Ginseng (Panax ginseng) leaf extract modulates the expression of heme oxygenase-1 to attenuate osteoclast differentiation.

Osteoporosis is an aging disease characterized by an imbalance between bone formation and resorption. However, drugs that inhibit bone resorption have various adverse effects. Ginseng (Panax ginseng), a prominent herbal medicine in East Asia for >2000 years, is renowned for its manifold beneficial properties, including antioxidant, anti-cancer, anti-diabetic, and anti-adipogenic activities. Despite its long history of use, the pharmacological functions of ginseng leaves are not yet fully comprehended. In this study, we evaluated the potential effects of ginseng leaf extract (GLE) on receptor activator of nuclear factor κB ligand (RANKL)-induced osteoclast differentiation in RAW264.7 macrophage cells. Tartrate-resistant acid phosphatase (TRAP) staining revealed that GLE had significant anti-osteoclastogenic activity. GLE significantly reduced mRNA levels of osteoclast differentiation markers including TRAP, nuclear factor of activated T cell cytoplasmic 1, and cathepsin K. It also suppressed the production of reactive oxygen species (ROS) and secretion of high mobility group box-1 (HMGB1) in RANKL-treated RAW264.7 cells. In addition, GLE upregulated dose- and time-dependently the expression of heme oxygenase-1 (HO-1), eventually suppressing ROS production and HMGB1 secretion. This effects of GLE were significantly reversed by Tin Protoporphyrin IX dichloride, an inhibitor of HO-1, and HO-1 shRNA, indicating that HO-1 potently inhibits RANKL-induced osteoclast differentiation by inhibiting ROS production and HMGB1 secretion. Taken together, these observations suggest that GLE could have therapeutic potential as a natural product-derived medicine for the treatment of bone disorders.

Red clover (Trifolium pratense L.) extract inhibits ferroptotic cell death by modulating cellular iron homeostasis.

ETHNOPHARMACOLOGICAL RELEVANCE: Red clover (Trifolium pratense L.) is a traditional Chinese medicine and use as herbal medicine which has the effects of regulating menopausal symptoms, heart problem, inflammatory disease, psoriasis and cognitive deficits. In previous reported, the studies of red clover were mainly focused on clinical practice. the pharmacological functions of red clover not fully elucidated. AIM OF THE STUDY: To identify the molecules that regulate ferroptosis, we examined whether red clover (Trifolium pratense L.) extracts (RCE) affected ferroptosis induced by chemical treatment or cystine/glutamate antiporter (xCT) deficiency. MATERIALS AND METHODS: Cellular models for ferroptosis were induced by erastin/Ras-selectiv lethal 3 (RSL3) treatment or xCT deficiency in mouse embryonic fibroblasts (MEFs). Intracellular iron and peroxidized lipid levels were determined using Calcein-AM and BODIPY-C11 fluorescence dyes, respectively. Protein and mRNA were quantified by Western blot and real-time polymerase chain reaction, respectively. RNA sequencing analysis was performed on xCT-/- MEFs. RESULTS: RCE significantly suppressed ferroptosis induced by both erastin/RSL3 treatment and xCT deficiency. The anti-ferroptotic effects of RCE correlated to ferroptotic phenotypic changes such as cellular iron accumulation and lipid peroxidation in cellular ferroptosis models. Importantly, RCE affected levels of iron metabolism-related proteins including iron regulatory protein 1, ferroportin 1 (FPN1), divalent metal transporter 1, and transferrin receptor. RNA sequencing analysis of xCT-/- MEFs identified that expression of cellular defense genes was upregulated, while expression of cell death-related genes was downregulated, by RCE. CONCLUSION: RCE potently suppressed ferroptosis triggered both by erastin/RSL3 treatment and xCT deficiency by modulating cellular iron homeostasis. This is the first report that RCE has therapeutic potential in diseases associated with ferroptotic cell death, particularly ferroptosis induced by dysregulation of cellular iron metabolism.

Zinc finger protein 251 deficiency impairs glucose metabolism by inducing adipocyte hypertrophy.

