👤 Mana Ito

Angiopoietin-like proteins (ANGPTLs) are key regulators of lipid metabolism; however, their response to lipid-lowering therapies remains incompletely understood. The PRESTIGE study compared the effects of pemafibrate add-on versus statin dose doubling on small dense low-density lipoprotein-cholesterol (sdLDL-C) in patients with type 2 diabetes and hypertriglyceridemia receiving statins. This post-hoc analysis investigated changes in circulating ANGPTL levels. Participants were randomized to receive either pemafibrate (0.2 mg/day; n = 48) or double-dose statin therapy (n = 49). Plasma ANGPTL levels and lipid parameters were assessed at baseline and after 12 weeks. ANGPTLs were quantified using specific human ELISA kits. sdLDL-C, LDL-triglycerides (TG), and HDL3-C were measured using the homogeneous assays. Pemafibrate treatment significantly increased circulating ANGPTL3 (+71%) and ANGPTL4 (+143%) levels, with no change in ANGPTL8, whereas statin dose doubling had no effect on ANGPTL levels. Pemafibrate markedly reduced TGs and sdLDL-C, while increasing large buoyant LDL-C, LDL-TG, HDL2,3-C, apolipoprotein AI, and apolipoprotein AII. The increase in ANGPTL3 was not correlated with changes in LDL subspecies but was positively associated with changes in HDL2,3-C. When participants were stratified by baseline ANGPTL3 levels, those in the low ANGPTL3 group showed an increase in LDL-C and LDL-TG in response to pemafibrate. The substantial elevation in ANGPTL4 induced by pemafibrate did not show associations with lipid changes. Pemafibrate markedly elevated circulating ANGPTL3 and ANGPTL4 levels, but these increases were not associated with pro-atherogenic changes in lipoprotein profiles. Notably, baseline ANGPTL3 concentrations may influence the effect of fibrates on LDL-C levels. Show less

Exercise training improves endothelial function and reduces vascular inflammation. However, whether aerobic exercise training-induced secretion of irisin, a myokine cleaved from fibronectin type III domain-containing protein 5 ( Show less

The dysregulated immune system, which drives chronic vascular inflammation and remodeling, plays a critical role in the pathogenesis of abdominal aortic aneurysm (AAA). CCR4 (C-C chemokine receptor 4), which is predominantly expressed on T cells and mediates their responses, has been shown to protect against inflammatory diseases including atherosclerosis. However, its role in AAA remains unknown. By analyzing hypercholesterolemic CCR4-deficient ( Genetic deletion of CCR4 on an CCR4 may serve as a potential therapeutic target for AAA. Show less

Current in vitro enzyme inhibition assays often involve subjective data analysis based on the researcher's experience. In this study, we developed a multi-dimensional quantitative integration platform (MDQIP) that uses a model to objectively calculate and rank compound activities, addressing the limitations of traditional "experience-driven" evaluations, accelerates the screening and evaluation of potential AChE inhibitors from Red Gastrodia elata, offering a more efficient approach to drug discovery. Ultrafiltration-LC screening identified parishin A as having the most stable binding, with binding degree and recovery rates of 98.85% and 99.39%, respectively. Molecular docking revealed that parishins A and C were the strongest AChE inhibitors, exhibiting stable binding through hydrogen bonds, π-alkyl, and π-π interactions. Molecular dynamics simulations confirmed the stability of these compounds, with binding energies of -82.65 ± 4.24 and - 80.69 ± 4.19 kcal/mol. Enzyme kinetics showed that parishins A and C are mixed-type inhibitors, with IC Show less

