Lactate dehydrogenase to albumin ratio is associated with in-hospital mortality in patients with acute heart failure: Data from the MIMIC-III database.

The effect of the lactate dehydrogenase to albumin ratio (LAR) on the survival of patients with acute heart failure (AHF) is unclear. We aimed to analyze the impact of LAR on survival in patients with AHF. We retrieved eligible patients for our study from the Monitoring in Intensive Care Database III. For each patient in our study, we gathered clinical data and demographic information. We conducted multivariate logistic regression modeling and smooth curve fitting to assess whether the LAR score could be used as an independent indicator for predicting the prognosis of AHF patients. A total of 2,177 patients were extracted from the database. Survivors had an average age of 69.88, whereas nonsurvivors had an average age of 71.95. The survivor group had a mean LAR ratio of 13.44, and the nonsurvivor group had a value of 17.38. LAR and in-hospital mortality had a nearly linear correlation, according to smooth curve fitting (P < 0.001). According to multivariate logistic regression, the LAR may be an independent risk factor in predicting the prognosis of patients with AHF (odd ratio = 1.09; P < 0.001). The LAR ratio is an independent risk factor associated with increased in-hospital mortality rates in patients with AHF.

Tumor somatic mutations also existing as germline polymorphisms may help to identify functional SNPs from genome-wide association studies.

We hypothesized that a joint analysis of cancer risk-associated single-nucleotide polymorphism (SNP) and somatic mutations in tumor samples can predict functional and potentially causal SNPs from GWASs. We used mutations reported in the Catalog of Somatic Mutations in Cancer (COSMIC). Confirmed somatic mutations were subdivided into two groups: (1) mutations reported as SNPs, which we call mutational/SNPs and (2) somatic mutations that are not reported as SNPs, which we call mutational/noSNPs. It is generally accepted that the number of times a somatic mutation is reported in COSMIC correlates with its selective advantage to tumors, with more frequently reported mutations being more functional and providing a stronger selective advantage to the tumor cell. We found that mutations reported ≥10 times in COSMIC-frequent mutational/SNPs (fmSNPs) are likely to be functional. We identified 12 cancer risk-associated SNPs reported in the Catalog of published GWASs at least 10 times as confirmed somatic mutations and therefore deemed to be functional. Additionally, we have identified 42 SNPs that are tightly linked (R2 ≥ 0.8) to SNPs reported in the Catalog of published GWASs as cancer risk associated and that are also reported as fmSNPs. As a result, 54 candidate functional/potentially causal cancer risk associated SNPs were identified. We found that fmSNPs are more likely to be located in evolutionarily conserved regions compared with cancer risk associated SNPs that are not fmSNPs. We also found that fmSNPs also underwent positive selection, which can explain why they exist as population polymorphisms.

Lentiviral Vector-Mediated SHC3 Silencing Exacerbates Oxidative Stress Injury in Nigral Dopamine Neurons by Regulating the PI3K-AKT-FoxO Signaling Pathway in Rats with Parkinson's Disease.

BACKGROUND/AIMS: Parkinson's disease (PD) is a prevalent disease that leads to motor and cognitive disabilities, and oxidative stress (OS) injury was found to be related to the etiology of PD. Increasing evidence has shown that SHC3 is aberrantly expressed in neurons. The current study examines the involvement of SHC3 silencing in OS injury in the nigral dopamine neurons in rats with PD via the PI3K-AKT-FoxO signaling pathway. METHODS: To study the mechanisms and functions of SHC3 silencing in PD at the tissue level, 170 rats were selected, and a lentivirus-based packaging system was designed to silence SHC3 expression in rats. Furthermore, PC12 cells were selected for in vitro experimentation. To evaluate the effect of SHC3 silencing in nigral dopamine neuronal growth, an MTT assay, propidium iodide (PI) single staining and Annexin V-PI double staining were performed to detect cell viability, cell cycle progression and cell apoptosis, respectively. RESULTS: SHC3 shRNA led to decreased SOD and MDA levels and enhanced GSH activity, indicating that SHC3 silencing leads to motor retardation. SHC3 silencing repressed the extent of Akt and FoxO phosphorylation, thereby inhibiting the PI3K-AKT-FoxO signaling pathway. Furthermore, in cell experiments, SHC3 silencing suppressed PC12 cell proliferation and cell cycle progression, whereas it enhanced cell apoptosis. CONCLUSION: The current study provides evidence suggesting that SHC3 silencing may aggravate OS injury in nigral dopamine neurons via downregulation of the PI3K-AKT-FoxO signaling pathway in PD rats.

