The mitochondrial quality control system: a new target for exercise therapeutic intervention in the treatment of brain insulin resistance-induced neurodegeneration in obesity.

Obesity is a major global health concern because of its strong association with metabolic and neurodegenerative diseases such as diabetes, dementia, and Alzheimer's disease. Unfortunately, brain insulin resistance in obesity is likely to lead to neuroplasticity deficits. Since the evidence shows that insulin resistance in brain regions abundant in insulin receptors significantly alters mitochondrial efficiency and function, strategies targeting the mitochondrial quality control system may be of therapeutic and practical value in obesity-induced cognitive decline. Exercise is considered as a powerful stimulant of mitochondria that improves insulin sensitivity and enhances neuroplasticity. It has great potential as a non-pharmacological intervention against the onset and progression of obesity associated neurodegeneration. Here, we integrate the current knowledge of the mechanisms of neurodegenration in obesity and focus on brain insulin resistance to explain the relationship between the impairment of neuronal plasticity and mitochondrial dysfunction. This knowledge was synthesised to explore the exercise paradigm as a feasible intervention for obese neurodegenration in terms of improving brain insulin signals and regulating the mitochondrial quality control system.

Dysregulation of Ruminococcaceae and Megamonas could be predictive markers for rapid progression of mild cognitive impairment.

BACKGROUND: Intestinal flora dysregulation may affect the development of Alzheimer's disease (AD). However, the correlation between intestinal flora and rapid progression of mild cognitive impairment (MCI) is rarely reported. Our aim was to investigate the features of the intestinal flora in patients with rapidly progressive MCI. METHOD: A total of 1013 participants were screened, in which 87 patients with MCI were followed up for two years. At the baseline time point, fecal samples of the patients were sequenced via the microbial diversity high-throughput 16 s-rDNA. RESULTS: After a two-year follow-up, 30 patients with MCI presented rapidly progressive cognitive impairment, whereas the 57 patients remained unprogressive. Analyses of their fecal samples showed that the abundance of 11 intestinal microflora were significantly different between the two groups at the baseline time point. Further analyses revealed that the decrease of Ruminococcaceae abundance and the increase of Megamonas abundance were significantly correlated with the progression of MCI. Also, the decreased Ruminococcaceae was independently associated with several factors such as P-tau181, and the increased Megamonas was independently associated with diabetes, low-density lipoprotein, median cell count. CONCLUSION: The decrease of Ruminococcaceae and the increase of Megamonas could act as predictive markers for the rapidly progressive MCI.

Predicting the Rapid Progression of Mild Cognitive Impairment by Intestinal Flora and Blood Indicators through Machine Learning Method.

INTRODUCTION: The aim of the work was to establish a prediction model of mild cognitive impairment (MCI) progression based on intestinal flora by machine learning method. METHOD: A total of 1,013 patients were recruited, in which 87 patients with MCI finished a two-year follow-up. To establish a prediction model, 61 patients were randomly divided into a training set and 26 patients were divided into a testing set. A total of 121 features including demographic characteristics, hematological indicators, and intestinal flora abundance were analyzed. RESULTS: Of the 87 patients who finished a two-year follow-up, 44 presented rapid progression. Model 1 was established based on 121 features with the accuracy 85%, sensitivity 85%, and specificity 83%. Model 2 was based on the first fifteen features of model 1 (triglyceride, uric acid, alanine transaminase, F-Clostridiaceae, G-Megamonas, S-Megamonas, G-Shigella, G-Shigella, S-Shigella, average hemoglobin concentration, G-Alistipes, S-Collinsella, median cell count, average hemoglobin volume, low-density lipoprotein), with the accuracy 97%, sensitivity 92%, and specificity 100%. Model 3 was based on the first ten features of model 1, with the accuracy 97%, sensitivity 86%, and specificity 100%. Other models based on the demographic characteristics, hematological indicators, or intestinal flora abundance features presented lower sensitivity and specificity. CONCLUSION: The 15 features (including intestinal flora abundance) could establish an effective model for predicting rapid MCI progression.

Single-Atom Nanozymes: Fabrication, Characterization, Surface Modification and Applications of ROS Scavenging and Antibacterial.

