Tribuli Fructus alleviates 1-methyl-4-phenyl 1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson's disease by suppressing neuroinflammation via JNK signaling.

Parkinson's disease (PD) is a neurodegenerative disease characterized by the loss of dopaminergic neurons. In particular, neuroinflammation associated with phosphorylation of c-Jun N-terminal kinase (JNK) is likely to cause the death of dopaminergic neurons. Therefore, protecting dopaminergic neurons through anti-neuroinflammation is a promising therapeutic strategy for PD.

Nasopharyngeal lymphatic plexus is a hub for cerebrospinal fluid drainage.

Cerebrospinal fluid (CSF) in the subarachnoid space around the brain has long been known to drain through the lymphatics to cervical lymph nodes, but the connections and regulation have been challenging to identify. Here, using fluorescent CSF tracers in Prox1-GFP lymphatic reporter mice, we found that the nasopharyngeal lymphatic plexus is a major hub for CSF outflow to deep cervical lymph nodes. This plexus had unusual valves and short lymphangions but no smooth-muscle coverage, whereas downstream deep cervical lymphatics had typical semilunar valves, long lymphangions and smooth muscle coverage that transported CSF to the deep cervical lymph nodes.

Immaturity of immune cells around the dural venous sinuses contributes to viral meningoencephalitis in neonates.

High neonatal susceptibility to meningitis has been attributed to the anatomical barriers that act to protect the central nervous system (CNS) from infection being immature and not fully developed. However, the mechanisms by which pathogens breach CNS barriers are poorly understood. Using the Armstrong strain of lymphocytic choriomeningitis virus (LCMV) to study virus propagation into the CNS during systemic infection, we demonstrate that mortality in neonatal, but not adult, mice is high after infection.

Endothelial cell-derived stem cell factor promotes lipid accumulation through c-Kit-mediated increase of lipogenic enzymes in brown adipocytes.

Active thermogenesis in the brown adipose tissue (BAT) facilitating the utilization of lipids and glucose is critical for maintaining body temperature and reducing metabolic diseases, whereas inactive BAT accumulates lipids in brown adipocytes (BAs), leading to BAT whitening. Although cellular crosstalk between endothelial cells (ECs) and adipocytes is essential for the transport and utilization of fatty acid in BAs, the angiocrine roles of ECs mediating this crosstalk remain poorly understood. Using single-nucleus RNA sequencing and knock-out male mice, we demonstrate that stem cell factor (SCF) derived from ECs upregulates gene expressions and protein levels of the enzymes for de novo lipogenesis, and promotes lipid accumulation by activating c-Kit in BAs.

Three-dimensional morphologic and molecular atlases of nasal vasculature.

Understanding the function of the nasal vasculature in homeostasis and pathogenesis of common nasal diseases is important. Here we describe an extensive network of venous sinusoids (VSs) in mouse and human nasal mucosa. The endothelium of the VSs expressed Prox1 (considered to be a constitutive marker of lymphatic endothelium) and high levels of VCAM-1 and exhibited unusual cell-to-cell junctions.

Fasudil alleviates the vascular endothelial dysfunction and several phenotypes of Fabry disease.

Fabry disease (FD), a lysosomal storage disorder, is caused by defective α-galactosidase (GLA) activity, which results in the accumulation of globotriaosylceramide (Gb3) in endothelial cells and leads to life-threatening complications such as left ventricular hypertrophy (LVH), renal failure, and stroke. Enzyme replacement therapy (ERT) results in Gb3 clearance; however, because of a short half-life in the body and the high immunogenicity of FD patients, ERT has a limited therapeutic effect, particularly in patients with late-onset disease or progressive complications. Because vascular endothelial cells (VECs) derived from FD-induced pluripotent stem cells display increased thrombospondin-1 (TSP1) expression and enhanced SMAD2 signaling, we screened for chemical compounds that could downregulate TSP1 and SMAD2 signaling.

Hyperactivation of YAP/TAZ Drives Alterations in Mesangial Cells through Stabilization of N-Myc in Diabetic Nephropathy.

Significance Statement: Mesangial cells (MCs) in the kidney are essential to maintaining glomerular integrity, and their impairment leads to major glomerular diseases including diabetic nephropathy (DN). Although high blood glucose elicits abnormal alterations in MCs, the underlying mechanism is poorly understood. We show that YAP/TAZ are increased in MCs of patients with DN and two animal models of DN.

Simultaneous quantification method for eleutheroside B, eleutheroside E, chiisanoside, and sesamin using reverse-phase high-performance liquid chromatography coupled with ultraviolet detection and integrated pulsed amperometric detection.

