Increasing evidence highlights the role of bacteria in promoting tumorigenesis. The underlying mechanisms may be diverse and remain poorly understood. Here, we report that Salmonella infection leads ...to extensive de/acetylation changes in host cell proteins. The acetylation of mammalian cell division cycle 42 (CDC42), a member of the Rho family of GTPases involved in many crucial signaling pathways in cancer cells, is drastically reduced after bacterial infection. CDC42 is deacetylated by SIRT2 and acetylated by p300/CBP. Non-acetylated CDC42 at lysine 153 shows an impaired binding of its downstream effector PAK4 and an attenuated phosphorylation of p38 and JNK, consequently reduces cell apoptosis. The reduction in K153 acetylation also enhances the migration and invasion ability of colon cancer cells. The low level of K153 acetylation in patients with colorectal cancer (CRC) predicts a poor prognosis. Taken together, our findings suggest a new mechanism of bacterial infection-induced promotion of colorectal tumorigenesis by modulation of the CDC42-PAK axis through manipulation of CDC42 acetylation.
Growing evidence has shown that alterations in gut microbiota composition are associated with multiple autoimmune diseases (ADs). However, it is unclear whether these associations reflect a causal ...relationship.
To reveal the causal association between gut microbiota and AD, we conducted a two-sample Mendelian randomization (MR) analysis.
We assessed genome-wide association study (GWAS) summary statistics for gut microbiota and six common ADs, namely, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, type 1 diabetes (T1D), and celiac disease (CeD), from published GWASs. Two-sample MR analyses were first performed to identify causal bacterial taxa for ADs in discovery samples. Significant bacterial taxa were further replicated in independent replication outcome samples. A series of sensitivity analyses was performed to validate the robustness of the results. Finally, a reverse MR analysis was performed to evaluate the possibility of reverse causation.
Combining the results from the discovery and replication stages, we identified one causal bacterial genus,
. A higher relative abundance of the
genus was associated with a higher risk of T1D odds ratio (OR): 1.605; 95% CI, 1.339-1.922;
= 4.19 × 10
and CeD (OR: 1.401; 95% CI, 1.139-1.722;
= 2.03 × 10
), respectively. Further sensitivity analyses validated the robustness of the above associations. The results of reverse MR analysis showed no evidence of reverse causality from T1D and CeD to the
genus.
This study implied a causal relationship between the
genus and T1D and CeD, thus providing novel insights into the gut microbiota-mediated development mechanism of ADs.
Evidence supports the observational associations of gut microbiota with a variety of psychiatric disorders, but the causal nature of such associations remains obscure. Aiming to comprehensively ...investigate their causal relationship and to identify specific causal microbe taxa for psychiatric diseases, we conducted a two-sample Mendelian randomization (MR) analysis of gut microbiome with 15 psychiatric diseases. Specifically, the microbiome genome-wide association study (GWAS) in 18,473 individuals from the MiBioGen study was used as exposure sample, and the GWAS for 15 psychiatric diseases was used as outcome samples. One-hundred ninety bacterial taxa from six levels were available for analysis. At a multiple-testing corrected significance level (phylum
< 5.56 × 10
, class
< 3.33 × 10
, order
< 2.63 × 10
, family
< 1.67 × 10
, genus
< 4.90 × 10
, and species
< 3.33 × 10
), the following eight causal associations from seven bacterial features (one phylum + three classes + one order + one family + one species) were identified: family
with autism spectrum disorder (
= 5.31 × 10
), class
with bipolar disorder (
= 1.53 × 10
), class
with schizophrenia (
= 1.33 × 10
), class
and order
with Tourette syndrome (
= 2.51 × 10
and 2.51 × 10
), phylum
and class
with extroversion (
= 8.22 × 10
and 1.09 × 10
), and species
with neuroticism (
= 8.92 × 10
). Sensitivity analysis showed no evidence of reverse causality, pleiotropy, and heterogeneity. Our findings offered novel insights into the gut microbiota-mediated development mechanism of psychiatric disorders.
