This research was intended to investigate the fetal origins of changed birth weight of the offspring born through assisted reproductive technology (ART). The association between hormone and lipid ...metabolism or body weight has been generally accepted, and as the basic and specific treatment in ART procedure, gonadotropin stimulation might have potential effects on intrauterine lipid metabolism. In our studies, the mice were superovulated with two doses of gonadotropin. The cholesterol metabolism in ovaries and the triglyceride metabolism in embryos were analyzed. The results showed gonadotropin probably accelerated luteinization and induced a longer time follicle development and ovulation, which resulted in histological and morphological alteration of ovary, and increased the cholesterol content and the expressions of steroidogenesis-related genes. In embryos, gonadotropin increased lipid accumulation and decreased fatty acid synthesis in a dose-dependent manner. Moreover, the changes of fatty acid composition were also shown in superovulation groups. Our studies firstly provided the evidence that the superovulation might affect the maternal and fetal lipid metabolism. These variations of lipid metabolism in our results may be associated with birth weight of ART infants.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The observational association between gut microbiome and systemic lupus erythematosus (SLE) has been well documented. However, whether the association is causal remains unclear. The present study ...used publicly available genome-wide association study (GWAS) summary data to perform two-sample Mendelian randomization (MR), aiming to examine the causal links between gut microbiome and SLE. Two sets of MR analyses were conducted. A group of single nucleotide polymorphisms (SNPs) that less than the genome-wide statistical significance threshold (5 × 10
-8
) served as instrumental variables. To obtain a comprehensive conclusion, the other group where SNPs were smaller than the locus-wide significance level (1 × 10
-5
) were selected as instrumental variables. Based on the locus-wide significance level, the results indicated that there were causal effects of gut microbiome components on SLE risk. The inverse variance weighted (IVW) method suggested that
Bacilli
and
Lactobacillales
were positively correlated with the risk of SLE and
Bacillales
,
Coprobacter
and
Lachnospira
were negatively correlated with SLE risk. The results of weighted median method supported that
Bacilli
,
Lactobacillales
, and
Eggerthella
were risk factors for SLE and
Bacillales
and
Coprobacter
served as protective factors for SLE. The estimates of MR Egger suggested that genetically predicted
Ruminiclostridium6
was negatively associated with SLE. Based on the genome-wide statistical significance threshold, the results showed that
Actinobacteria
might reduce the SLE risk. However, Mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO) detected significant horizontal pleiotropy between the instrumental variables of
Ruminiclostridium6
and outcome. This study support that there are beneficial or detrimental causal effects of gut microbiome components on SLE risk.
Scope
Multiple sclerosis (MS) is an inflammatory demyelinating autoimmune disorder, with increasing incidence worldwide but unknown etiology. 6‐Gingerol (6‐GIN), a major dietary compound found in ...ginger rhizome, has immunomodulatory activity. However, its role in autoimmune diseases, as well as the underlying mechanisms, are unclear. In this study, it is evaluated if 6‐GIN can effectively ameliorate the clinical disease severity of experimental autoimmune encephalomyelitis, an animal model of MS.
Methods and results
Clinical scores of experimental autoimmune encephalomyelitis (EAE) mice are recorded daily. Inflammation of periphery and neuroinflammation of EAE mice are determined by flow cytometry analysis, ELISA, and histopathological analysis, and results show that 6‐GIN significantly inhibits inflammatory cell infiltration from the periphery into the central nervous system and reduces neuroinflammation and demyelination. Flow cytometry analysis, ELISA, and quantitative PCR show that 6‐GIN could suppress lipolysaccharide‐induced dendritic cell (DC) activation and induce the tolerogenic DCs. Immunoblot analysis reveals that the phosphorylation of nuclear factor‐κB and mitogen‐activated protein kinase, two critical regulators of inflammatory signaling, are significantly inhibited in 6‐GIN‐treated DCs.
Conclusion
The results of this study demonstrate that 6‐GIN has significant potential as a novel anti‐inflammatory agent for the treatment of autoimmune diseases such as MS via direct modulatory effects on DCs.
6‐Gingerol alleviates the clinical signs of experimental autoimmune encephalomyelitis by suppressing dendritic cell (DC) activation and inducing the tolerogenic properties of DCs.