Zinc finger protein (ZFP) 251 is a member of the C2H2 ZFP family containing a Krüppel-associated box domain that might mainly act as a transcriptional repressor. However, its cellular function remains largely unknown. Here, we discovered that ZFP251 deficiency caused glucose intolerance in mice. This phenotype was associated with impaired insulin signaling due to hypertrophic changes in white adipose tissue (WAT). Gene ontology analysis revealed that ZFP251 deficiency affected the expression of genes associated with adipocyte differentiation and lipid and fatty acid metabolism. Consistent with in vivo results, hypertrophic changes were observed in Zfp251 knockdown (KD) 3T3-L1 adipocytes. In addition, Zfp251 KD 3T3-L1 preadipocytes exhibited cell cycle arrest in G0/G1 phase, leading to impaired differentiation into mature adipocytes, upon which abnormal mitotic clonal expansion and reduced expression of adipogenic markers were exhibited. These results suggest that ZFP251 deficiency causes impaired adipogenesis and adipocyte hypertrophy, leading to dysfunction of WAT.

Releasing of a Titanium Clamp (Craniofix®) Without Mechanical Defect After Craniotomy for Acute Subdural Hemorrhage.

After craniotomy, bone flap fixation can be performed using wires, sutures, microplates, and Craniofix®. Well-margined and fixed bone flaps are important not only for postoperative brain protection but also for esthetics. Herein, we report a case of cranioplasty due to bone flap dislocation by Craniofix® clamp loosening after craniotomy with acute subdural hemorrhage removal. Iatrogenic outward force during epidural drain removal adjacent to Craniofix®, insertion of the clamp around the circumference of the bone flap, increased intracranial pressure due to brain swelling and fluid collection, and external shock during postoperative patient management are thought to be the causes of bone flap dislocation. To our knowledge, this is the second reported case of craniotomy with a Craniofix® clamp release.

PPARδ Inhibits Hyperglycemia-Triggered Senescence of Retinal Pigment Epithelial Cells by Upregulating SIRT1.

Emerging evidence shows that peroxisome proliferator-activated receptor delta (PPARδ) plays a pivotal role in cellular aging. However, its function in retinal disease processes such as hyperglycemia-associated diabetic retinopathy is unclear. Here, we demonstrate that PPARδ inhibits premature senescence of retinal pigment epithelial (RPE) cells induced by high glucose (HG) through SIRT1 upregulation. A specific ligand GW501516-activation of PPARδ suppressed premature senescence and production of reactive oxygen species induced by HG in ARPE-19 cells, a spontaneously arising human RPE cell line. These effects were accompanied by the regulation of the premature senescence-associated genes p53, p21, and SMP-30. Furthermore, GW501516-activated PPARδ almost completely abolished the effects of HG treatment on the formation of phosphorylated H2A histone family member X (γ-H2A.X) foci, a molecular marker of aging. These inhibitory effects of GW501516 were significantly reversed in ARPE-19 cells stably expressing small hairpin RNA targeting PPARδ. Notably, GW501516 significantly increased the mRNA and protein levels of SIRT1, indicating that GW501516-activated PPARδ exerted its beneficial effects through SIRT1. In addition, GW501516 restored HG-suppressed SIRT1 expression, corroborating the role of SIRT1 in the anti-senescence function of PPARδ. The effects of PPARδ on HG-induced premature senescence and the expression of the senescence-associated genes p53, p21, and SMP-30 were mimicked by the SIRT1 activator resveratrol, but blocked by the SIRT1 inhibitor sirtinol. Collectively, these results indicate that GW501516-activated PPARδ inhibits HG-triggered premature senescence of RPE cells by modulating SIRT1 signaling.

PPARδ Activation Mitigates 6-OHDA-Induced Neuronal Damage by Regulating Intracellular Iron Levels.

