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During the development of the mouse dentate gyrus (DG), granule neuronal progenitors (GNPs) arise from glial fibrillary acidic protein (GFAP)-expressing neural stem cells in the dentate notch. However, the transcriptional regulators that control their stepwise differentiation remain poorly defined. Since neurogenesis involves epithelial-to-mesenchymal transition (EMT)-like processes, we investigated the spatio-temporal expression profiles of the EMT transcription factors Zeb1, Scratch2 (Scrt2) and Nkx6-2 in relation to known GNP markers. Our results show that Zeb1 and Scrt2 exhibit sequential, but partially overlapping expression across embryonic and postnatal stages of GNP differentiation. Zeb1 is highly enriched in gfap -GFP+/Sox2+ neural stem/progenitor pools and subsets of Tbr2+/Prox1+/NeuroD+ intermediate GNPs, whereas Scrt2 predominates in Tbr2+/Prox1+/NeuroD+ GNPs. Strikingly, the neuronal EMT regulator Nkx6-2 shows selective expression in postnatal Tbr2+/Prox1+ GNPs, but it is excluded from embryonic counterparts. This temporally coordinated yet distinct expression of Zeb1, Scrt2 and Nkx6-2 reveals discrete transcriptional programs orchestrating GNP differentiation and neurogenic progression at embryonic versus postnatal stages of DG neurogenesis.

Astrocytes are key components of the neurovascular unit. While we have recently identified Olig2+ astrocyte progenitors (ASPs) in the developing mouse dentate gyrus (DG), their molecular signature remains incompletely characterized. Here we demonstrate that Olig2+ ASPs predominantly express brain lipid-binding protein (BLBP), while only a small population of them expresses gfap -GFP. These Olig2+/BLBP+ ASPs co-express the transcription factors Sox3, Sox9 and the proteoglycan NG2 but not Sox10, a marker for oligodendrocyte progenitors (OLPs). Olig2+ ASPs appear from embryonic day 18 (E18) onwards and decline at postnatal day 14 (P14). Consistent with the proliferation of both Olig2+ and NG2+ glial cells after brain injury, intrauterine intermittent hypoxia (IH) led to an increase in Olig2+/NG2+/BLBP+ ASPs in the postnatal DG. IH also promoted both angiogenesis and vascular coupling of Olig2+/NG2+ ASPs. Our data suggest that IH-induced expression of HIF1a increases Olig2+/NG2+/BLBP+ ASPs in a cell non-autonomous manner. Our data also revealed increased vascular coupling of GFAP+ astrocytes following IH, while the number of GFAP+ astrocytes remains unchanged. Given that BLBP, Olig2 and NG2 are expressed in reactive astrocytes, our findings suggest that Olig2+/NG2+/BLBP+ ASPs represent a subtype of reactive astrocyte progenitors. Furthermore, the enhanced vascular coupling of Olig2+/NG2+/BLBP+ ASPs appears to be an adaptive response to hypoxic brain injury. This study provides new insights into the molecular characteristics of Olig2+/NG2+/BLBP+ ASPs and their potential role in the brain’s response to hypoxic injury, contributing to our understanding of neurovascular unit dynamics in both development and pathological conditions.

