The association between systemic inflammation markers and paroxysmal atrial fibrillation.

BACKGROUND: Systemic inflammation markers have recently been identified as being associated with cardiac disorders. However, limited research has been conducted to estimate the pre-diagnostic associations between these markers and paroxysmal atrial fibrillation (PAF). Our aim is to identify potential biomarkers for early detection of PAF. METHODS: 91 participants in the PAF group and 97 participants in the non-PAF group were included in this study. We investigated the correlations between three systemic inflammation markers, namely the systemic immune inflammation index (SII), system inflammation response index (SIRI), and aggregate index of systemic inflammation (AISI), and PAF. RESULTS: The proportion of patients with PAF gradually increased with increasing logSII, logSIRI, and logAISI tertiles. Compared to those in the lowest tertiles, the PAF risks in the highest logSII and logSIRI tertiles were 3.2-fold and 2.9-fold, respectively. Conversely, there was no significant correlation observed between logAISI and PAF risk within the highest tertile of logAISI. The restricted cubic splines (RCS) analysis revealed a non-linear relationship between the elevation of systemic inflammation markers and PAF risk. Specifically, the incidence of PAF is respectively increased by 56%, 95%, and 150% for each standard deviation increase in these variables. The ROC curve analysis of logSII, logSIRI and logAISI showed that they had AUC of 0.6, 0.7 and 0.6, respectively. It also demonstrated favorable sensitivity and specificity of these systemic inflammation markers in detecting the presence of PAF. CONCLUSIONS: In conclusion, our study reveals significant positive correlations between SII, SIRI, and AISI with the incidence of PAF.

Effect of dapagliflozin on left ventricular structure and function in patients with non-ischemic dilated cardiomyopathy: An observational study.

Non-ischemic dilated cardiomyopathy (NIDCM) is characterized by left ventricular dilatation and contractile dysfunction with severe morbidity and mortality. Sodium glucose cotransporter type 2 (SGLT2) inhibitors significantly reduce cardiovascular events for heart failure patients. We performed to investigate the impact of combined administration of SGLT2 inhibitors on cardiac structure and function in NIDCM patients undergoing conventional therapy. A total of 50 newly diagnosed NIDCM patients received conventional medical therapy, with 23 receiving dapagliflozin 10mg/day in addition (SGLT2i group) and the remaining 27 only receiving conventional therapy (non-SGLT2i group). After 12 months outpatient follow-up, NIDCM patients treated with conventional therapy alone showed a significant reduction of left ventricular end-diastolic dimensions (LVEDd), left ventricular end-systolic dimensions (LVESd), left ventricular end-diastolic volumes (LVEDV), left ventricular end-systolic volumes (LVESV), left ventricular end-diastolic volume index (LVEDVi) and left ventricular end-systolic volume index (LVESVi), while an increase in fractional shortening (FS) and left ventricular ejection fraction (LVEF). Patients receiving dapagliflozin combined with conventional treatment also demonstrated a significant reduction in left ventricular dimensions and volumes, and a marked increase in cardiac function. In non-SGLT2i groups, the % change in LVEDd, LVESd, LVEDV, LVESV, LVEDVi, LVESVi, FS and LVEF was -2.8%, -4.6%, -6.2%, -10.1%, -6.1%, -10.1%, +9.7%, +11%. A greater absolute % fall in left ventricular volume in SGLT2i groups compared to non-SGLT2i groups resulted in a significant improvement in cardiac function. The results showed that SGLT2i combined with conventional therapy has a better beneficial effect on left ventricular volumes and cardiac function in NIDCM patients.

Molecular mechanism of NAD+ and NMN binding to the Nudix homology domains of DBC1.

Deleted in breast cancer 1 (DBC1) is a human nuclear protein that modulates the activities of various proteins involved in cell survival and cancer progression. Oxidized form of nicotinamide adenine dinucleotide (NAD+) is suggested to bind to the Nudix homology domains (NHDs) of DBC1, thereby regulating DBC1-Poly (ADP-ribose) polymerase 1 (PARP1) interactions, resulting in the restoration of DNA repair. Using Nuclear Magnetic Resonance (NMR) and Isothermal Titration Calorimetry (ITC), we confirmed NAD+ and its precursor nicotinamide mononucleotide (NMN) both bind the NHD domain of DBC1 (DBC1354-396). NAD+ likely interacts with DBC1354-396 through hydrogen bonding, with a binding affinity (8.99 µM) nearly twice that of NMN (17.0 µM), and the key binding sites are primarily residues E363 and D372, in the agreement with Molecular Docking experiments. Molecular Dynamics (MD) simulation further demonstrated E363 and D372's anchoring role in the binding process. Additional mutagenesis experiments of E363 and D372 confirmed their critical involvement of ligand-protein interactions. These findings lead to a better understanding of how NAD+ and NMN regulate DBC1, thereby offering insights for the development of targeted therapies and drug research focused on DBC1-associated tumors.