Intracellular iron accumulation in dopaminergic neurons contributes to neuronal cell death in progressive neurodegenerative disorders such as Parkinson's disease. However, the mechanisms of iron homeostasis in this context remain incompletely understood. In the present study, we assessed the role of the nuclear receptor peroxisome proliferator-activated receptor δ (PPARδ) in cellular iron homeostasis. We identified that PPARδ inhibited 6-hydroxydopamine (6-OHDA)-triggered neurotoxicity in SH-SY5Y neuroblastoma cells. PPARδ activation with GW501516, a specific PPARδ agonist, mitigated 6-OHDA-induced neuronal damage. Further, PPARδ activation also suppressed iron accumulation, which contributes to 6-OHDA-induced neuronal damage. PPARδ activation attenuated 6-OHDA-induced neuronal damage in a similar manner to that of the iron chelator deferoxamine. We further elucidated that PPARδ modulated cellular iron homeostasis by regulating expression of divalent metal transporter 1, ferroportin 1, and ferritin, but not transferrin receptor 1, through iron regulatory protein 1 in 6-OHDA-treated cells. Interestingly, PPARδ activation suppressed 6-OHDA-triggered generation of reactive oxygen species and lipid peroxides. The effects of GW501516 were abrogated by shRNA knockdown of PPARδ, indicating that the effects of GW501516 were PPARδ-dependent. Taken together, these findings suggest that PPARδ attenuates 6-OHDA-induced neurotoxicity by preventing intracellular iron accumulation, thereby suppressing iron overload-associated generation of reactive oxygen species and lipid peroxides, key mediators of ferroptotic cell death.

Peroxisome proliferator-activated receptor δ rescues xCT-deficient cells from ferroptosis by targeting peroxisomes.

Ferroptosis is a recently recognized process of cell death characterized by accumulation of iron-dependent lipid peroxides. Herein, we demonstrate that peroxisome proliferator-activated receptor δ (PPARδ) inhibits ferroptosis of mouse embryonic fibroblasts (MEFs) derived from cysteine/glutamate transporter (xCT)-knockout mice. Activation of PPARδ by the specific ligand GW501516 led to a dose-dependent decrease in ferroptotic cell death triggered by xCT deficiency, along with decreased levels of intracellular iron accumulation and lipid peroxidation. These effects of GW501516 were abolished by PPARδ-targeting small interfering RNA (siRNA) and the PPARδ inhibitor GSK0660, indicating that PPARδ inhibits xCT deficiency-induced ferroptosis. In addition, GW501516-activated PPARδ time- and dose-dependently upregulated catalase expression at both the mRNA and protein levels. This PPARδ-mediated upregulation of catalase was markedly attenuated in cells treated with PPARδ-targeting siRNA and GSK0660, indicating that expression of catalase is dependent on PPARδ. Consistently, the effects of GW501516 on ferroptosis of xCT-deficient MEFs were counteracted in the presence of 3-amino-1,2,4-triazole, a specific inhibitor of catalase, suggesting that catalase is essential for the effect of PPARδ on ferroptosis triggered by xCT deficiency. GW501516-activated PPARδ stabilized peroxisomes through catalase upregulation by targeting peroxisomal hydrogen peroxide-mediated lysosomal rupture, which led to ferroptosis of xCT-deficient MEFs. Collectively, these results demonstrate that PPARδ modulates ferroptotic signals in xCT-deficient MEFs by regulating catalase expression.

Peroxisome proliferator-activated receptor-δ-mediated upregulation of catalase helps to reduce ultraviolet B-induced cellular injury in dermal fibroblasts.

