Multiplicative Effects of Essential Oils and Other Active Components on Skin Tissue and Skin Cancers.

Naturally derived essential oils and their active components are known to possess various properties, ranging from anti-oxidant, anti-inflammatory, anti-bacterial, anti-fungal, and anti-cancer activities. Numerous types of essential oils and active components have been discovered, and their permissive roles have been addressed in various fields. In this comprehensive review, we focused on the roles of essential oils and active components in skin diseases and cancers as discovered over the past three decades. In particular, we opted to highlight the effectiveness of essential oils and their active components in developing strategies against various skin diseases and skin cancers and to describe the effects of the identified essential-oil-derived major components from physiological and pathological perspectives. Overall, this review provides a basis for the development of novel therapies for skin diseases and cancers, especially melanoma.

Chloride/Multiple Anion Exchanger SLC26A Family: Systemic Roles of SLC26A4 in Various Organs.

Solute carrier family 26 member 4 (SLC26A4) is a member of the SLC26A transporter family and is expressed in various tissues, including the airway epithelium, kidney, thyroid, and tumors. It transports various ions, including bicarbonate, chloride, iodine, and oxalate. As a multiple-ion transporter, SLC26A4 is involved in the maintenance of hearing function, renal function, blood pressure, and hormone and pH regulation. In this review, we have summarized the various functions of SLC26A4 in multiple tissues and organs. Moreover, the relationships between SLC26A4 and other channels, such as cystic fibrosis transmembrane conductance regulator, epithelial sodium channel, and sodium chloride cotransporter, are highlighted. Although the modulation of SLC26A4 is critical for recovery from malfunctions of various organs, development of specific inducers or agonists of SLC26A4 remains challenging. This review contributes to providing a better understanding of the role of SLC26A4 and development of therapeutic approaches for the SLC26A4-associated hearing loss and SLC26A4-related dysfunction of various organs.

UBA6 Inhibition Accelerates Lysosomal TRPML1 Depletion and Exosomal Secretion in Lung Cancer Cells.

Ubiquitin-like modifier-activating enzyme 6 (UBA6) is a member of the E1 enzyme family, which initiates the ubiquitin-proteasome system (UPS). The UPS plays critical roles not only in protein degradation but also in various cellular functions, including neuronal signaling, myocardial remodeling, immune cell differentiation, and cancer development. However, the specific role of UBA6 in cellular functions is not fully elucidated in comparison with the roles of the UPS. It has been known that the E1 enzyme is associated with the motility of cancer cells. In this study, we verified the physiological roles of UBA6 in lung cancer cells through gene-silencing siRNA targeting UBA6 (siUBA6). The siUBA6 treatment attenuated the migration of H1975 cells, along with a decrease in lysosomal Ca2+ release. While autophagosomal proteins remained unchanged, lysosomal proteins, including TRPML1 and TPC2, were decreased in siUBA6-transfected cells. Moreover, siUBA6 induced the production of multivesicular bodies (MVBs), accompanied by an increase in MVB markers in siUBA6-transfected H1975 cells. Additionally, the expression of the exosomal marker CD63 and extracellular vesicles was increased by siUBA6 treatment. Our findings suggest that knock-down of UBA6 induces lysosomal TRPML1 depletion and inhibits endosomal trafficking to lysosome, and subsequently, leads to the accumulation of MVBs and enhanced exosomal secretion in lung cancer cells.

A Microlearning-Based Self-directed Learning Chatbot on Medication Administration for New Nurses: A Feasibility Study.

New nurses must acquire accurate knowledge of medication administration, as it directly affects patient safety. This study aimed to develop a microlearning-based self-directed learning chatbot on medication administration for novice nurses. Furthermore, the study had the objective of evaluating the chatbot feasibility. The chatbot covered two main topics: medication administration processes and drug-specific management, along with 21 subtopics. Fifty-eight newly hired nurses on standby were asked to use the chatbot over a 2-week period. Moreover, we evaluated the chatbot's feasibility through a survey that gauged changes in their confidence in medication administration knowledge, intrinsic learning motivation, satisfaction with the chatbot's learning content, and usability. After using the chatbot, participants' confidence in medication administration knowledge significantly improved in all topics (P < .001) except "Understanding a concept of 5Right" (P = .077). Their intrinsic learning motivation, satisfaction with the learning content, and usability scored above 5 out of 7 in all subdomains, except for pressure/tension (mean, 2.12; median, 1.90). They scored highest on ease of learning (mean, 6.69; median, 7.00). A microlearning-based chatbot can help new nurses improve their knowledge of medication administration through self-directed learning.