Nanozymes are nanomaterials with intrinsic natural enzyme-like catalytic properties. They have received extensive attention and have the potential to be an alternative to natural enzymes. Increasing the atom utilization rate of active centers in nanozymes has gradually become a concern of scientists. As the limit of designing nanozymes at the atomic level, single-atom nanozymes (SAzymes) have become the research frontier of the biomedical field recently because of their high atom utilization, well-defined active centers, and good natural enzyme mimicry. In this review, we first introduce the preparation of SAzymes through pyrolysis and defect engineering with regulated activity, then the characterization and surface modification methods of SAzymes are introduced. The possible influences of surface modification on the activity of SAzymes are discussed. Furthermore, we summarize the applications of SAzymes in the biomedical fields, especially in those of reactive oxygen species (ROS) scavenging and antibacterial. Finally, the challenges and opportunities of SAzymes are summarized and prospected.

Low-dose triptolide enhances antitumor effect of JQ1 on acute myeloid leukemia through inhibiting RNA polymerase II in vitro and in vivo.

The bromodomain and extra-terminal (BET) domain inhibitor JQ1 exerts potent anticancer activity in various cancer cells. However, the resistance to BET inhibitors in leukemia stem cells limits its implication in acute myeloid leukemia (AML). High concentration of triptolide (TPL) presents anticancer activities but with adverse effects. Here, we investigated whether the combination of low-dose TPL with JQ1 could help to circumvent the dilemma of drug resistance and side effect in treating AML. AML cell lines, primary cells from 10 AML patients with different status, as well as AML mice model were subjected to different treatments and apoptotic related protein expression were evaluated. Data showed that low-dose TPL combined with JQ1 effectively killed AML cell lines and primary cells from AML patients without exerting significantly greater lethal activity against normal cells. Mechanism study revealed that low-dose TPL combined with JQ1 triggered reactive oxygen species production and induced mitochondrial-mediated apoptosis in AML cells, in which the inhibition of RNA polymerase II to downregulate c-Myc was mainly responsible for the enhanced activity of TPL in combination with JQ1. In vivo study presented that cotreatment with low-dose TPL and JQ1 significantly reduced tumor burden of the NOD/SCID mice engrafted with MOLM-13 cells. In conclusion, low-dose TPL enhanced the antitumor effect of JQ1 on AML without increasing the side effects, supporting a potential option for AML treatment.

Fecal bacteria from Crohn's disease patients more potently activated NOD-like receptors and Toll-like receptors in macrophages, in an IL-4-repressible fashion.

Crohn's disease (CD) is characterized by a pathogenic intestinal inflammation mediated by a Th1-skewed immune system and a dysregulated intestinal mucosal community. In this study, we investigated the role of bacteria on the activation and function of monocytes, and its association with CD pathogenesis. To this end, fecal bacteria from CD patients and healthy controls were collected and used to stimulate autologous circulating monocytes. Fecal bacteria from CD patients were more effective at upregulating NOD2, NLRP3, TLR2, and TLR4 expression than fecal bacteria from healthy controls. Furthermore, the monocyte-derived macrophages (MDMs) induced by CD bacteria were more sensitive to E. coli stimulation than the MDMs induced by control bacteria, and demonstrated more M1 characteristics with high IL-6, TNF-α, and IL-12 and low IL-4 production. These effects mediated by fecal bacteria from CD patients could be repressed by the supplementation of IL-4. IL-4 not only suppressed the expression of NOD1, NOD2, NLRP3, TLR2, TLR4, and CD14 in MDMs induced by CD bacteria, but also suppressed E. coli-mediated expression of IL-6, TNF-α, and IL-12. Furthermore, IL-4-conditioned MDMs were more effective at supporting Th2 differentiation and inhibiting Th1 and Th17 differentiation of CD4+ T cells. Together, these studies demonstrated that fecal bacteria from CD patients presented enhanced capacity to upregulate pattern-recognition molecules in macrophages, which could be repressed by IL-4.

Circulating CXCR5+CD4+ T cells assist in the survival and growth of primary diffuse large B cell lymphoma cells through interleukin 10 pathway.

