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Sebocytes express Toll-like receptors (TLRs) and nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs), which participate in the innate immune response of the skin. Although the roles of TLRs and NLR family pyrin domain-containing 3 (NLRP3) in inflammatory responses in sebocytes have been reported, the expression and functions of other NLR members, such as NOD protein-1 and -2 (NOD1 and NOD2, respectively), remain unclear. In this study, we showed that, in sebocytes, the expression of NOD1 is higher than that of NOD2, and that NOD1 is involved in inflammatory responses, such as the secretion of proinflammatory cytokines. A NOD1 agonist, L-alanyl-γ-D-glutamyl-meso-diaminopimelic acid (Tri-DAP) induced the expression and secretion of interleukin-8 (IL-8) and activated the nuclear factor-kappa B and mitogen-activated protein kinase signaling pathways. On the other hand, a NOD2 agonist, muramyl dipeptide, did not. Either inhibition with a NOD1 inhibitor, ML130, or knockdown of NOD1 expression abolished Tri-DAP-induced inflammatory responses, suggesting that NOD1 is involved in the immunogenic signaling system of sebocytes. Furthermore, Tri-DAP and an agonist of TLR2 or TLR4 additively increased IL-8 expression compared with each agonist alone. Our results reveal the role of NOD1 in the inflammatory responses of sebocytes and may provide a novel therapeutic target for sebaceous gland inflammatory diseases, such as acne vulgaris., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)

Grafts from donors after cardiac death (DCD) have greatly contributed to expanding the donor organ pool. This study aimed to determine the benefits of subnormothermic extracorporeal membrane oxygenation (ECMO) and hypothermic machine perfusion (HMP) in a porcine model of DCD liver. Female domestic crossbred Large Yorkshire and Landrace pigs weighing approximately 20 kg were used. The abdominal aorta and inferior vena cava were cannulated and connected to an ECMO circuit for in situ perfusion of the abdominal organs at 22 °C for 60 min, 45 min after cardiac death. The pigs were divided into the cold storage (CS) group ( n = 3), where liver grafts were preserved at 4 °C, and the HMP group ( n = 3), where liver grafts were preserved by HMP at 8-10 °C. After 4 h of preservation, liver function was evaluated using an isolated liver reperfusion model for 2 h. Although the difference was insignificant, the liver effluent enzyme levels in the HMP group were lower than those in the CS group. Furthermore, morphological findings showed fewer injured hepatocytes in the HMP group than in the CS group. The combined use of in situ subnormothermic ECMO and HMP was beneficial for the functional improvement of DCD liver grafts.

Topochemical reactions provide selective products based on the molecular position; however, they generally require molecules to be placed in strictly limited orientations and distances, making them less versatile. In this study, we found that by confining trans -4-styrylpyridine (4-spy) as a reactive substrate in a flexible metal-organic framework (MOF) nanospace, [2+2] cycloadducts can be selectively obtained, even when the distance between two C═C bonds of 4-spy in the crystal is 5.9 Å, which is much larger than the conventionally observed upper limit (4.2 Å). Such an unusual cyclization reaction is suggested to occur due to the transient proximity of the 4-spy due to the "swing" motion in the nanospace. The MOF nanospace, with its high degree of molecular structural freedom, can be applied to different platforms that do not require the fine constraints of reactive distances for solid-phase reactions.

Background: The use of grafts from donors after cardiac death (DCD) would greatly contribute to the expansion of the donor organ pool. This study aims to determine the benefits of extracorporeal membrane oxygenation (ECMO) and hypothermic oxygenated machine perfusion (HOPE) in a large animal model of DCD liver., Methods: After cardiac arrest, the abdominal aorta and the inferior vena cava were cannulated and connected to an ECMO circuit. Porcine livers were perfused in situ with ECMO at 22°C for 60 minutes after 45 minutes of cardiac death. Then, the livers were perfused for 4 hours by cold storage (CS) or HOPE. In group 1, non-in situ ECMO and grafts were preserved by HOPE. In group 2, in situ ECMO and grafts were preserved by HOPE. In group 3, in situ ECMO and grafts were preserved by CS. After preservation, all grafts were evaluated using an isolated reperfusion model (IRM) with autologous blood for 2 hours., Results: During HOPE, aspartate aminotransferase (AST) levels and hepatic arterial pressure in group 2 tended to be lower than in group 1. Hematoxylin-eosin staining findings after HOPE showed more massive sinusoidal congestion and hepatocyte cytoplasmic vacuolization in group 1 than in group 2. The AST and LDH levels in group 2 at the start-up of IRM tended to be lower than in group 1., Conclusions: The combined use of in situ subnormothermic ECMO and HOPE is essential for the functional recovery of DCD liver grafts., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Here we report the development of an equimolar conjugate of a metal-organic cage (MOC) and DNA (MOC-DNA). Several MOC-DNA conjugates were assembled into a programmed structure by coordinating with a template DNA having a complementary base sequence. Moreover, conjugation with the MOC drastically enhanced the permeability of DNA through the lipid bilayer, presenting great potential as a drug delivery system.

