As the largest immune organ of the human body, the intestine also plays a vital role in nutrient digestion and absorption. Some vegetables are considered to have improvement effects on the intestine. This experiment explored the effects of freeze-dried asparagus, broccoli and cabbage powder on the intestinal immune homeostasis and microflora of mice. Thirty-two mice were divided into four groups (n = 8), including control group (fed normal diet), asparagus group (fed normal diet with 5% asparagus power), broccoli group (fed normal diet with 5% broccoli power) and cabbage group (fed normal diet with 5% cabbage power). The experiment lasted 21 days. The results showed that the serum immunoglobulin concentration (IgA and IgM) and intestinal cytokine content (like IFN-γ and TNF-α) were increased after vegetable powder supplement. The experiment also detected that vegetable powder supplementation changed intestinal flora and their metabolites (short-chain fatty acid), which showed that the abundance of Lachnospiraceae and Bacteroides were decreased, while the abundance of Firmicutes and Lactobacillus as well as propionic acid and butyric acid contents were increased. Together, these vegetable powders, especially cabbage, changed the intestinal immune response and microbial activity of mice.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has had a major impact on global human health. During the spread of SARS-CoV-2, weakened host immunity and the use of vaccines with low efficacy may result in the development of more-virulent strains or strains with resistance to existing vaccines and antibodies. The prevalence of SARS-CoV-2 mutant strains differs between regions, and this variation may have an impact on the effectiveness of vaccines. In this study, an epidemiological investigation of SARS-CoV-2 in Portugal was performed, and the VSV-ΔG-G* pseudovirus system was used to construct 12 spike protein epidemic mutants, D614G, A222V+D614G, B.1.1.7, S477N+D614G, P1162R+D614G+A222V, D839Y+D614G, L176F+D614G, B.1.1.7+L216F, B.1.1.7+M740V, B.1.258, B.1.258+L1063F, and B.1.258+N751Y. The mutant pseudoviruses were used to infect four susceptible cell lines (Huh7, hACE2-293T-293T, Vero, and LLC-MK2) and 14 cell lines overexpressing ACE2 from different species. Mutant strains did not show increased infectivity or cross-species transmission. Neutralization activity against these pseudoviruses was evaluated using mouse serum and 11 monoclonal antibodies. The neutralizing activity of immunized mouse serum was not significantly reduced with the mutant strains, but the mutant strains from Portugal could evade nine of the 11 monoclonal antibodies tested. Neutralization resistance was mainly caused by the mutations S477N, N439K, and N501Y in the spike-receptor binding domain. These findings emphasize the importance of SARS-CoV-2 mutation tracking in different regions for epidemic prevention and control.

As a global public health problem, postmenopausal osteoporosis (PMOP) poses a great threat to old women's health. Bone is the target organ of PMOP, and the dynamic changes of bone marrow could affect the bone status. Kidney is the main organ regulating calcium and phosphorus homeostasis. Kidney, bone marrow and bone play crucial roles in PMOP, but the relationships of the three tissues in the disease have not been completely described. Here, metabolomics was employed to investigate the disease mechanism of PMOP from the perspectives of kidney, bone marrow and bone, and the relationships among the three tissues were also discussed. Six-month-old female Sprague-Dawley (SD) rats were randomly divided into ovariectomized (OVX) group (with bilateral ovariectomy) and sham group (with sham surgery). 13 weeks after surgery, gas chromatography-mass spectrometry (GC-MS) was performed to analyze the metabolic profiling of two groups. Multivariate statistical analysis revealed that the number of differential metabolites in kidney, bone marrow and bone between the two groups were 37, 16 and 17, respectively. The common differential metabolites of the three tissues were N-methyl-L-alanine. Kidney and bone marrow had common differential metabolites, including N-methyl-L-alanine, 2-hydroxybutyric acid, (R)-3-hydroxybutyric acid (β-hydroxybutyric acid, βHBA), urea and dodecanoic acid. There were three common differential metabolites between kidney and bone, including N-methyl-L-alanine, α-tocopherol and isofucostanol. The common differential metabolite of bone marrow and bone was N-methyl-L-alanine. Some common metabolic pathways were disturbed in multiple tissues of OVX rats, such as glycine, serine and threonine metabolism, purine metabolism, tryptophan metabolism, ubiquinone and other terpenoid-quinone biosynthesis and fatty acid biosynthesis. In conclusion, our study demonstrated that profound metabolic changes have taken place in the kidney, bone marrow and bone, involving common differential metabolites and metabolic pathways. The evaluation of differential metabolites strengthened the understanding of the kidney-bone axis and the metabolic relationships among the three tissues of OVX rats.

