Bridging Energy Need and Feeding Behavior: The Impact of eIF2α Phosphorylation in AgRP Neurons.

Eukaryotic translation initiation factor 2α (eIF2α) is a key mediator of the endoplasmic reticulum (ER) stress-induced unfolded protein response (UPR). In mammals, eIF2α is phosphorylated by overnutrition-induced ER stress and is related to the development of obesity. Here, we studied the function of phosphorylated eIF2α (p-eIF2α) in agouti-related peptide (AgRP) neurons using a mouse model (AgRPeIF2αA/A) with an AgRP neuron-specific substitution from Ser 51 to Ala in eIF2α, which impairs eIF2α phosphorylation in AgRP neurons. These AgRPeIF2αA/A mice had decreases in starvation-induced AgRP neuronal activity and food intake and an increased responsiveness to leptin. Intriguingly, impairment of eIF2α phosphorylation produced decreases in the starvation-induced expression of UPR and autophagy genes in AgRP neurons. Collectively, these findings suggest that eIF2α phosphorylation regulates AgRP neuronal activity by affecting intracellular responses such as the UPR and autophagy during starvation, thereby participating in the homeostatic control of whole-body energy metabolism. ARTICLE HIGHLIGHTS: This study examines the impact of eukaryotic translation initiation factor 2α (eIF2α) phosphorylation, triggered by an energy deficit, on hypothalamic AgRP neurons and its subsequent influence on whole-body energy homeostasis. Impaired eIF2α phosphorylation diminishes the unfolded protein response and autophagy, both of which are crucial for energy deficit-induced activation of AgRP neurons. This study highlights the significance of eIF2α phosphorylation as a cellular marker indicating the availability of energy in AgRP neurons and as a molecular switch that regulates homeostatic feeding behavior.

Clinical Impact of Recipient-Derived Isoagglutinin Levels in ABO-Incompatible Hematopoietic Stem Cell Transplantation.

ABO incompatibility is not considered a contraindication for hematopoietic stem cell transplantation (HSCT). We hypothesized that recipient-derived isoagglutinin (RDI) levels could play a critical role in clinical outcomes. In this study, we compared clinical outcomes such as survival, GVHD, infection, relapse, transfusion, and engraftment, among ABO-compatible patients (ABOc), ABO-incompatible patients (ABOi) with low RDI, and ABOi patients with high RDI. The ABOi with high RDI group was defined as recipients with more than 1:16 RDI levels. We analyzed 103 recipients (ABOc, 53; ABOi with low RDI, 36; ABOi with high RDI, 14). The ABOi with high RDI group showed a decreased 1-year survival and increased acute GVHD grade IV and RBC transfusion (p = 0.017, 0.027, and 0.032, respectively). The ABOi with high RDI group was an independent risk factor for increased death, RBC transfusion, and poor platelet (PLT) engraftment (odds ratio (OR) = 3.20, p = 0.01; OR = 8.28, p = 0.02; OR = 0.18, p = 0.03, respectively). The ABOi with high RDI group showed significantly delayed PLT engraftment. In conclusion, this is the first study underscoring high RDI levels as a marker predicting unfavorable outcomes in ABOi HSCT.

Performance Evaluation of AFIAS ST2 and Ichroma ST2 Assays in Comparison with Presage ST2 Assay.

Background: Elevated soluble suppression of tumorigenicity 2 (sST2) levels may predict mortality in heart failure (HF) patients. The AFIAS ST2 assay (AFIAS ST2, Boditech Med Inc., Chuncheon, Korea) and ichroma ST2 assay (ichroma ST2, Boditech Med Inc.) are newly developed point-of-care (POC) assays for measuring sST2 level. We evaluated the performance of these assays, in terms of cut-off validation and prognosis, and compared them with that of the Presage ST2 assay (Presage ST2, Critical Diagnostics, San Diego, CA, USA). Methods: We validated the US FDA-claimed sST2 clinical cut-off of 35 ng/mL using 420 serum samples (298 samples from the universal sample bank of the American Association for Clinical Chemistry and 122 samples from reference individuals from Konkuk University Medical Center). We compared AFIAS ST2 and ichroma ST2 with Presage ST2, using 206 samples from patients with HF. We assessed prognosis using the three assays in 252 samples from the Barcelona ambulatory HF cohort subsets. Results: The upper reference limits of AFIAS ST2 and ichroma ST2 were within the clinical cut-off of Presage ST2. The results of AFIAS ST2 and ichroma ST2 were highly correlated with those of Presage ST2 (r = 0.82 and 0.81, respectively). Based on this cut-off, all three assays predicted cardiovascular death. Conclusions: The new POC assays, AFIAS ST2 and ichroma ST2, would be useful in clinical practice for managing HF patients, with performances equivalent to that of Presage ST2.

