Methyl Syringate Stimulates Glucose Uptake by Inhibiting Protein Tyrosine Phosphatases Relevant to Insulin Resistance.

Several protein tyrosine phosphatases (PTPs), particularly PTPN1, PTPN2, PTPN6, PTPN9, PTPN11, PTPRS, and DUSP9, are involved in insulin resistance. Therefore, these PTPs could be promising targets for the treatment of type 2 diabetes. Our previous studies revealed that PTPN2 and PTPN6 are potential antidiabetic targets. Therefore, the identification of dual-targeting inhibitors of PTPN2 and PTPN6 could be a potential therapeutic strategy for the treatment or prevention of type 2 diabetes. In this study, we demonstrate that methyl syringate inhibits the catalytic activity of PTPN2 and PTPN6 in vitro, indicating that methyl syringate acts as a dual-targeting inhibitor of PTPN2 and PTPN6. Furthermore, methyl syringate treatment significantly increased glucose uptake in mature 3T3-L1 adipocytes. Additionally, methyl syringate markedly enhanced phosphorylation of adenosine monophosphate-activated protein kinase (AMPK) in 3T3L1 adipocytes. Taken together, our results suggest that methyl syringate, a dual-targeting inhibitor of PTPN2 and PTPN6, is a promising therapeutic candidate for the treatment or prevention of type 2 diabetes.

Ethyl Gallate Dual-Targeting PTPN6 and PPARγ Shows Anti-Diabetic and Anti-Obese Effects.

The emergence of the high correlation between type 2 diabetes and obesity with complicated conditions has led to the coinage of the term "diabesity". AMP-activated protein kinase (AMPK) activators and peroxisome proliferator-activated receptor (PPARγ) antagonists have shown therapeutic activity for diabesity, respectively. Hence, the discovery of compounds that activate AMPK as well as antagonize PPARγ may lead to the discovery of novel therapeutic agents for diabesity. In this study, the knockdown of PTPN6 activated AMPK and suppressed adipogenesis in 3T3-L1 cells. By screening a library of 1033 natural products against PTPN6, we found ethyl gallate to be the most selective inhibitor of PTPN6 (Ki = 3.4 µM). Subsequent assay identified ethyl gallate as the best PPARγ antagonist (IC50 = 5.4 µM) among the hit compounds inhibiting PTPN6. Ethyl gallate upregulated glucose uptake and downregulated adipogenesis in 3T3-L1 cells as anticipated. These results strongly suggest that ethyl gallate, which targets both PTPN6 and PPARγ, is a potent therapeutic candidate to combat diabesity.

Nepetin Acts as a Multi-Targeting Inhibitor of Protein Tyrosine Phosphatases Relevant to Insulin Resistance.

Protein tyrosine phosphatases (PTPs) are essential modulators of signal transduction pathways and has been implicated in many human diseases such as cancer, diabetes, obesity, autoimmune disorders, and neurological diseases, indicating that PTPs are next-generation drug targets. Since PTPN1, PTPN2, and PTPN11 have been reported to be negative regulators of insulin action, the identification of PTP inhibitors may be an effective strategy to develop therapeutic agents for the treatment of type 2 diabetes. In this study, we observed for the first time that nepetin inhibits the catalytic activity of PTPN1, PTPN2, and PTPN11 in vitro, indicating that nepetin acts as a multi-targeting inhibitor of PTPN1, PTPN2, and PTPN11. Furthermore, treatment of mature 3T3-L1 adipocytes with 20 µM nepetin stimulates glucose uptake through AMPK activation. Taken together, our findings provide evidence that nepetin, a multi-targeting inhibitor of PTPN1, PTPN2, and PTPN11, could be a promising therapeutic candidate for the treatment of type 2 diabetes.

Estrogen Decreases Cytoskeletal Organization by Forming an ERα/SHP2/c-Src Complex in Osteoclasts to Protect against Ovariectomy-Induced Bone Loss in Mice.

