastases from pulmonary cancer. METHODS: The clinical data of 120 patients consistent with pulmonary cancer admitted to the First Affiliated Hospital of Hebei North University from March 2019 to December 2019 were selected for retrospective analysis, and they were divided into the bone metastasis group (n = 58) and non-bone metastasis group (n = 62) according to comprehensive evaluation result of X-ray, CT, MRI and clinical follow-up. The CT values of patients were obtained by SPECT/CT bone imaging to compare serum levels of ALP (alkaline phosphatase belongs to phosphoric monoester hydrolases, as a specific phosphatase, mainly in body tissues and body fluid) and BAP (bone alkaline phosphatase is formed by different modification and processing of alkaline phosphatase, and is mainly released by osteoblasts) and CT values of patients in both groups, using receiver operating characteristic (ROC) curve to evaluate the diagnostic efficacy of single detection and combined detection. RESULTS: SPECT/CT bone imaging in patients with bone metastasis from pulmonary cancer showed abnormal radioactive accumulation in spine, pelvis and bilateral ribs. Serum ALP, BAP and CT values in bone metastasis group were overtly higher than the non-bone metastasis group (P < 0.001). Logistic regression analysis showed that serum ALP, BAP and CT value were independent risk factors for bone metastasis from pulmonary cancer. The AUC value and Youden index of combined diagnosis were higher than those of single diagnosis. CONCLUSION: SPECT/CT bone imaging combined with serum detection of ALP and BAP in patients with pulmonary cancer is helpful for early diagnosis of bone metastasis, which provides more basis for the formulation and selection of clinical treatment options.

Influence of ganglioside combined with methylprednisolone sodium succinate on efficacy and neurological function in patients with acute myelitis.

BACKGROUND: Acute myelitis (AM) can lead to sudden sensory, motor and autonomic nervous dysfunction, which negatively affects their daily activities and quality of life, so it is necessary to explore optimization from a therapeutic perspective to curb the progression of the disease. AIM: To investigate the effect of ganglioside (GM) combined with methylprednisolone sodium succinate (MPSS) on the curative effect and neurological function of patients with AM. METHODS: First, we selected 108 AM patients visited between September 2019 and September 2022 and grouped them based on treatment modality, with 52 patients receiving gamma globulin (GG) + MPSS and 56 patients receiving GM + MPSS, assigned to the control group (Con) and observation group (Obs), respectively. The therapeutic effect, neurological function (sensory and motor function scores), adverse events (AEs), recovery (time to sphincter function recovery, time to limb muscle strength recovery above grade 2, and time to ambulation), inflammatory factors (IFs) [interleukin (IL)-6, C-reactive protein (CRP), and tumor necrosis factor (TNF)-α] and other data of the two groups were collected for evaluation and comparison. RESULTS: The Obs had: (1) A significantly higher response rate of treatment than the Con; (2) Higher scores of sensory and motor functions after treatment that were higher than the baseline (before treatment) and higher than the Con levels; (3) Lower incidence rates of skin rash, gastrointestinal discomfort, dyslipidemia, osteoporosis and other AEs; (4) Faster posttreatment recovery of sphincter function, limb muscle strength and ambulation; and (5) Markedly lower posttreatment IL-6, CRP and TNF-α levels than the baseline and the Con levels. CONCLUSION: From the above, it can be seen that GM + MPSS is highly effective in treating AM, with a favorable safety profile comparable to that of GG + MPSS. It can significantly improve patients' neurological function, speed up their recovery and inhibit serum IFs.

The Global Changes of N6-methyldeoxyadenosine in Response to Low Temperature in Arabidopsis thaliana and Rice.