"The armor phenomenon" in obese patients with penetrating thoracoabdominal injuries: A systematic review and meta-analysis.

BACKGROUND: Obesity represents a growing global health threat, which generally portends increased morbidity and mortality in the context of traumatic injuries. We hypothesized that there may exist a protective effect related to increased weight and truncal girth provided for obese patients in penetrating torso injuries, although this may not exert a significant positive impact overall upon clinical outcomes. METHODS: A comprehensive review of the literature was conducted across five databases up to March 2021 (Medline, Pubmed, Embase, Web of Science and the Cochrane library) to examine the effect of obesity on penetrating thoracoabdominal injuries. The primary outcome was to determine the rate of nonsignificant injury and injury patterns. Secondary outcomes examined were lengths of stay, complications, and mortality. Comparisons were drawn by meta-analysis. The study protocol was registered with PROSPERO under CRD42020216277. RESULTS: There were 2,952 publications assessed with 12 meeting the inclusion criteria for review. Nine studies were included for quantitative analysis, including 5,013 patients sustaining penetrating thoracoabdominal injuries, of which 29.6% were obese. Obese patients that sustained stab injuries underwent more nontherapeutic operations. Obese patients that sustained gunshot injuries had longer intensive care and total hospital length of stay. Obese patients suffered more respiratory complications and were at an increased risk of death during their admission. CONCLUSION: The "armor phenomenon" does not truly protect obese patients, a population that experiences increased morbidity and mortality following penetrating thoracoabdominal injuries. LEVEL OF EVIDENCE: Systematic Review and Meta-Analysis; Level IV.

Transcription Factor TonEBP Stimulates Hyperosmolality-Dependent Arginine Vasopressin Gene Expression in the Mouse Hypothalamus.

The hypothalamic neuroendocrine system is strongly implicated in body energy homeostasis. In particular, the degree of production and release of arginine vasopressin (AVP) in the hypothalamus is affected by plasma osmolality, and that hypothalamic AVP is responsible for thirst and osmolality-dependent water and metabolic balance. However, the osmolality-responsive intracellular mechanism within AVP cells that regulates AVP synthesis is not clearly understood. Here, we report a role for tonicity-responsive enhancer binding protein (TonEBP), a transcription factor sensitive to cellular tonicity, in regulating osmosensitive hypothalamic AVP gene transcription. Our immunohistochemical work shows that hypothalamic AVP cellular activity, as recognized by c-fos, was enhanced in parallel with an elevation in TonEBP expression within AVP cells following water deprivation. Interestingly, our in vitro investigations found a synchronized pattern of TonEBP and AVP gene expression in response to osmotic stress. Those results indicate a positive correlation between hypothalamic TonEBP and AVP production during dehydration. Promoter and chromatin immunoprecipitation assays confirmed that TonEBP can bind directly to conserved binding motifs in the 5'-flanking promoter regions of the AVP gene. Furthermore, dehydration- and TonEBP-mediated hypothalamic AVP gene activation was reduced in TonEBP haploinsufficiency mice, compared with wild TonEBP homozygote animals. Therefore, our result support the idea that TonEBP is directly necessary, at least in part, for the elevation of AVP transcription in dehydration conditions. Additionally, dehydration-induced reductions in body weight were rescued in TonEBP haploinsufficiency mice. Altogether, our results demonstrate an intracellular machinery within hypothalamic AVP cells that is responsible for dehydration-induced AVP synthesis.

Tonicity-responsive enhancer binding protein (TonEBP) regulates TNF-α-induced hypothalamic inflammation.

Tonicity-responsive enhancer binding protein (TonEBP) is a widely expressed transcription factor and is important in the regulation of inflammatory cytokines. Here, we have identified TonEBP expression in the hypothalamus, which is particularly high in proopiomelanocortin (POMC) neurons. TonEBP overexpression stimulates POMC transcription, and TonEBP haploinsufficiency in TonEBP (+/-) mice results in a decrease in hypothalamic POMC expression. TonEBP (+/-) mice show reduced sickness responses, which include anorexia and hyperthermia, that are initially induced by tumor necrosis factor (TNF)-α. TonEBP (+/-) mice also show lower levels of TNF-α-induced hypothalamic expression of POMC and pro-inflammatory cytokines. These results suggest that TonEBP is an important molecular regulator in the development of inflammatory sickness responses through the control of POMC and pro-inflammatory cytokine expression in the hypothalamus.

