Myricetin ameliorates the severity of pancreatitis in mice by regulating cathepsin B activity and inflammatory cytokine production.

Cathepsin B (CTSB) and inflammatory cytokines are critical in initiating and developing pancreatitis. Calcineurin, a central calcium (Ca)-responsive signaling molecule, mediates acinar cell death and inflammatory responses leading to pancreatitis. However, the detailed mechanisms for regulating CTSB activity and inflammatory cytokine production are unknown.

Role of ABCA2 and its single nucleotide polymorphisms (4873T>A and 4879G>C) in the regulation of multi-drug resistance in oral squamous carcinoma cells.

Lysosomal exocytosis is an essential cellular event for remodeling the extracellular matrix through secreting lysosomal enzymes and developing drug resistance. However, the detailed mechanism underlying the lysosomal exocytosis-driven acquisition of drug resistance is not completely understood. Genetic variations in gefitinib-sensitive (HSC3) and -resistant (HSC3/GR) oral squamous carcinoma cell lines were identified using whole-exome sequencing (WES).

Downregulation of Matriptase Inhibits Porphyromonas gingivalis Lipopolysaccharide-Induced Matrix Metalloproteinase-1 and Proinflammatory Cytokines by Suppressing the TLR4/NF-B Signaling Pathways in Human Gingival Fibroblasts.

Matriptases are cell surface proteolytic enzymes belonging to the type II transmembrane serine protease family that mediate inflammatory skin disorders and cancer progression. Matriptases may affect the development of periodontitis via protease-activated receptor-2 activity. However, the cellular mechanism by which matriptases are involved in periodontitis is unknown.

WJCPR11 reverses the TNF-α-induced inhibition of adipocyte differentiation and glucose uptake.

Berberine is a natural isoquinoline alkaloid present in various herbs and is effective against metabolic syndrome in the pre-diabetic stage and high insulin resistance. The present study aimed to determine the effectiveness of WJCPR11, a berberine derivative that is commonly used for diabetes treatment, in ameliorating insulin resistance and diabetes treatment. WJCPR11 promoted adipocyte differentiation to a higher extent than other berberine derivatives and showed no noticeable toxicity in its effective concentration range.

miR-4487 Enhances Gefitinib-Mediated Ubiquitination and Autophagic Degradation of EGFR in Non-Small Cell Lung Cancer Cells by Targeting USP37.

Purpose: With the identification of epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer (NSCLC) cells, EGFR-tyrosine kinase inhibitors (TKIs) are being used widely as the first-line of treatment in NSCLC. These inhibitors block auto-phosphorylation of activated EGFR by competing with ATP binding and mediate EGFR degradation independent of exogenous epidermal growth factor, which is associated with the mutation variants of EGFR. However, the precise mechanisms underlying the TKI-mediated EGFR degradation are still unclear.

Inhibitory Effect of Fructus Extracts on the Receptor Activator of NF-κB Ligand-Induced Osteoclastogenesis through Modulation of P38- and Ca-Mediated Nuclear Factor of Activated T-Cells Cytoplasmic 1 Expression.

Background: fructus (RMF), known to have anti-inflammatory and antioxidant properties, has been used as a traditional remedy for inflammatory diseases such as arthritis in Eastern Asia. However, its effect on osteoclasts, which play a crucial role in resorptive inflammatory bone diseases, is yet to be elucidated.

Methods: The effect of extract of RMF (RMF-E) on receptor activator of nuclear factor-κB ligand (RANKL)-mediated osteoclastogenesis was examined by tartrate-resistant acid phosphatase (TRAP) staining, real-time polymerase chain reaction and western blot analysis.

Exosomal release through TRPML1-mediated lysosomal exocytosis is required for adipogenesis.

The lysosomal Ca permeable channel TRPML1 (MCOLN1) plays key roles in lysosomal membrane trafficking, including the fusion of late endosomes to lysosomes and lysosomal exocytosis, both of which are essential for release of exosomes into the extracellular milieu. Multiple lines of evidence indicate that the contents of adipocyte-derived exosomes mediate diverse cellular responses, including adipogenic differentiation. In this study, we aimed to define the potential roles of TRPML1 in lysosomal membrane trafficking during adipogenesis and in exosomal release.