The β-secretase BACE1 (β-site amyloid precursor (APP) cleaving enzyme 1) is a major drug target for Alzheimer's disease (AD), as it catalyzes the first step in amyloid β (Aβ) generation, but has additional substrates and functions, in particular in the brain. Several advanced clinical trials with BACE1 inhibitors were stopped because of an adverse event, a mild cognitive worsening. The underlying mechanism is not yet known but may result from co-inhibition of the BACE1-homolog BACE2. While a cerebrospinal fluid (CSF) biomarker for measuring BACE2 activity is not yet established, VCAM-1 has been suggested as such a biomarker, but has not yet been tested upon prolonged dosing in vivo. Using CSF pharmacoproteomics and a subchronic dosing paradigm in non-human primates, we demonstrate that compound 89, a BACE inhibitor not yet tested in humans, and the clinically tested drug elenbecestat inhibit BACE1 in vivo, with little or no effect on BACE2, as seen with a reduction of substrates of BACE1, but not of the BACE2 substrate VCAM-1. As a control, verubecestat, which inhibits both BACE2 and BACE1, reduced CSF abundance of BACE1 substrates as well as of VCAM-1. This study demonstrates the suitability of VCAM-1 as a pharmacodynamic biomarker for measuring BACE2 target engagement in CSF. Show less

Crohn's disease (CD) is a chronic inflammatory bowel disease with unknown etiology. Inflammatory chemical mediators synthesized from arachidonic acid, an n-6 polyunsaturated fatty acid (PUFA), have been shown to activate CD. Additionally, n-3 PUFAs are metabolized by the same enzyme as n-6 PUFAs and known to inhibit the arachidonic acid cascade. Our previous study noted that the presence of erythrocyte membrane fatty acids is a characteristic finding in Japanese CD patients. It was thus speculated that To investigate the relationship of Using previously reported findings regarding The presence of the rs174538 mutation in The rs174538 mutation alters the fatty acid profile through strong linkage to the Show less

In the phase 3 CLEAR study, lenvatinib plus pembrolizumab showed improved efficacy versus sunitinib for patients with clear cell renal cell carcinoma (ccRCC). Previous preclinical studies demonstrated that lenvatinib attenuated tumor-associated macrophage (TAM) infiltration into tumor tissues by inhibiting fibroblast growth factor receptor (FGFR). However, the role of the FGFR pathway in ccRCC remains underexplored. This study aims to evaluate FGFR1-4 expression in ccRCC and investigate its relationship with the tumor microenvironment, particularly TAM. We primarily analyzed FGFR1-4 expression and CD163 positive cell count as estimation of TAM infiltration in 57 ccRCC specimens from patients undergoing nephrectomy using immunohistochemistry. Transcriptomic analysis was performed to assess immune-related gene signature and gene expressions. FGFR1 expression was elevated in over 80% of ccRCC samples and was significantly associated with increased CD163-positive TAM infiltration. FGFR1 expression was also negatively correlated with the IMmotion150 Teff gene signature and the expression of interferon-γ signaling targeted genes such as IFNG, GZMB, and CD274, suggesting an immunosuppressive phenotype. In contrast, FGFR2 and FGFR4 expression were less prevalent, and FGFR3 expression was not detected. This study provides the first comprehensive evaluation of FGFR1-4 expression in ccRCC and suggests that FGFR1 expression may contribute to the immunosuppressive tumor microenvironment by recruiting TAM. These findings indicate that FGFR1 could serve as a potential biomarker for therapeutic strategies and highlight the need for further research to explore FGFR-targeted therapies in ccRCC. Show less

Malignant phyllodes tumors (MPTs) are rare fibroepithelial breast tumors with no standard treatment for metastatic or recurrent cases. Comprehensive genomic profiling (CGP) has been conducted for MPT; however, its association with treatment remains unclear. A retrospective study was conducted on patients with advanced or recurrent MPTs treated with chemotherapy between 2013 and 2022 at two hospitals, analyzing clinical data, CGP, treatment outcomes, and survival. Five patients with metastatic MPTs who had received chemotherapy were identified. The median age was 55 years (range, 50-66), and all patients were female. As first-line treatment, four patients received doxorubicin plus ifosfamide (AI) combination therapy, while one received doxorubicin monotherapy. Among those treated with AI therapy, the best responses were partial response in three patients and stable disease in one. The median progression-free survival (PFS) for patients treated with AI therapy was 5.3 months. Of the five patients two proceeded to second-line therapy, and one patient received up to fourth-line treatment. Next-generation sequencing-based CGP testing was performed in four cases. One patient with an FGFR1-N546K-mutated MPT achieved a relatively long PFS of 6.8 months with pazopanib therapy, a multi-kinase inhibitor targeting FGFR1 among other kinases, as fourth-line therapy. AI therapy is useful for advanced or recurrent MPTs. The observed clinical benefit of pazopanib in a patient with FGFR1 N546K-mutated MPT suggests that FGFR1 kinase domain mutations may be a relevant factor in responsiveness of FGFR1-targeted therapy. Further data accumulation is warranted. Show less