The association between systemic inflammation markers and the prevalence of hypertension.

BACKGROUND: We conducted a large-scale epidemiological analysis to investigate the associations between systemic inflammation markers and hypertension prevalence. Our aim is to identify potential biomarkers for early detection of hypertension. METHODS: A cross-sectional study with 119664 individuals from the National Health and Nutrition Examination Survey was performed. We investigated the associations between three systemic inflammation markers, namely the systemic immune inflammation index (SII), system inflammation response index (SIRI), and aggregate index of systemic inflammation (AISI), and the prevalence of hypertension. RESULTS: The prevalence rates of hypertension gradually increased with increasing logSII, logSIRI, and logAISI quartiles. In continuous analyses, each unit increase in logSII, logSIRI, and logAISI was associated with a 20.3%, 20.1%, and 23.7% increased risk of hypertension. Compared to those in the lowest quartiles, the hypertension risks for subjects in the highest logSII, logSIRI, and logAISI quartiles were 1.114-fold,1.143-fold, and 1.186-fold. The restricted cubic splines (RCS) analysis revealed a non-linear relationship between the elevation of systemic inflammation markers and hypertension prevalence. Specifically, a per standard deviation increase in any of these variables is associated with a respective 9%, 16%, and 11% increase in hypertension prevalence. CONCLUSION: Our cross-sectional study reveals significant positive correlations between SII, SIRI, and AISI with the prevalence of hypertension.

Cell reprogramming in a predictable manner on the superhydrophobic microwell array chip.

Reprogramming of somatic cells into the pluripotent state is stochastic and inefficient using the conventional culture plates. Novel micro-culture systems employing precisely controlled biophysical cues can improve the reprogramming efficiencies dramatically. Here we perform iPSC induction on our previously developed superhydrophobic microwell array chip (SMAR-chip) where cells undergo distinctive morphology change, switching from 2D monolayers to 3D clumps, and develop into bona fide colonies in more than 90% of the microwells. The PDMS substrate, together with the microwell structure and the superhydrophobic layer constitute a well-controlled microenvironment favorable for the morphogenesis and pluripotency induction. Investigation of the molecular roadmap demonstrates that the SMAR-chip promotes the transition from the initiation phase to the maturation phase and overcomes the roadblocks for reprogramming. In addition, the SMAR-chip also promotes the reprogramming of human cells, opening our method for translational applications. In summary, our study provides a novel platform for efficient cell reprogramming and emphasizes the advantages of employing the insoluble microenvironmental cues for the precise control of cell fate conversion.

[Expression, purification and micelle reconstruction of the transmembrane domain of the human amyloid precursor protein for NMR studies].

The multiple-step cleavage of amyloid precursor protein (APP) generates amyloid-ß peptides (Aß), highly toxic molecules causing Alzheimer's disease (AD). The nonspecific cleavage between the transmembrane region of APP (APPTM) and γ-secretase is the key step of Aß generation. Reconstituting APPTM under physiologically-relevant conditions is crucial to investigate how it interacts with γ-secretase and for future AD drug discovery. Although producing recombinant APPTM was reported before, the large scale purification was hindered by the use of biological protease in the presence of membrane protein. Here, we expressed recombinant APPTM in Escherichia coli using the pMM-LR6 vector and recovered the fusion protein from inclusion bodies. By combining Ni-NTA chromatography, cyanogen bromide cleavage, and reverse phase high performance liquid chromatography (RP-HPLC), isotopically-labeled APPTM was obtained in high yield and high purity. The reconstitution of APPTM into dodecylphosphocholine (DPC) micelle generated mono dispersed 2D 15N-1H HSQC spectra in high quality. We successfully established an efficient and reliable method for the expression, purification and reconstruction of APPTM, which may facilitate future investigation of APPTM and its complex in more native like membrane mimetics such as bicelle and nanodiscs.

Application of electronic tongue in umami detection and soy sauce refining process.

