Distinct roles of centriole distal appendage proteins in ciliary assembly and disassembly.

The primary cilium is a cellular organelle whose assembly and disassembly are closely linked to the cell cycle. The centriole distal appendage (DA) is essential for the early stages of ciliogenesis by anchoring the mother centriole to the cell surface. Despite the identification of over twelve proteins constituting the DA, including CEP83, CEP89, CEP164, FBF1, and SCLT1, their specific functions in ciliary dynamics are not fully understood.

TMEM132A regulates Wnt/β-catenin signaling through stabilizing LRP6 during mouse embryonic development.

The Wnt/β-catenin signaling pathway is crucial for embryonic development and adult tissue homeostasis. Dysregulation of Wnt signaling is linked to various developmental anomalies and diseases, notably cancer. Although numerous regulators of the Wnt signaling pathway have been identified, their precise function during mouse embryo development remains unclear.

A novel indole derivative, 2-{3-[1-(benzylsulfonyl)piperidin-4-yl]-2-methyl-1H-indol-1-yl}-1-(pyrrolidin-1-yl)ethenone, suppresses hedgehog signaling and drug-resistant tumor growth.

The Hedgehog (Hh) signaling pathway plays important roles in various physiological functions. Several malignancies, such as basal cell carcinoma (BCC) and medulloblastoma (MB), have been linked to the aberrant activation of Hh signaling. Although therapeutic drugs have been developed to inhibit Hh pathway-dependent cancer growth, drug resistance remains a major obstacle in cancer treatment.

Fabrication of liraglutide-encapsulated triple layer hyaluronic acid microneedles (TLMs) for the treatment of obesity.

Obesity is a chronic metabolic disease that is prevalent worldwide, causing complications that affect the quality of life and longevity of humans. Currently, the low bioavailability upon subcutaneous injection of an appetite suppressant, liraglutide, and health problems in the locally injected region remain to be overcome. In this study, we developed a novel hyaluronic acid-based liraglutide-encapsulated triple-layer microneedle (TLM) as a painless and patient-friendly long-term drug delivery system.

Egg Microneedle for Transdermal Delivery of Active Liraglutide.

Liraglutide, a human glucagon-like peptide-1 (GLP-1) analog, is promising for safely treating type 2 diabetes mellitus (T2DM), compared to insulin, by significantly reducing the risk of glucose-dependent hypoglycemia. Concerns related to injection prevent T2DM patients from taking liraglutide regularly, even though once-a-day subcutaneous (SC) injections. Dissolving microneedles (DMNs) are promising substitutes for SC injection and for improving patient convenience.

Tissue-specific requirement of sodium channel and clathrin linker 1 (Sclt1) for ciliogenesis during limb development.

Primary cilia have essential roles as signaling centers during development and adult homeostasis. Disruption of ciliary structure or function causes congenital human disorders called ciliopathies. Centriolar distal appendage (DAP) proteins are important for anchoring cilia to the membrane.

KLC3 Regulates Ciliary Trafficking and Cyst Progression in CILK1 Deficiency-Related Polycystic Kidney Disease.

Background: Ciliogenesis-associated kinase 1 () is a ciliary gene that localizes in primary cilia and regulates ciliary transport. Mutations in cause various ciliopathies. However, the pathogenesis of CILK1-deficient kidney disease is unknown.

Dysregulation of sonic hedgehog signaling causes hearing loss in ciliopathy mouse models.

Defective primary cilia cause a range of diseases known as ciliopathies, including hearing loss. The etiology of hearing loss in ciliopathies, however, remains unclear. We analyzed cochleae from three ciliopathy mouse models exhibiting different ciliogenesis defects: (), (a.

Autophagy induction promotes renal cyst growth in polycystic kidney disease.

Background: Polycystic kidney disease (PKD) involves renal cysts arising from proliferating tubular cells. Autophagy has been recently suggested as a potential therapeutic target in PKD, and mammalian target of rapamycin (mTOR) is a key negative regulator of autophagy. However, the effect of autophagy regulation on cystogenesis has not been elucidated in PKD mice.

Combination of PD-L1 and PVR determines sensitivity to PD-1 blockade.

Expression of immune checkpoint ligands (ICLs) is necessary to trigger the inhibitory signal via immune checkpoint receptors (ICRs) in exhausted T cells under tumor immune microenvironment. Nevertheless,to our knowledge, ICL expression profile in cancer patients has not been investigated. Using previously reported RNA-seq data sets, we found that expression of ICLs was patient specific but their coexpression can be patterned in non-small-cell lung cancers (NSCLCs).