Esophageal squamous cell carcinoma (ESCC) is one of the most lethal gastrointestinal malignancies with high mortality. Recurrence develops within only a few years after curative resection and perioperative adjuvant therapy in 30-50% of these patients. Therefore, it is essential to identify postoperative recurrence biomarkers to facilitate selecting the following surveillance and therapeutic strategies. The general transcription factor IIE subunit beta (GTF2E2) is crucial for physiological and pathological functions, but its roles in the aggression and recurrence of ESCC remain ambiguous. In this study, we found that GTF2E2 was highly expressed in ESCC samples, and elevated GTF2E2 expression predicted early recurrence after surgery for ESCC patients. High expression of GTF2E2 associated with more aggressive clinic features and poor prognosis. GTF2E2 promoted the proliferation and mobility of ESCC cells in vitro and in vivo. We further revealed that miR-139-5p repressed GTF2E2 expression by downregulating its mRNA through binding with Argonaute 2 (Ago2). Rescue assays suggested that miR-139-5p affected GTF2E2-mediated ESCC progression. Moreover, GTF2E2 positively interacted with FUS promoter and regulated FUS expression, and the phenotype changes caused by GTF2E2 manipulation were recovered by rescuing FUS expression in ESCC cells. Additionally, we demonstrated that GTF2E2 promotes ESCC cells progression via activation of the AKT/ERK/mTOR pathway. In conclusion, GTF2E2 may serve as a novel biomarker for recurrence after surgery and a potential therapeutic target for ESCC patients, and it promotes ESCC progression via miR-139-5p/GTF2E2/FUS axis.

Hypoxic microenvironment represents the hallmark of solid tumors including colorectal cancer (CRC) and facilitates angiogenesis and chemoresistance, leading to poor prognosis. lncRNA NORAD acts as an oncogenic gene to orchestrate cancer progression by regulating cell proliferation and migration. Notably, an emerging study corroborates the elevation of NORAD during hypoxic conditions in pancreatic cancer. Nevertheless, its biological role in hypoxia-evoked CRC remains unclear. Herein, enhanced expression of NORAD and hypoxia-inducible factor-1α (HIF-1α) was validated in CRC tissues. Furthermore, there was a positive association between NORAD and HIF-1α in CRC tissues. CRC cells exposed to hypoxia exhibited a stronger ability to form vasculogenic mimicry (VM) and resistance to 5-fluorouracil (5-FU), concomitant with higher expression of NORAD. NORAD knockdown restrained hypoxia-induced VM formation and VM marker VE-cadherin expression. Moreover, knockdown of NORAD counteracted CRC cell resistance to 5-FU by decreasing cell viability and increasing cell apoptosis. Additionally, NORAD loss reduced hypoxia-induced HIF-1α expression and subsequent epithelial-mesenchymal transition (EMT) by increasing E-cadherin and inhibiting N-cadherin expression. Intriguingly, HIF-1α overexpression reversed NORAD downregulation-mediated inhibition of VM formation and 5-FU resistance. There was a low expression of miR-495-3p in CRC tissues. Furthermore, NORAD could act as a competitive endogenous RNA of miR-495-3p to regulate HIF-1α. Importantly, inhibition of miR-495-3p muted the efficacy of NORAD loss in hypoxia-induced EMT, VM, and chemoresistance. Thus, the current data highlight that NORAD knockdown may antagonize hypoxia-triggered CRC malignancy by suppressing VM formation and chemoresistance by sponging miR-495-3p/HIF-1α to regulate EMT, supporting a promising therapeutic target for refractory hypoxia in CRC.