The article systematically investigated the response behaviors of lipid-film equipped umami taste sensor to various umami compounds, including typical umami substances (umami amino acids, GMP, IMP, disodium succinate) and novel umami chemicals (umami peptide and Amadori rearrangement product of umami amino acid). The umami taste sensor has great specificity to all umami substances. Relationships between output values and concentrations of umami substances in certain ranges were consistent with Weber-Fechner law. The umami synergistic effect detected by the sensor was in great agreement with human sensory results as well, fitting logarithm model. Moreover, the taste profile mixing model of raw soy sauce was established using five different taste sensors and principal component analysis, realizing the simplification of soy sauce blending and acceleration of the soy sauce refining process. Thus, flexible design of the experimental procedure and multi-analysis of the sensor data is essential.

WIPK-NtLTP4 pathway confers resistance to Ralstonia solanacearum in tobacco.

KEY MESSAGE: WIPK-NtLTP4 module improves the resistance to R. solanacearum via upregulating the expression of defense-related genes, increasing the antioxidant enzyme activity, and promoting stomatal closure in tobacco. Lipid transfer proteins (LTPs) are a class of small lipid binding proteins that play important roles in biotic and abiotic stresses. The previous study revealed that NtLTP4 positively regulates salt and drought stresses in Nicotiana tabacum. However, the role of NtLTP4 in biotic stress, especially regarding its function in disease resistance remains unclear. Here, the critical role of NtLTP4 in regulating resistance to Ralstonia solanacearum (R. solanacearum), a causal agent of bacterial wilt disease in tobacco, was reported. The NtLTP4-overexpressing lines markedly improved the resistance to R. solanacearum by upregulating the expression of defense-related genes, increasing the antioxidant enzyme activity, and promoting stomatal closure. Moreover, NtLTP4 interacted with wound-induced protein kinase (WIPK; a homolog of MAPK3 in tobacco) and acted in a genetically epistatic manner to WIPK in planta. WIPK could directly phosphorylate NtLTP4 to positively regulate its protein abundance. Taken together, these results broaden the knowledge about the functions of the WIPK-NtLTP4 module in disease resistance and may provide valuable information for improving tobacco plant tolerance to R. solanacearum.

Elevated homocysteine levels in patients with heart failure: A systematic review and meta-analysis.

BACKGROUND: Elevated homocysteine (Hcy) levels showed increasing significance as the predisposing factor for the pathogenesis of atherosclerotic sequelae, including cardiovascular mortality, coronary artery disease, and stroke. There is increasing evidence linking plasma Hcy levels and heart failure (HF). The association between the elevated level of plasma Hcy and HF was examined by meta-analysis and systematic review in this study. METHODS: The PubMed and ScienceDirect databases until April 2020 were utilized to collect previous literature on plasma Hcy levels and the potential relation to HF. The pooled effects were evaluated depending on standardized mean differences (SMDs) with 95% confidence intervals (CIs), and the calculation was performed using Stata 12 software. Potential sources of heterogeneity were assessed with subgroup analysis and sensitivity analysis. RESULTS: A total of 12 research projects including 5506 subjects were selected. For pooled effect, the results confirmed that patients with HF had higher Hcy levels than the control subjects (SMD,1.148 and 95%CI, [0.715, 1.581]). Based on the classification of New York Heart Association (NYHA), the Hcy levels for the group of NYHA I or II (SMD, 1.484 and 95% CI, [0.442, 2.527]) and the group of NYHA III or IV (SMD, 3.361 and 95% CI, [1.902, 4.820]) were significantly increased compared to controls, while the increase was more intensive for the group of NYHA III or IV. Subgroup analyses revealed similar results. CONCLUSION: Our meta-analysis identified that plasma Hcy levels were significantly elevated in HF patients compared to control subjects, which is positively related to the advancement of NYHA class.

Genome-Wide Identification and Characterization of Potato Long Non-coding RNAs Associated With Phytophthora infestans Resistance.

Long non-coding RNA (lncRNA) is a crucial regulatory mechanism in the plant response to biotic and abiotic stress. However, their roles in potato (Solanum tuberosum L.) resistance to Phytophthora infestans (P. infestans) largely remain unknown. In this study, we identify 2857 lncRNAs and 33,150 mRNAs of the potato from large-scale published RNA sequencing data. Characteristic analysis indicates a similar distribution pattern of lncRNAs and mRNAs on the potato chromosomes, and the mRNAs were longer and had more exons than lncRNAs. Identification of alternative splicing (AS) shows that there were a total of 2491 lncRNAs generated from AS and the highest frequency (46.49%) of alternative acceptors (AA). We performed R package TCseq to cluster 133 specific differentially expressed lncRNAs from resistance lines and found that the lncRNAs of cluster 2 were upregulated. The lncRNA targets were subject to KEGG pathway enrichment analysis, and the interactive network between lncRNAs and mRNAs was constructed by using GENIE3, a random forest machine learning algorithm. Transient overexpression of StLNC0004 in Nicotiana benthamiana significantly suppresses P. infestans growth compared with a control, and the expression of extensin (NbEXT), the ortholog of the StLNC0004 target gene, was significantly upregulated in the overexpression line. Together, these results suggest that lncRNAs play potential functional roles in the potato response to P. infestans infection.