Lymphoplasmacytic lymphoma (LPL) is a rare, indolent B-cell malignancy, with the IgG subtype being particularly uncommon. We present a case of IgG-type LPL complicated by kidney dysfunction due to light chain deposition disease (LCDD), representing the first documented instance of LCDD-related kidney impairment in this lymphoma subtype. A 65-year-old man presented with lower extremity edema and was found to have significant kidney dysfunction. Laboratory tests revealed elevated serum creatinine, heavy proteinuria, and a markedly skewed free light chain κ/λ ratio. Immunofixation electrophoresis identified an IgG-κ monoclonal protein and Bence Jones protein (κ light chain). Bone marrow biopsy confirmed LPL with a MYD88 L265P mutation, while kidney biopsy demonstrated mesangial proliferation, interstitial fibrosis, and granular κ light chain deposits consistent with LCDD. Given the rarity of IgG-type LPL with kidney involvement, this case underscores the importance of a thorough diagnostic workup in patients presenting with both hematologic malignancy and kidney dysfunction. Early recognition and appropriate management are critical for improving patient outcomes. As non-IgM LPL cases have historically been associated with poorer prognoses compared to Waldenström macroglobulinemia, the identification of underlying kidney complications such as LCDD is essential. Further accumulation of similar cases is needed to establish optimal treatment strategies. Show less

Metformin, a biguanide antihyperglycemic agent, prevents angiotensin II (AngII)-induced abdominal aortic aneurysm formation in apolipoprotein E-deficient (ApoE-/-) mice. Low-density lipoprotein receptor-deficient (LDLR-/-) mice, a commonly used hypercholesterolemic model, closely mimics the lipoprotein distribution in humans. In addition, LDLR-/- mice exhibit characteristics of glucose metabolism that are distinct from ApoE-/- mice. However, it remains unknown whether metformin suppresses AngII-induced aortic aneurysm formation in LDLR-/- mice. Male LDLR-/- mice at 9 weeks of age were administered either vehicle or metformin in drinking water and fed a Western diet. Subsequently, AngII was infused into mice for 4 weeks. Mass spectrometry analysis determined plasma metformin concentrations in mice administered the drug. Metformin administration resulted in lower body weight compared to the vehicle group, indicating effective metformin administration. However, ex vivo measurements demonstrated that metformin failed to prevent AngII-induced ascending aortic dilatations, and did not reduce aortic diameters in the suprarenal abdominal region. In conclusion, metformin did not attenuate AngII-induced aortic aneurysm formation in either the ascending or suprarenal abdominal region of LDLR-/- mice. The online version contains supplementary material available at 10.1038/s41598-025-33367-y. Show less

The scaffold protein IQGAP3 is highly upregulated in most epithelial cancers. While recent studies have highlighted its pivotal roles in cancer cell proliferation and metastasis, a deeper mechanistic understanding of IQGAP3 is currently lacking. We have here used TurboID to map IQGAP3 proximity partners and identified the Wnt signaling members Axin1 and CK1α as IQGAP3-interacting proteins. Our functional studies demonstrated that overexpression of IQGAP3 increases β-catenin levels, while IQGAP3 depletion reduces β-catenin levels in gastric cancer cells. Mechanistically, IQGAP3 disrupts Axin1-CK1α interaction, thereby inhibiting β-catenin phosphorylation and ultimately leading to its accumulation. Importantly, we discovered that IQGAP3 itself is regulated by Wnt signaling, suggesting its involvement in a positive feedback loop in Wnt/β-catenin signaling through interactions with Axin1 and CK1α. These findings identify IQGAP3 as a novel mediator of β-catenin stabilization and underscore its potential as a target for cancer therapy. Show less