Systemic lupus erythematosus (SLE) is a complex autoimmune disease with a strong genetic predisposition, characterized by an upregulated type I interferon pathway. MicroRNAs are important regulators ...of immune homeostasis, and aberrant microRNA expression has been demonstrated in patients with autoimmune diseases. We recently identified miR-146a as a negative regulator of the interferon pathway and linked the abnormal activation of this pathway to the underexpression of miR-146a in SLE patients. To explore why the expression of miR-146a is reduced in SLE patients, we conducted short parallel sequencing of potentially regulatory regions of miR-146a and identified a novel genetic variant (rs57095329) in the promoter region exhibiting evidence for association with SLE that was replicated independently in 7,182 Asians (P(meta) = 2.74×10(-8), odds ratio = 1.29 1.18-1.40). The risk-associated G allele was linked to reduced expression of miR-146a in the peripheral blood leukocytes of the controls. Combined functional assays showed that the risk-associated G allele reduced the protein-binding affinity and activity of the promoter compared with those of the promoter containing the protective A allele. Transcription factor Ets-1, encoded by the lupus-susceptibility gene ETS1, identified in recent genome-wide association studies, binds near this variant. The manipulation of Ets-1 levels strongly affected miR-146a promoter activity in vitro; and the knockdown of Ets-1, mimicking its reduced expression in SLE, directly impaired the induction of miR-146a. We also observed additive effects of the risk alleles of miR-146a and ETS1. Our data identified and confirmed an association between a functional promoter variant of miR-146a and SLE. This risk allele had decreased binding to transcription factor Ets-1, contributing to reduced levels of miR-146a in SLE patients.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Systemic lupus erythematosus is a complex and potentially fatal autoimmune disease, characterized by autoantibody production and multi-organ damage. By a genome-wide association study (320 patients ...and 1,500 controls) and subsequent replication altogether involving a total of 3,300 Asian SLE patients from Hong Kong, Mainland China, and Thailand, as well as 4,200 ethnically and geographically matched controls, genetic variants in ETS1 and WDFY4 were found to be associated with SLE (ETS1: rs1128334, P = 2.33x10(-11), OR = 1.29; WDFY4: rs7097397, P = 8.15x10(-12), OR = 1.30). ETS1 encodes for a transcription factor known to be involved in a wide range of immune functions, including Th17 cell development and terminal differentiation of B lymphocytes. SNP rs1128334 is located in the 3'-UTR of ETS1, and allelic expression analysis from peripheral blood mononuclear cells showed significantly lower expression level from the risk allele. WDFY4 is a conserved protein with unknown function, but is predominantly expressed in primary and secondary immune tissues, and rs7097397 in WDFY4 changes an arginine residue to glutamine (R1816Q) in this protein. Our study also confirmed association of the HLA locus, STAT4, TNFSF4, BLK, BANK1, IRF5, and TNFAIP3 with SLE in Asians. These new genetic findings may help us to gain a better understanding of the disease and the functions of the genes involved.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Objectives
To investigate the prognosis including major adverse kidney events within 30 days (MAKE30) and 90-day and 1-year adverse outcome in hospitalized patients with post-contrast acute kidney ...injury (PC-AKI) to identify high-risk factors.
Methods
This retrospective observational study included 288 PC-AKI patients selected from 277,898 patients admitted to hospitals from January 2015 to December 2015. PC-AKI was defined according to the 2018 guideline of European Society of Urogenital Radiology. Multivariable Cox regression and logistic regression analyses were used to analyze main outcome and risk factors.
Results
PC-AKI patients with AKI stage ≥ 2 had much higher incidence of MAKE30 than those with AKI stage 1 (RR = 7.027, 95% CI 4.918–10.039). Persistent renal dysfunction, heart failure, central nervous system failure, baseline eGFR < 60 mL/min/1.73 m
2
, oliguria or anuria, blood urea nitrogen ≥ 7.14 mmol/L, respiratory failure, and shock were independent risk factors of 90-day or 1-year adverse prognosis (
p
< 0.05). Compared with transient renal dysfunction, PC-AKI patients with persistent renal dysfunction had a higher all-cause mortality rate (RR = 3.768, 95% CI 1.612–8.810; RR = 4.106, 95% CI 1.765–9.551) as well as combined endpoints of death, chronic kidney disease, or end-stage renal disease (OR = 3.685, 95% CI 1.628–8.340; OR = 5.209, 95% CI 1.730–15.681) within 90 days or 1 year.
Conclusions
PC-AKI is not always a transient, benign creatininopathy, but can result in adverse outcome. AKI stage is independently correlated to MAKE30 and persistent renal dysfunction may exaggerate the risk of long-term adverse events.
Key Points
• PC-AKI can result in adverse outcome such as persistent renal dysfunction, dialysis, chronic kidney disease (CKD), end-stage renal disease (ESRD), or death.
• AKI stage is independently correlated to MAKE30.
• Persistent renal dysfunction may exaggerate the risk of long-term adverse events.
Our previous study found that Qiong-Yu-Gao (QYG), a traditional Chinese medicine formula derived from Rehmanniae Radix, Poria, and Ginseng Radix, has protective effects against cisplatin-induced ...acute kidney injury (AKI), but the underlying mechanisms remain unknown. In the present study, the potential role of gut microbiota in the nephroprotective effects of QYG was investigated. We found that QYG treatment significantly attenuated cisplatin-induced AKI and gut dysbiosis, altered the levels of bacterial metabolites, with short-chain fatty acids (SCFAs) such as acetic acid and butyric acid increasing and uremic toxins such as indoxyl sulfate and
-cresyl sulfate reducing, and suppressed histone deacetylase expression and activity. Spearman's correlation analysis found that QYG-enriched fecal bacterial genera
,
,
, and
were correlated with the altered metabolites, and these metabolites were also correlated with the biomarkers of AKI, as well as the indicators of fibrosis and inflammation. The essential role of gut microbiota was further verified by both the diminished protective effects with antibiotics-induced gut microbiota depletion and the transferable renal protection with fecal microbiota transplantation. All these results suggested that gut microbiota mediates the nephroprotective effects of QYG against cisplatin-induced AKI, potentially via increasing the production of SCFAs, thus suppressing histone deacetylase expression and activity, and reducing the accumulation of uremic toxins, thereby alleviating fibrosis, inflammation, and apoptosis in renal tissue.