Multiple Regulatory Signals and Components in the Modulation of Bicarbonate Transporters.

Bicarbonate transporters are responsible for the appropriate flux of bicarbonate across the plasma membrane to perform various fundamental cellular functions. The functions of bicarbonate transporters, including pH regulation, cell migration, and inflammation, are highlighted in various cellular systems, encompassing their participation in both physiological and pathological processes. In this review, we focused on recently identified modulatory signaling components that regulate the expression and activity of bicarbonate transporters. Moreover, we addressed recent advances in our understanding of cooperative systems of bicarbonate transporters and channelopathies. This current review aims to provide a new, in-depth understanding of numerous human diseases associated with the dysfunction of bicarbonate transporters.

Niemann-Pick Disease Type C (NPDC) by Mutation of NPC1 and NPC2: Aberrant Lysosomal Cholesterol Trafficking and Oxidative Stress.

Cholesterol trafficking is initiated by the endocytic pathway and transported from endo/lysosomes to other intracellular organelles. Deficiencies in cholesterol-sensing and binding proteins NPC1 and NPC2 induce accumulation in lysosomes and the malfunction of trafficking to other organelles. Each organelle possesses regulatory factors to induce cholesterol trafficking. The mutation of NPC1 and NPC2 genes induces Niemann-Pick disease type C (NPDC), which is a hereditary disease and causes progressive neurodegeneration, developmental disability, hypotonia, and ataxia. Oxidative stress induces damage in NPDC-related intracellular organelles. Although studies on the relationship between NPDC and oxidation are relatively rare, several studies have reported the therapeutic potential of antioxidants in treating NPDC. Investigating antioxidant drugs to relieve oxidative stress and cholesterol accumulation is suggested to be a powerful tool for developing treatments for NPDC. Understanding NPDC provides challenging issues in understanding the oxidative stress-lysosome metabolism of the lipid axis. Thus, we elucidated the relationship between complexes of intracellular organelles and NPDC to develop our knowledge and suggested potential antioxidant reagents for NPDC therapy.

E3 ligase SOCS3 regulates NOD2 expression by ubiquitin proteasome system in lung cancer progression.

PURPOSE: Despite lung cancer is one of the leading causes of cancer-related deaths, it remains hard to discover effective diagnostic and therapeutic approaches. Moreover, the five-year survival rate is relatively lower than other tumors. So urgent needs for finding a new theranostic target to treat lung cancer effectively. This study aims to present SOCS3 and NOD2 proteins as novel targets for diagnosis and therapy. METHODS: We first confirmed SOCS3 expression level in patients' tissues. Then, we applied knockdown and overexpression of SOCS3 on lung cancer cell lines and performed proliferation, migration, and invasion assay. After that, we found NOD2 is a target of SOCS3 and introduced overexpression of NOD2 to A549 for verifying reduced tumorigenicity of lung cancer cells. RESULTS: We identified protein expression level of SOCS3 was frequently higher in tumor tissues than adjacent normal tissues. Truly, overexpression of SOCS3 promoted proliferation, migration, and invasion capacity of lung cancer cells. We found that SOCS3 interacts with NOD2 and SOCS3 ubiquitinates NOD2 directly. Furthermore, lung cancer tissues with higher SOCS3 expression showed lower NOD2 expression. We confirmed overexpression of NOD2 leads to suppressed tumorigenicity of lung cancer cells, and these effects occurred through MAPK pathway. CONCLUSION: Collectively, our work reveals novel roles of SOCS3 in lung tumorigenesis and proposes SOCS3 as a promising biomarker candidate for therapeutic and diagnostic target for lung cancer.

Trafficking of carbonic anhydrase 12 and bicarbonate transporters by histamine stimulation mediates intracellular acidic scenario in lung cancer cells.

