Associations between systemic inflammation and intestinal permeability with Onodera's prognostic nutritional index in critically ill patients

Background Malnutrition is a serious condition in critically ill patients. The aim of this study is to evaluate the relationships between the Onodera’s prognostic nutritional index (OPNI) and intestinal permeability and between OPNI and systemic inflammation in critically ill patients. Methods This was a cross-sectional study conducted in the general intensive care unit (ICU) of a university-affiliated hospital. A total of 162 patients admitted between May 2018 and December 2019, was included in the study. The OPNI was calculated at admission and categorized as ≤40 or >40. We assessed plasma endotoxin and zonulin concentrations as markers of intestinal permeability as well as serum interleukin-6 (IL-6) and high-sensitivity C-reactive protein (hs-CRP) as markers of systemic inflammation upon admission under stringent conditions. The relationships between these markers and OPNI were assessed after adjusting for potential confounders through estimation of a binary logistic regression model. Results Median (interquartile range) hs-CRP, IL-6 zonulin, and endotoxin were significantly greater in the low OPNI subgroup than in the high OPNI subgroup (all P<0.05). Multivariate analyses showed significant association between serum IL-6 (odds ratio [OR], 0.88; 95% confidence interval [CI], 0.64–0.96), serum hs-CRP (OR, 0.77; 95% CI, 0.53–0.92), plasma endotoxin (OR, 0.81; 95% CI, 0.72–0.93), and plasma zonulin (OR, 0.83; 95% CI, 0.75–0.98) levels with OPNI in the overall population. Conclusions Our results provide evidence that higher plasma endotoxin, zonulin, IL-6, and hs-CRP levels are associated with progressively lower OPNI in mixed ICU populations, particularly in surgical ICU patients

Regulation and Cytoprotective Role of Hexokinase III

Hexokinases (HKs) catalyze the first step in glucose metabolism. Of the three mammalian 100-kDa HK isoforms, HKI and II can bind to mitochondria and protect against cell death. HKIII does not bind mitochondria, and little is known about its regulation or cytoprotective effects. We studied the regulation of HKIII at the transcriptional and protein levels and investigated its role in cellular protection.We show that like HKII, HKIII expression is regulated by hypoxia, but other factors that regulate HKII expression have no effect on HKIII levels. This transcriptional regulation is partially dependent on hypoxia-inducible factor (HIF) signaling. We also demonstrate regulation at the protein level, as mutations in putative N-terminal substrate binding residues altered C-terminal catalytic activity, suggesting that HKIII activity is governed, in part, by interactions between these two domains. Overexpression of HKIII reduced oxidant-induced cell death, increased ATP levels, decreased the production of reactive oxygen species (ROS), and preserved mitochondrial membrane potential. HKIII overexpression was also associated with higher levels of transcription factors that regulate mitochondrial biogenesis, and greater total mitochondrial DNA content. Attempts to target HKIII to the mitochondria by replacing its N-terminal 32-amino-acid sequence with the mitochondrial-targeting sequence of HKII led to protein aggregation, suggesting that this region is necessary to maintain proper protein folding and solubility.These results suggest that HKIII is regulated by hypoxia and there are functional interactions between its two halves. Furthermore, HKIII exerts protective effects against oxidative stress, perhaps by increasing ATP levels, reducing oxidant-induced ROS production, preserving mitochondrial membrane potential, and increasing mitochondrial biogenesis

Association of vitamin D deficiency with COVID-19 severity and mortality in Iranian people: a prospective observational study

Background As the coronavirus disease 2019 (COVID-19) pandemic continues to escalate, it is important to identify the prognostic factors related to increased mortality and disease severity. To assess the possible associations of vitamin D level with disease severity and survival, we studied 248 hospitalized COVID-19 patients in a single center in a prospective observational study from October 2020 to May 2021 in Tehran, Iran. Methods Patients who had a record of their 25-hydroxyvitamin D level measured in the previous year before testing positive with COVID-19 were included. Serum 25-hydroxyvitamin D level was measured upon admission in COVID-19 patients. The associations between clinical outcomes of patients and 25-hydroxyvitamin D level were assessed by adjusting for potential confounders and estimating a multivariate logistic regression model. Results The median (interquartile range) age of patients was 60 years (44–74 years), and 53% were male. The median serum 25-hydroxyvitamin D level prior to admission decreased with increasing COVID-19 severity (P=0.009). Similar findings were obtained when comparing median serum 25-hydroxyvitamin D on admission between moderate and severe patients (P=0.014). A univariate logistic regression model showed that vitamin D deficiency prior to COVID-19 was associated with a significant increase in the odds of mortality (odds ratio, 2.01; P=0.041). The multivariate Cox model showed that vitamin D deficiency on admission was associated with a significant increase in risk for mortality (hazard ratio, 2.35; P=0.019). Conclusions: Based on our results, it is likely that deficient vitamin D status is associated with increased mortality in COVID-19 patients. Thus, evaluating vitamin D level in COVID-19 patients is warranted