Selenoprotein P is released from the liver and acts through LRP1 in the muscle to contribute to exercise resistance in mouse and man by inhibiting ROS levels via inhibition of AMPK and PGC-1α. Exercise has numerous health-promoting effects in humans 1 ; however, individual responsiveness to exercise with regard to endurance or metabolic health differs markedly 2 , 3 , 4 . This 'exercise resistance' is considered to be congenital, with no evident acquired causative factors. Here we show that the anti-oxidative hepatokine selenoprotein P (SeP) 5 , 6 , 7 causes exercise resistance through its muscle receptor low-density lipoprotein receptor–related protein 1 (LRP1) 8 . SeP-deficient mice showed a 'super-endurance' phenotype after exercise training, as well as enhanced reactive oxygen species (ROS) production, AMP-activated protein kinase (AMPK) phosphorylation 9 and peroxisome proliferative activated receptor γ coactivator (Ppargc)-1α (also known as PGC-1α; encoded by Ppargc1a ) 10 expression in skeletal muscle. Supplementation with the anti-oxidant N -acetylcysteine (NAC) reduced ROS production and the endurance capacity in SeP-deficient mice. SeP treatment impaired hydrogen-peroxide-induced adaptations through LRP1 in cultured myotubes and suppressed exercise-induced AMPK phosphorylation and Ppargc1a gene expression in mouse skeletal muscle—effects which were blunted in mice with a muscle-specific LRP1 deficiency. Furthermore, we found that increased amounts of circulating SeP predicted the ineffectiveness of training on endurance capacity in humans. Our study suggests that inhibitors of the SeP–LRP1 axis may function as exercise-enhancing drugs to treat diseases associated with a sedentary lifestyle.

Human hepatocytes are essential materials in pharmaceutical researches. Not only primary human hepatocytes (PHH) but also human iPS cell-derived hepatocyte-like cells (human iPS-HLCs) are expected to be applied as materials for pharmaceutical researches. To date, several culture media have been developed for culturing human hepatocytes. However, there have been no reports comparing these media to determine which is most suitable for culturing human hepatocytes. In this study, we compared five commercial media (Hepatocyte Culture Medium (HCM), HepatoZYME-SFM, Cellartis Power Primary HEP Medium, DMEM/F12, and William's E Medium (WEM)) to determine which is most suitable for culturing PHH and human iPS-HLCs. In hepatic differentiation of human iPS cells (day 14-25 of differentiation), albumin (ALB) and urea secretion abilities and CYP2C9, CYP2C19, and CYP3A4 activities were the highest when using HCM or WEM. During maintenance of human iPS-HLCs, ALB and urea producing abilities and CYP2C9, CYP2C19, and CYP3A4 activities were the highest when using HCM. Importantly, we found that human iPS-HLCs cultured in HCM were maintained for 3 weeks or more without impairment of their hepatic functions. These results suggest that it is necessary to select an optimal medium for hepatic differentiation and maintenance of human iPS-HLCs. In the case of PHH culture, there was little difference in hepatic functions among the five media. However, the CYP2C9, CYP2C19, and CYP3A4 activities were the highest when using HCM and WEM. In conclusion, it is important to select the optimal medium for specific application when carrying out pharmaceutical researches using human hepatocytes.

Retinoic acid-inducible gene (RIG)-I is an essential innate immune sensor that recognises pathogen RNAs and induces interferon (IFN) production. However, little is known about how host proteins regulate RIG-I activation. Here, we show that leukocyte cell-derived chemotaxin 2 (LECT2), a hepatokine and ligand of the MET receptor tyrosine kinase is an antiviral regulator that promotes the RIG-I-mediated innate immune response. Upon binding to MET, LECT2 induces the recruitment of the phosphatase PTP4A1 to MET and facilitates the dissociation and dephosphorylation of phosphorylated SHP2 from MET, thereby protecting RIG-I from SHP2/c-Cbl-mediated degradation. In vivo, LECT2 overexpression enhances RIG-I-dependent IFN production and inhibits lymphocytic choriomeningitis virus (LCMV) replication in the liver, whereas these changes are reversed in LECT2 knockout mice. Forced suppression of MET abolishes IFN production and antiviral activity in vitro and in vivo. Interestingly, hepatocyte growth factor (HGF), an original MET ligand, inhibits LECT2-mediated anti-viral signalling; conversely, LECT2-MET signalling competes with HGF-MET signalling. Our findings reveal previously unrecognized crosstalk between MET-mediated proliferation and innate immunity and suggest that targeting LECT2 may have therapeutic value in infectious diseases and cancer. The innate antiviral immune response is an important defense against infection. Here, the authors show that leukocyte cell-derived chemotaxin 2 (LECT2) promotes RIG-I-mediated innate immune responses by preventing its degradation, and inhibits lymphocytic choriomeningitis virus replication in the liver.

