Eukaryotic initiation factor 6 repression mitigates atherosclerosis progression by inhibiting macrophages expressing Fasn.

Atherosclerosis, a chronic inflammatory disease that often leads to myocardial infarction and stroke, is mainly caused by lipid accumulation. Eukaryotic initiation factor 6 (Eif6) is a rate-limiting factor in protein translation of transcription factors necessary for lipogenesis. To determine whether Eif6 affects atherosclerosis, Eif6+/- mice were crossed into Apoe-/- background. Apoe-/-/Eif6+/- mice on high fat diet showed significant reduction in atherosclerotic lesions and necrotic core content in aortic root sections in comparison with Apoe-/- mice. RNA-Seq was used to investigate the effect of Eif6 in aorta. Deficiency of Eif6 shows broad effect on cell metabolism. Expression of genes for fatty acid synthesis including Fatty acid synthase (Fasn), Elovl3, Elovl6 and Acaca are down-regulated in aortas. Importantly, Fasn is decreased in macrophages. Results suggest that Eif6 deficiency may decrease atherosclerosis through inhibition of Fasn and lipids metabolism in macrophages.

RHDV 3C protein antagonizes type I interferon signaling by cleaving interferon promoter stimulated 1 protein.

The host innate immune response to viral infection often involves the activation of type I interferons. Not surprisingly, many viruses have evolved various mechanisms to disable the interferon pathway and evade the antiviral response involving innate immunity. Rabbit hemorrhagic disease (RHD) is caused by RHD virus (RHDV), but whether it can antagonize the production of host interferon to establish infection has not been investigated. In this study, we found that during RHDV infection, the expressions of interferon and the interferon-stimulated gene were not activated. We constructed eukaryotic expression plasmids of all RHDV proteins, and found that RHDV 3C protein inhibited poly(I:C)-induced interferon expressions. Using siRNA to interfere with the expressions of TLR3 and MDA5, we found that the MDA5 signal pathway was used by the 3C protein to inhibit poly(I:C)-induced interferon expression. This effect was mediated by cleaving the interferon promoter stimulated 1 (IPS-1) protein. Finally, our study showed that interferon was effective against RHDV infection. In summary, our findings showed that the RHDV 3C protein was a new interferon antagonist. These results increase our understanding of the escape mechanism from innate immunity mediated by the RHDV 3C protein.

Sex effects in the association between airway microbiome and asthma.

BACKGROUND: Sex differences exist in asthma susceptibility and severity. Accumulating evidence has linked airway microbiome dysbiosis to asthma, and airway microbial communities have been found to differ by sex. However, whether sex modifies the link between airway microbiome and asthma has not been investigated. OBJECTIVE: To evaluate sex effects in the association between airway microbiome and asthma. METHODS: We analyzed induced sputum samples from 47 subjects (n = 23 patients with asthma and n = 24 normal controls) using 16S ribosomal RNA gene sequencing methods. The bacterial composition was analyzed for sex differences. Bacterial associations with asthma were assessed for each sex at the core taxa and genus levels. RESULTS: The microbiome in induced sputum differed in women vs men at the community level. A total of 5 core bacterial taxa were found in all samples. No sex-specific core taxa were detected. The most abundant core taxon, Streptococcus salivarius, was significantly enriched in women than in men (P = .02). Within each sex, individuals with relatively lower abundance of S salivarius were more likely to have asthma (P = .006). For both sexes, increased Lactobacillus species were found in sputum samples of patients with patients compared with normal controls (adjusted P = .01). Haemophilus species were associated with asthma in men and not in women. CONCLUSION: The airway microbiome differed by sex, and sex effects exist in the association of airway microbial markers and asthma. Future airway microbiome studies may yield better resolution if the context of specific sex is considered. The airway microbiome is a potential mechanism driving sex differences in asthma.

[Design of an adaptive radiation therapy system for target movement compensation].