Nicotiana alata is an ornamental horticultural plant with a variety of flower colors and a long flowering period. The genes in four different colored N. alata (white, purple, red, and lemon green) were analyzed to explain the differences in flower color using transcriptomes. A total of 32 differential expression genes in the chlorophyll biosynthesis pathway and 41 in the anthocyanin biosynthesis pathway were identified. The enrichment analysis showed that the chlorophyll biosynthesis pathway and anthocyanin biosynthesis pathway play critical roles in the color differences of N. alata. The HEMA of the chlorophyll biosynthesis pathway was up-regulated in lemon green flowers. Compared with white flowers, in the red and purple flowers, F3H, F3'5'H and DFR were significantly up-regulated, while FLS was significantly down-regulated. Seventeen differential expression genes homologous to transcription factor coding genes were obtained, and the homologues of HY5, MYB12, AN1 and AN4 were also involved in flower color differences. The discovery of these candidate genes related to flower color differences is significant for further research on the flower colors formation mechanism and color improvements of N. alata.

Cholangiocarcinoma (CCA) is a primary biliary epithelium malignancy with limited therapies, poor prognosis and high mortality rate. Nowadays, the molecular mechanisms of CCA remain elusive. SPARC has been proposed to be highly expressed in clinical CCA tissues, but few studies has been elucidated its functions in CCA. In the current study, we aimed to investigate the functional role of SPARC in the progression of CCA. In this study, a significantly increased expression of SPARC was observed in CCA tissues and cells. Knockdown of SPARC by RNA interference significantly impeded the proliferation of CCA cells. Moreover, SPARC silencing hampered the migration and invasion of CCA cells by inhibiting EMT. In parallel, overexpression of SPARC in RBE cells had the opposite effects. Mechanically, SPARC promoted proliferation, migration, invasion, and EMT of CCA cells in vitro via activating the PI3K-AKT signaling. Overall, our integrated analysis revealed that SPARC plays a crucial role in CCA progression via the PI3K-AKT signaling pathway, which suggests that targeting SPARC might represent a promising approach for improving CCA patient's clinical outcome.

Bile acids, the main organic solutes in bile, have been established to play an important role at physiological concentrations in gastrointestinal metabolism. However, under pathological conditions, such as cholestatic disease, cholestasis can damage hepatocytes/biliary epithelial cells leading to apoptosis or necrosis. Clinically, pancreatic head cancer usually presents with obstructive jaundice and increased serum bile acid levels, suggesting that pancreatic cancer is intricately correlated with a high bile acid environment in the human body. An increasing body of evidence suggests that bile acids are toxic to normal human and colon cancer cells. Nonetheless, the effect of bile acids on the occurrence and development of pancreatic cancer remains a matter of debate. In the present study, to explore the direct effects of high serum concentrations of bile acids on pancreatic cancer and the possible related mechanisms, human pancreatic cancer (PANC-1) cells were subject to different concentrations of bile acid mixtures to assess cell viability and the migration and invasion ability. Besides, we found that a high bile acid environment could inhibit the proliferation and migration of pancreatic cancer cells through ROS(Reactive oxygen species) induction and the EMT(epithelial-mesenchymal transition) pathway, thereby promoting the apoptosis of pancreatic cancer cells.Abbreviations BAs: Bile Acids; EMT: epithelial-mesenchymal transition; FBS: fatal bovine serum;CCK-8: Cell-Counting-Kit-8; ROS: reactive oxygen species; CA: cholic acid; CDCA: chenodeoxycholic acid; GCDCA: Glycochenodeoxycholic acid; PVDF: Poly vinylidene fluoride.

Microglia-mediated neuroinflammation and mitochondrial dysfunction play critical role in the pathogenic process of Parkinson's disease (PD). Mitophagy plays central role in mitochondrial quality control. Hence, regulation of microglial activation through mitophagy could be a valuable strategy in controlling microglia-mediated neurodegeneration and neuroinflammation. Urolithin A (UA) is a natural compound produced by gut bacteria from ingested ellagitannins (ETs) and ellagic acid (EA). Several preclinical studies have reported the beneficial effects of UA on age-related conditions by increasing mitophagy and blunting excessive inflammatory responses. However, the specific role of UA in pathology of PD remains unknown. In this study, we showed that treatment with UA reduced the loss of dopaminergic neurons, ameliorated behavioral deficits and neuroinflammation in MPTP mouse model of PD. Further study revealed that UA promotes mitophagy, restores mitochondrial function and attenuate proinflammatory response in BV2 microglial cells exposed to LPS. Moreover, UA also reduced NLRP3 inflammasome activation both in vitro and in vivo. Importantly, disruption of microglial mitophagy with pharmacological or genetic approach partly blunted the neuroprotective effects of UA in MPTP mouse model of PD. Collectively, these results provide strong evidence that UA protects against dopaminergic neurodegeneration and neuroinflammation. The mechanism may be related with its inhibition of NLRP3 inflammasome activation via promoting mitophagy in microglia.