BACKGROUND: Previous studies suggested that the nuclear receptor peroxisome proliferator-activated receptor (PPAR)-δ plays an essential role in cellular responses against oxidative stress. OBJECTIVE: To investigate how PPAR-δ elicits cellular responses against oxidative stress in primary human dermal fibroblasts (HDFs) exposed to ultraviolet B (UVB). METHODS: The present study was undertaken in HDFs by performing real-time polymerase chain reaction, gene silencing, cytotoxicity and reporter gene assay, analyses for catalase and reactive oxygen species, and immunoblot analyses. RESULTS: The PPAR-δ activator GW501516 upregulated expression of catalase and this upregulation was attenuated by PPAR-δ-targeting siRNA. GW501516-activated PPAR-δ induced catalase promoter activity through a direct repeat 1 response element. Mutation of this response element completely abrogated transcriptional activation, indicating that this site is a novel type of PPAR-δ response element. In addition, GW501516-activated PPAR-δ counteracted the reductions in activity and expression of catalase induced by UVB irradiation. These recovery effects were significantly attenuated in the presence of PPAR-δ-targeting siRNA or the specific PPAR-δ antagonist GSK0660. GW501516-activated PPAR-δ also protected HDFs from cellular damage triggered by UVB irradiation, and this PPAR-δ-mediated reduction of cellular damage was reversed by the catalase inhibitor or catalase-targeting siRNA. These effects of catalase blockade were positively correlated with accumulation of reactive oxygen species in HDFs exposed to UVB. Furthermore, GW501516-activated PPAR-δ targeted peroxisomal hydrogen peroxide through catalase in UVB-irradiated HDFs. CONCLUSION: The gene encoding catalase is a target of PPAR-δ, and this novel catalase-mediated pathway plays a critical role in the cellular response elicited by PPAR-δ against oxidative stress.

Catalase Mediates the Inhibitory Actions of PPARδ against Angiotensin II-Triggered Hypertrophy in H9c2 Cardiomyocytes.

Hypertrophy of myocytes has been implicated in cardiac dysfunctions affecting wall stress and patterns of gene expression. However, molecular targets potentially preventing cardiac hypertrophy have not been fully elucidated. In the present study, we demonstrate that upregulation of catalase by peroxisome proliferator-activated receptor δ (PPARδ) is involved in the anti-hypertrophic activity of PPARδ in angiotensin II (Ang II)-treated H9c2 cardiomyocytes. Activation of PPARδ by a specific ligand GW501516 significantly inhibited Ang II-induced hypertrophy and the generation of reactive oxygen species (ROS) in H9c2 cardiomyocytes. These effects of GW501516 were almost completely abolished in cells stably expressing small hairpin (sh)RNA targeting PPARδ, indicating that PPARδ mediates these effects. Significant concentration and time-dependent increases in catalase at both mRNA and protein levels were observed in GW501516-treated H9c2 cardiomyocytes. In addition, GW501516-activated PPARδ significantly enhanced catalase promoter activity and protein expression, even in the presence of Ang II. GW501516-activated PPARδ also inhibited the expression of atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP), which are both marker proteins for hypertrophy. The effects of GW501516 on the expression of ANP and BNP were reversed by 3-amino-1,2,4-triazole (3-AT), a catalase inhibitor. Inhibition or downregulation of catalase by 3-AT or small interfering (si)RNA, respectively, abrogated the effects of PPARδ on Ang II-induced hypertrophy and ROS generation, indicating that these effects of PPARδ are mediated through catalase induction. Furthermore, GW501516-activated PPARδ exerted catalase-dependent inhibitory effects on Ang II-induced hypertrophy by blocking p38 mitogen-activated protein kinase. Taken together, these results indicate that the anti-hypertrophic activity of PPARδ may be achieved, at least in part, by sequestering ROS through fine-tuning the expression of catalase in cardiomyocytes.

Ginseng leaf extract ameliorates the survival of endotoxemic mice by inhibiting the release of high mobility group box 1.