In order to decrease the radiotherapy error caused by target motion, an adaptive radiation therapy system for target movement compensation has been designed and passed by simulation test. The real-time position of the target labelled by a mark was captured by the control system and compared with the reference point. Then the treatment couch was controlled to move in the opposite direction for compensation according to that position information. The three dimensional movement of the treatment bed relied on three independent stepping motors which were controlled by a control system. Experiments showed that the adaptive radiation therapy system was able to reduce the therapy error caused by target movement. It would be useful in radiotherapy clinical practice with high real-time position precision.

Hypodermin A improves survival of skin allografts.

BACKGROUND: Hypodermin A (HA) is a serine esterase that degrades complement, a key element of the innate immune system. Immunosuppressive properties of HA have previously been studied in vitro. However, such properties have not been fully demonstrated in vivo. The aim of this study was to evaluate the effect of HA in inhibiting allograft rejection in an HA transgenic mouse model. METHODS: FVB (HA transgenic mice or wild-type mice) to BALB/c mice skin transplantation model were used. Skin grafts were analyzed by histology, immunohistochemistry, and Western blotting. RESULTS: HA overexpression resulted in significantly prolonged skin allograft survival. Histologic changes in the skin allografts paralleled the gross appearance of rejection. ELISA and Western blotting showed that HA significantly reduced the content of complement C3 and C9 in HA skin allografts. The expressions of CD4, B7-2, and MHC class II were all significantly suppressed in HA skin allografts compared with the control group. CONCLUSIONS: These findings suggest that HA effectively prolongs skin allograft survival. The study results provide insight into a promising strategy to improve the survival of grafts in humans.

Early Pregnancy Factor Enhances the Generation and Function of CD4+CD25+ Regulatory T Cells.

The mechanisms of fetal semi-allograft acceptance by the mother's immune system have been the target of many immunological studies. Early pregnancy factor (EPF) is a molecule present in the serum of pregnant mammals soon after conception that has been reported to have immunomodulatory effects. In the present study, we aimed to determine whether immune cells such as CD4+CD25+ regulatory T cells (Tregs) are involved in the suppressive mechanism of EPF. Accordingly, CD4+CD25- T cells were isolated from spleens of female C57BL/6 mice and stimulated with anti-CD3 antibody, anti-CD28 antibody and IL-2 in the presence or absence of EPF. Flow cytometry was used to analyze the differentiation of CD4+CD25- T cells to CD4+CD25+ Tregs. We thus found a remarkable rise in the Treg ratio in the EPF-treated cells. Higher mRNA and protein levels of fork head box P3 (Foxp3), a marker of the Treg lineage, were also observed in cells treated with EPF. Furthermore, the effect of EPF on Treg immunosuppressive capacity was evaluated. EPF treatment induced the expression of interleukin-10 and transforming growth factor ß1 in Tregs. The suppressive capacity of Tregs was further measured by their capability to inhibit T cell receptor-mediated proliferation of CD4+CD25- T cells. We thus found that EPF exposure can enhance the immunosuppressive functions of Tregs. Overall, our data suggest that EPF induces the differentiation of Tregs and increases their immunosuppressive activities, which might be an important mechanism to inhibit immune responses during pregnancy.

Association of IL8 -105G/A with mastitis somatic cell score in Chinese Holstein dairy cows.

The single nucleotide polymorphisms (SNPs) in the 5' upstream of bovine IL8 gene were investigated in 810 Chinese Holstein cows from 35 bull families in a dairy farm in Shanghai using polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) technique. The Real-time PCR and Western blot were used to detect the mRNA and protein levels of genotype Chinese Holstein dairy cows. The results showed that one SNP -105G>A was detected, designating three genotypes (GG, GA and AA) with respective frequencies of 0.38, 0.46, and 0.16. The significant association of the SNP -105G>A with somatic cell score (SCS) was identified. Genotype GG had a significantly lower SCS than genotype GA or AA (P < 0.01), and the relative mRNA expression and protein level of GG was found to be the highest. These results suggest that the genotype GG may be a useful genetic marker for mastitis resistance selection and breeding in Chinese Holstein dairy cows.

Intraperitoneal administration of doxorubicin-encapsulated Brucea javanica oil nanoemulsion against malignant ascites.