Hydrometallurgical recycling of surface-coated metals from automobile-discarded ABS plastic waste.

The ammoniacal leaching of surface-coated metals from automobile-discarded ABS plastics followed by their recovery through solvent extraction has been investigated. The leaching of ABS (typically containing 4.1% Cu, 1.

Acidification induces OGR1/Ca/calpain signaling in gingival fibroblasts.

Gingivitis, the mildest form of periodontitis, is generally considered a consequence of prolonged exposure of the gingiva to periodontal pathogens. On the other hand, several epidemiologic reports have suggested that other etiologic factors such as oral acidification may also increase the susceptibility of the periodontium to destruction. However, the pathologic mechanism underlying the effects of oral acidification on the gingiva is still largely unknown.

Thunb. ethanol extract suppresses RANKL-mediated osteoclastogenesis.

The constituents of Thunb. (PJ) exhibit biological and pharmacological activities, including anti-obesity, anti-oxidant and anti-allergic activities. The aim of the present study was to examine effects of PJ in RANKL-induced signaling pathways, which determine osteoclast differentiation.

The inhibitory effect of beta-lapachone on RANKL-induced osteoclastogenesis.

β-lapachone (β-L) is a substrate of reduced nicotinamide adenine dinucleotide (NADH): quinone oxidoreductase 1 (NQO1). NQO1 reduces quinones to hydroquinones using NADH as an electron donor and consequently increases the intracellular NAD+/NADH ratio. The activation of NQO1 by β-L has beneficial effects on several metabolic syndromes, such as obesity, hypertension, and renal injury.

Lysosomal Ca Signaling is Essential for Osteoclastogenesis and Bone Remodeling.

Lysosomal Ca emerges as a critical component of receptor-evoked Ca signaling and plays a crucial role in many lysosomal and physiological functions. Lysosomal Ca release is mediated by the transient receptor potential (TRP) family member TRPML1, mutations that cause the lysosomal storage disease mucolipidosis type 4. Lysosomes play a key role in osteoclast function.

The TRPCs, Orais and STIMs in ER/PM Junctions.

The Ca(2+) second messenger is initiated at ER/PM junctions and propagates into the cell interior to convey the receptor information. The signal is maintained by Ca(2+) influx across the plasma membrane through the Orai and TRPC channels. These Ca(2+) influx channels form complexes at ER/PM junctions with the ER Ca(2+) sensor STIM1, which activates the channels.

Fusion of lysosomes with secretory organelles leads to uncontrolled exocytosis in the lysosomal storage disease mucolipidosis type IV.

Mutations in TRPML1 cause the lysosomal storage disease mucolipidosis type IV (MLIV). The role of TRPML1 in cell function and how the mutations cause the disease are not well understood. Most studies focus on the role of TRPML1 in constitutive membrane trafficking to and from the lysosomes.

Harpagoside Inhibits RANKL-Induced Osteoclastogenesis via Syk-Btk-PLCγ2-Ca(2+) Signaling Pathway and Prevents Inflammation-Mediated Bone Loss.

Harpagoside (HAR) is a natural compound isolated from Harpagophytum procumbens (devil's claw) that is reported to have anti-inflammatory effects; however, these effects have not been investigated in the context of bone development. The current study describes for the first time that HAR inhibits receptor activator of nuclear factor κB ligand (RANKL)-induced osteoclastogenesis in vitro and suppresses inflammation-induced bone loss in a mouse model. HAR also inhibited the formation of osteoclasts from mouse bone marrow macrophages (BMMs) in a dose-dependent manner as well as the activity of mature osteoclasts, including filamentous actin (F-actin) ring formation and bone matrix breakdown.

The inhibitory effect of vitamin K on RANKL-induced osteoclast differentiation and bone resorption.