Cell cycle-related kinase is a crucial regulator for ciliogenesis and Hedgehog signaling in embryonic mouse lung development.

Cell cycle-related kinase (CCRK) has a conserved role in ciliogenesis, and Ccrk defects in mice lead to developmental defects, including exencephaly, preaxial polydactyly, skeletal abnormalities, retinal degeneration, and polycystic kidney. Here, we found that Ccrk is highly expressed in mouse trachea and bronchioles. Ccrk mutants exhibited pulmonary hypoplasia and abnormal branching morphogenesis in respiratory organ development.

Activation of sonic hedgehog signaling by a Smoothened agonist restores congenital defects in mouse models of endocrine-cerebro-osteodysplasia syndrome.

Background: Endocrine-cerebro-osteodysplasia (ECO) syndrome is a genetic disorder associated with congenital defects of the endocrine, cerebral, and skeletal systems in humans. ECO syndrome is caused by mutations of the intestinal cell kinase (ICK) gene, which encodes a mitogen-activated protein (MAP) kinase-related kinase that plays a critical role in controlling the length of primary cilia. Lack of ICK function disrupts transduction of sonic hedgehog (SHH) signaling, which is important for development and homeostasis in humans and mice.

Fibroblast growth factor receptor influences primary cilium length through an interaction with intestinal cell kinase.

Vertebrate primary cilium is a Hedgehog signaling center but the extent of its involvement in other signaling systems is less well understood. This report delineates a mechanism by which fibroblast growth factor (FGF) controls primary cilia. Employing proteomic approaches to characterize proteins associated with the FGF-receptor, FGFR3, we identified the serine/threonine kinase intestinal cell kinase (ICK) as an FGFR interactor.

Multilayer fabrication of unobtrusive poly(dimethylsiloxane) nanobrush for tunable cell adhesion.

Precise modulation of polymer brush in its thickness and grafting density can cause unexpected cell behaviors and regulated bioactivities. Herein, a nanoscale poly(dimethylsiloxane) (PDMS) brush was employed to use as a controllable material for cell adhesion. Facile fabrication of ultrathin monolayer PDMS nanobrush on an underlying substrate facilitated regaining cell adhesion through long-range cell attractive forces such as the van der Waals forces.

Repeated restraint stress promotes hippocampal neuronal cell ciliogenesis and proliferation in mice.

Stress severely disturbs physiological and mental homeostasis which includes adult neurogenesis in hippocampus. Neurogenesis in hippocampus is a key feature to adapt to environmental changes and highly regulated by multiple cellular signaling pathways. The primary cilium is a cellular organelle, which acts as a signaling center during development and neurogenesis in adult mice.

Sauchinone controls hepatic cholesterol homeostasis by the negative regulation of PCSK9 transcriptional network.

Whole-transcriptome analysis and western blotting of sauchinone-treated HepG2 cells demonstrated that sauchinone regulated genes relevant to cholesterol metabolism and synthesis. In particular, it was found that the expression of proprotein convertase subtilisin/kexin type 9 (PCSK9) was downregulated, and the expression of low density lipoprotein receptor (LDLR) was upregulated in sauchinone-treated HepG2 cells. Consequently, LDL-cholesterol (LDL-C) uptake was increased.

PEGylated hyaluronic acid-coated liposome for enhanced in vivo efficacy of sorafenib via active tumor cell targeting and prolonged systemic exposure.

This study aimed to design an effective formulation for enhancing the tumor-targeted delivery of sorafenib. Three sorafenib-loaded liposomal formulations including uncoated liposome (SF-Lip), hyaluronic acid-coated liposome (HA-SF-Lip), and PEGylated hyaluronic acid-coated liposome (PEG-HA-SF-Lip) were developed with narrow size distribution and high encapsulation efficiency. The cellular uptake and cytotoxicity of HA-SF-Lip and PEG-HA-SF-Lip were greater than those of SF-Lip in MDA-MB-231 cells overexpressing CD44, whereas there were no significant differences in MCF-7 cells with low CD44 expression, indicating the CD44-mediated cellular uptake of coated liposomes.

Cell Cycle-Related Kinase (CCRK) regulates ciliogenesis and Hedgehog signaling in mice.