N6-methyldeoxyadenosine (6mA) is a recently discovered DNA modification involved in regulating plant adaptation to abiotic stresses. However, the mechanisms and changes of 6mA under cold stress in plants are not yet fully understood. Here, we conducted a genome-wide analysis of 6mA and observed that 6mA peaks were predominantly present within the gene body regions under both normal and cold conditions. In addition, the global level of 6mA increased both in Arabidopsis and rice after the cold treatment. The genes that exhibited an up-methylation showed enrichment in various biological processes, whereas there was no significant enrichment observed among the down-methylated genes. The association analysis revealed a positive correlation between the 6mA level and the gene expression level. Joint analysis of the 6mA methylome and transcriptome of Arabidopsis and rice unraveled that fluctuations in 6mA levels caused by cold exposure were not correlated to changes in transcript levels. Furthermore, we discovered that orthologous genes modified by 6mA showed high expression levels; however, only a minor amount of differentially 6mA-methylated orthologous genes were shared between Arabidopsis and rice under low-temperature conditions. In conclusion, our study provides information on the role of 6mA in response to cold stress and reveals its potential for regulating the expression of stress-related genes.

HCMV-IE2 promotes atherosclerosis by inhibiting vascular smooth muscle cells' pyroptosis.

Atherosclerosis is still the main cause of death in developed and developing countries. Vascular smooth muscle cells (VSMCs) death disorder is a key pathogens of atherosclerosis. During the early stage of human cytomegalovirus (HCMV) infection, immediate early protein 2 (IE2) is critical in regulating its host cell death to ensure HCMV replication. Abnormal cell death induced by HCMV infection contributes to the development of numerous diseases, including atherosclerosis. Hitherto, the underlying mechanism of HCMV involved in the progression of atherosclerosis is still unclear. In this study, the infection models in vitro and in vivo were constructed to explore the pathogenesis of HCMV-related atherosclerosis. Our results indicated that HCMV could contribute to the progression of atherosclerosis by enhancing the proliferation, invasion, and inhibiting the pyroptosis of VSMCs under inflammatory conditions. Meanwhile, IE2 played a key role in these events. Our present research revealed a novel pathogenesis of HCMV-related atherosclerosis, which might help develop new therapeutic strategies.

Polygalacin D inhibits the growth of hepatocellular carcinoma cells through BNIP3L-mediated mitophagy and endogenous apoptosis pathways.

Platycodon grandiflorum (Jacq.) A. DC. is a famous medicinal plant commonly used in East Asia. Triterpene saponins isolated from P. grandiflorum are the main biologically active compounds, among which polygalacin D (PGD) has been reported to be an anti-tumor agent. However, its anti-tumor mechanism against hepatocellular carcinoma is unknown. This study aimed to explore the inhibitory effect of PGD in hepatocellular carcinoma cells and related mechanisms of action. We found that PGD exerted significant inhibitory effect on hepatocellular carcinoma cells through apoptosis and autophagy. Analysis of the expression of apoptosis-related proteins and autophagy-related proteins revealed that this phenomenon was attributed to the mitochondrial apoptosis and mitophagy pathways. Subsequently, using specific inhibitors, we found that apoptosis and autophagy had mutually reinforcing effects. In addition, further analysis of autophagy showed that PGD induced mitophagy by increasing BCL2 interacting protein 3 like (BNIP3L) levels.In vivo experiments demonstrated that PGD significantly inhibited tumor growth and increased the levels of apoptosis and autophagy in tumors. Overall, our findings showed that PGD induced cell death of hepatocellular carcinoma cells primarily through mitochondrial apoptosis and mitophagy pathways. Therefore, PGD can be used as an apoptosis and autophagy agonist in the research and development of antitumor agents.

Gut microbiota induces hepatic steatosis by modulating the T cells balance in high fructose diet mice.