Cisplatin-induced acute kidney injury is the main limiting factor restricting cisplatin's clinical application. Accumulating evidence indicated the important role of gut microbiota in pathogenesis of acute kidney injury. In the present study, we have demonstrated that gut microbiota mediates the protective effects of traditional Chinese medicine formula Qiong-Yu-Gao against cisplatin-induced acute kidney injury. The outputs of this study would provide scientific basis for future clinical applications of QYG as prebiotics to treat cisplatin-induced acute kidney injury, and gut microbiota may be a promising therapeutic target for chemotherapy-induced nephrotoxicity.
The present study aimed to discover novel susceptibility loci associated with risk of rheumatoid arthritis (RA).
We performed a new genome-wide association study (GWAS) in Chinese subjects (1027 RA ...cases and 2879 controls) and further conducted an expanded meta-analysis with previous GWAS summary data and replication studies. The functional roles of the associated loci were interrogated using publicly available databases. Dual-luciferase reporter and cytokine assay were also used for exploring variant function.
We identified five new susceptibility loci (
,
,
,
and
; p
<5.00E-08) with same effect direction in each study cohort. The sensitivity analyses showed that the genetic association of at least three loci was reliable and robust. All these lead variants are expression quantitative trait loci and overlapped with epigenetic marks in immune cells. Furthermore, genes within the five loci are genetically associated with risk of other autoimmune diseases, and genes within four loci are known functional players in autoimmunity, which supports the validity of our findings. The reporter assay showed that the risk allele of rs8030390 in
have significantly increased reporter activity in HEK293T cells. In addition, the cytokine assay found that the risk allele of rs244672 in
was most significantly associated with increased plasma IL-17A levels in healthy controls. Finally, identified likely causal genes in these loci significantly interacted with RA drug targets.
This study identified novel RA risk loci and highlighted that comprehensive genetic study can provide important information for RA pathogenesis and drug therapy.
To date, there are no prognostic/predictive biomarkers to select chemotherapy, immunotherapy, and radiotherapy in individual non-small cell lung cancer (NSCLC) patients. Major immune-checkpoint ...inhibitors (ICIs) have more DNA copy number variations (CNV) than mutations in The Cancer Genome Atlas (TCGA) NSCLC tumors. Nevertheless, CNV-mediated dysregulated gene expression in NSCLC is not well understood. Integrated CNV and transcriptional profiles in NSCLC tumors (
= 371) were analyzed using Boolean implication networks for the identification of a multi-omics
,
, and
network, containing novel prognostic genes and proliferation genes. A 5-gene (
,
,
,
, and
prognostic model was developed and validated for patient stratification (
< 0.02, Kaplan-Meier analyses) in NSCLC tumors (
= 1163). A total of 13 genes (
,
,
,
,
,
,
,
,
,
,
,
, and
) had a significant impact on proliferation in 100% of the NSCLC cell lines in both CRISPR-Cas9 (
= 78) and RNA interference (RNAi) assays (
= 92). Multiple identified genes were associated with chemoresponse and radiotherapy response in NSCLC cell lines (
= 117) and patient tumors (
= 966). Repurposing drugs were discovered based on this immune-omics network to improve NSCLC treatment.
The rapid discovery of novel viruses using next generation sequencing (NGS) technologies including DNA-Seq and RNA-Seq, has greatly expanded our understanding of viral diversity in recent years. The ...timely identification of novel viruses using NGS technologies is also important for us to control emerging infectious diseases caused by novel viruses. In this study, we identified a novel duck coronavirus (CoV), distinct with chicken infectious bronchitis virus (IBV), using RNA-Seq. The novel duck-specific CoV was a potential novel species within the genus Gammacoronavirus, as indicated by sequences of three regions in the viral 1b gene. We also performed a survey of CoVs in domestic fowls in China using reverse-transcription polymerase chain reaction (RT-PCR), targeting the viral nucleocapsid (N) gene. A total of 102 CoV positives were identified through the survey. Phylogenetic analysis of the viral N sequences suggested that CoVs in domestic fowls have diverged into several region-specific or host-specific clades or subclades in the world, and IBVs can infect ducks, geese and pigeons, although they mainly circulate in chickens. Moreover, this study provided novel data supporting the notion that some host-specific CoVs other than IBVs circulate in ducks, geese and pigeons, and indicated that the novel duck-specific CoV identified through RNA-Seq in this study is genetically closer to some CoVs circulating in wild water fowls. Taken together, this study shed new insight into the diversity, distribution, evolution and control of avian CoVs.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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