Acetylcholinesterase (AChE) inhibitors are crucial for the symptomatic management of Alzheimer's disease (AD), with natural products-particularly botanical sources like Yellow Gastrodia elata (YGE)-serving as promising reservoirs of such inhibitors. Nevertheless, comprehensive screening and mechanistic characterization of their inhibitory potential remain limited. This study sought to identify potent AChE inhibitors from YGE, investigate their mechanisms of action, and assess their therapeutic prospects for AD. Methodologically, an integrated approach was employed, combining ultrafiltration-liquid chromatography (UF-LC) for rapid inhibitor screening, molecular docking and dynamics simulations for mechanistic insight, two-stage high-speed countercurrent chromatography for compound isolation, enzyme kinetics to delineate inhibition modalities, and network pharmacology to uncover relevant AD-related targets. The findings identified seven active constituents with notable AChE inhibition, among which parishins A and G were obtained at high purity (98.26% and 97.26%, respectively) and exhibited mixed-type inhibition with low IC Show less

Muscle-invasive bladder cancer (MIBC) is an aggressive malignancy with high recurrence and poor survival, accounting for the majority of bladder cancer-related deaths. A subset of MIBC harbors FGFR1 amplification or overexpression, associated with increased proliferation and poor prognosis. Although the pan-FGFR inhibitor erdafitinib has demonstrated clinical benefit in patients with FGFR3/FGFR2 alterations, primarily in non-MIBC, its efficacy is limited by resistance and toxicity. Moreover, its effectiveness in FGFR1-driven MIBC remains unclear. To address this gap, we investigated erdafitinib response and resistance mechanisms in JMSU1 cells, a model of FGFR1-amplified MIBC. While erdafitinib initially suppressed tumor growth, prolonged treatment led to resistance, characterized by persistent activation of ERK, AKT, and STAT1 signaling pathways. Mechanistic studies identified MET activation, driven by MET gene amplification, as a key driver of resistance. Notably, exogenous hepatocyte growth factor (HGF) not only induced resistance but also accelerated the emergence of MET-amplified, HGF-independent subpopulations under drug pressure. We also identified SHP2 as a critical mediator of FGFR1-driven ERK activation in parental cells. In resistant cells, MET activation enhanced SHP2-ERK signaling through the adaptor protein GAB1, reinforcing the resistant phenotype. Combined inhibition of FGFR1 and MET significantly suppressed tumor growth in resistant cells. These findings establish MET amplification and GAB1-SHP2 signaling as central mediators of erdafitinib resistance in FGFR1-amplified MIBC and support dual FGFR1/MET targeting as a promising therapeutic strategy. Show less

Cardiac fibrosis drives dysfunction in dilated cardiomyopathy (DCM); yet, effective therapies are limited. This study identifies FGFR1 as a critical target in cardiac fibrosis using transcriptomic and histological analyses of 58 human DCM biopsies. FGFR1 expression correlated with fibrosis severity, and inhibition by AZD4547 reduced fibrosis and improved cardiac function in organoid and murine models. These findings validate FGFR1 inhibition as a promising therapeutic strategy for mitigating fibrosis and improving outcomes in heart failure associated with DCM. Show less

Histologic transformation from adenocarcinoma to SCLC is a recognized mechanism of resistance in lung cancer. However, the transformation into squamous cell carcinoma is less common, and the associated genomic alterations remain unclear. Here, we present a case of lung adenocarcinoma harboring an EGFR ( Show less

Myeloid/lymphoid neoplasm with FGFR1 rearrangement (MLNF) is one of the rare hematologic malignancies with variable clinical presentations, including a chronic phase resembling myeloproliferative neoplasms and an acute phase presenting as myeloid/lymphoid leukemia or lymphoma, often associated with eosinophilia. The prognosis of MLNF has been poor, and allogeneic hematopoietic stem cell transplantation (HSCT) remains the only curative approach, although selective FGFR1 inhibitors, such as pemigatinib, have recently emerged as therapeutic options. Nevertheless, the efficacy of pemigatinib in aggressive or blast-phase MLNF remains unclear. Herein, we report a case of a 67-year-old woman initially diagnosed with Richter's syndrome. The patient achieved a complete response with six cycles of rituximab-based chemoimmunotherapy followed by acalabrutinib maintenance. Two years later, the patient developed leukocytosis, eosinophilia, and recurrent lymphadenopathy. Bone marrow examination revealed disease recurrence with marked eosinophilia, and FGFR1 rearrangement was confirmed by fluorescence in situ hybridization. The rearrangement was also confirmed from the lymph node specimen of the initial diagnosis; thus, we revised the diagnosis to relapsed MLNF. The patient received pemigatinib, but rapid disease progression was observed. The patient was ineligible for HSCT and salvage chemotherapies were unsuccessful, resulting in death four months later. The present case report highlights a rare lymphoma-like clinical presentation of MLNF, and we discuss the therapeutic options, including pemigatinib. Show less

