Organoid Modeling of the Tumor Immune Microenvironment.

In vitro cancer cultures, including three-dimensional organoids, typically contain exclusively neoplastic epithelium but require artificial reconstitution to recapitulate the tumor microenvironment (TME). The co-culture of primary tumor epithelia with endogenous, syngeneic tumor-infiltrating lymphocytes (TILs) as a cohesive unit has been particularly elusive. Here, an air-liquid interface (ALI) method propagated patient-derived organoids (PDOs) from >100 human biopsies or mouse tumors in syngeneic immunocompetent hosts as tumor epithelia with native embedded immune cells (T, B, NK, macrophages). Robust droplet-based, single-cell simultaneous determination of gene expression and immune repertoire indicated that PDO TILs accurately preserved the original tumor T cell receptor (TCR) spectrum. Crucially, human and murine PDOs successfully modeled immune checkpoint blockade (ICB) with anti-PD-1- and/or anti-PD-L1 expanding and activating tumor antigen-specific TILs and eliciting tumor cytotoxicity. Organoid-based propagation of primary tumor epithelium en bloc with endogenous immune stroma should enable immuno-oncology investigations within the TME and facilitate personalized immunotherapy testing.

Opposing T cell responses in experimental autoimmune encephalomyelitis.

Experimental autoimmune encephalomyelitis is a model for multiple sclerosis. Here we show that induction generates successive waves of clonally expanded CD4+, CD8+ and γδ+ T cells in the blood and central nervous system, similar to gluten-challenge studies of patients with coeliac disease. We also find major expansions of CD8+ T cells in patients with multiple sclerosis. In autoimmune encephalomyelitis, we find that most expanded CD4+ T cells are specific for the inducing myelin peptide MOG35-55. By contrast, surrogate peptides derived from a yeast peptide major histocompatibility complex library of some of the clonally expanded CD8+ T cells inhibit disease by suppressing the proliferation of MOG-specific CD4+ T cells. These results suggest that the induction of autoreactive CD4+ T cells triggers an opposing mobilization of regulatory CD8+ T cells.

QM/MM Study of the Catalytic Mechanism and Substrate Specificity of the Aromatic Substrate C-Methyltransferase Fur6.

In the field of medical chemistry and other organic chemistry, introducing a methyl group into a designed position has been difficult to achieve. However, owing to the vigorous developments in the field of enzymology, methyltransferases are considered potential tools for addressing this problem. Within the methyltransferase family, Fur6 catalyzes the methylation of C3 of 1,2,4,5,7-pentahydroxynaphthalene (PHN) using S-adenosyl-l-methionine (SAM) as the methyl donor. Here, we report the catalytic mechanism and substrate specificity of Fur6 based on computational studies. Our molecular dynamics (MD) simulation studies reveal the reactive form of PHN and its interactions with the enzyme. Our hybrid quantum mechanics/molecular mechanics (QM/MM) calculations suggest the reaction pathway of the methyl transfer step in which the energy barrier is 8.6 kcal mol-1. Our free-energy calculations with a polarizable continuum model (PCM) indicate that the final deprotonation step of the methylated intermediate occurs after it is ejected into the water solvent from the active center pocket of Fur6. Additionally, our studies on the protonation states, the highest occupied molecular orbital (HOMOs), and the energy barriers of the methylation reaction for the analogs of PHN demonstrate the mechanism of the specificity to PHN. Our study provides valuable insights into Fur6 chemistry, contributing to a deeper understanding of molecular mechanisms and offering an opportunity to engineer the enzyme to achieve high yields of the desired product(s).

Advances in Aqueous Zinc Ion Batteries based on Conversion Mechanism: Challenges, Strategies, and Prospects.