Loss of ovarian function is closely related to estrogen (E2) deficiency, which is responsible for increased osteoclast (OC) differentiation and activity. We aimed to investigate the action mechanism of E2 to decrease bone resorption in OCs to protect from ovariectomy (OVX)-induced bone loss in mice. In vivo, tartrate-resistant acid phosphatase (TRAP) staining in femur and serum carboxy-terminal collagen crosslinks-1 (CTX-1) were analyzed upon E2 injection after OVX in mice. In vitro, OCs were analyzed by TRAP staining, actin ring formation, carboxymethylation, determination of reactive oxygen species (ROS) level, and immunoprecipitation coupled with Western blot. In vivo and in vitro, E2 decreased OC size more dramatically than OC number and Methyl-piperidino-pyrazole hydrate dihydrochloride (MPPD), an estrogen receptor alpha (ERα) antagonist, augmented the OC size. ERα was found in plasma membranes and E2/ERα signaling affected receptor activator of nuclear factor κB ligand (RANKL)-induced actin ring formation by rapidly decreasing a proto-oncogene tyrosine-protein kinase, cellular sarcoma (c-Src) (Y416) phosphorylation in OCs. E2 exposure decreased physical interactions between NADPH oxidase 1 (NOX1) and the oxidized form of c-Src homology 2 (SH2)-containing protein tyrosine phosphatase 2 (SHP2), leading to higher levels of reduced SHP2. ERα formed a complex with the reduced form of SHP2 and c-Src to decrease c-Src activation upon E2 exposure, which blocked a signal for actin ring formation by decreased Vav guanine nucleotide exchange factor 3 (Vav3) (p-Y) and Ras-related C3 botulinum toxin substrate 1 (Rac1) (GTP) activation in OCs. E2/ERα signals consistently inhibited bone resorption in vitro. In conclusion, our study suggests that E2-binding to ERα forms a complex with SHP2/c-Src to attenuate c-Src activation that was induced upon RANKL stimulation in a non-genomic manner, resulting in an impaired actin ring formation and reducing bone resorption.

Phloridzin Acts as an Inhibitor of Protein-Tyrosine Phosphatase MEG2 Relevant to Insulin Resistance.

Inhibition of the megakaryocyte protein tyrosine phosphatase 2 (PTP-MEG2, also named PTPN9) activity has been shown to be a potential therapeutic strategy for the treatment of type 2 diabetes. Previously, we reported that PTP-MEG2 knockdown enhances adenosine monophosphate activated protein kinase (AMPK) phosphorylation, suggesting that PTP-MEG2 may be a potential antidiabetic target. In this study, we found that phloridzin, isolated from Ulmus davidiana var. japonica, inhibits the catalytic activity of PTP-MEG2 (half-inhibitory concentration, IC50 = 32 ± 1.06 µM) in vitro, indicating that it could be a potential antidiabetic drug candidate. Importantly, phloridzin stimulated glucose uptake by differentiated 3T3-L1 adipocytes and C2C12 muscle cells compared to that by the control cells. Moreover, phloridzin led to the enhanced phosphorylation of AMPK and Akt relevant to increased insulin sensitivity. Importantly, phloridzin attenuated palmitate-induced insulin resistance in C2C12 muscle cells. We also found that phloridzin did not accelerate adipocyte differentiation, suggesting that phloridzin improves insulin sensitivity without significant lipid accumulation. Taken together, our results demonstrate that phloridzin, an inhibitor of PTP-MEG2, stimulates glucose uptake through the activation of both AMPK and Akt signaling pathways. These results strongly suggest that phloridzin could be used as a potential therapeutic candidate for the treatment of type 2 diabetes.

A Randomized, Noninferiority Trial Comparing ICS + LABA with ICS + LABA + LAMA in Asthma-COPD Overlap (ACO) Treatment: The ACO Treatment with Optimal Medications (ATOMIC) Study.