Nuclear factor E2-related factor 2 (Nrf2) is an important transcription factor which plays a pivotal role in detoxifying reactive oxygen species (ROS) and has been more recently shown to regulate inflammatory and antiviral responses. However, the role of Nrf2 in Herpes Simplex Virus type 1 (HSV-1) infection is still unclear. In this study, the interaction between the Nrf2 and HSV-1 replication was investigated.

Background: Streptococcus pneumoniae is an important human pathogen that can cause severe invasive pneumococcal diseases (IPDs). The aim of this multicenter study was to investigate the serotype and sequence type (ST) distribution, antimicrobial susceptibility, and virulence of S. pneumoniae strains causing IPD in China. Methods: A total of 300 invasive S. pneumoniae isolates were included in this study. The serotype, ST, and antimicrobial susceptibility of the strains, were determined by the Quellung reaction, multi-locus sequence typing (MLST) and broth microdilution method, respectively. The virulence level of the strains in the most prevalent serotypes was evaluated by a mouse sepsis model, and the expression level of well-known virulence genes was measured by RT-PCR. Results: The most common serotypes in this study were 23F, 19A, 19F, 3, and 14. The serotype coverages of PCV7, PCV10, PCV13, and PPV23 vaccines on the strain collection were 42.3, 45.3, 73.3 and 79.3%, respectively. The most common STs were ST320, ST81, ST271, ST876, and ST3173. All strains were susceptible to ertapenem, levofloxacin, moxifloxacin, linezolid, and vancomycin, but a very high proportion (>95%) was resistant to macrolides and clindamycin. Based on the oral, meningitis and non-meningitis breakpoints, penicillin non-susceptible Streptococcus pneumoniae (PNSP) accounted for 67.7, 67.7 and 4.3% of the isolates, respectively. Serotype 3 strains were characterized by high virulence levels and low antimicrobial-resistance rates, while strains of serotypes 23F, 19F, 19A, and 14, exhibited low virulence and high resistance rates to antibiotics. Capsular polysaccharide and non-capsular virulence factors were collectively responsible for the virulence diversity of S. pneumoniae strains. Conclusion: Our study provides a comprehensive insight into the epidemiology and virulence diversity of S. pneumoniae strains causing IPD in China.

Atherosclerosis (AS) is recognized as the original cause of most cardiovascular and cerebrovascular diseases. The dual-protein (DP) nutrition that consists of soy protein and whey protein is reported to be associated with a reduction in AS; however, the relationship between DP and AS remains ambiguous. Therefore, this study aimed to verify the effect of DP on AS and explore the optimal DP intake to improve AS. ApoE-/- mice were administrated with low- (LDP), middle- (MDP), and high-dose (HDP) DP. The MDP group exhibited significant improvements in AS. In terms of lipid metabolism, the levels of plasma total triglyceride and LDL-C and the mRNA expression levels of Cyp7a1 and PCSK9 were markedly tuned in the MDP group. In addition, the MDP treatment group had a substantially lower inflammatory response and better intestinal barrier function than LDP and HDP groups. The species richness demonstrated by the Chao1 index was distinctly increased in the MDP group, and the relative abundance of intestinal-permeability-protective microbes Blautia and Akkermansia was significantly elevated. In summary, an adequate intake of DP was able to counteract atherosclerosis development in ApoE-/- mice, and this study provides a scientific theoretical basis for the application of DP in the food and pharmaceutical fields.

Stroke is an illness with high morbidity, disability and mortality that presents a major clinical challenge. Sanhua decoction (SHD) has been widely used to treat ischaemic stroke in the clinic. However, the potential mechanism of SHD remains unknown.

