Oral Ingestion of AP Collagen Peptide Leads to Systemic Absorption of Gly-Pro-Hyp, Alleviating H2O2-Induced Dermal Fibroblast Aging.

Collagen-derived dipeptides and tripeptides have various physiological activities. In this study, we compared the plasma kinetics of free Hyp, peptide-derived Hyp, Pro-Hyp, cyclo(Pro-Hyp), Hyp-Gly, Gly-Pro-Hyp, and Gly-Pro-Ala after ingestion of four different collagen samples: AP collagen peptide (APCP), general collagen peptide, collagen, and APCP and γ-aminobutyric acid (GABA) combination. Each peptide was measured by high-performance liquid chromatography and triple quadrupole mass spectrometer. We found that, among all the peptides that were analyzed, only Gly-Pro-Hyp was significantly increased after ingestion of APCP compared with that of general collagen peptides and collagen. In addition, ingestion of the APCP and GABA combination improved the absorption efficiency of Gly-Pro-Ala. Finally, we reveal that Gly-Pro-Hyp was effective for preventing H2O2-induced reduction in extracellular matrix (ECM)-related genes, COL1A, elastin, and fibronectin, in dermal fibroblasts. Taken together, APCP significantly enhances the absorption of Gly-Pro-Hyp, which might act as an ECM-associated signaling factor in dermal fibroblasts, and the APCP and GABA combination promotes Gly-Pro-Ala absorption. Clinical Trial Registration number: UMIN000047972.

UVB-dependent inhibition of lipin-1 protects against proinflammatory responses in human keratinocytes.

Lipin-1 is an Mg2+-dependent phosphatidate phosphatase (PAP1) that catalyzes a critical step in the synthesis of glycerophospholipids and is also a cotranscriptional regulator. The role of lipin-1 in the regulation of inflammatory responses has been extensively studied in various cell types but not in skin cells. In the present study, the function of lipin-1 in UVB-induced proinflammatory responses was assessed in normal human epidermal keratinocytes (NHEKs). UVB radiation downregulated lipin-1 expression. Lipin-1 inhibition was mediated by UVB-dependent sterol-response element binding protein-1 (SREBP-1) inhibition. The UVB-dependent inhibition of lipin-1 and SREBP-1 was mediated by AMPK activation. UVB-induced activation of JNK was dependent on AMPK activation and mediated lipin-1 inhibition. Prevention of UVB-mediated lipin-1 repression by introducing a lipin-1 expression vector stimulated IL-6 and IL-8 production, suggesting that lipin-1 inhibition attenuates UVB-induced IL-6 and IL-8 production. The downregulation of lipin-1 ameliorated UVB-induced NF-ĸB phosphorylation, which might be attributed to the suppression of UVB-induced accumulation of free fatty acids (FFAs). Pharmacological inhibition of PAP1 with propranolol suppressed UVB-induced production of IL-6 and IL-8 in NHEKs and reconstituted human skin models. Taken together, lipin-1 is downregulated by exposure to UVB radiation, which confers protection against UVB-induced proinflammatory responses; therefore, the inhibition of lipin-1 is a potential strategy for photoaging.

Risk Stratification of Intermediate-Risk Children With Minor Head Injury.

The Pediatric Emergency Care Applied Research Network rule helps emergency physicians identify very low-risk children with minor head injury who can forgo head computed tomography. This rule contributes to reduction in lifetime risk of radiation-induced cancers while minimizing missing clinically important traumatic brain injury. However, in intermediate-risk children, decisions on whether to perform computed tomography remain at the emergency physicians' discretion. To reduce this gray zone, this review summarizes evidence for risk stratification of intermediate-risk children with minor head injury.

Triple rule-out computed tomography for risk stratification of patients with acute chest pain.