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by selective motor neuron cell death. A GGGGCC hexanucleotide repeat expansion (HRE) within the chromosome 9 open reading frame 72 (C9orf72) gene is a major causative factor in ALS. This abnormal HRE triggers five types of dipeptide repeat protein (DPR), each composed of two alternating amino acid expressions. Among the DPRs, arginine-rich Poly-PR localizes predominantly to the nucleus, exerting particularly strong toxicity on motor and cortical neurons. Several mechanisms have been proposed for poly-PR-induced neurotoxicity. In this study, poly-PR-expressing NSC34 motor neuron-like cells showed an increase in oxidative stress. Fibroblast growth factor receptor 1 (FGFR1) is known to promote neurogenesis and inhibit apoptosis in neurons. However, its neuroprotective effects against DPR-induced toxicity have not been previously reported. Here, we demonstrated that FGFR1 activation reduced oxidative stress by upregulating nuclear factor erythroid 2-related factor 2 (NRF2) expression. Furthermore, we propose that the increase in NRF2 through FGFR1 activation may result from the alleviation of protein translation impairment. Overall, these findings suggest that FGFR1 activation provides neuroprotection against poly-PR toxicity and may represent a potential therapeutic strategy for ALS. Show less

A GGGGCC hexanucleotide repeat expansion (HRE) within the C9orf72 gene is a major causative factor in amyotrophic lateral sclerosis (ALS). This aberrant HRE results in the generation of five distinct dipeptide repeat proteins (DPRs). Among the DPRs, poly-PR accumulates in the nucleus and exhibits particularly strong toxicity to motor and cortical neurons. Fibroblast growth factor receptor 1 (FGFR1) is known to promote neurogenesis and inhibit apoptosis in neurons. Nevertheless, there has been no previous report of its neuroprotective effects against poly-PR toxicity. The objective of this study was to investigate the neuroprotective effects of FGFR1 activation in poly-PR-expressing NSC34 motor neuron-like cells. RT-qPCR analysis in NSC34 cells showed that Fgfr1 was the most highly expressed member of the Fgfr family in NSC34 cells. The activation of FGFR1 by FGF2, a common ligand for all FGFRs, exerted neuroprotective effects against the toxicity of poly-PR. Additionally, FGFR1 activation was observed to enhance cell viability through the PI3K-AKT pathway, while the contribution of the MEK-ERK pathway was found to be limited. Furthermore, FGFR1 activation suppressed the accumulation of p53 protein and promoted its degradation through increased murine double minute 2 (MDM2), an E3 ubiquitin ligase that targets p53. The neuroprotective effects were attenuated by PD173074, a selective FGFR1 inhibitor or Nutlin-3a, an inhibitor of the p53-MDM2 interaction. Overall, these findings suggest that FGFR1 activation provides neuroprotection against poly-PR toxicity. Consequently, this study suggests the potential utility of FGFR1 activation as a therapeutic strategy for ALS. Show less

Post-ischemic inflammation is an essential step in the progression of brain ischemia-reperfusion injury. Cytokines such as interleukins 17 and 23 (IL-17, IL-23) have been involved in stroke. IL-27 is a member of the IL-12 family that consists of IL-27p28 and Epstein-Barr virus-induced gene 3 (EBI3), having anti-inflammatory properties and regulating T cell polarization and cytokine production. However, whether IL-27 plays an important role in the acute stage of brain ischemia remains unclear. In the acute stage, IL-27 was upregulated after intracerebral ischemia in wild-type mice while mice lacking IL-27 showed decreased infarction area and suppressed inflammatory cytokines. These findings suggest that IL-27 may be involved in cerebral ischemia and could be a potential therapeutic target for mitigating inflammation and avoiding increasing the initial damage in cerebral ischemia. Show less