Recently, aqueous zinc-ion batteries with conversion mechanisms have received wide attention in energy storage systems on account of excellent specific capacity, high power density, and energy density. Unfortunately, some characteristics of cathode material, zinc anode, and electrolyte still limit the development of aqueous zinc-ion batteries possessing conversion mechanism. Consequently, this paper provides a detailed summary of the development for numerous aqueous zinc-based batteries: zinc-sulfur (Zn-S) batteries, zinc-selenium (Zn-Se) batteries, zinc-tellurium (Zn-Te) batteries, zinc-iodine (Zn-I2) batteries, and zinc-bromine (Zn-Br2) batteries. Meanwhile, the reaction conversion mechanism of zinc-based batteries with conversion mechanism and the research progress in the investigation of composite cathode, zinc anode materials, and selection of electrolytes are systematically introduced. Finally, this review comprehensively describes the prospects and outlook of aqueous zinc-ion batteries with conversion mechanism, aiming to promote the rapid development of aqueous zinc-based batteries.

Medicaid Expansion and Racial-Ethnic and Sex Disparities in Cardiovascular Diseases Over 6 Years: A Generalized Synthetic Control Approach.

BACKGROUND: Studies have suggested Medicaid expansion enacted in 2014 has resulted in a reduction in overall cardiovascular disease (CVD) mortality in the United States. However, it is unknown whether Medicaid expansion has a similar effect across race-ethnicity and sex. We investigated the effect of Medicaid expansion on CVD mortality across race-ethnicity and sex. METHODS: Data come from the behavioral risk factor surveillance system and the US Centers for Disease Control's Wide-ranging Online Data for Epidemiologic Research, spanning the period 2000-2019. We used the generalized synthetic control method, a quasi-experimental approach, to estimate effects. RESULTS: Medicaid expansion was associated with -5.36 (mean difference [MD], 95% confidence interval [CI] = -22.63, 11.91) CVD deaths per 100,000 persons per year among Blacks; -4.28 (MD, 95% CI = -30.08, 21.52) among Hispanics; -3.18 (MD, 95% CI = -8.30, 1.94) among Whites; -5.96 (MD, 95% CI = -15.42, 3.50) among men; and -3.34 (MD, 95% CI = -8.05, 1.37) among women. The difference in mean difference (DMD) between the effect of Medicaid expansion in Blacks compared with Whites was -2.18; (DMD, 95% CI = -20.20, 15.83); between that in Hispanics compared with Whites: -1.10; (DMD, 95% CI = -27.40, 25.20) and between that in women compared with men: 2.62; (DMD, 95% CI = -7.95, 13.19). CONCLUSIONS: Medicaid expansion was associated with a reduction in CVD mortality overall and in White, Black, Hispanic, male, and female subpopulations. Also, our study did not find any difference or disparity in the effect of Medicaid on CVD across race-ethnicity and sex-gender subpopulations, likely owing to imprecise estimates.

In Situ Fabrication of SnO2 Nanowalls for Robust Acetylene Sensing at Low Temperature.

Acetylene (C2 H2 ) monitoring in real time and online is essential for erasing transformer risks and guaranteeing normal equipment operation and operator safety. This study examines the direct fabrication of ultrathin SnO2 nanowalls on Ag-Pd substrates using a simple solvothermal method that doesn't demand the use of any additional motivators or templates. The thickness and shape of the nanowalls can be controlled by varying the cetyl trimethyl ammonium bromide (CTAB) concentration in the solvent. As observed, the gas sensor (SnO2 -3) fabricated by 2.4 g CTAB exhibits superior gas-sensing features. This is primarily due to the hollow structure constructed by the arrangement of nanowalls, which delivers not only enough gas diffusion pathways but also enough reaction sites during the gas sensing processes. The findings suggest that low-cost SnO2 nanowalls created using a straightforward procedure could be taken into consideration as prospective candidates for use in industrial C2 H2 sensing applications.

ALKBH5 facilitates the progression of infantile hemangioma by increasing FOXF1 expression in a m6A-YTHDF2 dependent manner to activate HK-2 signaling.