Many animal studies have shown that oral administration of the nicotinamide adenine dinucleotide (NAD + ) precursor nicotinamide mononucleotide (NMN) prevents the reduction of NAD + levels in organs and tissues, helping alleviate aging-related diseases. However, there are very few clinical reports of NMN supplementation in humans. Thus, this study aimed to investigate the influence of a 12-week NMN oral supplementation on biochemical and metabolic health parameters. A 12-week randomized, double-blind, placebo-controlled, parallel-group clinical trial was conducted. A total of 36 healthy middle-aged participants received one capsule of either 125 mg NMN or placebo twice a day. Among the NAD + metabolites, the levels of nicotinamide in the serum were significantly higher in the NMN intake group than in the placebo group. Pulse wave velocity values indicating arterial stiffness tended to decrease in the NMN intake group. However, no significant difference was found between the two groups. Long-term NMN supplementation at 250 mg/day was well tolerated and did not cause adverse events. NMN safely and effectively elevated NAD + metabolism in healthy middle-aged adults. Additionally, NMN supplementation showed potential in alleviating arterial stiffness., (© 2023. The Author(s).)

Objective: In the acute stage of ruptured cerebral aneurysms, limited devices are available, making the treatment difficult. We aimed to evaluate the outcomes of the coil embolization with stenting for the ruptured cerebral aneurysms in the acute stage., Methods: We assessed 22 cases treated with stenting among 134 of 169 consecutive patients with subarachnoid hemorrhages undergoing an endovascular treatment between April 2014 and December 2021, of which 134 underwent an embolization during the acute stage. A stent was used in the patients wherein the treatment with the balloon-assisted or double catheter technique was difficult. Stenting was performed under the loading of two or more antiplatelet agents., Results: The mean age of the patients was 68.9 years, of which five were male and 14 (63.6%) had severe grade (World Federation of Neurosurgeons grade IV, V). The aneurysm site was the anterior communicating artery in four cases, internal carotid artery in nine, middle cerebral artery in two, vertebrobasilar artery in six, and posterior cerebral artery in one. The aneurysm shape was saccular in 13 cases, dissection in seven, and fusiform in two. Stents were used for wide-neck aneurysms in 12 cases, vascular preservation in seven, and rescue in three. The mean maximum diameter was 9.6 mm. The mean neck size was 6.4 mm. Complete occlusion and neck remnant were found in eight and seven cases, respectively. The perioperative complication rate was 45.5% (thromboembolism in five cases, stent occlusion in two, re-bleeding in two, and cerebral hemorrhage in one). The outcomes included modified Rankin Scale 0-2 in seven cases, 4-5 in five, and 6 in nine. Stent-related death occurred in one case. The rate of morbidity and mortality was 18.2%. Although stents were used in the acute stage of rupture, they were used for the right reasons. However, a high rate of complications occurred: two cases of re-bleeding, in which an incomplete occlusion was a factor., Conclusion: Stent placement in patients with the acute ruptured cerebral aneurysms should be carefully determined and efforts should be made to reduce the embolic and hemorrhagic complications. However, it may be an effective treatment option when other options could be extremely difficult., Competing Interests: The authors declare that they have no conflicts of interest., (©2023 The Japanese Society for Neuroendovascular Therapy.)