Epigallocatechin-3-O-gallate decreases tumor necrosis factor-alpha-induced fractalkine expression in endothelial cells by suppressing NF-kappaB.

Epigallocatechin-3-O-gallate (EGCG), the main catechin in green tea, has anti-oxidant, anti-atherosclerotic and anti-inflammatory properties. Fractalkine, a chemokine involved in inflammation and early atherosclerotic processes, acts as a chemoattractant as well as an adhesion molecule in endothelial cells activated by proinflammatory cytokines. In the present study, we investigated the effect of EGCG on fractalkine expression in TNF-alpha-induced human umbilical vein endothelial cells (HUVECs). EGCG decreased TNF-alpha-induced fractalkine mRNA and protein expression in HUVECs in a time-dependent manner. EGCG suppressed the TNF-alpha-induced phosphorylation and degradation of IkappaB-alpha, thereby decreasing the phosphorylation and nuclear translocation of the NF-kappaB p65 subunit in HUVECs. The DNA binding activity of the NF-kappaB p65 subunit was lower in EGCG-pretreated HUVECs than in those treated with TNF-alpha alone. Furthermore, EGCG inhibited monocyte adhesion to HUVECs stimulated by TNF-alpha. The silencing of fractalkine with an siRNA or treatment with a blocking antibody against fractalkine suppressed the TNF-alpha-induced increase in monocyte adhesion. These results demonstrate that EGCG prevents TNF-alpha-induced vascular endothelial fractalkine expression.

COMP-angiopoietin-1 decreases lipopolysaccharide-induced acute kidney injury.

During sepsis endothelial dysfunction is an important pathogenetic mechanism in acute kidney injury (AKI). Lipopolysaccharide (LPS)-induced endotoxemia is associated with renal hemodynamic changes such as alterations of renal blood flow (RBF), vascular resistance, and glomerular filtration rate. We used adenoviral delivery of an engineered variant of native angiopoietin-1 (COMP-angiopoietin-1) containing anti-inflammatory and anti-permeability functions, to determine if regulation of renal endothelial cell dysfunction may have a beneficial role in preventing AKI during LPS-induced endotoxemia in mice. This treatment prevented the endotoxin-induced decrease of RBF and mean arterial pressure while improving glomerular filtration rate. Treatment also mitigated the effects of LPS on renal intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 protein expression, the number of ER-HR3-positive macrophages that infiltrated the kidney, serum nitrate/nitrite levels, renal inducible nitric oxide synthase protein expression, the induction of tubular epithelial reactive oxygen and nitrogen species, and renal microvascular permeability. Our findings show that COMP-angiopoietin-1, an endothelium-oriented therapeutic agent, protects against AKI caused by endotoxemia.

Mast cells decrease renal fibrosis in unilateral ureteral obstruction.

Mast cells regulate both inflammatory responses and tissue repair in human diseases but there are conflicting reports on the role of these cells in the pathogenesis of various kidney diseases. Here we measured mast cell function in unilateral ureteral obstruction, a well-characterized model of renal fibrosis, using Kit(W)/Kit(W-v) mice genetically deficient in mast cells, wild-type mice, and deficient mice reconstituted by adoptive transfer with mast cells from the wild-type animals. Mast cell-deficient mice had higher levels of renal tubular damage, more stromal fibrosis, higher numbers of infiltrating ERHR3-positive macrophages and CD3-positive T cells, and higher tissue levels of profibrotic transforming growth factor-beta1 than wild-type mice or mice reconstituted by adoptive transfer of mast cells 3 weeks after ureteral obstruction. Similarly, while wild-type and adoptively transferred mice had increased alpha-smooth muscle actin and decreased E-cadherin expression, which are indicators of epithelial-mesenchymal transition, the obstructed kidneys of the mast cell-deficient mice had significant attenuation of those indicators. Thus, our study suggests that mast cells protect the kidney against fibrosis by modulation of inflammatory cell infiltration and by transforming growth factor-beta1-driven epithelial-to-mesenchymal transitions.