BACKGROUND: Current guidelines for the treatment of asthma and chronic obstructive pulmonary disease overlap (ACO) recommend initial treatment using inhaled corticosteroids (ICSs) plus 1 or more bronchodilators. OBJECTIVE: To clarify which therapeutic effect is better between the ICS + long-acting ß2 agonist (LABA) and ICS + LABA + long-acting muscarinic antagonist (LAMA) treatment in patients with ACO. METHODS: We conducted a multicenter, 48-week, randomized, noninferiority trial. Patients with ACO were enrolled if they were treated with a moderate to high dose of ICS + LABA. In total, 303 patients were involved in the present trial, with 149 receiving ICS + LABA + LAMA. The primary end point was the time to first exacerbation. Secondary outcomes included changes in FEV1, forced vital capacity, FEV1/forced vital capacity ratio, asthma control, blood eosinophil count, and fractional exhaled nitric oxide. RESULTS: In the ICS + LABA treatment group, 29 of 154 patients (18.83%) experienced exacerbation, whereas 28 of 149 patients (18.79%) experienced exacerbation in the ICS + LABA + LAMA treatment group. The results of this noninferiority study were ultimately inconclusive (hazard ratio, 1.1; 95% CI, 0.66-1.84). However, the patients treated with the addition of LAMA showed significant improvements in FEV1 and forced vital capacity (P < .001). Asthma control did not improve in either group. CONCLUSIONS: Although this study was unable to conclude that ICS + LABA treatment is not inferior to ICS + LABA + LAMA in terms of exacerbation, it is obvious that the ICS + LABA + LAMA treatment group had improved lung function in ACO.

Keratinocyte-Expressed Podoplanin is Dispensable for Multi-Step Skin Carcinogenesis.

Podoplanin is a small transmembrane mucin-like glycoprotein that plays a crucial role in the development of the lung, heart and lymphatic vascular system. Its expression is upregulated in several types of human carcinomas and podoplanin levels in squamous cell carcinomas (SCCs) of the oral cavity and the lung correlate with cancer invasiveness, lymph node metastasis and shorter survival time of patients, indicating that podoplanin promotes tumor progression. However, its role during the early stages of carcinogenesis remain unclear. We generated mice with a specific deletion of podoplanin in epidermal keratinocytes (K5-Cre;Pdpnflox/flox mice) and subjected them to a multistep chemical skin carcinogenesis regimen. The rate of tumor initiation; the number, size and differentiation of tumors; and the malignant transformation rate were comparable in K5-Cre;Pdpnflox/flox mice and Pdpnflox/flox control mice. However, tumor cell invasion was reduced in K5-Cre;Pdpnflox/flox mice, in particular single cell invasion. Quantitative immunofluorescence analyses revealed that peritumoral lymphangiogenesis was reduced in K5-Cre;Pdpnflox/flox mice, whereas there were no major changes of tumor-associated immune cell subpopulations. Thus, keratinocyte-expressed podoplanin is dispensable for the early steps of skin carcinogenesis but contributes to the progression of established tumors.

Identification of Vaccinia-H1 Related Phosphatase as an Anticancer Target for 1,2,3,4,6-O-Pentagalloylglucose.

Protein tyrosine phosphatases are involved in diverse human diseases, including cancer, diabetes and inflammatory disorders. Loss of Vaccinia-H1 related phosphatase (VHR) has been shown to arrest at the G1-S and G2-M transitions of the cell cycle, and to increases cell death of prostate cancer cells through JNK activation, suggesting that VHR can be considered as an anticancer target. In this study, 658 natural products were screened through in vitro enzyme assay to identify VHR inhibitor. Among the VHR-inhibitory compounds, 1,2,3,4,6-O-pentagalloylglucose (PGG) was selected for further study as it has been reported to show antitumor effects against tumor model mice, but its direct target has not been identified. PGG inhibited the catalytic activity of VHR (Ki =53 nm) in vitro. Furthermore, the incubation of HeLa cervical cancer cells with PGG dramatically decreased cell viability and markedly increased the protein levels of the cleaved PARP, a hallmark of apoptosis. In addition, treatment of HeLa cells with PGG significantly reduced the protein levels of cyclin D1, Bcl-2 and STAT3 phosphorylation. Taken together, these results suggest that PGG could be a potential therapeutic candidate for the treatment of cervical cancer through VHR inhibition.

An important role of cutaneous lymphatic vessels in coordinating and promoting anagen hair follicle growth.

The lymphatic vascular system plays important roles in the control of tissue fluid homeostasis and immune responses. While VEGF-A-induced angiogenesis promotes hair follicle (HF) growth, the potential role of lymphatic vessels (LVs) in HF cycling has remained unknown. In this study, we found that LVs are localized in close proximity to the HF bulge area throughout the postnatal and depilation-induced hair cycle in mice and that a network of LVs directly connects the individual HFs. Increased LV density in the skin of K14-VEGF-C transgenic mice was associated with prolongation of anagen HF growth. Conversely, HF entry into the catagen phase was accelerated in K14-sVEGFR3 transgenic mice that lack cutaneous LVs. Importantly, repeated intradermal injections of VEGF-C promoted hair growth in mice. Conditioned media from lymphatic endothelial cells promoted human dermal papilla cell (DPC) growth and expression of IGF-1 and alkaline phosphatase, both activators of DPCs. Our results reveal an unexpected role of LVs in coordinating and promoting HF growth and identify potential new therapeutic strategies for hair loss-associated conditions.