Nicotinamide adenine dinucleotide (NAD) is an essential cofactor for numerous enzymes involved in energy metabolism. Because decreasing NAD levels is a common hallmark of the aging process in various tissues and organs, maintaining NAD levels has recently been of interest for the prevention of aging and age-related diseases. Although placental extract (PE) are known to possess several anti-aging effects, the NAD-boosting activity of PE remains unknown. In this study, we found that porcine PE (PPE) significantly increased intracellular NAD levels in normal human epidermal keratinocytes (NHEKs). PPE also attenuated the NAD depletion induced by FK866, an inhibitor of nicotinamide phosphoribosyltransferase (NAMPT). Interestingly, only the fraction containing nicotinamide mononucleotide (NMN), nicotinamide riboside (NR), and nicotinamide (NAM) restored NAD content in NHEKs in the absence of NAMPT activity. These results suggest that PPE increases intracellular NAD by providing NAD precursors such as NMN, NR, and NAM. Finally, we showed that the application of PPE to the stratum corneum of the reconstructed human epidermis significantly ameliorated FK866-induced NAD depletion, suggesting that topical PPE may be helpful for increasing skin NAD levels. This is the first study to report the novel biological activity of PE as an NAD booster in human epidermal cells., (© 2022. The Author(s).)

The nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing protein (NLRP) inflammasome is a key inflammatory signaling pathway activated via a two-step signaling process consisting of priming and activation steps. Several studies have shown that 1,25-dihydroxyvitamin D3 (1,25(OH) 2 VD 3 ) inhibits the priming step required for NLRP3 inflammasome activation in immune cells. However, as activating the NLRP1 inflammasome in keratinocytes does not necessarily require a priming step, whether 1,25(OH) 2 VD 3 inhibits NLRP1 activation in unprimed keratinocytes is currently unknown. In this study, we showed that 1,25(OH) 2 VD 3 inhibits nigericin-induced NLRP1 inflammasome activation in unprimed keratinocytes. 1,25(OH) 2 VD 3 suppressed nigericin-induced interleukin-1β (IL-1β) secretion and caspase-1 activation in human primary keratinocytes. In addition, 1,25(OH) 2 VD 3 significantly inhibited the formation of apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) oligomers and specks, but not caspase-1 enzymatic activity, suggesting that 1,25(OH) 2 VD 3 prevents NLRP1-ASC complex assembly in keratinocytes. Vitamin D receptor (VDR)-knockdown abolished the inhibitory effects of 1,25(OH) 2 VD 3 on nigericin-induced ASC oligomerization and IL-1β secretion, suggesting that 1,25(OH) 2 VD 3 suppresses inflammasome activation via VDR signaling. Furthermore, nigericin induced K + efflux and cellular reactive oxygen species (ROS) production, and 1,25(OH) 2 VD 3 pretreatment suppressed nigericin-induced ROS production. 1,25(OH) 2 VD 3 increased the expression of both nuclear factor erythroid 2-related factor 2 (NRF2) and heme oxygenase-1 (HO-1), whereas HO-1 inhibition or NRF2 and HO-1 knockdown abrogated the inhibitory effects of 1,25(OH) 2 VD 3 on IL-1β secretion. Our results indicate that 1,25(OH) 2 VD 3 inhibits nigericin-induced activation step of NLRP1 inflammasome activation in unprimed keratinocytes. Our findings reveal the mechanism underlying the inhibitory effect of 1,25(OH) 2 VD 3 , which involves NRF2-HO-1 pathway activation through the VDR, providing further insight into the potential function of 1,25(OH) 2 VD 3 as a therapeutic agent for inflammasome-related skin diseases., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

We synthesized a metal-organic framework (MOF) using a ligand bearing haloalkoxy chains as a radical precursor. The radicals generated in the MOF upon photoirradiation were stable even at 250 K or under an O 2 atmosphere, despite radicals generated from the ligand decomposing at 200 K; thus, the regular arrangement of radicals effectively stabilized them. Moreover, a unique photoproduct was obtained only in the MOF, indicating that the confinement effect in the nanospace enabled a specific reaction that did not occur in the bulk state. We propose a new platform for exploring chemical reactions and materials based on reactive species.