Alkylation repair homolog protein 5 (ALKBH5) is reported to participate in infantile hemangioma (IH) progression. However, the underlying mechanism of ALKBH5 in IH remains unclear. Using qRT-PCR and Western blotting, ALKBH5, forkhead box F1 (FOXF1) and hexokinase 2 (HK-2) expressions in IH tissues and IH-derived endothelial cells XPTS-1 were assessed. The Me-RIP assay was used to analyze FOXF1 m6A level. CCK8, colony formation, flow cytometry and transwell assays were employed to determine IH cell viability, proliferation, apoptosis, migration and invasion. The interactions between YTH (YT521-B homology) domain 2 (YTHDF2), FOXF1 and HK-2 were analyzed by RIP, dual luciferase reporter gene assay and/or ChIP assay. The in vivo IH growth was evaluated in immunocompromised mice. FOXF1 was overexpressed in IH tissues, and its silencing inhibited IH cell proliferation, migration and invasion whereas promoting cell apoptosis in vitro. ALKBH5 upregulation facilitated FOXF1 mRNA stability and expression in IH cells in a m6A-YTHDF2-dependent manner. FOXF1 downregulation reversed the impact of ALKBH5 upregulation on IH cellular phenotypes. It also turned out that FOXF1 positively regulated HK-2 expression in IH cells through interacting with the HK-2 promoter. HK-2 upregulation abolished FOXF1 knockdown's inhibition on IH cell aggressive behaviors. ALKBH5 or FOXF1 silencing suppressed IH tumor development via HK-2 signaling in immunocompromised mice. ALKBH5 promoted FOXF1 expression m6A-YTHDF2 dependently, which in turn elevated HK-2 expression, thereby accelerating IH development.

NPAT Supports CD8+ Immature Single-Positive Thymocyte Proliferation and Thymic Development.

Thymocytes need to proliferate into a significant cell mass to allow a subsequent selection process during the double-positive (DP) stage. However, it is not clear at what stage this massive cell proliferation occurs. Immature CD8 single-positive (ISP) cells are a well-defined thymocyte subpopulation. However, the function of this cell subset has not yet been characterized. In this study, we analyzed the transcription pattern of mouse ISP cells and observed higher expression levels of cell cycling genes. We also found out that ISP cells exhibited the highest cell proliferative capacity among thymocytes in different developmental stages. Nuclear protein ataxia-telangiectasia (NPAT/p220) is one of the highly expressed cell cycling genes in ISP cells, which is known to play a critical role in coordinating histone gene expression necessary for rapid cell proliferation. Selective deletion of NPAT at the ISP stage led to reduced thymus size and significant loss of DP cells, secondary to reduced histone gene expression and impaired ISP cell proliferation capacity. A block of thymocyte development at the ISP stage was also observed, which was due to increased IL-7R expression. Continuous IL-7R signal served as a compensating mechanism for cell proliferation upon NPAT deletion, but in turn inhibited the expression of transcription factors TCF-1 and LEF-1, which is essential for the transition of ISP to DP cells. In summary, our study revealed the proliferation capacity of the ISP subpopulation during thymocyte differentiation as well as a vital role of NPAT in this developmental stage.

Nanoparticle-enabled innate immune stimulation activates endogenous tumor-infiltrating T cells with broad antigen specificities.

Tumors are often infiltrated by T lymphocytes recognizing either self- or mutated antigens but are generally inactive, although they often show signs of prior clonal expansion. Hypothesizing that this may be due to peripheral tolerance, we formulated nanoparticles containing innate immune stimulants that we found were sufficient to activate self-specific CD8+ T cells and injected them into two different mouse tumor models, B16F10 and MC38. These nanoparticles robustly activated and/or expanded antigen-specific CD8+ tumor-infiltrating T cells, along with a decrease in regulatory CD4+ T cells and an increase in Interleukin-17 producers, resulting in significant tumor growth retardation or elimination and the establishment of immune memory in surviving mice. Furthermore, nanoparticles with modification of stimulating human T cells enabled the robust activation of endogenous T cells in patient-derived tumor organoids. These results indicate that breaking peripheral tolerance without regard to the antigen specificity creates a promising pathway for cancer immunotherapy.

The therapeutic effects of fermented milk with lactic acid bacteria from traditional Daqu on hypertensive mice.