Lysophosphatidic acid (LPA) is a bioactive phospholipid that mediates a variety of biological actions through binding to G protein-coupled receptors known as LPA receptors (LPARs). In mammals, six LPAR subtypes (LPAR1-6) have been identified. This study aimed to determine the expression of LPAR4 in the developing mouse brain. Brains samples were prepared from mice in various stages of development and biochemical and immunohistochemical analyses were conducted using anti-LPAR4. Western blot analysis detected two LPAR4-immunoreactive species at ∼50 kDa and ∼42 kDa from embryonic day 16.5 (E16.5). The ∼50 kDa molecule increased during development, reaching a peak at postnatal day 3 (P3), and then gradually decreased through P22. In contrast, the ∼42 kDa molecule continued to increase up to P22. Immunohistochemical analyses demonstrated strong LPAR4 expression in neural cells in the intermediate zone and cortical plate of the E15.5 cerebral cortex, whereas neural progenitors in the ventricular and subventricular zones exhibited weaker expression. At P15, fiber-like staining resembling the apical dendrites of cortical neurons and hippocampal pyramidal cells was also observed. This study demonstrated dynamic, spatiotemporal changes of LPAR4 expression in the brain from embryonic to postnatal stages. These findings support a potential role for LPAR4 in neural development. Show less

The global distribution of lipoprotein(a) [Lp(a)] levels varies due to racial and ethnic differences. However, the clinical relevance of Lp(a) levels in Japanese patients has not been fully explored. We investigated the association of Lp(a) levels, the Suita score, and the presence of high-risk plaque (HRP) as well as that of ≥ 50% stenosis, quantitative plaque volume, and the value of coronary artery calcium score in coronary computed tomographic angiography (CCTA), among 272 Japanese patients (mean age: 65 years) in whom serum Lp(a) levels were measured due to suspected coronary artery disease. HRP was defined as positive remodeling and/or low attenuation. Plaque volume was quantified as the percent plaque volume. HRP was identified in 33 (12.1%) patients. The prevalence of HRP, ≥ 50% stenosis, and percent plaque volume progressively increased with higher Lp (a) levels and Suita scores. In multivariate analyses, Lp(a) and the Suita score independently predicted HRP when assessed as continuous (p = 0.02, p＜0.001, respectively) or categorical variables (p = 0.005, p = 0.007, respectively). Patients in the highest tertile of Lp(a) and classified as high- or intermediate-risk by the Suita score had the highest HRP risk, whereas those in the lower 2 tertiles and low-risk group had the lowest. Incorporating Lp(a) into the Suita score improved the prediction of HRP beyond the Suita score alone (p = 0.005). The combinatorial value of assessing Lp(a) levels and Suita score may provide useful insight regarding Japanese patients undergoing CCTA for the prediction of HRP. Show less

Non-Waldenström macroglobulinemia (non-WM) lymphoplasmacytic lymphoma (LPL) is a rare subtype with limited clinical evidence and no confirmed treatment guidelines. Bruton tyrosine kinase (BTK) inhibitors represent one of the mainstay therapies in WM, but their role in non-WM LPL remains unclear. We report a case of IgG-type non-WM LPL successfully treated with a second-generation BTK inhibitor, tirabrutinib. The patient demonstrated a rapid decline in M-protein and improvement in anemia, with a durable partial response. This case adds to the limited literature supporting BTK inhibitor use in non-WM LPL and highlights the need for further studies to define optimal treatment strategies. Show less