The clove essential oil (CEO) loaded nano and pickering emulsions prepared with Tween 80 and whey protein isolate/inulin mixture, respectively were incorporated into pullulan-gelatin film base fluid ...at three levels (0.2%, 0.4%, and 0.6%). The droplet sizes of NE and PE loaded with CEO were 15.93 nm and 266.9 nm, respectively. The PDI of CEOs with stable NE and PE were 0.262 and 0.259, respectively. Our results showed the improved compatibility between pullulan-gelatin and essential oil-loaded nanocarriers. The active film composed of PE carrier had the structural characteristics of high density, low water content, and low permeability, thus exhibiting excellent mechanical properties, water barrier properties, and appreciable antioxidant activities. Compared with NE, it was found that the CEO-loaded PE showed slow-release profile in the film sample. The prepared active film containing PE possessed a great potential to be used as effective and natural alternatives for active food packaging.
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•The clove essential oil (CEO) nano and pickering emulsions were incorporated into pullulan-gelatin film.•CEO loaded emulsions and active films exhibited strong antimicrobial and antioxidant activity, respectively.•The fabricated films particularly with PE showed higher mechanical and water barrier properties.•The encapsulation of CEO with PE provided slower release profile in the films compared to NE.
The large-scale open access whole-exome sequencing (WES) data of the UK Biobank ~200,000 participants is accelerating a new wave of genetic association studies aiming to identify rare and functional ...loss-of-function (LoF) variants associated with complex traits and diseases. We proposed to merge the WES genotypes and the genome-wide genotyping (GWAS) genotypes of 167,000 UKB homogeneous European participants into a combined reference panel, and then to impute 241,911 UKB homogeneous European participants who had the GWAS genotypes only. We then used the imputed data to replicate association identified in the discovery WES sample. The average imputation accuracy measure r
is modest to high for LoF variants at all minor allele frequency intervals: 0.942 at MAF interval (0.01, 0.5), 0.807 at (1.0 × 10
, 0.01), 0.805 at (1.0 × 10
, 1.0 × 10
), 0.664 at (1.0 × 10
, 1.0 × 10
) and 0.410 at (0, 1.0 × 10
). As applications, we studied associations of LoF variants with estimated heel BMD and four lipid traits. In addition to replicating dozens of previously reported genes, we also identified three novel associations, two genes PLIN1 and ANGPTL3 for high-density-lipoprotein cholesterol and one gene PDE3B for triglycerides. Our results highlighted the strength of WES based genotype imputation as well as provided useful imputed data within the UKB cohort.
Recent studies have shown the relevance of gut microbiota in the occurrence and development of colorectal cancer (CRC), but the causal relationship remains unclear in the human population. The ...present study aims to assess the causal relationship from the gut microbiota to CRC and to identify specific causal microbe taxa via genome-wide association study (GWAS) summary statistics based two-sample Mendelian randomization (MR) analyses. Microbiome GWAS (MGWAS) in the TwinsUK 1,126 twin pairs was used as discovery exposure sample, and MGWAS in 1,812 northern German participants was used as replication exposure sample. GWAS of CRC in 387,156 participants from the UK Biobank (UKB) was used as the outcome sample. Bacteria were grouped into taxa features at both family and genus levels. In the discovery sample, a total of 30 bacteria features including 15 families and 15 genera were analyzed. Five features, including 2 families (Verrucomicrobiaceae and Enterobacteriaceae) and 3 genera (Akkermansia, Blautia, and Ruminococcus), were nominally significant. In the replication sample, the genus Blautia (discovery beta=-0.01, P = 0.04) was successfully replicated (replication beta=-0.18, P = 0.01) with consistent effect direction. Our findings identified genus Blautia that was causally associated with CRC, thus offering novel insights into the microbiota-mediated CRC development mechanism.