Zoonosis-based epidemics are inevitable unless we revisit our relationship with the natural world, protect habitats, and regulate wildlife trade, including live animals and non-sustenance products. To prevent future zoonoses, governments must establish effective legislation addressing wildlife trade, protection of habitats, and reduction of the wildlife-livestock-human interface.

Acidithiobacillus ferrooxidans ATCC23270 is a gram-negative and autotrophic bacillus acquiring energy via the oxidation of iron and sulfur. The pet II operon is involved in the sulfur metabolism of A. ferrooxidans. However, the mechanisms that control the expression of the pet II operon are poorly understood. We previously described that the AFE2726 protein is associated with the expression of the pet II operon. Here, we attempted to analyze the involvement of AFE2726 in the regulation of pet II operon expression. First, pEGF recombinant vectors driven by the promotor of the pet II operon, denoted pEGF-pet II, were constructed. Then, DH5α E. coli cultures containing the vector mentioned above were cultivated in Na2S2O3, as this medium substantially enhances the expression of green fluorescent proteins. To examine the regulatory effect of AFE2726 on the pet II operon, the C62/V and C72/V mutants for AFE2726 were constructed in pEGF-pet II vectors using the site-directed deletion method. Compared to pEFG-pet II and pEFG-pet II-Δ-C62/V, pEFG-pet II-Δ-C72/V reduced the expression of green fluorescent proteins dramatically when transformed into DH5α E.coli in Na2S2O3 medium. This suggested that the 72nd cysteine was a crucial residue of the AFE2726 protein, affecting the response of the pet II operon to sodium thiosulfate. Furthermore, the binding site of AFE2726 on the promotor of the pet II operon was identified using the electrophoretic mobility shift assay (EMSA), and it was found to be a 34bp inverted repeat sequence (named IR4), which ranged from -65 to -32. In summary, our results indicated that the AFE2726 protein regulates the pet II operon by binding to the IR4 sequence in its promotor region, whose function is likely affected by Na2S2O3 binding to its Cys72 residue counterpart.

Exercise therapies has been shown to be safe and effective as a non-pharmacological management for treating heart failure, At the same time, many clinical trials, systematic review, and meta-analyses have demonstrated the advantages of exercise therapies in heart failure. However, the methodological quality of these systematic reviews and the differences in efficacy between different exercise modes are unclear. Therefore, this study intends to overview of systematic reviews and network meta-analysis of exercise therapies intervention in heart failure, and finally to rank the effects of exercise therapies in the intervention of heart failure, so as to provide certain reference for clinical decision-making.

Diabetic nephropathy is a common and serious complication of diabetes mellitus (DM) and is one of the leading causes of end-stage renal disease worldwide. Although there have been many investigations on biomarkers for DN, there is no consistent conclusion about reliable biomarkers. The purpose of this study was to perform a systematic review and meta-analysis of the role of circulating retinol-binding protein 4 (RBP4) in the type 2 diabetes mellitus (T2DM) patients with kidney diseases.

Macrophages help defend the host against Mycobacterium tuberculosis (Mtb), the major cause of tuberculosis (TB). Once phagocytized, Mtb resists killing by macrophages, replicates inside them, and leads to their death, releasing Mtb that can infect other cells. We found that the death of Mtb-infected mouse macrophages in vitro does not appear to proceed by a currently known pathway. Through genome-wide CRISPR-Cas9 screening, we identified a critical role for autocrine or paracrine signaling by macrophage-derived type I IFNs in the death of Mtb-infected macrophages in vitro, and blockade of type I IFN signaling augmented the effect of rifampin, a first-line TB drug, in Mtb-infected mice. Further definition of the pathway of type I IFN-mediated macrophage death may allow for host-directed therapy of TB that is more selective than systemic blockade of type I IFN signaling.

Malignant ascites (MA) effusion is mainly caused by hepatocellular, ovarian, and breast cancer etc. It has been reported that Euphorbia kansui (EK), the root of Euphorbia kansui S.L.Liou ex S.B.Ho, possessing a therapeutic effect on MA. However, the clinical applications of EK are seriously restricted for its severe toxicity. Although studies demonstrated that vinegar-processing can reduce the toxicity and retain the water expelling effect of EK, its specific mechanism remains unknown.

To develop a clinical model for predicting postoperative acute kidney injury (AKI) in patients of advanced age undergoing cardiac surgery.