Nicotinamide adenine dinucleotide (NAD + ) is a crucial coenzyme in energy production. The imbalance of NAD + synthesis has been found to trigger age-related diseases, such as metabolic disorders, cancer, and neurodegenerative diseases. Also, UV irradiation induces NAD + depletion in the skin. In mammals, nicotinamide phosphoribosyltransferase (NAMPT) is the rate-limiting enzyme in the NAD + salvage pathway and essential for NAD + homeostasis. However, but few studies have focused on the role of NAMPT in response to UV irradiation. Here, we show that NAMPT prevents NAD + depletion in epidermal keratinocytes to protect against the mild-dose UVA and UVB (UVA/B)-induced proliferation defects. We showed that poly(ADP-ribose) polymerase (PARP) inhibitor rescued the NAD + depletion in UVA/B-irradiated human keratinocytes, confirming that PAPR transiently exhausts cellular NAD + to repair DNA damage. Notably, the treatment with a NAMPT inhibitor exacerbated the UVA/B-induced loss of energy production and cell viability. Moreover, the NAMPT inhibitor abrogated the sirtuin-1 (SIRT1)-mediated deacetylation of p53 and significantly inhibited the proliferation of UVA/B-irradiated cells, suggesting that the NAMPT-NAD + -SIRT1 axis regulates p53 functions upon UVA/B stress. The supplementation with NAD + intermediates, nicotinamide mononucleotide and nicotinamide riboside, rescued the UVA/B-induced phenotypes in the absence of NAMPT activity. Therefore, NAD + homeostasis is likely essential for the protection of keratinocytes from UV stress in mild doses. Since the skin is continuously exposed to UVA/B irradiation, understanding the protective role of NAMPT in UV stress will help prevent and treat skin photoaging., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Triplet carbenes ( TC s) are of great interest due to their magnetic properties and reactivity, which descend from TC s' unique electronic state. However, the reactivity and stability of TC s are usually a trade-off, and it is difficult to achieve both at the same time. In this work, we were able to enhance the thermal stability of a TC species while maintaining its reactivity by confining them in the nanospace of a metal-organic framework (MOF). We synthesized a new MOF using a TC precursor; subsequently, TC s were generated by photostimulation. The TC s generated in the MOF nanospace were detectable up to 170 K, whereas their non-MOF-confined counterparts (bare ligand) could not be detected above 100 K. In addition, the reactivity of TC generated in MOF with O 2 was drastically improved compared to that of bare ligand. Our approach is generally applicable to the stabilization of highly reactive species, whose reactivity needs to be preserved.

Objective: We report the usefulness and pitfalls of coil embolization using the T or half T-stent technique for aneurysms located at internal carotid artery-posterior communicating artery (ICA-P-com) bifurcation in which the neck is wide and the P-com must be kept patent due to it being the fetal-type with a hypoplastic P1 segment., Case Presentations: Two cases were treated using the T-stent technique and two were treated using the half T-stent technique. The average age of the patients was 70.3 years and all were females. One aneurysm ruptured. The average size of aneurysms and neck was 12 mm and 8.5 mm, respectively, in the T-stent group, and 7.4 mm and 6.7 mm, respectively, in the half T-stent group. An S- or pigtail-shaped microcatheter (MC) was used to navigate into the P-com. Stent deployment was successful in all the cases. Retreatment was required in one case treated using the T-stent technique due to major recurrence., Conclusion: T or half T-stent-assisted coil embolization can be an alternative endovascular treatment method for wide-necked ICA-P-com aneurysms in which the P-com must be kept patent due to it being the fetal-type with a hypoplastic P1 segment., Competing Interests: The authors declare no conflicts of interest., (©2021 The Japanese Society for Neuroendovascular Therapy.)

Objective: We report the use of a Goose Neck microsnare for cervical internal carotid artery (ICA) occlusion in a patient with dolichoarteriopathy in whom it was difficult to achieve recanalization., Case Presentation: A 65-year-old woman underwent thrombectomy for a tandem lesion of left M1 occlusion and left cervical ICA occlusion. Recanalization of left M1 occlusion was achieved. For left cervical ICA occlusion, we attempted multiple thrombectomy using an existing device, but a hard clot with mobility was caught due to dolichoarteriopathy, which made thrombectomy difficult. Using a Goose Neck microsnare, we were able to capture the thrombus and achieve recanalization., Conclusion: Thrombectomy by capturing the thrombus using a Goose Neck microsnare may be useful for capturing hard clots with mobility when it is difficult to achieve recanalization with existing devices., Competing Interests: Hirotaka Okumura received rewards, such as lecture fees, from Medtronic Japan Co., Ltd. The other authors declare no conflicts of interest., (©2021 The Japanese Society for Neuroendovascular Therapy.)