High mobility group box 1 (HMGB1) is a well-defined mediator involved in the pathophysiologic response to endotoxemia and sepsis. However, the mechanisms and therapeutic agents that could prevent its release are not fully elucidated. Here, the present study demonstrates that the ginseng leaf extract (GLE) regulates lipopolysaccharide (LPS)-triggered release of HMGB1 in macrophages and endotoxemic animal model. Treatment of RAW264.7 macrophages with GLE significantly inhibited the release of HMGB1 stimulated by LPS. GLE also suppressed the generation of nitric oxide (NO) and expression of inducible NO synthase (iNOS) in a dose-dependent manner. These effects of GLE were accompanied by inhibition of HMGB1 release stimulated by LPS, indicating a potential mechanism by which GLE regulates HMGB1 release through NO signaling. Furthermore, induction of suppressor of cytokine signaling 1 by GLE-mediated GLE-dependent suppression of HMGB1 release and NO/iNOS induction by inhibiting Janus kinase 2/signal transducer and activator of transcription 1 signal in RAW 264.7 cells exposed to LPS. Finally, administration of the GLE ameliorated the survival rate of LPS-injected endotoxemic mice in a NO-dependent manner. Thus, GLE may block the LPS-stimulated release of HMGB1 by regulating cellular signal networks, thereby providing a therapeutic strategy for endotoxemia as a functional food. PRACTICAL APPLICATIONS: High mobility group box 1 (HMGB1) is released into the extracellular milieu when immune cells are exposed to pathogen-related molecules such as lipopolysaccharide (LPS), in which it acts as a critical mediator of lethality in sepsis and endotoxemia. The extract of ginseng leaf, which is a part that can be easily thrown away, ameliorated the survival rate of endotoxemic mice by inhibiting HMGB1 secretion in a NO-dependent manner. Thus, this study suggests that ginseng leaf can be used as a functional food by resolving the immune responses in the pathology of endotoxemia.

Hyperthyroidism Symptoms, Management, and Outcomes in Children and Adults Seeking Definitive Surgical Treatment.

OBJECTIVE: To identify the difference in presentation, time to treatment, and outcomes between hyperthyroid adults and children referred to surgical evaluation. BACKGROUND: There is little data on differences in presenting symptoms, time to treatment, and outcomes between adults and children presenting for thyroidectomy for Graves' disease. METHODS: We retrospectively reviewed records of patients with hyperthyroidism referred for thyroidectomy between January 2016 and April 2017. We divided our cohort into 2 groups based on age, children (age ≤18 years), and adults (age >18), and evaluated the difference in prevalence of symptoms, time from diagnosis, and initiation of antithyroid medications to surgery, and outcomes. RESULTS: We identified 38 patients (27 adults and 11 children) with data on hyperthyroidism symptoms referred for thyroidectomy. Relative to hyperthyroid adults, children with hyperthyroidism were more likely to present with hoarseness (55% vs 15%, P = 0.01) and difficulty concentrating (45% vs 7%, P = 0.01) at initial presentation. There was no statistically significant difference in prevalence of vision changes, exophthalmos, pretibial myxedema, palpitations, fatigue, temperature intolerance, dysphagia, tremors, or constitutional symptoms. A median of 15 months elapsed from diagnosis to thyroidectomy among adult and 6 months among pediatric patients. Adult and pediatric patients waited a median of 13 and 6 months from initiation of antithyroid medications to thyroidectomy, respectively. There was no significant difference in outcomes. CONCLUSIONS: Children with hyperthyroidism were more likely to present with hoarseness and difficulty concentrating than adults. Concentration and communication are critical skills in developing children, and early intervention with definitive therapy may improve such symptoms.

Taurine and Ginsenoside Rf Induce BDNF Expression in SH-SY5Y Cells: A Potential Role of BDNF in Corticosterone-Triggered Cellular Damage.

This study shows that taurine and ginsenoside Rf act synergistically to increase the expression of brain-derived neurotrophic factor (BDNF) in SH-SY5Y human neuroblastoma cells in a dose- and time-dependent manner. The increase of BDNF mRNA by taurine and ginsenoside Rf was markedly attenuated by inhibitors of extracellular signal-regulated kinase and p38 mitogen-activated protein kinase. In addition, taurine and ginsenoside Rf protected cells from corticosterone-induced BDNF suppression and reduced cell viability and lactate dehydrogenase release. The results from this study showed that combined treatment with both taurine and ginsenoside Rf enhanced BDNF expression and protected cells against corticosterone-induced damage.

Ring finger protein 219 regulates inflammatory responses by stabilizing sirtuin 1.