Diffuse large B cell lymphoma (DLBCL) is a common and aggressive cancer caused by the malignant transformation of B cells. Although it has been established that the follicular helper T (Tfh) cells play a central role in B cell development, little information is available on their involvement in DLBCL pathogenesis. We studied the role of the peripheral Tfh equivalent, the CXCR5+ CD4+ T cells, in DLBCL. Data showed that compared to CXCR5- CD4+ T cells, CXCR5+ CD4+ T cells were significantly more effective at promoting the proliferation as well as inhibiting the apoptosis of primary autologous DLBCL tumor cells. Surprisingly, we found that at equal cell numbers, CXCR5+ CD4+ T cells in DLBCL patients secreted significantly less interleukin (IL)-21 than CXCR5- CD4+ T cells, while the level of IL-10 secretion was significant elevated in the CXCR5+ compartment compared to the CXCR5- compartment. Neutralization of IL-10 in the primary DLBCL-CXCR5+ CD4+ T cell coculture compromised the CXCR5+ CD4+ T cell-mediated pro-tumor effects, in a manner that was dependent on the concentration of anti-IL-10 antibodies. The CXCR5+ compartment also contained significantly lower frequencies of cytotoxic CD4+ T cells than the CXCR5- compartment. In conclusion, our investigations discovered a previously unknown pro-tumor role of CXCR5-expressing circulating CD4+ T cells, which assisted the survival and proliferation of primary DLBCL cells through IL-10.

Reactivity toward Bifidobacterium longum and Enterococcus hirae demonstrate robust CD8+ T cell response and better prognosis in HBV-related hepatocellular carcinoma.

Recent studies suggest that several bacterial species are involved in tumor immunosurveillance and antitumor immunity. The role of bacteria in immune responses in HBV-related hepatocellular carcinoma (HCC) patients is still unknown. In this study, we examined the bacteria-reactive CD8+ T cell response in patients with HBV-related HCC. We found that circulating CD8+ T cells from healthy individuals demonstrated minimal or zero specificity toward a series of commensals and bacteria previously associated with antitumor effects, including Escherichia coli, Enterococcus faecium, Bifidobacterium longum, Bacteroides fragilis, and Enterococcus hirae. In contrast, the circulating CD8+ T cells from HBV-related HCC patients presented significantly elevated bacteria-reactive responses, albeit with high variations among different HCC individuals. Reactivity toward bacteria was also identified in tumor-infiltrating CD8+ T cells. These bacteria-reactive responses were not primarily induced by TLR ligand, but were dependent on the presence of antigen-presenting monocytes, and were MHC class I-restricted. Interestingly, we observed that the CD8+ T cell-to-Foxp3+ regulatory T cell ratio was positively correlated with the proportions of Bifidobacterium longum-reactive and Enterococcus hirae-reactive CD8+ T cells, while the frequency of PD-1+ CD8+ T cells was negatively correlated with the frequency of Enterococcus hirae-reactive CD8+ T cells. Furthermore, the disease-free survival time of HCC patients after tumor resection was positively correlated with the frequencies of Bifidobacterium longum-reactive and Enterococcus hirae-reactive CD8+ T cells. Together, these results suggested that certain bacterial species might present valuable antitumor effects.

Stimulatory role of interleukin 10 in CD8+ T cells through STATs in gastric cancer.

CD8+ T cells are considered to be critical in tumor surveillance and elimination. Increased CD8+ T cell frequency and function is associated with better prognosis in cancer patients. Interleukin 10 is a cytokine with controversial roles in CD8+ T cell-mediated anti-tumor immunity. We therefore examined the interleukin 10 expression and consumption in CD8+ T cells harvested from the peripheral blood and resected tumors of gastric cancer patients of stages II-IV. We found that the gastric cancer patients presented significantly elevated frequencies of interleukin 10-expressing cells in both CD4+ and CD8+ T cells compared to healthy controls. But distinctive from the interleukin 10-expressing CD4+ T cells, which increased in frequency in advanced cancer, the interleukin 10-expressing CD8+ T cells did not increase with cancer stage in the peripheral blood and actually decreased with cancer stage in resected tumor. Interleukin 10 and interleukin 10 receptor expression was also enriched in interferon gamma-expressing activated CD8+ T cells. Compared to interleukin 10-nonexpressing CD8+ T cells, interleukin 10 receptor-expressing CD8+ T cells secreted significantly elevated interferon gamma levels. Treatment of anti-CD3/CD28-stimulated, purified CD8+ T cells with interleukin 10 alone could significantly enhance CD8+ T cell survival, an effect dependent on interleukin 10 receptor expression. Interleukin 10 also increased CD8+ T cell proliferation synergistically with interferon gamma but not alone. Analysis of downstream signal transducer and activator of transcription molecules showed that interleukin 10 treatment significantly increased the phosphorylation of signal transducer and activator of transcription 3 and signal transducer and activator of transcription 1 to lesser extent. Together, these results demonstrate that interleukin 10 possessed stimulatory roles in activated CD8+ T cells from gastric cancer patients.