Carbonic anhydrase 12 is considered an oncogenic and acidic microenvironmental factor in cancer cells. To verify the role of histamine signalling as an anti-cancer signal, we determined the roles of CA12 and its associated bicarbonate transporters. In this study, histamine stimulation mediated mislocalization of CA12 in lung cancer cells. Histamine receptor activation-mediated CA12 endocytosis and pH were restored by CaMKII inhibition. CA12-associated AE2 expression was enhanced, whereas NBCn1 expression and its activity were reduced by histamine stimulation. Histamine receptor activation-mediated acidification was induced by internalised CA12 and NBCn1 and, at the same time by increased bicarbonate efflux through enhanced AE2 expression. Inhibition of protein trafficking by bafilomycin restored CA12 and AE2 localisation and diminished cellular acidosis. Thus, we verified that histamine stimulation induced an acidic scenario, which revealed trafficking of CA12 and its associated bicarbonate transporters in lung cancer cells and its dysregulated pH modulation may be involved in the histamine signalling-mediated anti-cancer process.

Modulation of Lysosomal Cl- Mediates Migration and Apoptosis through the TRPML1 as a Lysosomal Cl- Sensor.

Lysosomes are responsible for protein degradation and clearance in cellular recycling centers. It has been known that the lysosomal chloride level is enriched and involved in the intrinsic lysosomal function. However, the mechanism by which chloride levels can be sensed and that of the chloride-mediated lysosomal function is unknown. In this study, we verified that reduced chloride levels acutely induced lysosomal calcium release through TRPML1 and lysosomal repositioning toward the juxtanuclear region. Functionally, low chloride-induced lysosomal calcium release attenuated cellular migration. In addition, spontaneous exposure to low chloride levels dysregulated lysosomal biogenesis and subsequently induced delayed migration and promoted apoptosis. Two chloride-sensing GXXXP motifs in the TRPML1 were identified. Mutations in the GXXXP motif of TRPML1 did not affect chloride levels, and there were no changes in migratory ability. In this study, we demonstrated that the depletion of chloride induces reformation of the lysosomal calcium pool and subsequently dysregulated cancer progression, which will assist in improving therapeutic strategies for lysosomal accumulation-associated diseases or cancer cell apoptosis.

Utilizing standardized nursing terminologies in implementing an AI-powered fall-prevention tool to improve patient outcomes: a multihospital study.

OBJECTIVES: Standardized nursing terminologies (SNTs) are necessary to ensure consistent knowledge expression and compare the effectiveness of nursing practice across settings. This study investigated whether SNTs can support semantic interoperability and outcoming tracking over time by implementing an AI-powered CDS tool for fall prevention across multiple EMR systems. MATERIALS AND METHODS: The study involved 3 tertiary academic hospitals and 1 public hospital with different EMR systems and nursing terms, and employed an AI-powered CDS tool that determines the fall risk within the next hour (prediction model) and recommends tailored care plans (CDS functions; represented by SNTs). The prediction model was mapped to local data elements and optimized using local data sets. The local nursing statements in CDS functions were mapped using an ICNP-based inpatient fall-prevention catalog. Four implementation models were compared, and patient outcomes and nursing activities were observed longitudinally at one site. RESULTS: The postimplementation approach was practical for disseminating the AI-powered CDS tool for nursing. The 4 hospitals successfully implemented prediction models with little performance variation; the AUROCs were 0.8051-0.9581. The nursing process data contributed markedly to fall-risk predictions. The local nursing statements on preventing falls covered 48.0%-86.7% of statements. There was no significant longitudinal decrease in the fall rate (P = .160, 95% CI = -1.21 to 0.21 per 1000 hospital days), but rates of interventions provided by nurses were notably increased. CONCLUSION: SNTs contributed to achieving semantic interoperability among multiple EMR systems to disseminate AI-powered CDS tools and automatically track nursing and patient outcomes.

Multiple-Factors-Induced Rheumatoid Arthritis Synoviocyte Activation Is Attenuated by the α2-Adrenergic Receptor Agonist Dexmedetomidine.