BACKGROUND AND PURPOSE: Ring finger protein 219 (RNF219), a protein containing the C3 HC4 -type RING-HC motif, has been identified as a binding partner of the histone deacetylase sirtuin 1 (SIRT1). To explore the functions of RNF219, we examined its possible roles in the cellular responses to inflammation. EXPERIMENTAL APPROACH: Effects of RNF219 on SIRT1 were studied in vitro using RAW264.7 cells and in male BALB/c mice, treated with LPS or IFN-γ. Western blots, RT-PCR, co-immunoprecipitation and ubiquitination assays were used, along with LC-MS/MS analysis. In vivo, survival and serum cytokines and tissue levels of RNF219 and SIRT1 were measured. KEY RESULTS: Binding of RNF219 to SIRT1 inhibited degradation of SIRT1 by preventing its ubiquitination, thereby prolonging SIRT1-mediated anti-inflammatory signalling. LPS caused RNF219 deacetylation, leading to instability of RNF219 and preventing its association with SIRT1. Accordingly, the acetylation status of RNF219 is a critical determinant in its interaction with SIRT1, affecting the response to inflammatory stimuli. The deacetylase inhibitor trichostatin A, increased acetylation and stability of RNF219 and survival of mice injected with LPS, through the interaction of RNF219 with SIRT1. CONCLUSION AND IMPLICATIONS: RNF219 is involved in a novel mechanism to stabilize SIRT1 protein by protein-protein interaction, leading to the resolution of cellular inflammation. These observations provide new insights into the function of RNF219 in modulation of cellular inflammation, and may aid and encourage the development of new anti-inflammatory drugs.

Ginsenoside Re Mitigates 6-Hydroxydopamine-Induced Oxidative Stress through Upregulation of GPX4.

Ginsenosides are active components found abundantly in ginseng which has been used as a medicinal herb to modify disease status for thousands of years. However, the pharmacological activity of ginsenoside Re in the neuronal system remains to be elucidated. Neuroprotective activity of ginsenoside Re was investigated in SH-SY5Y cells exposed to 6-hydroxydopamine (6-OHDA) to induce cellular injury. Ginsenoside Re significantly inhibited 6-OHDA-triggered cellular damage as judged by analysis of tetrazolium dye reduction and lactose dehydrogenase release. In addition, ginsenoside Re induced the expression of the antioxidant protein glutathione peroxidase 4 (GPX4) but not catalase, glutathione peroxidase 1, glutathione reductase, or superoxide dismutase-1. Furthermore, upregulation of GPX4 by ginsenoside Re was mediated by phosphoinositide 3-kinase and extracellular signal-regulated kinase but not by p38 mitogen-activated protein kinase or c-Jun N-terminal kinase. Ginsenoside Re also suppressed 6-OHDA-triggered cellular accumulation of reactive oxygen species and peroxidation of membrane lipids. The GPX4 inhibitor (1S,3R)-RSL3 reversed ginsenoside Re-mediated inhibition of cellular damage in SH-SY5Y cells exposed to 6-OHDA, indicating that the neuronal activity of ginsenoside Re is due to upregulation of GPX4. These findings suggest that ginsenoside Re-dependent upregulation of GPX4 reduces oxidative stress and thereby alleviates 6-OHDA-induced neuronal damage.

Comparative effects of nanoemulsions loaded with duck oil and lard oil on palmitate-induced lipotoxicity.

The effects of duck oil and lard oil on lipotoxicity induced by saturated long-chain fatty acids were evaluated in HepG2 cells. Lipotoxicity triggered by palmitate, a saturated fatty acid, was inhibited more by duck oil-loaded nanoemulsion (DO-NE) than by lard oil-loaded nanoemulsion (LO-NE) and control nanoemulsion (NE) in HepG2 cells. Accumulation of reactive oxygen species and lipid vacuoles in HepG2 cells induced by palmitate treatment was inhibited by DO-NE but not by LO-NE. Consistently, treatment of HepG2 cells with DO-NE, but not with NE or LO-NE, significantly reduced the expression levels of peroxisome proliferator-activated receptor-γ2 and sterol regulatory element-binding protein-1, which are key regulatory proteins in hepatic lipid accumulation. In addition, the cleavage of poly (ADP-ribose) polymerase and caspase-3 were reduced more by DO-NE than by LO-NE, indicating that DO-NE directly attenuates cellular damage induced by palmitate. Collectively, these results imply that the biological activity of duck oil against palmitate-induced cellular damage is more potent than that of lard oil. PRACTICAL APPLICATIONS: Accumulated lipids in nonadipose tissues, especially the liver, cause lipotoxicity, a pathologic feature of hepatic disorders, by inducing oxidative stress. A nanoemulsion loaded with duck oil, which is a functional food widely consumed by Korean people, inhibited lipotoxicity by suppressing lipid accumulation in HepG2 cells exposed to palmitate, which mimic nonalcoholic fatty liver disease. Thus, we propose that duck oil can be used as a functional food to improve lipid-induced hepatic disorders.

