Facial erythema in patients with atopic dermatitis treated with Dupilumab - a descriptive study of morphology and Aetiology.

BACKGROUND: The development of dermatitis on face and neck, which was not described in phase 3 clinical trials, has been reported in the literature in patients treated with dupilumab. Little is known regarding the causes or defining features of the facial dermatitis. OBJECTIVES: We conducted surveys of consecutive patients with AD on dupilumab to describe its clinical features, morphology and aetiology. METHODS: A multi-centre prospective cohort study was conducted from 1 January 2020, to 31 December 31 2020. A total of 162 patients under dupilumab treatment were asked to complete a questionnaire and patients were evaluated by dermatologists. RESULTS: Of all 162 patients, 137 (84.6%) patients reported pre-existing facial dermatitis prior to dupilumab therapy. One hundred and twenty-one (88.3%) patients with pre-existing facial dermatitis reported improvement of their facial dermatitis with dupilumab therapy, nine (6.6%) patients reported no change after the treatment and seven (4.3%) patients of them got worse after the treatment (exacerbation group). Of 25 patients who reported no pre-existing active facial dermatitis, six (24%) patients reported new-onset facial erythema after the starting dupilumab therapy (new-onset group). A large proportion of the patients in both the exacerbation (86%) and new-onset groups (67%) had a history of facial TCS use. Both groups showed similar clinical manifestations and distribution with few differences. CONCLUSIONS: The vast majority of patients treated with dupilumab in academic institutions from Korea and the United States experienced improvement in their facial dermatitis with dupilumab therapy. A small proportion of patients had new onset and exacerbation. Although the mechanisms of this adverse event remain unclear, steroid withdrawal should be considered as a diagnosis of the erythema in some patients.

Association between air pollution and chronic rhinosinusitis: a nested case-control study using meteorological data and national health screening cohort data.

BACKGROUND: Inconsistent results about the effect of air pollution on chronic rhinosinusitis (CRS) have been reported. This study aimed to evaluate the impact of meteorological conditions/air pollution on the prevalence of CRS in adult Koreans. METHODOLOGY: The data from the Korean National Health Insurance Service-Health Screening Cohort from 2002 through 2015 were used. A CRS group (defined as ICD-10 codes J32, n=6159) was matched with a control group (n=24,636) in 1:4 ratios by age, sex, income, and region of residence. The meteorological conditions and air pollution data included the daily mean, highest, and lowest temperature (°C), daily temperature range (°C), relative humidity (%), ambient atmospheric pressure (hPa), sunshine duration (hr), and the rainfall (mm), SO2 (ppm), NO2 (ppm), O3 (ppm), CO (ppm), and PM10 (λg/m3) levels before the CRS diagnosis. Crude and adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for CRS were analyzed using logistic regression analyses. RESULTS: When the NO2 level increased by 0.1 ppm, the odds for CRS increased 5.40 times, and when the CO level increased by 1 ppm and PM10 increased by 10 λg/m3, the odds for CRS decreased 0.75 times and 0.93 times, respectively. Other meteorological conditions, such as the mean/highest/lowest temperature, temperature range, rainfall and other air pollution, such as SO2 and O3, were not statistically significant. NO2 for 90 days before the index date increased the risk of CRS in all subgroups, except for the nasal polyp and older age subgroups. CONCLUSION: CRS is related to high concentrations of NO2.

Mask-induced dermatoses during the COVID-19 pandemic: a questionnaire-based study in 12 Korean hospitals.

BACKGROUND: During the coronavirus disease 2019 (COVID-19) pandemic, various adverse skin reactions to long-term mask wearing have been reported. AIM: To assess the clinical features of mask-induced dermatoses and to recommend prevention and treatment options. METHODS: From April to August 2020, questionnaires including topics such as demographic information, pre-existing skin disorders, reported mask-related symptoms, daily mask-wearing duration and frequency, types of masks used and whether the participant was a healthcare worker, were distributed to patients in 12 hospitals. Dermatologists assessed skin lesions, confirmed diagnosis and recorded treatments. RESULTS: Itchiness was the most frequent symptom, mostly affecting the cheeks. The most common skin disease was new-onset contact dermatitis (33.94%), followed by new-onset acne (16.97%) and worsening of pre-existing acne (16.97%). Daily wearing of masks was significantly (P = 0.02) associated with new-onset contact dermatitis. More than half of patients with pre-existing skin problems experienced disease worsening while wearing masks. Longer duration of wearing (> 6 h/day, P = 0.04) and use of cotton masks (P < 0.001) significantly increased acne flare-up. Healthcare workers had a higher incidence of skin disease. Skin lesions were generally mild and well tolerated with topical treatment. The study had some limitations: the effect of seasonal characteristics and other risk factors were not assessed, and the patients were visiting dermatological clinics and had interest in their skin status, thus, there may have been selection bias. CONCLUSION: Mask-induced/-triggered dermatoses contribute to increase the dermatological burden during the pandemic.