We developed a method combining ultraviolet (UV) detection and integrated pulsed amperometric detection (IPAD) to simultaneously analyze eleutheroside B, eleutheroside E, chiisanoside, and sesamin. The gradient elution system allowed complete separation of all target components within 35 min, and showed limits of detection of 0.006-0.

Development of Certified Reference Material for Amino Acids in Dried Blood Spots and Accuracy Assessment of Disc Sampling.

To achieve the measurement reliability of amino acids used as diagnostic markers in clinical fields, establishing a reference measurement system is required, in which certified reference materials (CRMs) are an essential step in the hierarchy of measurement traceability. This study describes the development of dried blood spot (DBS) CRMs for amino acid analysis with complete measurement traceability to the International System of Units (SI). Six essential amino acids─proline, valine, isoleucine, leucine, phenylalanine, and tyrosine─were analyzed using isotope-dilution liquid chromatography-mass spectrometry (ID-MS).

DA-9805, a Herbal Mixture, Restores Motor Manifestations in 6-Hydroxydopamine-induced Parkinson's Disease Mouse Model by Regulating Striatal Dopamine and Acetylcholine Levels.

Loss of dopamine (DA) is one of the primary features of Parkinson's disease (PD); however, imbalances of non-dopaminergic neurotransmitters significantly contribute to the disabilities noted in advanced PD patients. DA-9805 is the ethanolic extraction of the root bark of × Andrews (), the root of (Hoffm.) Benth.

Pericyte Loss Leads to Capillary Stalling Through Increased Leukocyte-Endothelial Cell Interaction in the Brain.

The neurovascular unit is a functional unit composed of neurons, glial cells, pericytes, and endothelial cells which sustain brain activity. While pericyte is a key component of the neurovascular unit, its role in cerebral blood flow regulation remains elusive. Recently, capillary stalling, which means the transient interruption of microcirculation in capillaries, has been shown to have an outsized impact on microcirculatory changes in several neurological diseases.

Structural insights into the clustering and activation of Tie2 receptor mediated by Tie2 agonistic antibody.

Angiopoietin (Angpt)-Tie receptor 2 (Tie2) plays key roles in vascular development and homeostasis as well as pathological vascular remodeling. Therefore, Tie2-agonistic antibody and engineered Angpt1 variants have been developed as potential therapeutics for ischemic and inflammatory vascular diseases. However, their underlying mechanisms for Tie2 clustering and activation remain elusive and the poor manufacturability and stability of Angpt1 variants limit their clinical application.

Nasal ciliated cells are primary targets for SARS-CoV-2 replication in the early stage of COVID-19.

The upper respiratory tract is compromised in the early period of COVID-19, but SARS-CoV-2 tropism at the cellular level is not fully defined. Unlike recent single-cell RNA-Seq analyses indicating uniformly low mRNA expression of SARS-CoV-2 entry-related host molecules in all nasal epithelial cells, we show that the protein levels are relatively high and that their localizations are restricted to the apical side of multiciliated epithelial cells. In addition, we provide evidence in patients with COVID-19 that SARS-CoV-2 is massively detected and replicated within the multiciliated cells.

Three-Dimensional Human Alveolar Stem Cell Culture Models Reveal Infection Response to SARS-CoV-2.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is the cause of a present pandemic, infects human lung alveolar type 2 (hAT2) cells. Characterizing pathogenesis is crucial for developing vaccines and therapeutics. However, the lack of models mirroring the cellular physiology and pathology of hAT2 cells limits the study.

Distinct fibroblast subsets regulate lacteal integrity through YAP/TAZ-induced VEGF-C in intestinal villi.

Emerging evidence suggests that intestinal stromal cells (IntSCs) play essential roles in maintaining intestinal homeostasis. However, the extent of heterogeneity within the villi stromal compartment and how IntSCs regulate the structure and function of specialized intestinal lymphatic capillary called lacteal remain elusive. Here we show that selective hyperactivation or depletion of YAP/TAZ in PDGFRβ IntSCs leads to lacteal sprouting or regression with junctional disintegration and impaired dietary fat uptake.

Simultaneous quantification of six nonpolar ginsenosides in white ginseng by reverse-phase high-performance liquid chromatography coupled with integrated pulsed amperometric detection.

Background: White ginseng consists of the roots and rhizomes of the species, and red ginseng is made by steaming and drying white ginseng. While red ginseng has both polar and nonpolar ginsenosides, previous studies showed white ginseng to have only polar ginsenosides. Because nonpolar ginsenosides are formed through the manufacture of red ginseng from white ginseng, researchers have generally thought that nonpolar ginsenosides do not exist in white ginseng.

YAP/TAZ direct commitment and maturation of lymph node fibroblastic reticular cells.