PurposeMidline abdominal incisions (MAIs) are widely used in both open and minimally invasive surgery. Incisional hernia (IH) accounts for most long-term postoperative wound complications. This study explored the risk factors for IH due to MAI in patients with clean-contaminated wounds after elective gastroenterological surgery.MethodsThe present study targeted patients enrolled in 2 randomized controlled trials to evaluate the efficacy of intraoperative interventions for incisional SSI prevention after gastroenterological surgery for clean-contaminated wounds. The patients were reassessed, and pre- and intraoperative variables and postoperative outcomes were collected. IH was defined as any abdominal wall gap, regardless of bulge, in the area of a postoperative scar that was perceptible or palpable on clinical examination or computed tomography according to the European Hernia Society guidelines. The risk factors for IH were identified using univariate and multivariate analyses.ResultsThe study population included 1,281 patients, of whom 273 (21.3%) developed IH. Seventy-four (5.8%) patients developed incisional SSI. Multivariate logistic regression analysis revealed that female sex (odds ratio [OR], 1.39; 95% confidence interval [CI] 1.03–1.86, p = 0.031), high preoperative body mass index (OR, 1.81; 95% CI 1.19–2.77, p = 0.006), incisional SSI (OR, 2.29; 95% CI 1.34–3.93, p = 0.003), and postoperative body weight increase (OR, 1.49; 95% CI 1.09–2.04, p = 0.012) were independent risk factors for IH due to MAI in patients who underwent elective gastroenterological surgery.ConclusionWe identified postoperative body weight increase at one year as a novel risk factor for IH in patients with MAI after elective gastroenterological surgery.

Background: Olfactory dysfunction is a common symptom in patients with coronavirus disease 2019, and it significantly deteriorates patients’ quality of life. Effective treatments remain unknown. Purpose: To assess the effect of Japanese traditional (Kampo) medicine on coronavirus disease 2019-related olfactory dysfunction. Study Design: Retrospective observational study. Methods: In total, 87 patients aged ≥18 years with coronavirus disease 2019 and severe dysosmia or anosmia (Numeric Rating Scale, ≥7) at isolation facilities in Miyagi Prefecture, Japan, were enrolled from October 2020 to March 2021. Patients were divided into the Kampo group ( N = 52) and the control group ( N = 35) based on the treatment received. Changes in Numeric Rating Scale scores were evaluated at the first visit and 2 weeks after. Results: The median reduction in the olfactory dysfunction score at both 1 and 2 weeks after the first visit was significantly greater in the Kampo group (6 and 8, respectively; p = 0.03) than in the control group (3 and 7, respectively; p = 0.04). We defined improvement in olfactory dysfunction as a median reduction in the olfactory dysfunction score of ≥5. Multiple logistic regression analysis demonstrated that only Kampo treatment was significantly associated with improvement in olfactory dysfunction. Conclusion: This study suggests that Kampo medication promotes early recovery from coronavirus disease 2019-related olfactory dysfunction.

Rhinovirus (RV) is a primary etiologic agent of common cold that can subsequently acutely exacerbate bronchial asthma or chronic obstructive pulmonary disease. Kakkonto (Ge-gen-tang in Chinese), one of the most frequently prescribed traditional Japanese (Kampo) medicines, is used for treating common cold, shoulder stiffness, or inflammatory diseases of the upper body. Previous experimental studies have indicated that kakkonto exerts antiviral and anti-inflammatory effects on the influenza virus and the human respiratory syncytial virus. However, there is a lack of reports investigating the efficacy of kakkonto in RV infection. Hence, the aim of the current study was to investigate the effects of kakkonto on RV infection of human nasal epithelial (HNE) cells. HNE cells obtained via endoscopic sinus surgery were cultured and infected with RV14, with or without kakkonto treatment. The supernatants from the cells were collected, and the RV14 titer and cytokine levels were assessed. Reverse transcription-polymerase chain reaction was performed to determine the amount of viral RNA, while the level of nuclear factor kappa B (NF-κB) subunits in the nucleus was assessed by enzyme-linked immunosorbent assay. Although kakkonto treatment did not reduce RV14 titer or RNA levels, indicating that it did not inhibit RV14 proliferation, it was found to reduce the production of specific pro-inflammatory cytokines, including interleukin (IL)-8, tumor necrosis factor (TNF)-α, and monocyte chemotactic protein-1 (MCP-1). Unlike that observed with the kakkonto extract, none of the crude drugs contained in kakkonto reduced IL-8 level. Furthermore, though kakkonto treatment significantly reduced p50 levels, it did not impact the p65 subunit of NF-κB. These results indicated that kakkonto can inhibit inflammation caused by RV infection and may exert an immunomodulatory effect on HNE cells. This is the first report to elucidate the effects of kakkonto extract on RV infection in primary cultures of HNE cells, providing evidence that kakkonto may act as an effective therapy for RV infection and subsequent airway inflammation.