Dexmedetomidine (Dex) has analgesic and sedative properties and anti-inflammatory functions. Although the effects of Dex on arthritis have been revealed, the physiological mechanism underlying the interaction between Dex and rheumatoid arthritis (RA)-mediated inflammatory cytokines has not been fully studied. Inflamed and migrated fibroblast-like synoviocytes (FLSs) are involved in RA severity. Thus, we aimed to determine the effects of Dex on RA-FLSs treated with inflammatory cytokines and a growth factor as multiple stimulating inputs. TNF-α, IL-6, and EGF as multiple stimulating inputs increased the cAMP concentration of RA-FLSs, while Dex treatment reduced cAMP concentration. Dex reduced electroneutral sodium-bicarbonate cotransporter 1 (NBCn1) expression, NBC activity, and subsequent RA-FLS migration. The mRNA expression levels of RA-related factors, such as inflammatory cytokines and osteoclastogenesis factors, were enhanced by multiple-input treatment. Notably, Dex effectively reduced these expression levels in RA-FLSs. These results indicate that multiple inflammatory or stimulating inputs enhance RA-FLS migration, and treatment with Dex relieves activated RA-FLSs, suggesting that Dex is a potential therapeutic drug for RA.

Overview of cellular homeostasis-associated nuclear envelope lamins and associated input signals.

With the discovery of the role of the nuclear envelope protein lamin in human genetic diseases, further diverse roles of lamins have been elucidated. The roles of lamins have been addressed in cellular homeostasis including gene regulation, cell cycle, cellular senescence, adipogenesis, bone remodeling as well as modulation of cancer biology. Features of laminopathies line with oxidative stress-associated cellular senescence, differentiation, and longevity and share with downstream of aging-oxidative stress. Thus, in this review, we highlighted various roles of lamin as key molecule of nuclear maintenance, specially lamin-A/C, and mutated LMNA gene clearly reveal aging-related genetic phenotypes, such as enhanced differentiation, adipogenesis, and osteoporosis. The modulatory roles of lamin-A/C in stem cell differentiation, skin, cardiac regulation, and oncology have also been elucidated. In addition to recent advances in laminopathies, we highlighted for the first kinase-dependent nuclear lamin biology and recently developed modulatory mechanisms or effector signals of lamin regulation. Advanced knowledge of the lamin-A/C proteins as diverse signaling modulators might be biological key to unlocking the complex signaling of aging-related human diseases and homeostasis in cellular process.

Candesartan, an angiotensin-II receptor blocker, ameliorates insulin resistance and hepatosteatosis by reducing intracellular calcium overload and lipid accumulation.

Insulin resistance is a major contributor to the pathogenesis of several human diseases, including type 2 diabetes, hypertension, and hyperlipidemia. Notably, insulin resistance and hypertension share common abnormalities, including increased oxidative stress, inflammation, and organelle dysfunction. Recently, we showed that excess intracellular Ca2+, a known pathogenic factor in hypertension, acts as a critical negative regulator of insulin signaling by forming Ca2+-phosphoinositides that prevent the membrane localization of AKT, a key serine/threonine kinase signaling molecule. Whether preventing intracellular Ca2+ overload improves insulin sensitivity, however, has not yet been investigated. Here, we show that the antihypertensive agent candesartan, compared with other angiotensin-II receptor blockers, has previously unrecognized beneficial effects on attenuating insulin resistance. We found that candesartan markedly reduced palmitic acid (PA)-induced intracellular Ca2+ overload and lipid accumulation by normalizing dysregulated store-operated channel (SOC)-mediated Ca2+ entry into cells, which alleviated PA-induced insulin resistance by promoting insulin-stimulated AKT membrane localization and increased the phosphorylation of AKT and its downstream substrates. As pharmacological approaches to attenuate intracellular Ca2+ overload in vivo, administering candesartan to obese mice successfully decreased insulin resistance, hepatic steatosis, dyslipidemia, and tissue inflammation by inhibiting dysregulated SOC-mediated Ca2+ entry and ectopic lipid accumulation. The resulting alterations in the phosphorylation of key signaling molecules consequently alleviate impaired insulin signaling by increasing the postprandial membrane localization and phosphorylation of AKT. Thus, our findings provide robust evidence for the pleiotropic contribution of intracellular Ca2+ overload in the pathogenesis of insulin resistance and suggest that there are viable approved drugs that can be repurposed for the treatment of insulin resistance and hypertension.

Activated PyK2 and Its Associated Molecules Transduce Cellular Signaling from the Cancerous Milieu for Cancer Metastasis.