Lactic acid bacteria (LAB), a type of microorganism widely used in functional foods, has gained notable research attention in recent years. Certain strains possess the proteolytic ability to release potentially antihypertensive peptides from dairy proteins, which prompted us to explore the LAB strains from an understudied and unique ingredient, Daqu. We screened for 67 strains of LAB strains from traditional Daqu using the calcium dissolution ring method. Sixteen strains exhibiting angiotensin-converting enzyme inhibition (ACE-I) activity exceeding 50% were chosen for 16S rDNA sequencing and safety assessment. It is noteworthy that Enterococcus faecium CP640 and Lacticaseibacillus rhamnosus CP658 exhibited significant ACE-I activity, which was the result of strain fermentation in reconstituted skim milk. These 2 strains did not exhibit hemolytic activity or antibiotic resistance. They also did not produce biogenic amines and showed high survival rates in the gastrointestinal tract. Additionally, Enterococcus faecium CP640 and Lacticaseibacillus rhamnosus CP658 fermented milk exhibited a notable reduction in blood pressure levels in spontaneously hypertensive rats (SHR) compared with negative controls in SHR. Importantly, no adverse effect was observed in normal Wistar-Kyoto rats. Through the analysis of physiological, serum, and urine-related indicators, it was observed that Enterococcus faecium CP640 and Lacticaseibacillus rhamnosus CP658 have the potential to promote weight gain in SHR, alleviate excessive heart rate, improve renal function indicators, and effectively regulate blood sugar and uric acid levels in SHR. These 2 strains showed optimal properties in lowering blood pressure and have the potential to be used in functional dairy products in the future.

Enhancing the antioxidant capacity and quality attributes of fermented goat milk through the synergistic action of Limosilactobacillus fermentum WXZ 2-1 with a starter culture.

This study evaluated 75 strains of lactic acid bacteria (LAB) isolated from traditional dairy products in western China for their probiotic properties. Among them, Limosilactobacillus fermentum WXZ 2-1, Lactiplantibacillus plantarum TXZ 2-35, Companilactobacillus crustorum QHS 9, and Companilactobacillus crustorum QHS 10 demonstrated potential probiotic characteristics. The antioxidant capacity of these 4 strains was assessed, revealing that L. fermentum WXZ 2-1 exhibited the highest antioxidant capacity. Furthermore, when cocultured with Streptococcus salivarius ssp. thermophilus and Lactobacillus delbrueckii ssp. bulgaricus, L. fermentum WXZ 2-1 demonstrated a synergistic effect in growth medium and goat milk. To explore its effect on goat milk fermentation, different amounts of L. fermentum WXZ 2-1 were added to goat milk, and its physicochemical properties, antioxidant activity, flavor substances, and metabolomics were analyzed. The study found that the incorporation of L. fermentum WXZ 2-1 in goat milk fermentation significantly improved the texture characteristics, antioxidant capacity, and flavor of fermented goat milk. These findings highlight the potential of L. fermentum WXZ 2-1 as a valuable probiotic strain for enhancing the functionality and desirability of fermented goat milk, contributing to the development of novel functional foods with improved health benefits and enhanced quality attributes.

MiR-20a-5p alleviates kidney ischemia/reperfusion injury by targeting ACSL4-dependent ferroptosis.

Ischemia/reperfusion injury (IRI) is prone to occur after kidney transplantation, leading to delayed graft function (DGF). MicroRNAs play a crucial role in the pathogenesis of ischemia/reperfusion-induced acute kidney injury, and miR-20a-5p was found to be the most significantly upregulated gene in a DGF patient cohort. However, the roles of microRNAs in transplanted kidneys remain largely unknown. In this study, we found that miR-20a-5p was upregulated in the kidneys of acute kidney injury mice and in patients with DGF. We identified early growth response-1 as a critical upstream target and verified the binding of early growth response-1 to a predicted sequence in the promoter region of the miR-20a-5p gene. Functionally, the miR-20a-5p mimic attenuated IRI and postischemic renal fibrosis, whereas the miR-20a-5p inhibitor delivery aggravated IRI and fibrosis. Importantly, delivery of the miR-20a-5p mimic or inhibitor in the donor kidneys attenuated or aggravated renal loss and structural damage in cold storage transplantation injury. Furthermore, our study identified miR-20a-5p as a negative regulator of acyl-CoA synthetase long-chain family member 4 (ACSL4) by targeting the 3' untranslated region of ACSL4 mRNA, thereby inhibiting ACSL4-dependent ferroptosis. Our results suggest a potential therapeutic application of miR-20a-5p in kidney transplantation through the inhibition of ACSL4-dependent ferroptosis.