Malignant ascites is a common complication of advanced cancers, which reduces survival rates and diminishes patients' quality of life. Intraperitoneal chemotherapy is a conventional method for treating cancer-related ascites, but the poor drug retention of conventional drugs requires frequent administration to maintain sustained anti-tumor effects. In this study, we encapsulated doxorubicin (DOX) into Brucea javanica oil (BJO) to develop a water-in-oil (W/O) nanoemulsion called BJO@DOX for the treatment of malignant ascites through in-situ intraperitoneal administration. BJO significantly induced apoptosis of S180 cells by upregulating the expression of p53 and caspase-3 (cleaved). Additionally, BJO notably downregulated the expression of Bcl-2, further promoting apoptosis of S180 cells. Cell apoptosis significantly inhibited ascites formation and tumor cell proliferation in a mouse model. The combination of DOX and BJO exhibited satisfactory synergistic effects, consequently prolonging the survival period of mice. Histological examination of major organs indicated that the nanoemulsion had excellent biosafety in vivo. The BJO@DOX nanoemulsion represents a promising platform for in-situ chemotherapy of malignant ascites.

An oral bioactive chitosan-decorated doxorubicin nanoparticles/bacteria bioconjugates enhance chemotherapy efficacy in an in-situ breast cancer model.

Breast cancer is the second leading cause of cancer-related deaths among women worldwide. Despite significant advancements in chemotherapy, its effectiveness is often limited by poor drug distribution and systemic toxicity caused by the weak targeting ability of conventional therapeutic agents. The hypoxic tumor microenvironment (TME) also plays a vital role in treatment outcomes. Oral anticancer therapeutic agents have gained popularity and show promising results due to their ease of repeated administration. This study introduces autopilot biohybrids (Bif@BDC-NPs) for the effective delivery of doxorubicin (DOX) to the tumor site. This hybrid combines albumin-encapsulated DOX nanoparticles (BD-NPs) coated with chitosan (CS) for breast cancer chemotherapy, along with anaerobic Bifidobacterium infantis (B. infantis, Bif) serving as self-propelled motors. Due to Bif's specific anaerobic properties, Bif@BDC-NPs precisely anchor hypoxic regions of tumor tissue and significantly increase drug accumulation at the tumor site, thereby promoting tumor cell death. In an in-situ mouse breast cancer model, Bif@BDC-NPs achieved 94 % tumor inhibition, significantly prolonging the median survival of mice to 62 days, and reducing the toxic side effects of DOX. Therefore, the new bacteria-driven oral drug delivery system, Bif@BDC-NPs, overcomes multiple physiological barriers and holds great potential for the precise treatment of solid tumors.

Heme-heme oxygenase-2 reduces the atherosclerosis by preventing inflammation.

Objective: Heme oxygenase (HO) has been shown to have important antioxidant and anti-inflammatory properties, resulting in a vascular antitherogenic effect. This study was undertaken to evaluate the role of HO-2 in atherosclerosis. Method and results: The expression levels of HO-2 were evaluated in M1 and M2 bone marrow macrophage induced by LPS and IL4. The expression of HO-2 was significantly higher in M2 macrophage than in M1 macrophage. Western diet (WD) caused a significant increase in HO-2 expression in ApoE-/- mice. The adeno-associated viral (AAV) vectors expressing HO-2 was constructed, and the mice were received saline (ApoE-/-), AAV (ApoE-/-), AAV-HO-2 (ApoE-/-) on WD at 12 weeks and their plasma lipids, inflammatory cytokines, atherosclerosis were evaluated for 16 weeks. The results showed AAV-HO-2 was robust, with a significant decrease in the en face aortas, lipids levels, inflammatory cytokines and M1 macrophage content in AAV-HO-2 ApoE-/- compared to control AAV-ApoE-/-. Conclusion: HO-2 expression in macrophages plays an important role of the antiatherogenic effect, decreasing the inflammatory component of atherosclerotic lesions. These results suggest that HO-2 may be a novel therapeutic target for cardiovascular diseases.

Regulation of adipose tissue development and energy metabolism by VEGFB isoforms.