PyK2 is a member of the proline-rich tyrosine kinase and focal adhesion kinase families and is ubiquitously expressed. PyK2 is mainly activated by stimuli, such as activated Src kinases and intracellular acidic pH. The mechanism of PyK2 activation in cancer cells has been addressed extensively. The up-regulation of PyK2 through overexpression and enhanced phosphorylation is a key feature of tumorigenesis and cancer migration. In this review, we summarized the cancer milieu, including acidification and cancer-associated molecules, such as chemical reagents, interactive proteins, chemokine-related molecules, calcium channels/transporters, and oxidative molecules that affect the fate of PyK2. The inhibition of PyK2 leads to a beneficial strategy to attenuate cancer cell development, including metastasis. Thus, we highlighted the effect of PyK2 on various cancer cell types and the distribution of molecules that affect PyK2 activation. In particular, we underlined the relationship between PyK2 and cancer metastasis and its potential to treat cancer cells.

Addition of oh8dG to Cardioplegia Attenuated Myocardial Oxidative Injury through the Inhibition of Sodium Bicarbonate Cotransporter Activity.

The biomarker 8-hydroxy-2'-deoxyguanosine (oh8dG) is derived from oxidized nucleic acids or products of oxidant-mediated DNA damage. Enhanced sodium bicarbonate cotransporter (NBC) activity is caused by reactive oxygen species (ROS) production in ventricular myocytes. Thus, we hypothesized that cardioplegia-solution-mediated ROS generation may be involved in the regulation of NBC activity in cardiomyocytes and that oh8dG treatment may modulate ROS and associated NBC activity. Langendorff-free cardioplegia-arrested cardiac strips and cardiomyocytes were isolated to determine the NBC activity and effects of oh8dG on oxidative-stress-mediated cardiac damage markers. We first determined the histidine-tryptophan-ketoglutarate (HTK) solution mediated NBC activity in cardiac strips and cells. The oh8dG treatment attenuated NBC activity in the electroneutral or electrogenic form of NBC. Additionally, exposure to HTK solution induced ROS, whereas co-administration of oh8dG attenuated ROS-mediated NBC activity, reduced ROS levels, and decreased the expression of apoptotic markers and fibrosis-associated proteins in cardiac cells. The oh8dG-administrated cardiac tissues were also protected from enhanced HTK-induced damage markers, heat shock protein 60 and polyADP-ribose. Our results show that oh8dG has a protective role against myocardial oxidative damage and provides a useful treatment strategy for restoring cardiac function.

Development and validation of interpretable machine learning models for inpatient fall events and electronic medical record integration.

OBJECTIVE: Falls are one of the most frequently occurring adverse events among hospitalized patients. The Morse Fall Scale, which has been widely used for fall risk assessment, has the two limitations of low specificity and difficulty in practical implementation. The aim of this study was to develop and validate an interpretable machine learning model for prediction of falls to be integrated in an electronic medical record (EMR) system. METHODS: This was a retrospective study involving a tertiary teaching hospital in Seoul, Korea. Based on the literature, 83 known predictors were grouped into seven categories. Interpretable fall event prediction models were developed using multiple machine learning models including gradient boosting and Shapley values. RESULTS: Overall, 191,778 cases with 272 fall events (0.1%) were included in the analysis. With the validation cohort of 2020, the area under the receiver operating curve (AUROC) of the gradient boosting model was 0.817 (95% confidence interval [CI], 0.720-0.904), better performance than random forest (AUROC, 0.801; 95% CI, 0.708-0.890), logistic regression (AUROC, 0.802; 95% CI, 0.721-0.878), artificial neural net (AUROC, 0.736; 95% CI, 0.650-0.821), and conventional Morse fall score (AUROC, 0.652; 95% CI, 0.570-0.715). The model's interpretability was enhanced at both the population and patient levels. The algorithm was later integrated into the current EMR system. CONCLUSION: We developed an interpretable machine learning prediction model for inpatient fall events using EMR integration formats.

Lamin-A/C Is Modulated by the Involvement of Histamine-Mediated Calcium/Calmodulin-Dependent Kinase II in Lung Cancer Cells.

Lamins are nuclear envelope proteins involved in various cellular functions, such as DNA modulation, cellular differentiation, and development. In this study, we investigate the role of histamine in lung cancer biology. Since it is known that lamin-A/C is negatively regulated in lung cancer, we hypothesize that histamine signaling is related to nuclear lamin-A/C regulation and cancer progression. Our findings reveal that histamine stimulation enhances lamin-A/C expression in lung cancer cells. Lamin-A/C expression is dependent on histamine-mediated intracellular calcium signaling and subsequent calcium/calmodulin-dependent kinase II (Ca/CaMKII) activation. The nuclear protein nestin, which stabilizes lamin-A/C expression, is also modulated by Ca/CaMKII. However, histamine-mediated lamin-A/C expression is independent of Akt/focal adhesion kinase or autophagy signaling. Histamine stimulation attenuates lung cancer motility in the presence of enhanced lamin-A/C expression. In conclusion, we propose a regulatory mechanism that accounts for the modulation of lamin-A/C levels through the involvement of Ca/CaMKII in cancer cells and provides molecular evidence of histamine signaling in lamin-A/C biology.