Metabolic diseases are often associated with high fructose (HF) consumption. HF has also been found to alter the gut microbiota, which then favors the development of nonalcoholic fatty liver disease. However, the mechanisms underlying of the gut microbiota on this metabolic disturbance are yet to be determined. Thus, in this study, we further explored the effect the gut microbiota concerning the T cells balance in an HF diet mouse model. We fed mice 60% fructose-enriched diet for 12 weeks. At 4 weeks, HF diet did not affect the liver, but it caused injury to the intestine and adipose tissues. After 12 weeks, the lipid droplet aggregation was markedly increased in the liver of HF-fed mice. Further analysis of the gut microbial composition showed that HF decreased the Bacteroidetes/Firmicutes ratio and increased the levels of Blautia, Lachnoclostridium, and Oscillibacter. In addition, HF can increase the expression of pro-inflammatory cytokines (TNF-α, IL-6, and IL-1ß) in the serum. T helper type 1 cells were significantly increased, and regulatory T(Treg) cells were markedly decreased in the mesenteric lymph nodes of the HF-fed mice. Furthermore, fecal microbiota transplantation alleviates systemic metabolic disorder by maintaining liver and intestinal immune homeostasis. Overall, our data indicated that intestinal structure injury and intestinal inflammation might be early, and liver inflammation and hepatic steatosis may be a subsequent effect following HF diets. Gut microbiota disorders impairing the intestinal barrier function and triggering immune homeostasis imbalance may be an importantly responsible for long-term HF diets induced hepatic steatosis.

Pre-Induced ICD Membrane-Coated Carrier-Free Nanoparticles for the Personalized Lung Cancer Immunotherapy.

Immunotherapy is a required adjuvant method in lung cancer therapy clinically. The single immune adjuvant failed to show the expected clinical therapeutic efficacy due to its rapid drug metabolism and inability to accumulate in the tumor site efficiently. Immunogenic cell death (ICD) is a new anti-tumor strategy combined with immune adjuvants. It can provide tumor-associated antigens, activate dendritic cells, and attract lymphoid T cells into the tumor microenvironment. Here doxorubicin-induced tumor membrane-coated iron (II)-cytosine-phosphate-guanine nanoparticles (DM@NPs) are shown for efficient co-delivery of tumor-associated antigens and adjuvant. Higher expression of ICD-related membrane proteins on the surface of the DM@NPs leads to the enhanced uptake of DM@NPs by dendritic cells (DCs), thereby promoting the DCs maturation and pro-inflammatory cytokines release. DM@NPs can remarkably increase the T cell infiltrations, remodel the tumor immune microenvironment and inhibit tumor progression in vivo. These findings reveal that pre-induced ICD tumor cell membrane-encapsulated nanoparticles can enhance immunotherapy responses and provide an effective biomimetic nanomaterial-based therapeutic strategy for lung cancer.

Human Cytomegalovirus IE2 Disrupts Neural Progenitor Development and Induces Microcephaly in Transgenic Mouse.

Human cytomegalovirus (HCMV) is a significant contributor to congenital birth defects. Limited by the lack of animal models, the pathogenesis of neurological damage in vivo caused by HCMV infection and the role of individual viral genes remain to be elucidated. Immediate early (IE2) protein may play a function in neurodevelopmental problems caused by HCMV infection. Here, this study intended to investigate IE2's long-term effects on development of the brain in IE2-expressing transgenic mice (Rosa26-LSL-IE2+/-, Camk2α-Cre) aimed to observe the phenotype of postnatal mice. The expression of IE2 in transgenic mice was confirmed by PCR and Western blot technology. We collected mouse brain tissue at 2, 4, 6, 8, and 10 days postpartum to analyze the developmental process of neural stem cells by immunofluorescence. We discovered that transgenic mice (Rosa26-LSL-IE2+/-, Camk2α-Cre) can reliably produce IE2 in the brain at various postpartum phases. Furthermore, we also observed the symptoms of microcephaly in postnatal transgenic mice, and IE2 can damage the amount of neural stem cells, prevent them from proliferating and differentiating, and activate microglia and astrocytes, creating an unbalanced environment in the brain's neurons. In conclusion, we demonstrate that long-term expression of HCMV-IE2 can cause microcephaly through molecular mechanisms affecting the differentiation and development of neural stem cells in vivo. This work establishes a theoretical and experimental foundation for elucidating the molecular mechanism of fetal microcephaly brought by HCMV infection in throughout the period of neural development of pregnancy.