Genetic and Pharmacologic Inhibition of the Chemokine Receptor CXCR2 Prevents Experimental Hypertension and Vascular Dysfunction.

BACKGROUND: The recruitment of leukocytes to the vascular wall is a key step in hypertension development. Chemokine receptor CXCR2 mediates inflammatory cell chemotaxis in several diseases. However, the role of CXCR2 in hypertension development and the underlying mechanisms remain unknown. METHODS: Angiotensin II (490 ng·kg-1·min-1) or deoxycorticosterone acetate (DOCA) salt-induced mouse hypertensive models in genetic ablation, pharmacologic inhibition of CXCR2, and adoptive bone marrow transfer mice were used to determine the role of CXCR2 in hypertension (measured by radiotelemetry and tail-cuff system), inflammation (verified by flow cytometry and quantitative real-time polymerase chain reaction [PCR] analysis), vascular remodeling (studied by haematoxylin and eosin and Masson's trichrome staining), vascular dysfunction (assessed by aortic ring), and oxidative stress (indicated by nicotinamide adenine dinucleotide phosphate [NADPH] oxidase activity, dihydroethidium staining, and quantitative real-time PCR analysis). Moreover, the blood CXCR2+ cells in normotensive controls and hypertension patients were analyzed by flow cytometry. RESULTS: Angiotensin II significantly upregulated the expression of CXCR2 mRNA and protein and increased the number of CD45+ CXCR2+ cells in mouse aorta (n=8 per group). Selective CXCR2 knockout (CXCR2-/-) or pharmacological inhibition of CXCR2 markedly reduced angiotensin II- or DOCA-salt-induced blood pressure elevation, aortic thickness and collagen deposition, accumulation of proinflammatory cells into the vascular wall, and expression of cytokines (n=8 per group). CXCR2 inhibition also ameliorated angiotensin II-induced vascular dysfunction and reduced vascular superoxide formation, NADPH activity, and expression of NADPH oxidase subunits (n=6 per group). Bone marrow reconstitution of wild-type mice with CXCR2-/- bone marrow cells also significantly abolished angiotensin II-induced responses (n=6 per group). It is important to note that CXCR2 blockade reversed established hypertension induced by angiotensin II or DOCA-salt challenge (n=10 per group). Furthermore, we demonstrated that CXCR2+ proinflammatory cells were higher in hypertensive patients (n=30) compared with normotensive individuals (n=20). CONCLUSIONS: Infiltration of CXCR2+ cells plays a pathogenic role in arterial hypertension and vascular dysfunction. Inhibition of CXCR2 pathway may represent a novel therapeutic approach to treat hypertension.

Gene expression profile in the early stage of angiotensin II-induced cardiac remodeling: a time series microarray study in a mouse model.

BACKGROUND/AIMS: Angiotensin II (Ang II) plays a critical role in the cardiac remodeling contributing to heart failure. However, the gene expression profiles induced by Ang II in the early stage of cardiac remodeling remain unknown. METHODS: Wild-type male mice (C57BL/6 background, 10-weeek-old) were infused with Ang II (1500 ng/kg/min) for 7 days. Blood pressure was measured. Cardiac function and remodeling were examined by echocardiography, H&E and Masson staining. The time series microarrays were then conducted to detected gene expression profiles. RESULTS: Microarray results identified that 1,489 genes were differentially expressed in the hearts at day 1, 3 and 7 of Ang II injection. These genes were further classified into 26 profiles by hierarchical cluster analysis. Of them, 4 profiles were significant (No. 19, 8, 21 and 22) and contained 904 genes. Gene Ontology showed that these genes mainly participate in metabolic process, oxidation-reduction process, extracellular matrix organization, apoptotic process, immune response, and others. Significant pathways included focal adhesion, ECM-receptor interaction, cytokine-cytokine receptor interaction, MAPK and insulin signaling pathways, which were known to play important roles in Ang II-induced cardiac remodeling. Moreover, gene co-expression networks analysis suggested that serine/cysteine peptidase inhibitor, member 1 (Serpine1, also known as PAI-1) localized in the core of the network. CONCLUSIONS: Our results indicate that many genes are mainly involved in metabolism, inflammation, cardiac fibrosis and hypertrophy. Serpine1 may play a central role in the development of Ang II-induced cardiac remodeling at the early stage.