Physiological Overview of the Potential Link between the UPS and Ca2+ Signaling.

The ubiquitin-proteasome system (UPS) is the main proteolytic pathway by which damaged target proteins are degraded after ubiquitination and the recruit of ubiquitinated proteins, thus regulating diverse physiological functions and the maintenance in various tissues and cells. Ca2+ signaling is raised by oxidative or ER stress. Although the basic function of the UPS has been extensively elucidated and has been continued to define its mechanism, the precise relationship between the UPS and Ca2+ signaling remains unclear. In the present review, we describe the relationship between the UPS and Ca2+ signaling, including Ca2+-associated proteins, to understand the end point of oxidative stress. The UPS modulates Ca2+ signaling via the degradation of Ca2+-related proteins, including Ca2+ channels and transporters. Conversely, the modulation of UPS is driven by increases in the intracellular Ca2+ concentration. The multifaceted relationship between the UPS and Ca2+ plays critical roles in different tissue systems. Thus, we highlight the potential crosstalk between the UPS and Ca2+ signaling by providing an overview of the UPS in different organ systems and illuminating the relationship between the UPS and autophagy.

Estrogen treatment reduced oxalate transporting activity and enhanced migration through the involvement of SLC26A6 in lung cancer cells.

Estrogen therapy has used to prevent bone loss in postmenopausal women. Although therapeutically enhanced estrogen levels have been suggested, patients are exposed to greater risks of nephrolithiasis and cancer. It has been known that oxalate or bicarbonate transporter SLC26A6 is involved in oxalate homeostasis and its deletion results in kidney stone formation and addressed that patients with kidney stones possess higher cancer risk. Thus, the mechanism of the interaction between estrogen and SLC26A6 and the effect of SLC26A6 on cancer cells should be elucidated. In this study, we investigated whether ß-estradiol treatment modulates SLC26A6 expression and its bicarbonate or oxalate transporting activity and affects the proliferative and migratory ability of A549 cells. The ß-estradiol stimulation attenuated oxalate or bicarbonate transporting activities through SLC26A6. Knockdown of SLC26A6 reduced transporter activity whereas enhanced cellular migration. ß-estradiol-mediated cellular migration was independent of SLC26A6 transporter activity, whereas enhanced SLC26A6 expression attenuated cellular migration even in the presence of ß-estradiol treatment. These results indicate ß-estradiol treatment enhances cancer cell migration and dysregulates oxalate transport by inhibiting SLC26A6 activity, suggesting reduced oxalate transporting activity may involve in the oxalate homeostasis.

Dynamic synovial fibroblasts are modulated by NBCn1 as a potential target in rheumatoid arthritis.

Rheumatoid arthritis (RA) is an autoimmune disease characterized by aggressive fibroblast-like synoviocytes (FLSs) and pannus formation. Various therapeutic strategies have been developed against inflammatory cytokines in RA in recent decades. Based on the migratory features of FLSs, we examined whether modulation of the migratory module attenuates RA severity. In this study, inflamed synovial fluid-stimulated FLSs exhibited enhanced migration and migratory apparatus expression, and sodium bicarbonate cotransporter n1 (NBCn1) was identified in primary cultured RA-FLSs for the first time. The NBC inhibitor S0859 attenuated the migration of FLSs induced with synovial fluid from patients with RA or with TNF-α stimulation. Inhibition of NBCs with S0859 in a collagen-induced arthritis (CIA) mouse model reduced joint swelling and destruction without blood, hepatic, or renal toxicity. Primary FLSs isolated from the CIA-induced mouse model also showed reduced migration in the presence of S0859. Our results suggest that inflammatory mediators in synovial fluid, including TNF-α, recruit NBCn1 to the plasma membrane of FLSs to provide dynamic properties and that modulation of NBCn1 could be developed into a therapeutic strategy for RA.