Inhibition of CPAP-tubulin interaction prevents proliferation of centrosome-amplified cancer cells.

Centrosome amplification is a hallmark of human cancers that can trigger cancer cell invasion. To survive, cancer cells cluster amplified extra centrosomes and achieve pseudobipolar division. Here, we set out to prevent clustering of extra centrosomes. Tubulin, by interacting with the centrosomal protein CPAP, negatively regulates CPAP-dependent peri-centriolar material recruitment, and concurrently microtubule nucleation. Screening for compounds that perturb CPAP-tubulin interaction led to the identification of CCB02, which selectively binds at the CPAP binding site of tubulin. Genetic and chemical perturbation of CPAP-tubulin interaction activates extra centrosomes to nucleate enhanced numbers of microtubules prior to mitosis. This causes cells to undergo centrosome de-clustering, prolonged multipolar mitosis, and cell death. 3D-organotypic invasion assays reveal that CCB02 has broad anti-invasive activity in various cancer models, including tyrosine kinase inhibitor (TKI)-resistant EGFR-mutant non-small-cell lung cancers. Thus, we have identified a vulnerability of cancer cells to activation of extra centrosomes, which may serve as a global approach to target various tumors, including drug-resistant cancers exhibiting high incidence of centrosome amplification.

MoO2 Nanoclusters Embedded in Hierarchical Nitrogen Doped Carbon Nanoflower as Electrocatalytic Mediators in Aqueous Zinc-Tellurium Batteries: Enhancing Electrochemical Kinetics of Tellurium Redox Reaction.

Aqueous zinc-ion batteries (AZIBs) are considered to be one of the most promising devices for large-scale energy storage systems owing to their high theoretical capacity, environmental friendliness, and safety. However, the ionic intercalation or surface redox mechanisms in conventional cathode materials generally result in unsatisfactory capacities. Conversion-type aqueous zinc-tellurium (Zn-Te) batteries have recently gained widespread attention owing to their high theoretical specific capacities. However, it remains an enormous challenge to improve the slow kinetics of the aqueous Zn-Te batteries. Here, MoO2 nanoclusters embedded in hierarchical nitrogen-doped carbon nanoflower (MoO2 /NC) hosts are successfully synthesized and loaded with Te in aqueous Zn-Te batteries. Benefitting from the highly dispersed MoO2 nanoclusters and hierarchical nanoflower structure with a large specific surface area, the electrochemical kinetics of the Te redox reaction are significantly improved. As a result, the Te-MoO2 /NC electrode exhibits superior cycling stability and a high specific capacity of 493 mAh g-1 at 0.1 A g-1 . Meanwhile, the conversion mechanism is systematically explored using a variety of ex situ characterization methods. Therefore, this study provides a novel approach for enhancing the kinetics of the Te redox reaction in aqueous Zn-Te batteries.

Template Based Synthesis of Porous Graphdiyne Nanosheet for Reversible and Fast NO2 Detection by UV Irradiation.

Two-dimensional graphdiyne (GDY) formed by sp and sp2 hybridized carbon has been found to be an efficient toxic gas sensing material by density functional theory (DFT). However, little experimental research concerning its gas sensing capability has been reported owing to the complex preparation process and harsh experimental conditions. Herein, porous GDY nanosheets are successfully synthesized through a facile solvothermal synthesis technique by using CuO microspheres (MSs) as both template and source of catalyst. The porous GDY nanosheets exhibit a broadband optical absorption, rendering it suitable for the light-driven optoelectronic gas sensing applications. The GDY-based gas sensor was demonstrated to have excellent reversible to NO2 behaviors at 25 °C for the first time. More importantly, higher response value and faster response-recovery time once exposed to NO2 gas molecules are achieved by the illumination of UV light. In this way, our work paves the way for the exploration of GDY-based gas detection experimentally.

The role of toll-like receptors in immune tolerance induced by Helicobacter pylori infection.