Early Recruitment of IL-10-Producing B Cells Into Alveoli Improved the Resolution of Acute Lung Injury.

BACKGROUND: Acute lung injury (ALI) is characterized by rapid induction of inflammation at the alveolar-capillary membrane, and immunosuppressive mechanisms were shown to contribute to its resolution. Despite the central role of lymphocytes in initiating and mediating an inflammatory response, their influx dynamics in ALI has not been examined. METHODS: We collected mini-BAL samples from the lung of ALI patients over a maximum period of 7 days, and examined the lymphocyte composition. RESULTS: CD3+CD4+IFN-gamma+ Th1 cells were detected early on in all patients examined, while IL-10-producing B cells and CD3+CD4+CD25hiFoxp3+ Treg cells appeared later. Interestingly, IL-10-producing B cells appeared earlier than Tregs in most subjects, which possibly exerted anti-inflammatory function before Tregs. We then found that in patients with earlier recruitment of IL-10-producing B cells, the magnitude of Th1 inflammation decreased significantly over time, which was not observed in patients with later recruitment of IL-10-producing B cells. Furthermore, early IL-10-producing B cell recruiters also had significantly earlier recruitment of Tregs and better survival than late IL-10-producing B cell recruiters. CONCLUSION: This study provided data on the alveolar infiltration of lymphocytes during ALI, which suggested an inhibitory role of IL-10-producing B cells in ALI and emphasized the importance of controlling inflammation during the initial stage of ALI.

Ultrafine particles in the airway aggravated experimental lung injury through impairment in Treg function.

Acute lung injury (ALI) is a life-threatening condition characterized by rapid-onset alveolar-capillary damage mediated by pathogenic proinflammatory immune responses. Since exposure to airway particulate matter (PM) could significantly change the inflammatory status of the individual, we investigated whether PM instillation in the airway could alter the course of ALI, using a murine model with experimental lung injury induced by intratracheal LPS challenge. We found that PM-treated mice presented significantly aggravated lung injury, which was characterized by further reductions in body weight, increased protein concentration in the bronchoalveolar lavage (BAL), and higher mortality rate, compared to control saline-treated mice. The PM-treated mice also presented elevated lung and systemic type 1 T helper cell (Th1) frequency as well as reduced lung regulatory T cell (Treg) frequency, which was associated with severity of lung injury. Further examinations revealed that the Treg function was impaired in PM-treated mice, characterized by significantly repressed transforming growth factor beta production. Adoptive transfer of functional Tregs from control mice to PM-treated mice significantly improved their prognosis after intratracheal LPS challenge. Together, these results demonstrated that first, PM in the airway aggravated lung injury; second, severity of lung injury was associated with T cell subset imbalance in PM-treated mice; and third, PM treatment induced quantitative as well as qualitative changes in the Tregs.

LINE-1 retrotransposable element DNA accumulates in HIV-1-infected cells.

Type 1 long-interspersed nuclear elements (L1s) are autonomous retrotransposable elements that retain the potential for activity in the human genome but are suppressed by host factors. Retrotransposition of L1s into chromosomal DNA can lead to genomic instability, whereas reverse transcription of L1 in the cytosol has the potential to activate innate immune sensors. We hypothesized that HIV-1 infection would compromise cellular control of L1 elements, resulting in the induction of retrotransposition events. Here, we show that HIV-1 infection enhances L1 retrotransposition in Jurkat cells in a Vif- and Vpr-dependent manner. In primary CD4(+) cells, HIV-1 infection results in the accumulation of L1 DNA, at least the majority of which is extrachromosomal. These data expose an unrecognized interaction between HIV-1 and endogenous retrotransposable elements, which may have implications for the innate immune response to HIV-1 infection, as well as for HIV-1-induced genomic instability and cytopathicity.