Rosiglitazone-dependent dissociation of HuR from PPAR-γ regulates adiponectin expression at the posttranscriptional level.

Peroxisome proliferator-activated receptor (PPAR)-γ has been implicated as a key player in the regulation of adiponectin levels via both transcriptional and posttranscriptional mechanisms. Herein, we show that PPAR-γ interacts with human antigen R (HuR) and that the PPAR-γ-HuR complex dissociates following activation of PPAR-γ by rosiglitazone, a specific ligand of PPAR-γ. This rosiglitazone-dependent dissociation of HuR from PPAR-γ leads to nucleocytoplasmic shuttling of HuR and its binding to the 3'-UTR of adiponectin mRNA. PPAR-γ with H321A and H447A double mutation (PPAR-γH321/447A), a mutant lacking ligand-binding activity, impaired HuR dissociation from the PPAR-γ-HuR complex, resulting in reduced nucleocytoplasmic shuttling, even in the presence of rosiglitazone. Consequently, rosiglitazone up-regulated adiponectin levels by modulating the stability of adiponectin mRNA, whereas these effects were abolished by HuR ablation or blocked in cells expressing the PPAR-γH321/447A mutant, indicating that the interaction of PPAR-γ and HuR is a critical event during adiponectin expression. Taken together, the findings demonstrate a novel mechanism for regulating adiponectin expression at the posttranscriptional level and suggest that ligand-mediated activation of PPAR-γ to interfere with interaction of HuR could offer a therapeutic strategy for inflammation-associated diseases that involve decreased adiponectin mRNA stability.-Hwang, J. S., Lee, W. J., Hur, J., Lee, H. G., Kim, E., Lee, G. H., Choi, M.-J., Lim, D.-S., Paek, K. S., Seo, H. G. Rosiglitazone-dependent dissociation of HuR from PPAR-γ regulates adiponectin expression at the posttranscriptional level.

Nanoemulsions improve the efficacy of turmeric in palmitate- and high fat diet-induced cellular and animal models.

Turmeric is a well-known functional food exhibiting multiple biological activities in health and disease. However, low aqueous solubility and poor bioavailability limit its therapeutic potential. Herein, we investigated the utility of nanoemulsions as a carrier to improve the efficacy of turmeric. Compared with turmeric extract (TE), 5% TE-loaded nanoemulsion (TE-NE), which contains 20-fold lower curcumin content than TE, achieved similar inhibition of palmitate-induced lipotoxicity in HepG2 cells. Exposure of HepG2 cells to 5% TE-NE also suppressed the palmitate-induced accumulation of lipid vacuoles and reactive oxygen species comparably with TE, and was accompanied by decreased levels of sterol regulatory element-binding protein (SREBP)-1, peroxisome proliferator-activated receptor-γ2 (PPAR-γ2), cleaved caspase-3, and poly (ADP-ribose) polymerase (PARP). Consistent with these effects in HepG2 cells, oral administration of 5% TE-NE to mice fed a high fat diet (HFD) markedly suppressed lipid accumulation in liver, leading to a significant reduction in body weight and adipose tissue weight, equivalent to the effects observed with TE. Compared with TE, 5% TE-NE also equivalently inhibited the levels of SREBP-1, PPAR-γ2, cleaved caspase-3, and PARP in the liver of mice fed a HFD. Furthermore, TE and 5% TE-NE significantly improved serum lipid profiles in a similar manner. These observations indicate that nanoemulsions can improve the efficacy of turmeric, thereby eliciting more potent biological efficacy against palmitate- and high fat diet (HFD)-induced cellular damage.