AIMS: Clinical evidence supporting triple rule-out computed tomography (TRO-CT) for rapid screening of cardiovascular disease is limited. We investigated the clinical value of TRO-CT in patients with acute chest pain. METHODS: We retrospectively enrolled 1024 patients who visited the emergency department (ED) with acute chest pain and underwent TRO-CT using a 128-slice CT system. TRO-CT was classified as "positive" if it revealed clinically significant cardiovascular disease including obstructive coronary artery disease, pulmonary thromboembolism, or acute aortic syndrome. The clinical endpoint was occurrence of a major adverse cardiovascular event (MACE) within 30 days, defined by a composite of all cause death, myocardial infarction, revascularization, major cardiovascular surgery, or thrombolytic therapy. Clinical risk scores for acute chest pain including TIMI, GRACE, Diamond-Forrester, and HEART were determined and compared to the TRO-CT findings. RESULTS: TRO-CT revealed clinically significant cardiovascular disease in 239 patients (23.3%). MACE occurred in 119 patients (49.8%) with positive TRO-CT and in 7 patients (0.9%) with negative TRO-CT (p < 0.001). Sensitivity, specificity, positive predictive value, and negative predictive value of TRO-CT was 95%, 88%, 54%, and 99%, respectively. TRO-CT was a better discriminator between patients with vs. without events as compared to clinical risk scores (c-statistics = 0.91 versus 0.64 to 0.71; integrated discrimination improvement = 0.31 to 0.37; p < 0.001 for all comparisons). Patients with a negative TRO-CT showed shorter ED stay times and admission rates compared to patients with positive TRO-CT, irrespective of clinical risk scores (p < 0.001 for all comparisons). CONCLUSION: Triple rule-out CT has high predictive performance for 30-day MACE and permits rapid triage and low admission rates irrespective of clinical risk scores.

Lipin-1 expression is critical for keratinocyte differentiation.

Lipin-1 is an Mg(2+)-dependent phosphatidate phosphatase that facilitates the dephosphorylation of phosphatidic acid to generate diacylglycerol. Little is known about the expression and function of lipin-1 in normal human epidermal keratinocytes (NHEKs). Here, we demonstrate that lipin-1 is present in basal and spinous layers of the normal human epidermis, and lipin-1 expression is gradually downregulated during NHEK differentiation. Interestingly, lipin-1 knockdown (KD) inhibited keratinocyte differentiation and caused G1 arrest by upregulating p21 expression. Cell cycle arrest by p21 is required for commitment of keratinocytes to differentiation, but must be downregulated for the progress of keratinocyte differentiation. Therefore, reduced keratinocyte differentiation results from sustained upregulation of p21 by lipin-1 KD. Lipin-1 KD also decreased the phosphorylation/activation of protein kinase C (PKC)α, whereas lipin-1 overexpression increased PKCα phosphorylation. Treatment with PKCα inhibitors, like lipin-1 KD, stimulated p21 expression, while lipin-1 overexpression reduced p21 expression, implicating PKCα in lipin-1-induced regulation of p21 expression. Taken together, these results suggest that lipin-1-mediated downregulation of p21 is critical for the progress of keratinocyte differentiation after the initial commitment of keratinocytes to differentiation induced by p21, and that PKCα is involved in p21 expression regulation by lipin-1.

Successful fibrinolytic and therapeutic hypothermic management of cardiac arrest following massive pulmonary embolism.

Massive pulmonary embolism (MPE) with hemodynamic instability is a clinical condition with a poor prognosis and high mortality rates. There are no definitive treatment options for cardiac arrest due to MPE. A 52-year-old female presented at our emergency department with cardiac arrest, and a 62-year-old female presented after achieving return of spontaneous circulation of cardiac arrest from a local hospital, respectively. In each case, computed tomographic pulmonary angiography after return of spontaneous circulation demonstrated heavy burdens of pulmonary embolism in the pulmonary arteries. We immediately started therapeutic hypothermia and fibrinolytic therapy. They were transferred to the thoracic surgery and cardiology departments respectively, and then discharged with a cerebral performance categories scale score of 1. In summary, we report two cases of out-of-hospital cardiac arrest due to MPE in which fibrinolytic therapy was successfully combined with therapeutic hypothermia.