Functional IRGM polymorphism is associated with language impairment in glioma and upregulates cytokine expressions.

Immunity-related GTPase family M protein (IRGM) is a human protein recently highlighted for its contribution to autophagy upon infections. Evidences have shown that IRGM may also play critical roles in the pathogenesis of cancer. However, correlation between IRGM and glioma remains unclear. In the current study, we investigated two IRGM genetic polymorphisms, rs10065172C/T and rs13361189T/C, in glioma and their effects on cytokine expression. Data showed that prevalences of rs13361189TC genotype were significantly increased in glioma patients than in healthy controls (odds ratio (OR) = 1.53, 95 % confidence interval (CI) 1.05-2.24, P = 0.028), and frequency of polymorphic rs13361189CC genotype was further elevated (OR = 2.43, 95 % CI 1.43-4.14, P = 0.001). Interestingly, rs13361189TC and CC genotypes revealed a strong association with language impairment in glioma patients (OR = 2.16, P = 0.023; OR = 3.71, P = 0.001, respectively). When analyzing these two polymorphisms with related cytokine expression, we observed that subjects carrying rs13361189CC genotype had higher serum level of interferon-gamma (IFN-γ) than those with wild-type TT genotype (P < 0.01). In addition, subjects with rs13361189TC and CC genotypes presented elevated serum level of interleukin 4 (IL-4) than those with TT genotype. These data indicate a potential role of IRGM in the development of glioma probably by affecting IFN-γ and IL-4.

Alterations of circulating follicular helper T cells and interleukin 21 in diffuse large B-cell lymphoma.

CD4+ CXCR5+ T cell in peripheral blood is known as circulating follicular helper T cell (Tfh), which can produce interleukin 21 (IL-21). In the current study, we investigated changes of circulating Tfh and its correlation with IL-21 in diffuse large B-cell lymphoma (DLBCL). Circulating Tfh and its subtypes were detected by flow cytometry in the peripheral blood of 32 healthy donors and 62 DLBCL cases. Data demonstrated that percentage of circulating Tfh in CD4+ T cells was significantly increased in DLBCL (11.3 %) than in controls (8.5 %) (p = 0.001). Studying the subtypes of Tfh revealed that the upregulation of circulating Tfh was contributed by Tfh-Th2 subtype and Tfh-Th17 subtype. Also, we identified that prevalence of Tfh was significantly elevated in cases with advanced stages (stages III and IV). Interestingly, the elevation of circulating Tfh was negatively correlated with serum IL-21 in DLBCL patients. In addition, a positive correlation between circulating Tfh and IL-21 receptor on CD + 8 T cells was observed in patients. This study suggests involvement of circulating Tfh and IL-21 in the pathogenesis and progression of DLBCL and provides a potential target for treating this disease.

Fibroblast growth factor receptor 4 polymorphisms and the prognosis of non-Hodgkin lymphoma.

Fibroblast growth factors and their receptors (FGFRs) play important roles in blood system. FGFR4 rs351855 (Gly388Arg) polymorphism has shown to be a risk factor for many diseases. The aim of this study was to investigate the association between FGFR4 polymorphisms and the susceptibility to non-Hodgkin lymphoma (NHL) in the Chinese population. We identified two polymorphisms in the FGFR4 gene, rs351855G/A (Gly388Arg), and rs147603016G/A, by polymerase chain reaction-restriction fragment length polymorphism in 412 NHL cases and 476 healthy controls. Results showed that frequencies of AA genotype and A allele in rs351855 (Gly388Arg) polymorphism were significantly higher in patients than in controls (odds ratio (OR) 2.12, 95 % confidence intervals (CI) 1.99-3.48, P < 0.0001; OR 1.45, 95 % CI 1.21-1.88, P < 0.0001, respectively; data were adjusted for age and sex). The rs147603016G/A polymorphism did not show any correlation with NHL. When analyzing the survival time of NHL patients with FGFR4 rs351855G/A polymorphism, cases with AA genotype had significantly shorter survival time compared to the patients with GG and GA genotypes (P = 0.002). These results suggested polymorphism in FGFR4 gene was associated with increased susceptibility to NHL and could be used as a prognostic marker for this malignancy.