Lymphomatoid granulomatosis (LYG) is a rare Epstein-Barr virus-driven B-cell lymphoproliferative disease that often progresses to high-grade lymphoma. We describe a case of high-grade LYG causing Pancoast syndrome, diagnosed via transbronchial biopsy after a failed incisional biopsy. Complete remission was achieved with R-CHOP (rituximab, doxorubicin, cyclophosphamide, vincristine, and prednisolone), but 2.5 years later, the patient developed lymphoplasmacytic lymphoma/Waldenström's macroglobulinemia (LPL/WM). Despite bendamustine-rituximab improving LPL/WM, LYG recurred, underscoring its treatment challenges. This case highlights LYG's diagnostic complexity, its potential link with other hematologic malignancies, and therapeutic limitations. Further research is needed to elucidate LYG's pathogenesis and develop effective treatments for relapsed cases. Show less

Congenital myasthenic syndromes (CMS) are a heterogeneous group of disorders characterized by compromised neuromuscular signal transmission due to pathogenic germline variants in genes expressed at the neuromuscular junction (NMJ). A total of 40 genes have been reported in CMS (AGRN, ALG14, ALG2, CHAT, CHD8, CHRNA1, CHRNB1, CHRND, CHRNE, CHRNG, COL13A1, COLQ, DES, DOK7, DPAGT1, GFPT1, GMPPB, LAMA5, LAMB2, LRP4, MACF1, MUSK, MYO9A, PLEC, PREPL, PTPN11, PURA, RAPSN, RPH3A, SCN4A, SLC18A3, SLC25A1, SLC5A7, SNAP25, SYT2, TEFM, TOR1AIP1, UNC13A, UNC50 and VAMP1). The 40 genes are putatively classified into 13 subtypes by pathomechanical, clinical, and therapeutic features. A unique feature shared by recently identified genes is that CMS is concomitantly recognized in other mostly severer diseases. For example, four recently identified genes exhibit the following phenotypes: PURA-CMS, developmental delay; TEFM-CMS, mitochondrial disease; PTPN11-CMS, Noonan syndrome/Leopard syndrome; and DES-CMS, desmin myopathy. Conversely, these diseases are not always associated with CMS, although genetic and/or environmental factors that determine the involvement of the NMJ remain to be identified. In this review, particular emphasis will be placed on five recently identified genes (MACF1, TEFM, PTPN11, DES and UNC50). Show less

Type 1 diabetes mellitus is a major risk factor for both sarcopenia and osteoporosis, primarily due to the body's inability to utilize glucose as a result of insulin deficiency. Impairments in insulin and glucose signaling can accelerate the decline in muscle and bone health. To investigate this interaction, we examined whether insulin deficiency exacerbates muscle and bone deterioration in Show less

Follicular thyroid carcinoma (FTC) is a common thyroid malignancy that poses diagnostic challenges because of its cytological similarity to benign follicular thyroid adenoma (FTA). The present study aimed to identify characteristic protein signatures in serum-derived extracellular vesicles (EVs) of FTC and FTA for potential diagnostic and therapeutic applications. Serum EVs from patients with FTC and FTA were purified using the phosphatidylserine affinity method. Proteomics analysis via nano liquid chromatography-tandem mass spectrometry identified 18 significantly differentially expressed proteins between the two patient groups. RAB21, a small GTPase involved in cellular trafficking, was markedly elevated in serum EVs from patients with FTC. Furthermore, cell invasion and migration assays of a human FTC cell line revealed that RAB21 knockdown reduced cell migratory ability, suggesting its role in the malignant phenotype of FTC. The present findings indicated that RAB21 in serum EVs may be a candidate biomarker able to distinguish FTC from FTA, and that RAB21 could be a potential therapeutic target for FTC. Show less

Alternative RNA splicing adds diverse variations to gene function, and its abnormalities are occasionally associated with the etiology of disease. We examined this possibility in pre-eclampsia. We performed transcriptome analysis of placentas from pre-eclamptic and normotensive pregnancies and screened for disease-specific aberrant splicing. We identified aberrant splicing at exon 14 in the ZC3H4 gene. This in-frame exon is generally skipped in placentas from normal pregnancies but often observed in those from pre-eclampsia patients. The level of exon inclusion did not correlate with disease severity, such as blood pressure or fetal weight, but showed an association with the decrease in placental weight. Significantly, placental blood flow resistance measured by Doppler ultrasound correlated with the level of ZC3H4 exon 14 inclusion, suggesting that this retention leads to the onset and/or symptoms of pre-eclampsia. ZC3H4 is known to act on transcriptional regulation via suppression of lncRNA expression. Moreover, the SOD1 gene, encoding superoxide dismutase that eliminates toxic free superoxide radicals, was identified in the downstream gene group for ZC3H4. Indeed, the expression of SOD1 was found in this current study to be decreased in the pre-eclamptic placenta in correlation with the levels of ZC3H4 exon 14 retention. Aberrant splicing of ZC3H4 gene may induce excessive oxidative stress in the placenta via the downregulation of downstream SOD1 expression thereby leading to the onset and development of pre-eclampsia. Show less