Natural killer cell (NK cell)-based immunotherapy of cancer is hampered by the transient effector function of NK cells. Recently, mouse IL-12/15/18-preactivated NK cells were shown to persist with ...sustained effector function in vivo. Our study investigated the antitumor activity of such NK cells. A single injection of syngeneic IL-12/15/18-preactivated NK cells, but neither naive nor IL-15- or IL-2-pretreated NK cells, combined with irradiation substantially reduced growth of established mouse tumors. Radiation therapy (RT) was essential for the antitumor activity of transferred NK cells. IL-12/15/18-preactivated NK cells expressed high levels of IL-2Rα (CD25), and their rapid in vivo proliferation depended on IL-2 produced by CD4+ T cells. IL-12/15/18-preactivated NK cells accumulated in the tumor tissue and persisted at high cell numbers with potent effector function that required the presence of CD4+ T cells. RT greatly increased numbers and function of transferred NK cells. Human IL-12/15/18-preactivated NK cells also displayed sustained effector function in vitro. Our study provides a better understanding for the rational design of immunotherapies of cancer that incorporate NK cells. Moreover, our results reveal an essential role of CD4+ T cell help for sustained antitumor activity by NK cells linking adaptive and innate immunity.
To estimate the acute analgesic efficacy of combined Pregabalin and Celecoxib after operation via a systematic review and meta-analysis.
Studies for inclusion were randomized controlled trials, ...reporting on relevant outcomes (0-6 hours, 24 hours, 7 days pain scores) with treatment with combined Pregabalin and Celecoxib.
The pooled results from meta-analysis demonstrated that compared with placebo, combined Pregabalin and Celecoxib reduced pain scores at 0 to 6 hours in 3 articles, 24 hours in 5 articles, 7 days in 2 articles (standard mean difference SMD, -3.10 at 0-6 hours, -2.80 at 24 hours, -1.32 at 7 days, respectively). Combined Pregabalin and Celecoxib could significantly reduce the postoperative narcotic consumption in 3 studies (SMD, -1.99 at 36 hour).
This work suggested that combined Pregabalin and Celecoxib were efficacious in reduction of postoperative pain and narcotic requirements after surgery, whereas more trials are needed to further identify the efficacy of combined Pregabalin and Celecoxib in the management of acute postoperative pain.
Background. According to recent studies, ferroptosis is closely related to the efficacy and prognosis of tumour treatment. However, the role of ferroptosis in esophageal squamous cell carcinoma ...(ESCC) has not been explored comprehensively. Materials and Methods. The esophageal cancer (EC) transcriptome data was downloaded from The Cancer Genome Atlas (TCGA), then analyzed, to obtain the differentially expressed messenger RNA (mRNA), microRNA (miRNA), and long noncoding RNA (lncRNA) between groups with the low and high Ferroptosis Potential Index (FPI) and construct a ferroptosis-associated ceRNA network. In addition, the expression of ARHGEF26-AS1 and miR-372-3p in ESCC cell lines was assessed, and the appropriate cell lines were selected. The interaction between ARHGEF26-AS1, miR-372-3p, and ADAM23 was also determined through a dual-luciferase reporter assay. Moreover, the Western blot, Cell Counting Kit-8 (CCK-8), wound healing, cell viability, and cell death assays were conducted to establish the biological functions of the ARHGEF26-AS1/miR-372-3p/ADAM23 pathway in ESCCs. Results. An FPI scoring model reflecting the activity of the ferroptosis pathway was constructed, and a ferroptosis-associated ceRNA network was established. The findings revealed that low expression of ADAM23 and ARHGEF26-AS1 as well as high expression of miR-372-3p was associated with poor prognosis and a lower FPI score in EC patients. Functionally, overexpression of ADAM23 and ARHGEF26-AS1 and the miR-372-3p inhibitor not only promoted ferroptosis in ESCC cells in vitro but also inhibited the proliferation and migration of cells. Mechanistically, ARHGEF26-AS1 upregulated the expression of ADAM23 by competitively binding to miR-372-3p. Conclusions. The study showed that the lncRNA, ARHGEF26-AS1 acts as a miR-372-3p sponge that regulates the neuropeptide LGI1 receptor ADAM23 expression. This in turn not only inhibits the proliferation and migration of ESCC cells but also upregulates the ferroptosis pathway. A neuropeptide-related ferroptosis regulatory pathway was identified in this study.
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