Helicobacter pylori (H. pylori) is a gram-negative, microaerobic bacterium that colonizes the gastric mucosa in about half of the world's population. H. pylori infection can lead to various diseases. Chronic infection by H. pylori exposes the gastric mucosa to bacterial components such as lipopolysaccharide (LPS), outer membrane vesicles (OMVs), and several toxic proteins. Infected with H. pylori activates the release of pro-inflammatory factors and triggers inflammatory responses that damage the gastric mucosa. As the only microorganism that permanently colonizes the human stomach, H. pylori can suppress host immunity to achieve long-term colonization. Toll-like receptors (TLRs) play a crucial role in T-cell activation, promoting innate immune responses and immune tolerance during H. pylori infection. Among the 10 TLRs found in humans, TLR2, TLR4, TLR5, and TLR9 have been thoroughly investigated in relation to H. pylori-linked immune regulation. In the present review, we provide a comprehensive analysis of the various mechanisms employed by different TLRs in the induction of immune tolerance upon H. pylori infection, which will contribute to the research of pathogenic mechanism of H. pylori.

Predictive value of intravoxel incoherent motion combined with diffusion kurtosis imaging for breast cancer axillary lymph node metastasis: a retrospective study.

BACKGROUND: Non-invasive imaging technologies for assessing axillary lymph node (ALN) metastasis of breast cancer are needed in clinical practice. PURPOSE: To explore the clinical value of intravoxel incoherent motion (IVIM) and diffusional kurtosis imaging (DKI) for predicting ALN metastasis of breast cancer. MATERIAL AND METHODS: A total of 194 patients with pathologically confirmed breast cancer who underwent IVIM and DKI examination were reviewed retrospectively. The IVIM derived parameters of D, D*, and f and DKI-derived parameters of MD and MK were measured. The independent samples t-test was used to compare the parameters between the ALN metastasis and non-ALN metastasis groups. Receiver operating characteristic (ROC) curve analysis was also performed. RESULTS: The D and MD in the ALN metastasis group were significantly lower than those in the non-ALN metastasis group (P < 0.001, P < 0.001). The D*, f, and MK were higher in the ALN metastasis group than in the non-ALN metastasis group (P = 0.015, P = 0.014, and P = 0.001, respectively). The area under the ROC curve (AUC) of D (0.768) was highest. In addition, the diagnostic efficiency of both IVIM and DKI were higher than that of the conventional MRI (P = 0.002, P = 0.048). The diagnostic efficiency of IVIM + DKI were higher than that of the IVIM or DKI alone (P = 0.021, P = 0.004). CONCLUSION: IVIM and DKI can be used for predicting breast cancer ALN metastasis with D as the most meaningful parameter.

A Middle Eocene lowland humid subtropical "Shangri-La" ecosystem in central Tibet.

Tibet's ancient topography and its role in climatic and biotic evolution remain speculative due to a paucity of quantitative surface-height measurements through time and space, and sparse fossil records. However, newly discovered fossils from a present elevation of ∼4,850 m in central Tibet improve substantially our knowledge of the ancient Tibetan environment. The 70 plant fossil taxa so far recovered include the first occurrences of several modern Asian lineages and represent a Middle Eocene (∼47 Mya) humid subtropical ecosystem. The fossils not only record the diverse composition of the ancient Tibetan biota, but also allow us to constrain the Middle Eocene land surface height in central Tibet to ∼1,500 ± 900 m, and quantify the prevailing thermal and hydrological regime. This "Shangri-La"-like ecosystem experienced monsoon seasonality with a mean annual temperature of ∼19 °C, and frosts were rare. It contained few Gondwanan taxa, yet was compositionally similar to contemporaneous floras in both North America and Europe. Our discovery quantifies a key part of Tibetan Paleogene topography and climate, and highlights the importance of Tibet in regard to the origin of modern Asian plant species and the evolution of global biodiversity.

The Predictive Value of NGF, TMAO, SIRT1 and apoA1 in Patients With Ischemic Heart Failure.