The aim of this study was to investigate the effects of aspirin eugenol ester (AEE) on liver oxidative damage and energy metabolism in immune-stressed broilers. In total, 312 broilers were divided into 4 groups (saline, LPS, SAEE, and LAEE). Broilers in the saline and LPS groups were fed a basal diet; the SAEE and LAEE groups had an added 0.01% AEE in their diet. Broilers in the LPS and LAEE groups were injected with lipopolysaccharides, while the saline and SAEE groups were injected with saline. Results showed that AEE increased the body weight, average daily gain, and average daily feed intake, as well as decreasing the feed conversion ratio of immune-stressed broilers. AEE protects against oxidative damage in immune-stressed broiler livers by elevating the total antioxidant capacity, superoxide dismutase activity, and glutathione S-transferase alpha 3 ( Show less

The β-secretase β-site APP cleaving enzyme (BACE1) is a central drug target for Alzheimer's disease. Clinically tested, BACE1-directed inhibitors also block the homologous protease BACE2. Yet little is known about physiological BACE2 substrates and functions in vivo. Here, we identify BACE2 as the protease shedding the lymphangiogenic vascular endothelial growth factor receptor 3 (VEGFR3). Inactivation of BACE2, but not BACE1, inhibited shedding of VEGFR3 from primary human lymphatic endothelial cells (LECs) and reduced release of the shed, soluble VEGFR3 (sVEGFR3) ectodomain into the blood of mice, nonhuman primates, and humans. Functionally, BACE2 inactivation increased full-length VEGFR3 and enhanced VEGFR3 signaling in LECs and also in vivo in zebrafish, where enhanced migration of LECs was observed. Thus, this study identifies BACE2 as a modulator of lymphangiogenic VEGFR3 signaling and demonstrates the utility of sVEGFR3 as a pharmacodynamic plasma marker for BACE2 activity in vivo, a prerequisite for developing BACE1-selective inhibitors for safer prevention of Alzheimer's disease. Show less

Signal transduction at the neuromuscular junction (NMJ) is compromised in a diverse array of diseases including congenital myasthenic syndromes (CMS). Germline mutations in CHRNE encoding the acetylcholine receptor (AChR) ε subunit are the most common cause of CMS. An active form of vitamin D, calcitriol, binds to vitamin D receptor (VDR) and regulates gene expressions. We found that calcitriol enhanced MuSK phosphorylation, AChR clustering, and myotube twitching in co-cultured C2C12 myotubes and NSC34 motor neurons. RNA-seq analysis of co-cultured cells showed that calcitriol increased the expressions of Rspo2, Rapsn, and Dusp6. ChIP-seq of VDR revealed that VDR binds to a region approximately 15 ​kbp upstream to Rspo2. Biallelic deletion of the VDR-binding site of Rspo2 by CRISPR/Cas9 in C2C12 myoblasts/myotubes nullified the calcitriol-mediated induction of Rspo2 expression and MuSK phosphorylation. We generated Chrne knockout (Chrne KO) mouse by CRISPR/Cas9. Intraperitoneal administration of calcitriol markedly increased the number of AChR clusters, as well as the area, the intensity, and the number of synaptophysin-positive synaptic vesicles, in Chrne KO mice. In addition, calcitriol ameliorated motor deficits and prolonged survival of Chrne KO mice. In the skeletal muscle, calcitriol increased the gene expressions of Rspo2, Rapsn, and Dusp6. We propose that calcitriol is a potential therapeutic agent for CMS and other diseases with defective neuromuscular signal transmission. Show less