Hepatic tristetraprolin promotes insulin resistance through RNA destabilization of FGF21

The role of posttranscriptional metabolic gene regulatory programs in diabetes is not well understood. Here, we show that the RNA-binding protein tristetraprolin (TTP) is reduced in the livers of diabetic mice and humans and is transcriptionally induced in response to insulin treatment in murine livers in vitro and in vivo. Liver-specific Ttp-KO (lsTtp-KO) mice challenged with high-fat diet (HFD) have improved glucose tolerance and peripheral insulin sensitivity compared with littermate controls. Analysis of secreted hepatic factors demonstrated that fibroblast growth factor 21 (FGF21) is posttranscriptionally repressed by TTP. Consistent with increased FGF21, lsTtp-KO mice fed HFD have increased brown fat activation, peripheral tissue glucose uptake, and adiponectin production compared with littermate controls. Downregulation of hepatic Fgf21 via an adeno-associated virus-driven shRNA in mice fed HFD reverses the insulin-sensitizing effects of hepatic Ttp deletion. Thus, hepatic TTP posttranscriptionally regulates systemic insulin sensitivity in diabetes through liver-derived FGF21

Priorities in Cardio-Oncology Basic and Translational Science

Despite improvements in cancer survival, cancer therapy–related cardiovascular toxicity has risen to become a prominent clinical challenge. This has led to the growth of the burgeoning field of cardio-oncology, which aims to advance the cardiovascular health of cancer patients and survivors, through actionable and translatable science. In these Global Cardio-Oncology Symposium 2023 scientific symposium proceedings, we present a focused review on the mechanisms that contribute to common cardiovascular toxicities discussed at this meeting, the ongoing international collaborative efforts to improve patient outcomes, and the bidirectional challenges of translating basic research to clinical care. We acknowledge that there are many additional therapies that are of significance but were not topics of discussion at this symposium. We hope that through this symposium-based review we can highlight the knowledge gaps and clinical priorities to inform the design of future studies that aim to prevent and mitigate cardiovascular disease in cancer patients and survivors.</p

Role of the mitochondrial ATP-sensitive K+ channels in cardioprotection.

The mitochondrial ATP-sensitive K+ (mitoKATP) channel was discovered more than a decade ago. Since then, several pharmacological studies have identified agents that target this channel some of which selectively target mitoKATP. These and other studies have also suggested that mitoKATP plays a key role in the process of ischemic preconditioning (IPC) and prevention of apoptosis. The mechanism by which mitoKATP exerts its protective effects is unclear, however, changes in mitochondrial Ca2+ uptake and levels of reactive oxygen species, and mitochondrial matrix swelling are believed to be involved. Despite major advances, several important issues regarding mitoKATP remain unanswered. These questions include, but are not limited to: the molecular structure of mitoKATP, the downstream and upstream mechanisms that leads to IPC and cell death, and the pharmacological profile of the channel. This review attempts to provide an up-to-date overview of the role of mitoKATP in cardioprotection

Ho\v{r}ava-Lifshitz scalar field cosmology: classical and quantum viewpoints

In this paper, we study a projectable Ho\v{r}ava-Lifshitz cosmology without the detailed balance condition minimally coupled to a non-linear self-coupling scalar field. In the minisuperspace framework, the super Hamiltonian of the presented model is constructed by means of which, some classical solutions for scale factor and scalar field are obtained. Since these solutions exhibit various types of singularities, we came up with the quantization of the model in the context of the Wheeler-DeWitt approach of quantum cosmology. The resulting quantum wave functions are then used to investigate the possibility of the avoidance of classical singularities due to quantum effects which show themselves important near these singularities.Comment: 17 pages, 12 figures, typos corrected, Refs. added, Final versio