The potential of chrysophanol in protecting against high fat-induced cardiac injury through Nrf2-regulated anti-inflammation, anti-oxidant and anti-fibrosis in Nrf2 knockout mice.

Cardiovascular complications induced by high fat are one of the most challenging health problems presently. Oxidative stress, inflammation and fibrosis are major components included in the pathology of diabetic cardiomyopathy. Nuclear factor erythroid 2-related factor 2 (Nrf2) has been reported as an essential therapeutic target in various diseases for its induction of anti-oxidant enzymes, and other protective enzymes. Additionally, a number of Nrf2 activators showed strong anti-inflammatory properties. In the study, we calculated the Nrf2-dependent anti-oxidant, anti-inflammatory and anti-fibrosis effects of chrysophanol in high fat diet-induced diabetic heart injury. The underlying mechanisms of chrysophanol were explored using H9C2 cells in vitro. For the in vivo experiment, cardiac injury was triggered in wild type (Nrf2+/+) and Nrf2-knockout (Nrf2-/-) mice by high fat diet, and chrysophanol was administered after high fat feeding for two weeks. In Nrf2+/+ mice, but not the Nrf2-/- animals, chrysophanol ameliorated metabolic disorders, improved cardiac function, reduced pathological changes, attenuated oxidative injury, down-regulated inflammatory response and fibrosis progression through regulating different signaling pathways. Our data indicated that the anti-oxidant, anti-inflammatory and anti-fibrosis effects of chrysophanol are regulated by Nrf2 expression. Thus, we supposed that chrysophanol could be used as a safe therapeutic strategy to ameliorate cardiac injury induced by high fat diet.

NLRP4 is an essential negative regulator of fructose-induced cardiac injury in vitro and in vivo.

High fructose consumption leads to metabolic syndrome and enhances cardiovascular disease risk. However, our knowledge of the molecular mechanism underlying the cardiac disease caused by fructose feeding is still poor. Nod-like receptors (NLRs) are intracellular sensors, responding to a variety of intracellular danger signals to induce injuries. NLRP4 is a negative regulator of nuclear factor-κB (NF-κB) signaling pathway through interactions with kinase IκB kinase (IKK). Here, we illustrated that NLRP4 attenuates pro-inflammatory cytokines releasing, including Transforming growth factor (TGF-ß1), Tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), interleukin-18 (IL-18) and interleukin-6 (IL-6), in fructose-treated cardiac cells by means of RT-qPCR, and western blotting analysis. In addition, NLRP4 could reduce the expression of TANK-binding kinase 1/interferon regulatory factor 3 (TBK1/IRF3), reducing inflammation response and achieving its anti-hypertrophic action. TBK1 plays critical roles in the IRF3 signaling pathway, modulating inflammation response. The inhibition of IKK/NF-κB signaling pathway by NLRP4 is confirmed by NLRP4 over-expression and knockdown. In vivo, high fructose feeding induced cardiac injury, accompanied with reduced expression of NLRP4 in heart tissue samples, indicating the possible role of NLRP4 in ameliorating heart injury. In conclusion, the findings above indicated that NLRP4 is an important mediator of cardiac remodeling in vitro and in vivo through negatively regulating TBK1/IRF3 and IKK/NF-κB signaling pathways, indicating that NLRP4 might be a promising therapeutic target against cardiac inflammation.

Thermal conductivity, Fermi pockets and superconductivity in underdoped cuprates.

The electronic contribution to thermal conductivity is studied in models of underdoped cuprates where the normal state has a pocketed Fermi surface with circumference ∼x (hole concentration) and the superconducting state is formed by opening a gap in the Fermi pocket. The physical consequences of the Fermi pocket are studied by comparing the thermal conductivity computed in four different models: (1) an ordinary d-wave superconductor with four Dirac Fermi points; (2) a normal metal with a pocketed Fermi surface; (3) a superconductor formed by spinon-holon binding in the t-J model; (4) a phenomenological d-wave Bardeen-Cooper-Schrieffer (BCS) superconductor with superconductivity formed by opening a gap on the pocketed Fermi surface. Our results suggest that thermal conductivity provides useful information to distinguish between different scenarios of the normal-to-superconducting transition in underdoped cuprates.