Fibroblastic reticular cells (FRCs) are immunologically specialized myofibroblasts of lymphoid organ, and FRC maturation is essential for structural and functional properties of lymph nodes (LNs). Here we show that YAP and TAZ (YAP/TAZ), the final effectors of Hippo signaling, regulate FRC commitment and maturation. Selective depletion of YAP/TAZ in FRCs impairs FRC growth and differentiation and compromises the structural organization of LNs, whereas hyperactivation of YAP/TAZ enhances myofibroblastic characteristics of FRCs and aggravates LN fibrosis.

Protective effects of DA-9805 on dopaminergic neurons against 6-hydroxydopamine-induced neurotoxicity in the models of Parkinson's disease.

With the elderly population rapidly growing, the prevalence of Parkinson's disease (PD) is quickly increasing because neurodegenerative disorders are usually late-onset. Herbal medicines and formula are adjuvant therapies of conventional PD agents, which result in serious side effects with long-term use. This study evaluated the neuroprotective effects of DA-9805, a standardized herbal formula that consists of an ethanolic extract of Moutan Cortex Radix, Angelica Dahuricae Radix, and Bupleuri Radix against 6-hydroxydopamine (6-OHDA)-induced cytotoxicity in vitro and in vivo.

Certification and stability assessment of recombinant human growth hormone as a certified reference material for protein quantification.

A certified reference material (CRM) for the quantification of protein, essential to manage quality control and quality assurance in protein-related works, has been developed. Amino acid analysis with conventional acid hydrolysis and isotope dilution HPLC-MS was used to establish an SI-traceable absolute protein quantification method using recombinant human growth hormone (hGH) as a model protein. The certification method was verified by comparative studies between 1) different methods of protein quantification based on microwave-assisted hydrolysis, and 2) different labs as part of the Asian Collaboration on Reference Material project with Japan, China, and Korea.

Meningeal lymphatic vessels at the skull base drain cerebrospinal fluid.

Recent work has shown that meningeal lymphatic vessels (mLVs), mainly in the dorsal part of the skull, are involved in the clearance of cerebrospinal fluid (CSF), but the precise route of CSF drainage is still unknown. Here we reveal the importance of mLVs in the basal part of the skull for this process by visualizing their distinct anatomical location and characterizing their specialized morphological features, which facilitate the uptake and drainage of CSF. Unlike dorsal mLVs, basal mLVs have lymphatic valves and capillaries located adjacent to the subarachnoid space in mice.

A MST1-FOXO1 cascade establishes endothelial tip cell polarity and facilitates sprouting angiogenesis.

Hypoxia is a main driver of sprouting angiogenesis, but how tip endothelial cells are directed to hypoxic regions remains poorly understood. Here, we show that an endothelial MST1-FOXO1 cascade is essential for directional migration of tip cells towards hypoxic regions. In mice, endothelial-specific deletion of either MST1 or FOXO1 leads to the loss of tip cell polarity and subsequent impairment of sprouting angiogenesis.

Gut microbiota regulates lacteal integrity by inducing VEGF-C in intestinal villus macrophages.

A lacteal is a blunt-ended, long, tube-like lymphatic vessel located in the center of each intestinal villus that provides a unique route for drainage of absorbed lipids from the small intestine. However, key regulators for maintaining lacteal integrity are poorly understood. Here, we explore whether and how the gut microbiota regulates lacteal integrity.

Regenerative potential of mouse embryonic stem cell-derived PDGFRα cardiac lineage committed cells in infarcted myocardium.

Background: Pluripotent stem cell-derived cardiomyocytes (CMs) have become one of the most attractive cellular resources for cell-based therapy to rescue damaged cardiac tissue.

Aim: We investigated the regenerative potential of mouse embryonic stem cell (ESC)-derived platelet-derived growth factor receptor-α (DGFRα) cardiac lineage-committed cells (CLCs), which have a proliferative capacity but are in a morphologically and functionally immature state compared with differentiated CMs.

Methods: We induced mouse ESCs into PDGFRα CLCs and αMHC CMs using a combination of the small molecule cyclosporin A, the rho-associated coiled-coil kinase inhibitor Y27632, the antioxidant Trolox, and the ALK5 inhibitor EW7197.

Triple herbal extract DA-9805 exerts a neuroprotective effect via amelioration of mitochondrial damage in experimental models of Parkinson's disease.

Moutan cortex, Angelica Dahurica root, and Bupleurum root are traditional herbal medicines used in Asian countries to treat various diseases caused by oxidative stress or inflammation. Parkinson's disease (PD) has been associated with mitochondrial dysfunction, but no effective treatment for mitochondrial dysfunction has yet been identified. In this study we investigated the neuroprotective effects of the triple herbal extract DA-9805 in experimental models of PD.