The Hedgehog (Hh) signaling pathway plays a key role in cell fate specification, proliferation, and survival during mammalian development. Cells require a small organelle, the primary cilium, to respond properly to Hh signals and the key regulators of Hh signal transduction exhibit dynamic localization to this organelle when the pathway is activated. Here, we investigate the role of Cell Cycle Related kinase (CCRK) in regulation of cilium-dependent Hh signaling in the mouse.

Mangosteen Extract Prevents Dextran Sulfate Sodium-Induced Colitis in Mice by Suppressing NF-κB Activation and Inflammation.

In this study, the anti-inflammatory effects of mangosteen extract (MGE) on dextran sulfate sodium (DSS)-induced colitis in mice and nuclear factor (NF)-κB pathway modulation were investigated. Acute colitis was induced by administering 3% DSS in drinking water for 7 days, and three groups of Institute of Cancer Research mice were treated with 30 and 120 mg/kg MGE or 5-aminosalicylic acid for 7 days; an additional two groups of mice served as healthy and disease controls. The results indicated that MGE significantly prevented weight loss, reduced disease activity index scores, and preserved colon length compared with the findings in the untreated colitis group.

α-Mangostin ameliorates dextran sulfate sodium-induced colitis through inhibition of NF-κB and MAPK pathways.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease (IBD) of the colon as a target site. Previous reports regarding the efficacy of α-mangostin (αMG) to inhibit nuclear factor-kappa B (NF-κB) and mitogen-activated protein kinases (MAPKs) as well as relatively high distribution to the colon suggested the therapeutic potential of this compound in UC model. In dextran sodium sulfate (DSS)-induced colitis mice (DSS mice), the disease activity index scores involving diarrhea, bloody stool, body weight reduction, and myeloperoxidase (MPO) activities of the esophagus and colon increased with the reduced colon length.

Vaccinia-related kinase 3 (VRK3) sets the circadian period and amplitude by affecting the subcellular localization of clock proteins in mammalian cells.

In the eukaryotic circadian clock machinery, negative feedback repression of CLOCK (CLK) and BMAL1 transcriptional activity by PERIOD (PER) and CRYPTOCHROME (CRY) underlies the basis for 24 h rhythmic gene expression. Thus, precise regulation of the time-dependent nuclear entry of circadian repressors is crucial to generating normal circadian rhythms. Here, we sought to identify novel kinase(s) that regulate nuclear entry of mammalian CRY1 (mCRY1) with an unbiased screening using red fluorescent protein (RFP)-tagged human kinome expression plasmids in mammalian cells.

Injury-stimulated Sonic hedgehog expression in microglia contributes to neuroinflammatory response in the MPTP model of Parkinson's disease.

Parkinson's disease (PD) is a progressive neurodegenerative disorder in which dopamine (DA) neurons in the substantia nigra pars compacta (SNpc) region are selectively destroyed. Sonic hedgehog (Shh) has been well known to play a key role in a variety of processes such as embryogenesis, cell proliferation and protection, and tissue repair during inflammation. However, the evidences for the innate role of Shh in adult brain injury are presently lacking and studies have been needed to unveil the importance of Shh in the process of neurodegeneration.

Design, synthesis, and biological evaluation of structurally modified isoindolinone and quinazolinone derivatives as hedgehog pathway inhibitors.

The Hedgehog (Hh) signaling pathway is associated with diverse aspects of cellular events, such as cell migration, proliferation, and differentiation throughout embryonic development and tissue patterning. An abnormal Hh signaling pathway is linked to numerous human cancers, including basal cell carcinoma (BCC), medulloblastoma (MB), lung cancer, prostate cancer, and ovarian cancer, and it is therefore a promising target in cancer therapy. Using a structure-hopping approach, we designed new Hh signaling pathway inhibitors with isoindolinone or quinazolinone moieties, which were synthesized and biologically evaluated using an 8xGli-luciferase (Gli-Luc) reporter assay in NIH3T3 cells.

Ciliary smoothened-mediated noncanonical hedgehog signaling promotes tubulin acetylation.

Hedgehog (Hh) signaling plays key roles in animal development and tissue homeostasis. Binding of the secreted ligand to its Ptch1 receptor triggers Hh signaling through distinct canonical or noncanonical signaling pathways. Canonical Hh signaling leads to the activation of Gli transcription factors to induce Hh target-gene expression.