Red Cell Distribution Width is Related to Mild Cognitive Impairment: A Cross-Sectional Study of Community Residents.

BACKGROUND AND OBJECTIVE: Previous literature has reported that red cell distribution width (RDW) correlated with Alzheimer's disease (AD), but the correlation with mild cognitive impairment (MCI) was not clear. This study aimed to investigate MCI in the residents aged ≥65 living in the suburban of Shanghai, China. MATERIALS AND METHODS: A total of 550 participants were recruited as MCI (MCI group, 226) and normal (NC group, 284) groups and received blood examination voluntarily. Blood routine indexes were tested by blood tests using Sysmex XT-4000i (Japan). The Chi-square test, t-test, and linear regression analysis were used to find the statistical difference and correlation of data, respectively. RESULTS: Each cognition domain of MCI was found to be impaired, the weight of which, however, was different in integral damage. Most MCI people had impairment of attention among cognitive domains (235, 88.3%). According to the results of the binary logistic regression, the highest weight among impaired cognitive domains was for attention in MCI, and the Wald value of attention was higher than those of others (Wald = 51.83). Additionally, RDW had the greatest negative correlation with attention score (P < 0.05). CONCLUSIONS: Increased RDW may be considered as a biomarker of MCI.

SPDEF drives pancreatic adenocarcinoma progression via transcriptional upregulation of S100A16 and activation of the PI3K/AKT signaling pathway.

Pancreatic adenocarcinoma (PAAD) is a notably aggressive malignancy with limited treatment options and an unfavorable prognosis for patients. We aimed to investigate molecular mechanisms by which Sam's pointed domain-containing ETS transcription factor (SPDEF) exerts effects on PAAD progression. We analyzed differentially expressed genes (DEGs) and their integration with ETS family members using the The Cancer Genome Atlas (TCGA) database, hence identifying SPDEF as a core gene in PAAD. Kaplan-Meier survival analysis confirmed SPDEF's prognostic potential. In vitro experiments validated the association with cell proliferation and apoptosis, affecting pancreatic cancer cell dynamics. We detected increased SPDEF expression in PAAD tumor samples. Our in vitro studies revealed that SPDEF regulates mRNA and protein expression levels, and significantly affects cell proliferation. Moreover, SPDEF was associated with reduced apoptosis and enhanced cell migration and invasion. In-depth analysis of SPDEF-targeted genes revealed four crucial genes for advanced prognostic model, among which S100A16 was significantly correlated with SPDEF. Mechanistic analysis showed that SPDEF enhances the transcription of S100A16, which in turn enhances PAAD cell migration, proliferation, and invasion by activating the PI3K/AKT signaling pathway. Our study revealed the critical role of SPDEF in promoting PAAD by upregulating S100A16 transcription and stimulating the PI3K/AKT signaling pathway. This knowledge deepened our understanding of pancreatic cancer's molecular progression and unveiled potential therapeutic strategies targeting SPDEF-driven pathways.

Metabolites of intestinal fora can be used as diagnostic and progressive markers for mild cognitive impairment.

Purpose: The aim of the work was to analyze the metabolites of the intestinal microbiota from the patients with mild cognitive impairment (MCI) and progressive MCI due to Alzheimer's disease (AD). Method: Two cohorts were established. The first one included 87 subjects with 30 healthy controls (NC), 22 patients with MCI due to AD, and 35 patients with AD. The second cohort included 87 patients with MCI due to AD, who were followed up for 2 years and finally were divided into progressive MCI due to AD group (P-G) and unprogressive MCI due to AD group (U-G) according their cognitive levels. Fecal samples were collected to all patients at the baseline time point. Differential metabolites were subjected to pathway analysis by MetaboAnalyst. Results: In the first cohort, we found 21 different metabolites among the three groups (AD, MCI, and NC). In the second cohort, we identified 19 differential metabolites between the P-G and U-G groups. By machine learning analysis, we found that seven characteristic metabolites [Erythrodiol, alpha-Curcumene, Synephrine, o-Hydroxylaminobenzoate, 3-Amino-4-hydroxybenzoic acid, 2-Deoxystreptamine, and 9(S] were of characteristic significance for the diagnosis of MCI due to AD, and six metabolites (Indolelactate, Indole-3-acetaldehyde, L-Proline, Perillyl, Mesaconate, and Sphingosine) were the characteristic metabolites of early warning for the progression of MCI due to AD. D-Glucuronic acid was negatively correlated with Apolipoprotein E4 (APOE4). Perillyl alcohol was negatively correlated with all of the five biomarkers [P-tau181, Neurofilament light chain (NF-light), Aß1-42, Aß1-40, and glial fibrillary acidic protein (GFAP)], but Indoleacetaldehyde was positively correlated with three biomarkers (P-tau181, Aß1-42, and GFAP). Three characteristic metabolites (3-Amino-4-hydroxybenzoate, 2-Deoxystreptamine, and p-Synephrine) were positively correlated with Aß1-42. 2-Deoxystreptamine, 9(S)-HPOT, and Indoleacetaldehyde were positively correlated with GFAP. L-Proline and Indoleacetaldehyde were positively correlated with NF-light. Conclusion: Specific metabolites of intestinal fora can be used as diagnostic and progressive markers for MCI.