Label-Free Detection of Protein Tyrosine Phosphatase 1B (PTP1B) by Using a Rationally Designed Förster Resonance Energy Transfer (FRET) Probe.

A highly selective detection method of native protein tyrosine phosphatase 1B (PTP1B) is described using a target specific probe equipped with 1-naphthylamine (λex =330 nm, λem =445 nm). Irradiation of a mixture of PTP1B and Probe 1 with ultraviolet light of 280 nm (corresponding to PTP1B excitation maximum) resulted in significant fluorescence increase at 445 nm, following FRET characteristics. This phenomenon does not occur with other closely related phosphatases or cellular abundant alkaline phosphatase (APP). Probe 1, the most potent and selective probe, was found to competitively inhibit PTP1B (Ki ≈42 nm), whereas APP inhibition was found to be in the low micromolar range. Furthermore, Probe 1 discriminates between PTP1B and several other phosphatases. Here, we report real-time label-free FRET detection of pure PTP1B as well as induced human PTP1B in Escherichia coli cell lysate. In contrast to 6,8-difluoro-4-methylumbelliferyl phosphate (DiFMUP), a representative fluorescence turn-on PTP substrate, our FRET probe successfully differentiated human cervical carcinoma cell lysate, SiHa, which has a high expression level of PTP1B, from PTP1B-knockdown SiHa cell lysate (that is, siRNA was used for PTP1B knockdown).

S-adenosylmethionine reduces airway inflammation and fibrosis in a murine model of chronic severe asthma via suppression of oxidative stress.

Increased oxidative stress has an important role in asthmatic airway inflammation and remodeling. A potent methyl donor, S-adenosylmethionine (SAMe), is known to protect against tissue injury and fibrosis through modulation of oxidative stress. The aim of this study was to evaluate the effect of SAMe on airway inflammation and remodeling in a murine model of chronic asthma. A mouse model was generated by repeated intranasal challenge with ovalbumin and Aspergillus fungal protease twice a week for 8 weeks. SAMe was orally administered every 24 h for 8 weeks. We performed bronchoalveolar lavage (BAL) fluid analysis and histopathological examination. The levels of various cytokines and 4-hydroxy-2-nonenal (HNE) were measured in the lung tissue. Cultured macrophages and fibroblasts were employed to evaluate the underlying anti-inflammatory and antifibrotic mechanisms of SAMe. The magnitude of airway inflammation and fibrosis, as well as the total BAL cell counts, were significantly suppressed in the SAMe-treated groups. A reduction in T helper type 2 pro-inflammatory cytokines and HNE levels was observed in mouse lung tissue after SAMe administration. Macrophages cultured with SAMe also showed reduced cellular oxidative stress and pro-inflammatory cytokine production. Moreover, SAMe treatment attenuated transforming growth factor-ß (TGF-ß)-induced fibronectin expression in cultured fibroblasts. SAMe had a suppressive effect on airway inflammation and fibrosis in a mouse model of chronic asthma, at least partially through the attenuation of oxidative stress and TGF-ß-induced fibronectin expression. The results of this study suggest a potential role for SAMe as a novel therapeutic agent in chronic asthma.

Serum progranulin as an indicator of neutrophilic airway inflammation and asthma severity.