Obesity is caused by imbalanced energy intake and expenditure. Excessive energy intake and storage in adipose tissues are associated with many diseases. Several studies have demonstrated that vascular growth endothelial factor B (VEGFB) deficiency induces obese phenotypes. However, the roles of VEGFB isoforms VEGFB167 and VEGFB186 in adipose tissue development and function are still not clear. In this study, genetic mouse models of adipose-specific VEGFB167 and VEGFB186 overexpression (aP2-Vegfb167 tg/+and aP2-Vegfb186tg/+) were generated and their biologic roles were investigated. On regular chow, adipose-specific VEGFB186 is negatively associated with white adipose tissues (WATs) and positively regulates brown adipose tissues (BATs). VEGFB186 upregulates energy metabolism and metabolism-associated genes. In contrast, VEGFB167 has a nominal role in adipose development and function. On high-fat diet, VEGFB186 expression can reverse the phenotypes of VEGFB deletion. VEGFB186 overexpression upregulates BAT-associated genes and downregulates WAT-associated genes. VEGFB186 and VEGFB167 have very distinct roles in the regulation of adipose development and energy metabolism. As a key regulator of adipose tissue development and energy metabolism, VEGFB186 may be a target for obesity prevention and treatment.

Pan-cancer analysis reveals DDX21 as a potential biomarker for the prognosis of multiple tumor types.

Background: DExD-box helicase 21 (DDX21) is an essential member of the RNA helicase family. DDX21 is involved in the carcinogenesis of various malignancies, but there has been no comprehensive research on its involvement in different types of cancer. Method: This study used TCGA, CPTAC, GTEx, GEO, FANTOM5, BioGRID, TIMER2, GEPIA2, cBioPortal, STRING, and Metascape databases and Survival ROC software to evaluate DDX21 gene expression, protein expression, immunohistochemistry, gene mutation, immune infiltration, and protein phosphorylation in 33 TCGA tumor types, as well as the prognostic relationship between DDX21 and different tumors, by survival analysis and similar gene enrichment analysis. Furthermore, Cell Counting Kit-8 (CCK-8) and Transwell studies were employed to assess the effect of DDX21 expression on lung adenocarcinoma (LUAD) cell proliferation and migration. Result: The DDX21 gene was highly expressed in most cancers, and overexpression was associated with poor overall survival (OS) and disease-free survival (DFS). DDX21 mutations were most common in uterine corpus endometrial carcinoma (UCEC; >5%), and DDX21 expression was positively correlated with the degree of infiltration of CAF and CD8+ cells in several tumor types. Numerous genes were co-expressed with DDX21. Gene enrichment analysis revealed close links between DDX21, RNA metabolism, and ribosomal protein production. In vitro analysis of LUAD cells showed that DDX21 expression was positively correlated with cell proliferation and migration capacity, consistent with prior bioinformatics studies. Conclusions: DDX21 is overexpressed in a variety of cancers, and overexpression in some cancers is associated with poor prognosis. Immune infiltration and DDX21-related gene enrichment analyses indicated that DDX21 may affect cancer development through mechanisms that regulate tumor immunity, RNA metabolism, and ribosomal protein synthesis. This pan-cancer study revealed the prognostic value and the oncogenic role of DDX21.

Polymorphisms of the IL8 gene correlate with milking traits, SCS and mRNA level in Chinese Holstein.