T-cell immunoglobulin- and mucin-domain-containing molecule 3 gene polymorphisms and prognosis of non-small-cell lung cancer.

Lung cancer is the leading cause of death worldwide. Non-small-cell lung cancer (NSCLC) accounts for most of these cases. T-cell immunoglobulin- and mucin-domain-containing molecule 3 (TIM-3) has been established as a negative regulatory molecule and plays a critical role in immune tolerance. Studies have shown that polymorphisms in TIM-3 gene can be associated with various diseases. The aim of this study was to investigate whether polymorphisms in the TIM-3 gene were associated with susceptibility to NSCLC. Three polymorphisms in TIM-3 gene (-1516G/T, -574G/T, and +4259T/G) were identified by polymerase chain reaction-restriction fragment length polymorphism in 432 NSCLC patients and 466 healthy controls. Results showed that frequencies of TIM-3 +4259TG genotype for cases and controls were 10.9 and 4.1 %, respectively; subjects carrying the +4259TG genotype had a 2.81-fold increased risk of NSCLC compared to the wild-type genotype (P < 0.0001). The TIM-3 -1516G/T and -574G/T polymorphisms did not show any correlation with NSCLC. In addition, when analyzing the survival time of NSCLC patients with TIM-3 +4259T/G polymorphism, cases with +4259TG genotype had significantly shorter survival time compared to the wild-type patients (15.2 months vs. 26.7 months, P = 0.007). These results suggested polymorphism in TIM-3 gene is associated with increased susceptibility to NSCLC and could be used as prognostic factor for this malignancy.

Monocyte chemotactic protein-1 and CC chemokine receptor 2 polymorphisms and prognosis of renal cell carcinoma.

Monocyte chemoattractant protein-1 (MCP-1) and its receptor CC chemokine receptor 2 (CCR2) play a major role in inflammation and proliferation of cancers. We investigated a possible association between polymorphisms in MCP-1 and CCR2 genes (MCP-1 -2518A/G and CCR2 190G/A or V64I) and the risk as well as prognosis of renal cell carcinoma (RCC). Genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism in 416 RCC cases and 458 age-matched healthy controls. Frequency of MCP-1 2518GG genotype for cases and controls was 0.384 and 0.286, respectively; individuals carrying the GG genotype had a 1.89-fold increased risk of RCC than those with AA genotype (95 % confidence interval [CI] 1.24-2.81, p = 0.002; data were adjusted for age and sex). Frequency of CCR2 190AA (64I/64I) genotype for cases and controls was 0.175 and 0.076, respectively; subjects having AA genotype had a 2.68-fold increased risk of RCC compared to those with the wild-type GG genotype (95 %CI 1.71-4.17, p = 4.3 × 10(-6); data were adjusted for age and sex). When analyzing the survival rate of RCC, patients with MCP-1 -2518GG genotype revealed significantly shorter survival time compared to cases with MCP-1 -2518AA and AG genotypes (p = 0.003). Similarly, RCC cases carrying CCR2 190AA genotype showed significantly shorter survival rate than patients with GG or GA genotypes (p < 0.001). These data suggested that MCP-1 -2518A/G and CCR2 190G/A polymorphisms are new risk factors for RCC and could be used as prognostic markers for this malignancy.