BACKGROUND: Progranulin, a protein secreted from the airway epithelium, is known to attenuate the downstream cascade of neutrophilic inflammation in particular. We hypothesized that progranulin may have a role in inflammatory regulation in asthma. OBJECTIVE: To investigate the association between serum progranulin levels and various clinical features in patients with asthma. METHODS: Serum samples and clinical data of 475 patients with asthma and 35 healthy controls at a tertiary referral hospital and its affiliated health promotion center were collected. Serum progranulin levels were compared between patients with asthma and healthy controls and then were compared within the patients with asthma in terms of pulmonary function and measures of inflammatory status. Univariate and multivariate analyses were performed to identify factors associated with severity of asthma. RESULTS: Serum progranulin levels were significantly lower in the asthma group than in healthy group and were positively correlated with prebronchodilator forced expiratory volume in 1 second predicted within patients with asthma. We found a negative correlation between serum progranulin levels and blood neutrophil counts. Multivariate analysis revealed that higher serum progranulin levels were associated with a lower risk of severe asthma (odds ratio, 0.888; 95% confidence interval, 0.846-0.932; P < .001) after adjustment for other variables, such as age, sex, smoking status, blood neutrophil count, and current use of systemic corticosteroids. CONCLUSION: Although the exact mechanism of the anti-inflammatory action of progranulin remains unknown, we suggest that serum progranulin may be an indicator of severe asthma with airflow limitation. Future studies with comprehensive airway sampling strategies are warranted to clarify its role, particularly in neutrophilic asthma.

Spontaneous Pulmonary Hematoma with No Underlying Causes: A Case Report.

A 57-year-old male patient was admitted to our center because of a cystic mass on the lower portion of the right major fissure that was found incidentally by chest X-ray. He did not have a history of trauma or anticoagulant use. The lesion was removed by video-assisted thoracoscopic surgery. Pathological examination revealed an organizing pulmonary hematoma without any complications, and a follow-up chest X-ray after 1 year showed no recurrence.

Effect of pregnancy in asthma on health care use and perinatal outcomes.

BACKGROUND: It is generally known that pregnancy in asthmatic patients increases the risk of asthma exacerbations and poor perinatal outcomes. However, the effect of pregnancy in asthmatic patients on health care use is not known well. In addition, its effect on perinatal outcomes is still controversial because of study limitations caused by ethical issues. National Health Insurance claim data are an ideal resource for studying real-world health care use patterns of asthma. OBJECTIVE: We sought to evaluate the effect of pregnancy on asthma in terms of asthma-related health care use and prescription patterns in concert with the effect of asthma exacerbations on adverse pregnancy outcomes. METHODS: Among all asthmatic patients in the Korean National Health Insurance claim database from January 2009 to December 2013, pregnant women who delivered in 2011 with pre-existing asthma were enrolled. Analyses included asthma-related health care use and prescription patterns compared between pregnant asthmatic women and nonpregnant female asthmatic control subjects, as well as within the pregnant subjects from before pregnancy throughout postpartum periods. In addition, the association between asthma exacerbation during pregnancy and adverse pregnancy outcomes was assessed. RESULTS: A total of 3,357 pregnant asthmatic patients were compared with 50,355 nonpregnant asthmatic patients, and 10,311 pregnant patients were included to determine the effect of asthma exacerbations on adverse pregnancy outcome in the study. Pregnant asthmatic patients underwent more asthma-related hospitalizations (1.3% vs 0.8%, P = .005) but had significantly fewer outpatient visits and prescriptions for most asthma medications than nonpregnant asthmatic patients. The proportion of patients ever hospitalized gradually increased throughout pregnancy (first trimester, 0.2%; second trimester, 0.5%; and third trimester, 0.7%; P = .018). The prevalence of asthma exacerbation during pregnancy was 5.3%, and the patients who had acute exacerbation during pregnancy had significantly higher asthma-related health care use in terms of hospitalization, intensive care unit admission, and emergency department and outpatient visits within 1 year before delivery than those who had not. However, asthma exacerbation during pregnancy was not significantly related to adverse perinatal outcomes, except for cesarean section (27.1% vs 18.9%, P < .001). All exacerbations were managed with systemic corticosteroids, and the patients who ever experienced acute exacerbations maintained asthma medications, including inhaled corticosteroid-based inhalers, throughout the pregnancy period. CONCLUSION: Pregnancy profoundly affects asthma-related health care use but to a different degree depending on whether the patient experienced an exacerbation. Asthma exacerbation during pregnancy is not associated with adverse pregnancy outcomes while managed appropriately with systemic corticosteroids. However, further studies are needed to clarify the effect of asthma control on perinatal outcome and delivery method.

A role of placental growth factor in hair growth.