Objective: The present study aimed to explore the predictive value and prognosis of SYNTAX score, nerve growth factor (NGF), trimethylamino oxide (TMAO), silent information regulator 1 (SIRT1), and apolipoprotein A1 (apoA1) for ischemic heart failure (IHF) patients. Methods: From January 2020 to January 2021, 87 patients diagnosed with IHF in the Sixth Hospital of Wuhan, Affiliated Hospital of Jianghan University, and 42 healthy people were included and analyzed retrospectively. The 87 patients were divided into 3 subgroups according to New York Heart Association (NYHA) heart function classification, as group 1 (n=9, classes I-II heart function), group 2 (n = 7, class III heart function), and group 3 (n = 31, class IV heart function). The levels of left ventricular ejection fraction (LVEF), left ventricular end-diastolic diameter (LVEDD), left atrium diameter (LAD), NGF, TMAO, SIRT1, SYNTAX score, and apoA1 were compared among these groups. Results: The SIRT1 and apoA1 of patients with classes I-II, III, and IV heart function were significantly lower than that of healthy people in the control group, while TMAO and NGF were significantly higher than those of healthy people (all P < .05). The SYNTAX score of grade I-II, grade III, and grade IV groups was significantly lower than that of the healthy group (P < .05). The two groups had no significant difference in the number of coronary artery lesions (P > .05). The SIRT1 and apoA1 of patients with classes III and IV heart function were significantly lower than that of patients with classes I -II heart function, while TMAO and NGF were significantly higher than those of class I-II people (all P < .05). The SIRT1 and apoA1 of patients with class IV heart function were significantly lower than those of patients with class III heart function, while TMAO and NGF were significantly higher than those of patients with class III heart function (all P < .05). After 1 year follow-up of these IHF patients, 22 patients were readmission because of cardiac events, and 6 patients died in hospital or during follow-up. These 28 patients were allocated to the event group, while the rest 59 patients were allocated to the events-free group. The SIRT1 and apoA1 level in event group was significantly lower than those of event-free group, while the TMAO, SYNTAX score, and NGF level were significantly higher than those of the event-free group (all P < .001). Baseline characters and heart function with significant differences (LVEF, LAD and LVEDD) among these groups, and NGF, TMAO, SIRT1, SYNTAX score and apoA1 were enrolled into Logistic regression. SYNTAX score, NGF, TMAO, SIRT1 and apoA1 were independent risk factors for the prognosis of IHF patients (all P < .05). Conclusion: SIRT1, apoA1, TMAO and NGF serum levels in patients with IHF are abnormally expressed and closely related to cardiac function. The levels of SYNTAX score, NGF, TMAO, SIRT1, and apoA can effectively predict adverse events in patients with IHF.

Expression of urinary exosomal miRNA-615-3p and miRNA-3147 in diabetic kidney disease and their association with inflammation and fibrosis.

BACKGROUND: Diabetic kidney disease (DKD) is one of the most common chronic complications of type 2 diabetes mellitus (T2DM), and it is particularly important to identify a high-quality method for evaluating disease progression. Urinary exosomes contain microRNA that might promise early diagnostic and monitoring markers of DKD. The present study aimed to identify novel exosome-related markers associated with inflammation and fibrosis to assess the progression of DKD. METHOD: Exosomes were extracted from the urine of 83 participants to determine the expression levels of miRNA-615-3p and miRNA-3147 in 20 healthy people, 21 patients with T2DM and 42 patients with DKD, as determined by RT-qPCR. The circulating expression level of TGF-ß1 was detected by ELISA. Serum Cystatin C was measured by a latex-enhanced immunoturbidimetric method. The correlation analyses were performed for all clinical and laboratory parameters. RESULT: The expression level of urinary exosomal miRNA-615-3p in DKD patients was significantly higher than that in the control group and the T2DM group by RT-qPCR. The expression of miRNA-3147 showed an upward trend in the three groups of subjects, but it was not statistically significant. The urinary exosomal miRNA-615-3p was positively correlated with serum Cystatin C, plasma TGF-ß1, creatinine, BUN, PCR and 24-h urine protein, and negatively correlated with eGFR and albumin. The diagnostic efficacy of urinary exosomal miRNA-615-3p combined with the ACR was higher than that of ACR alone. CONCLUSIONS: Urinary exosomal miRNA-615-3p may be used as a novel biomarker for evaluating the progression of DKD, and may be involved in the process of inflammation and fibrosis in DKD. The combined diagnosis of urinary exosomal miRNA-615-3p and ACR may be used as more stable and sensitive diagnostic criteria for DKD.