Background The recent guidelines from the European and American Hernia Societies recommend a continuous small-bite suturing technique with slowly absorbable sutures for fascial closure of midline abdominal wall incisions to reduce the incidence of wound complications, especially for incisional hernia. However, this is based on low-certainty evidence. We could not find any recommendations for skin closure. The wound closure technique is an important determinant of the risk of wound complications, and a comprehensive approach to prevent wound complications should be developed. Methods We propose a single-institute, prospective, randomized, blinded-endpoint trial to assess the superiority of the combination of continuous suturing of the fascia without peritoneal closure and continuous suturing of the subcuticular tissue (study group) over that of interrupted suturing of the fascia together with the peritoneum and interrupted suturing of the subcuticular tissue (control group) for reducing the incidence of midline abdominal wall incision wound complications after elective gastroenterological surgery with a clean-contaminated wound. Permuted-block randomization with an allocation ratio of 1:1 and blocking will be used. We hypothesize that the study group will show a 50% reduction in the incidence of wound complications. The target number of cases is set at 284. The primary outcome is the incidence of wound complications, including incisional surgical site infection, hemorrhage, seroma, wound dehiscence within 30 days after surgery, and incisional hernia at approximately 1 year after surgery. Discussion This trial will provide initial evidence on the ideal combination of fascial and skin closure for midline abdominal wall incision to reduce the incidence of overall postoperative wound complications after gastroenterological surgery with a clean-contaminated wound. This trial is expected to generate high-quality evidence that supports the current guidelines for the closure of abdominal wall incisions from the European and American Hernia Societies and to contribute to their next updates. Trial registration UMIN-CTR UMIN000048442. Registered on 1 August 2022. https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000055205

The traditional Japanese (Kampo) medicine, kakkonto with shosaikotokakikyosekko, has antiviral and anti-inflammatory effects. In this randomized trial, patients with mild and moderate coronavirus disease (COVID-19) were randomly allocated to the control group receiving conventional treatment for symptom relief such as antipyretics and antitussives or the Kampo group receiving mixed extract granules of kakkonto (2.5 g) and shosaikotokakikyosekko (2.5 g) three times a day for 14 days in addition to conventional treatment. The main outcome was the number of days until total symptom relief. The secondary outcome was the number of days until each symptom’s relief and whether the disease progressed to respiratory failure. We enrolled a total of 161 patients (Kampo group, n = 81; control group, n = 80). The results from Kaplan–Meier estimates of symptom relief showed that there are no significant differences between the groups. However, covariate-adjusted cumulative incidence of fever relief considering competitive risk showed that the recovery was significantly faster in the Kampo group than in the control group (HR 1.76, 95% CI 1.03–3.01). Additionally, the risk of disease progression to moderate COVID-19 requiring oxygen inhalation was lower in the Kampo group than in the control group (Risk Difference −0.13, 95% CI −0.27–0.01). No significant drug-related side effects were observed. Kakkonto with shosaikotokakikyosekko is effective for fever relief with suppression of disease progression in COVID-19 patients. Clinical Trial Registration: https://jrct.niph.go.jp/en-latest-detail/jRCTs021200020 , identifier [jRCTs021200020]