BACKGROUND: The dermal papilla (DP) comprises specialized mesenchymal cells at the bottom of the hair follicle and plays a pivotal role in hair formation, anagen induction and the hair cycle. In this study, DPs were isolated from human hair follicles and serially subcultured. From each subculture at passages 1, 3, and 5 (n=4), we compared gene expression profiles using mRNA sequencing. Among the growth factors that were down-regulated in later passages of human DP cells (hDPCs), placental growth factor (PlGF) was selected. OBJECTIVE: To elucidate the effect of PlGF on hair growth. METHODS: We evaluated the effect of PlGF on hDPCs and on ex vivo hair organ culture. We investigated the effect of PlGF on an in vivo model of depilation-induced hair regeneration. RESULTS: We confirmed that the mRNA and protein expression levels of PlGF significantly decreased following subculture of the cells. It was shown that PlGF enhanced hair shaft elongation in ex vivo hair organ culture. Furthermore, PlGF significantly accelerated hair follicle growth and markedly prolonged anagen hair growth in an in vivo model of depilation-induced hair regeneration. PlGF prevented cell death by increasing the levels of phosphorylated extracellular signal-regulated kinase (ERK) and cyclin D1 and promoted survival by up-regulation of phosphorylated Akt and Bcl2, as determined by Western blotting. CONCLUSION: Our results suggest that PlGF plays a role in the promotion of hair growth and therefore may serve as an additional therapeutic target for the treatment of alopecia.

Interleukin-32γ suppresses allergic airway inflammation in mouse models of asthma.

Asthma is a chronic airway inflammatory disease typically associated with T helper cell type 2 (Th2) cytokines. IL-32, first reported as an inducer of tumor necrosis factor (TNF)-α, is an inflammatory cytokine involved in various autoinflammatory diseases, viral infection, and cancer-related inflammation. However, the role of IL-32γ in asthma has not been clearly elucidated. In this study, the levels of IL-32γ in sputum from patients with asthma were measured by ELISA, and IL-32γ function was investigated in murine models of asthma with human IL-32γ-overexpressed transgenic (IL-32γ TG) mice. The therapeutic effect of recombinant IL-32γ (rIL-32γ) on allergic inflammation was also evaluated through bronchoalveolar lavage fluid analysis and histopathologic examinations. Sputum IL-32γ levels from patients with asthma were lower than those from healthy control subjects. In an acute mouse model of asthma, IL-32γ TG mice exhibited significantly reduced airway inflammation compared with that in wild-type mice. The production of Th1 cytokines, such as TNF-α and IFN-γ, and Th2 cytokines, such as IL-4, IL-5, and IL-13, was decreased in the lungs of IL-32γTG mice. On the contrary, the expression of IL-10 and IL-10-producing CD11b(+) monocytic cells was significantly increased in the lungs of ovalbumin-sensitized IL-32γ TG mice. In addition, rIL-32γ treatment revealed a suppressive effect on the airway inflammation in a chronic mouse model of asthma. The results of this study suggest that IL-32γ may have a preventive role in the development of allergic airway inflammation and could be a potential novel therapeutic target for bronchial asthma.

Characteristics of liver injury in drug-induced systemic hypersensitivity reactions.

BACKGROUND: The liver is the most commonly involved internal organ in drug-induced systemic hypersensitivity. However, data obtained from these patients have yet to be analyzed in depth with respect to liver injury. METHODS: The medical records of 136 patients who developed delayed-type drug hypersensitivity were reviewed at a tertiary referral hospital. Culprit drugs, the pattern and degree of liver injury, and the effect of systemic corticosteroids were evaluated in the group of patients with drug-induced systemic hypersensitivity and liver dysfunction (aspartate aminotransferase or alanine aminotransferase ≥80 IU/L). Clinical characteristics of patients with drug-induced systemic hypersensitivity and liver injury were analyzed. RESULTS: Among the 61 patients with drug-induced systemic hypersensitivity and liver dysfunction, the clinical phenotypes were drug reaction with eosinophilia and systemic symptoms (n = 29, 48%), Stevens-Johnson syndrome/toxic epidermal necrolysis (n = 11, 18%), and maculopapular rash (n = 17, 28%). Antibiotics (n = 27, 44%) were the most common cause of drug-induced systemic hypersensitivity with liver dysfunction. Whereas patients with Stevens-Johnson syndrome/toxic epidermal necrolysis had mild hepatocellular-type liver injury of relatively brief duration, those with drug reaction with eosinophilia and systemic symptoms/drug-induced hypersensitivity syndrome had more severe and prolonged hepatocellular injury in addition to moderate to severe cholestatic-type liver injury. The use of systemic corticosteroids did not significantly affect either recovery from liver injury or mortality. LIMITATIONS: This study was retrospective and the number of subjects was small. CONCLUSION: The results suggest that the severity, pattern, and duration of liver injury differ according to the drug-hypersensitivity phenotype. Further studies are needed to evaluate the role of systemic corticosteroids in drug-induced systemic hypersensitivity and liver injury.