To explore the relation of Interleukin-8 (IL8) gene polymorphism with immunity against mastitis in dairy cow, the polymorphism of IL8 gene was investigated in 610 Chinese Holstein cow from 30 bull families in a dairy farm in Shanghai using polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) technique, and milk yield, milk fat percentage, milk protein percentage, 305 day corrected milk yield, 305 day milk fat yield, 305 day milk protein yield and somatic cell score (SCS) were measured and analyzed, and the mRNA levels of IL8 genotypes in blood were detected by real-time PCR. The results showed that three genotypes, KK, KA and AA were detected with frequencies of 0.187, 0.451, and 0.362, respectively. The gene frequencies of K and A were 0.412 and 0.588, respectively. The significant association of the IL8 mutations with milk yield, 305 day milk protein yield, 305 day corrected milk yield and 305 day milk fat yield, SCS, and significant association with milk protein percentage were identified, while their association with milk fat percentage were not significant. KK had higher milk yield, 305 day milk protein yield, 305 day corrected milk yield and 305 day milk fat yield than AA or KA, and the least square mean of SCS of KK was significantly lower than that of AA or KA. AA had significant lower milk protein yield than KK or KA. The relative IL8 mRNA level of KK in blood was the highest. These findings demonstrated that IL8 genotype significantly correlated with mastitis resistance and the locus could be a useful genetic marker for mastitis resistance selection and breeding in Chinese Holstein.

SNPs of CXCR1 gene and its associations with somatic cell score in Chinese Holstein cattle.

Mastitis is one of the most prevalent diseases in dairy cattle; CXCR1 plays a key role in mastitis resistance via IL8 signaling pathway, with the CXCR1 SNPs showing a different degree of mastitis resistance. To investigate the situation of CXCR1 polymorphisms in Chinese Holstein cattle and determine the relationship between the CXCR1 SNPs and mastitis resistance, the CXCR1 SNPs in 610 Chinese Holstein cattle of 30 families were investigated using polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) technique. The results showed that four SNPs, -1830A > G, -1768T > A, -344T > C, and 783C > A were detected at 5' upstream and coding region. The correlation analysis demonstrated that -1830AA, -1768TT, and -344TT correlated significantly with the lowest SCS for each site, respectively. Haplotype analysis revealed Haplo2 (ATTA) correlated significantly with the lowest SCS. These findings indicated a prospect genetic marker of mastitis resistance in dairy cattle.

[Genetic polymorphism of the IL8 gene and its associations with milk traits and SCS in Chinese Holstein].

The polymorphism of Interleukin-8 (IL8) gene were investigated for 610 Chinese Holstein cows of 30 bull families from a dairy farm in Shanghai using Polymerase Chain Reaction-Single Strand Conformation Polymorphism (PCR-SSCP) technique with a mixed animal model to verify the effects of the polymorphisms on some milk productive performance, tested day milk yield, tested day fat percentage, tested day milk protein percentage, 305 d corrected milk yield, 305 d milk fat yield, 305 d milk protein yield, and somatic cell score (SCS). The aim was to explore the significant molecular marker in practical dairy production. Three genotypes were identified and the genotypic frequencies of KK, KA, and AA were 0.187, 0.451, and 0.362, respectively. The gene frequencies of K and A were 0.412 and 0.588. The results showed highly significant (P < 0.01) association of IL8 mutations with tested day milk yield, 305 d milk protein yield, 305 d corrected milk yield and 305 d milk fat yield, SCS and tested day milk protein percentage (P < 0.05). However, no association (P > 0.05) with tested day milk fat percentage was recorded. The cows with KK genotype had higher tested day milk yield, 305 d milk protein yield, 305 d corrected milk yield and 305 d milk fat yield than those with AA and KA genotypes (P < 0.01). The least square mean of SCS for KK was significantly lower than that with AA and KA genotypes (P < 0.01). AA genotype was significant lower in tested day milk protein percentage than KK and KA genotypes (P < 0.05). The IL8 gene genetic diversity has a great genetic effect on milk traits and mastitis resistance and could be a useful genetic marker for Chinese Holstein breeding.

Research Progress on the Relationship between Atherosclerosis and Inflammation.

Atherosclerosis is a chronic inflammatory disease; unstable atherosclerotic plaque rupture, vascular stenosis, or occlusion caused by platelet aggregation and thrombosis lead to acute cardiovascular disease. Atherosclerosis-related inflammation is mediated by proinflammatory cytokines, inflammatory signaling pathways, bioactive lipids, and adhesion molecules. This review discusses the effects of inflammation and the systemic inflammatory signaling pathway on atherosclerosis, the role of related signaling pathways in inflammation, the formation of atherosclerosis plaques, and the prospects of treating atherosclerosis by inhibiting inflammation.