To further understand the correlation between vitamin K and bone metabolism, the effects of vitamins K1, menaquinone-4 (MK-4), and menaquinone-7 (MK-7) on RANKL-induced osteoclast differentiation and bone resorption were comparatively investigated. Vitamin K2 groups (MK-4 and MK-7) were found to significantly inhibit RANKL-medicated osteoclast cell formation of bone marrow macrophages (BMMs) in a dose-dependent manner, without any evidence of cytotoxicity. The mRNA expression of specific osteoclast differentiation markers, such as c-Fos, NFATc1, OSCAR, and TRAP, as well as NFATc1 protein expression and TRAP activity in RANKL-treated BMMs were inhibited by vitamin K2, although MK-4 exhibited a significantly greater efficiency compared to MK-7.

WHI-131 Promotes Osteoblast Differentiation and Prevents Osteoclast Formation and Resorption in Mice.

The small molecule WHI-131 is a potent therapeutic agent with anti-inflammatory, antiallergic, and antileukemic potential. However, the regulatory effects of WHI-131 on osteoblast and osteoclast activity are unclear. We examined the effects of WHI-131 on osteoblast and osteoclast differentiation with respect to bone remodeling.

Attenuated RANKL-induced cytotoxicity by Portulaca oleracea ethanol extract enhances RANKL-mediated osteoclastogenesis.

Background: Portulaca oleracea (PO) has been widely used as traditional medicine because of its pharmacological activities. However, the effects of PO on osteoclasts that modulate bone homeostasis are still elusive.

Methods: In this study, we examined the effects of PO ethanol extract (POEE) on receptor activator of nuclear factor-κB ligand (RANKL)-mediated Ca(2+) mobilization, nuclear factor of activated T-cell c1 (NFATc1) amplification, tartrate-resistant acid phosphatase-positive (TRAP+) multinucleated cell (MNC) formation, and cytotoxicity.

The TRPCs-STIM1-Orai interaction.

Ca(2+) signaling entails receptor-stimulated Ca(2+) release from the ER stores that serves as a signal to activate Ca(2+) influx channels present at the plasma membrane, the store-operated Ca(2+) channels (SOCs). The two known SOCs are the Orai and TRPC channels. The SOC-dependent Ca(2+) influx mediates and sustains virtually all Ca(2+)-dependent regulatory functions.

Anti-osteoclastogenic activity of praeruptorin A via inhibition of p38/Akt-c-Fos-NFATc1 signaling and PLCγ-independent Ca2+ oscillation.

Background: A decrease of bone mass is a major risk factor for fracture. Several natural products have traditionally been used as herbal medicines to prevent and/or treat bone disorders including osteoporosis. Praeruptorin A is isolated from the dry root extract of Peucedanum praeruptorum Dunn and has several biological activities, but its anti-osteoporotic activity has not been studied yet.

Oleanolic acid acetate inhibits osteoclast differentiation by downregulating PLCγ2-Ca(2+)-NFATc1 signaling, and suppresses bone loss in mice.

Owing to their potential pharmacological activities in human disease, natural plant-derived compounds have recently become the focus of increased research interest. In this study, we first isolated oleanolic acid acetate (OAA), a triterpenoid compound, from Vigna angularis (azuki bean) to discover anti-bone resorptive agents. Many studies have identified and described the various medicinal effects of V.

Activation of G Proteins by Aluminum Fluoride Enhances RANKL-Mediated Osteoclastogenesis.

Receptor activator of NF-κB ligand (RANKL)-induced osteoclastogenesis is accompanied by intracellular Ca(2+) mobilization in a form of oscillations, which plays essential roles by activating sequentially Ca(2+)/calmodulin-dependent protein kinase, calcineurin and NFATc1, necessary in the osteoclast differentiation. However, it is not known whether Ca(2+) mobilization which is evoked in RANKL-independent way induces to differentiate into osteoclasts. In present study, we investigated Ca(2+) mobilization induced by aluminum fluoride (AlF4 (-)), a G-protein activator, with or without RANKL and the effects of AlF4 (-) on the osteoclastogenesis in primary cultured mouse bone marrow-derived macrophages (BMMs).