Clinical significance of asthma clusters by longitudinal analysis in Korean asthma cohort.

BACKGROUND: We have previously identified four distinct groups of asthma patients in KOREAN cohorts using cluster analysis: (A) smoking asthma, (B) severe obstructive asthma, (C) early-onset atopic asthma, and (D) late-onset mild asthma. METHODS AND RESULTS: A longitudinal analysis of each cluster in a Korean adult asthma cohort was performed to investigate the clinical significance of asthma clusters over 12 months. Cluster A showed relatively high asthma control test (ACT) scores but relatively low FEV1 scores, despite a high percentage of systemic corticosteroid use. Cluster B had the lowest mean FEV1, ACT, and the quality of life questionnaire for adult Korean asthmatics (QLQAKA) scores throughout the year, even though the percentage of systemic corticosteroid use was the highest among the four clusters. Cluster C was ranked second in terms of FEV1, with the second lowest percentage of systemic corticosteroid use, and showed a marked improvement in subjective symptoms over time. Cluster D consistently showed the highest FEV1, the lowest systemic corticosteroid use, and had high ACT and QLQAKA scores. CONCLUSION: Our asthma clusters had clinical significance with consistency among clusters over 12 months. These distinctive phenotypes may be useful in classifying asthma in real practice.

Induction of hair growth by insulin-like growth factor-1 in 1,763 MHz radiofrequency-irradiated hair follicle cells.

Radiofrequency (RF) radiation does not transfer high energy to break the covalent bonds of macromolecules, but these low energy stimuli might be sufficient to induce molecular responses in a specific manner. We monitored the effect of 1,763 MHz RF radiation on cultured human dermal papilla cells (hDPCs) by evaluating changes in the expression of cytokines related to hair growth. The expression of insulin-like growth factor-1 (IGF-1) mRNA in hDPCs was significantly induced upon RF radiation at the specific absorption rate of 10 W/kg, which resulted in increased expression of B-cell chronic lymphocytic leukemia/lymphoma 2 (BCL-2) and cyclin D1 (CCND1) proteins and increased phosphorylation of MAPK1 protein. Exposure to 10 W/kg RF radiation 1 h per day for 7 days significantly enhanced hair shaft elongation in ex vivo hair organ cultures. In RF-exposed follicular matrix keratinocytes in the hair bulb, the expression of Ki-67 was increased, while the signal for terminal deoxynucleotidyl transferase dUTP nick end labeling was reduced. From these results, we suggest that 1,763 MHz RF exposure stimulates hair growth in vitro through the induction of IGF-1 in hDPCs.

Geldanamycin inhibits TGF-beta signaling through induction of Hsp70.

Dysregulation of transforming growth factor-beta (TGF-beta) signaling has been implicated in the pathogenesis of a variety of diseases including cancer; therefore, pharmacological inhibitors that target the TGF-beta signaling pathway might be promising drugs for disease therapy. In this study, we investigated the mechanism of inhibition of TGF-beta signaling by the Hsp90 inhibitor geldanamycin (GA). Treatment with GA suppressed TGF-beta signaling, as evidenced by inhibition of TGF-beta-induced phosphorylation and transcriptional activity of Smad3 and decreased induction of target genes. Western blot analysis revealed that GA induced degradation of TGF-beta type I and type II receptors through a proteasome-dependent pathway. Notably, induction of Hsp70 by GA correlated with inhibition of TGF-beta signaling. Suppression of Hsp70 expression by Hsp70 siRNA or KNK437, an inhibitor of Hsp70 synthesis, blocked the inhibition of TGF-beta signaling by GA. Furthermore, Hsp70 interacted directly with TGF-beta receptors following GA treatment. Our results suggest that GA-mediated induction of Hsp70 and its subsequent interaction with TGF-beta receptors plays a crucial role in inhibition of TGF-beta signaling.