Heme oxygenase-2 suppresses acute inflammation and improves the survival of skin allografts.

The heme oxygenase (HO) system is an important regulatory arm of the intrinsic cytoprotective and anti-inflammatory system. HO-2 plays an important role in regulating inflammation following injury. The aim of this study was to evaluate the effect of HO-2 overexpression on inflammatory responses. A skin transplantation model, involving the application of skin grafts from wild-type or HO-2 overexpressing mice to BALB/c mice, was used for investigation. HO-2 overexpression suppressed the production of pro-inflammatory cytokines (IL-1ß, TNF-α, and IL-6) in macrophages compared to that in macrophages obtained from control mice. HO-2 overexpression also significantly prolonged the survival of allografted skin. Our findings suggest that HO-2 attenuates inflammatory responses and effectively prolongs skin graft survival.

Dosimetric analysis of rib interference of the CTV during interstitial brachytherapy of lung tumors.

PURPOSE: In interstitial brachytherapy for lung tumors, the placement and alignment of the source needles are influenced by the ribs, which can affect the dose distribution. This study evaluated the change in dose to the target by comparing the dose between the actual interstitial brachytherapy plan (AIBP, what is deliverable due to anatomic constraints), and the virtual interstitial brachytherapy plan (VIBP, pretreatment-modified dose distribution). MATERIAL AND METHODS: AIBPs and VIBPs were designed for 20 lung tumors. The VIBP was designed with uniform spacing between needles, regardless of the presence of ribs. The prescription dose was 30 Gy. The percentage of normal ipsilateral lung volume that received a dose ≥ 5 Gy (V5), conformity index (COIN), incremental dose percentage (IDP) to the target, and the dose covering 95% (D95) of the clinical target volume (CTV) were calculated. RESULTS: The V5 of the VIBPs was significantly smaller than that of the AIBPs (p < 0.01). The mean COIN value was 0.41 ± 0.12 for the AIBPs, which was significantly smaller than the value 0.54 ± 0.12 for the VIBPs (p < 0.01). The D95 of CTV in VIBP-adjusted was greater than that in AIBPs (p < 0.01). The mean IDP was 44% ± 40%. The Dmax of the ribs was 20.16 Gy ± 15.76 Gy in AIBPs, and 18.57 Gy ± 15.14 Gy in VIBPs, which was not significantly different (p > 0.05). CONCLUSIONS: The regular geometric alignment of needles is important for increasing the target dose and limiting the normal lung dose in interstitial brachytherapy for thoracic tumors. Thus, we recommend that radiation oncologists attempt to achieve the regular alignment of needles during implantation.

The effect of constitutive over-expression of insulin-like growth factor 1 on the cognitive function in aged mice.

The neurotrophic factor insulin-like growth factor (IGF)-1 promotes neurogenesis in the mammalian brain and provides protection against brain injury. However, studies regarding the effects of IGF-1 on cognitive function in aged mice remain limited. We investigated the effects of overexpression of IGF-1 specifically in neural stem cells of the hippocampal dentate gyrus on the recognitive function in 18-month-old transgenic mice. Immunohistocytochemistry and Nissl staining revealed the increased population of BrdU-positive cells as well as the upregulated expression of Nestin and neuronal nuclei (NeuN), respective markers for neural progenitors and neurons, in the hippocampus of the aged IGF-1 transgenic mice versus the wild-type, suggesting that IGF-1 overexpression promotes neurogenesis. In addition, the IGF-1 receptor (IGF-1R), the phosphorylation of Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) and extracellular signal-regulated kinase (ERK) were enhanced in the transgenic mice than in the wild-type. Transgenic mice also showed superior performance in the Morris water maze and step-down memory tests to their wild-type counterparts. Moreover, the learning and memory abilities of transgenic mice were significantly undermined with the blockage of CaMKII and ERK signaling pathway. Accordingly, our findings indicated that IGF-1 may mitigate the aged-associated cognitive decline via promoting neurogenesis in the hippocampus and activating CaMKII and ERK signaling by binding with IGF-1R.