To admit or not to admit? Experience with outpatient thyroidectomy for Graves' disease in a high-volume tertiary care center.

BACKGROUND: Outpatient thyroidectomy is increasingly performed. Thyroidectomy for Graves' disease, however, has greater risk of periprocedural complications, limiting use of same-day procedures. We sought to demonstrate that these patients may be managed with ambulatory surgery. METHODS: The experience of one endocrine surgeon with thyroidectomy for Graves' was examined from January 2016-November 2017. Forty-one patients met criteria. Patient demographics, perioperative parameters, and postoperative outcomes including emergency department utilization and readmission were recorded. RESULTS: Mean age was 31.5 ±â€¯17.0 years, with 80% females. Mode ASA score was 3, and median operative time was 77 minutes (43-132). Complications included transient hypocalcaemia in 12%, and temporary laryngeal nerve palsy in 9.7%, with no permanent complications. Two patients were admitted immediately postoperatively for non-medical reasons. Thirty-day emergency rdepartment visits were noted in 9.7%, with subsequent readmission of 7%. CONCLUSIONS: Outpatient total thyroidectomy is safe and effective with acceptable morbidity in the Graves' patient.

Ligand-Dependent Interaction of PPARδ With T-Cell Protein Tyrosine Phosphatase 45 Enhances Insulin Signaling.

Peroxisome proliferator-activated receptor (PPAR) δ plays a pivotal role in metabolic homeostasis through its effect on insulin signaling. Although diverse genomic actions of PPARδ are postulated, the specific molecular mechanisms whereby PPARδ controls insulin signaling have not been fully elucidated. We demonstrate here that short-term activation of PPARδ results in the formation of a stable complex with nuclear T-cell protein tyrosine phosphatase 45 (TCPTP45) isoform. This interaction of PPARδ with TCPTP45 blocked translocation of TCPTP45 into the cytoplasm, thereby preventing its interaction with the insulin receptor, which inhibits insulin signaling. Interaction of PPARδ with TCPTP45 blunted interleukin 6-induced insulin resistance, leading to retention of TCPTP45 in the nucleus, thereby facilitating deactivation of the signal transducer and activator of transcription 3 (STAT3)-suppressor of cytokine signaling 3 (SOCS3) signal. Finally, GW501516-activated PPARδ improved insulin signaling and glucose intolerance in mice fed a high-fat diet through its interaction with TCPTP45. This novel interaction of PPARδ constitutes the most upstream component identified of the mechanism downregulating insulin signaling.

ADAMTS1-mediated targeting of TSP-1 by PPARδ suppresses migration and invasion of breast cancer cells.

Migration and invasion of cancer cells into surrounding tissue is a key stage of cancer metastasis. Here, we show that peroxisome proliferator-activated receptor (PPAR) δ regulates migration and invasion of human breast cancer cells via thrombospondin-1 (TSP-1) and its degrading protease, a disintegrin and metalloprotease domains with thrombospondin motifs 1 (ADAMTS1). Activation of PPARδ by GW501516, a specific ligand for PPARδ, led to marked inhibition in the cell migration and TSP-1 expression of breast cancer. These effects were suppressed by small interfering RNA-mediated knock-down of ADAMTS1, indicating that ADAMTS1 is involved in PPARδ-mediated inhibition of migration and TSP-1 expression in breast cancer cells. In addition, ligand-activated PPARδ upregulated expression of ADAMTS1 at the transcriptional level via binding of PPARδ to a direct repeat-1 site within the ADAMTS1 gene promoter. Furthermore, ligand-activated PPARδ suppressed invasion of breast cancer cells in an ADAMTS1-dependent manner. Taken together, these results demonstrate that PPARδ suppresses migration and invasion of breast cancer cells by downregulating TSP-1 in a process mediated by upregulation of ADAMTS1.