Chronic rhinosinusitis and progression of cognitive impairment in dementia.

AIM: The relationship between chronic inflammatory disease and cognitive decline is still unclear, but there is increasing evidence to support the role of systemic inflammation. The aim of this study was to investigate if chronic rhinosinusitis (CRS) in dementia or mild cognitive impairment (MCI) is associated with the progression of cognitive decline. MATERIAL AND METHODS: We retrospectively reviewed the data of patients who complained of memory impairment, and underwent brain magnetic resonance imaging (MRI) from January 2006 to April 2019. According to the Mini-Mental State Examination (MMSE) score, subjects (n=661) were divided into three groups: dementia (≤17), MCI (18-23), and normal (≥24). CRS was defined as a total score of greater than or equal to 4 according to the Lund-Mackay scoring system using brain MRI. Multiple logistic regression analyses estimated adjusted odds ratio (aOR) for the association between CRS and dementia or MCI. Among the subjects with follow-up MMSE (n=286), a repeated-measures ANOVA was used to assess the difference of changes in MMSE scores between the groups with and without CRS. RESULTS: According to the initial MMSE score, there were 221 subjects with dementia, 195 with MCI, and 245 with normal results. CRS was not significantly associated with dementia (aOR=1.519, CI=0.909-2.538, P=0.111), while being suggestively associated with MCI (aOR=1.740, CI=1.041-2.906, P=0.034). The MMSE scores at follow-up decreased further in subjects with CRS than in those without CRS (P=0.009). Especially, in the initial dementia group, there was a significant between-group difference in the MMSE score from baseline to follow-up (13.6±4.3 to 11.1±6.3 in CRS group vs. 13.5±3.3 to 14.4±5.4 in no CRS group, P=0.002). CONCLUSION: The result of the present study implies a potential association between CRS and progression of cognitive decline. Physicians should be aware of this possibility in patients with clinically diagnosed CRS.

Clinical Characteristics of Developmentally Delayed Children based on Interdisciplinary Evaluation.

The aim of this study is to examine the clinical characteristics of children suspected to have neurodevelopmental disorders and to present features that could be helpful diagnostic clues at the clinical assessment stage. All children who visited the interdisciplinary clinic for developmental problems from May 2001 to December 2014 were eligible for this study. Medical records of the children were reviewed. A total of 1,877 children were enrolled in this study. Most children were classified into four major diagnostic groups: global developmental delay (GDD), autism spectrum disorder (ASD), developmental language disorder (DLD) and motor delay (MD). GDD was the most common (43.9%), and boys were significantly more predominant than girls in all groups. When evaluating the predictive power of numerous risk factors, the probability of GDD was lower than the probability of ASD among boys, while the probability of GDD increased as independent walking age increased. Compared with GDD and DLD, the probability of GDD was increased when there was neonatal history or when the independent walking age was late. Comparison of ASD and DLD showed that the probability of ASD decreased when a maternal history was present, whereas the probability of ASD increased with male gender. To conclude, the present study revealed the clinical features of children with various neurodevelopmental disorders. These results are expected to be helpful for more effectively flagging children with potential neurodevelopmental disorders in the clinical setting.

Hypereosinophilic syndrome presenting with bilateral ear fullness.

INTRODUCTION: Hypereosinophilic syndrome is a rare disease with hypereosinophilia resulting in end-organ dysfunction. Patients present with organ-associated symptoms, and the targets frequently affected are heart, lung, skin, or the nervous system, and the middle ear involvement is rare. CASE REPORT: A 30-year-old female with left ear fullness and hearing loss, which persisted for 6months, was finally diagnosed with hypereosinophilic syndrome (HES). After high dose systemic steroids treatment, all symptoms improved. CONCLUSION: Eosinophilic otitis media and HES involving the middle ear share many clinical manifestations. Prompt and accurate differential diagnosis is required for these diseases to ameliorate symptoms and promote recovery.

Analysis of the number of enlarged pores according to site, age, and sex.

BACKGROUND: Increasing the number of enlarged pores causes cosmetic problems. The difference in the number of enlarged pores according to facial site, age, and sex is unclear. OBJECTIVE: To analyze the distribution of the number of enlarged pores according to facial site, age, and sex. METHODS AND MATERIALS: We analyzed the number of the enlarged pores and the percentage of wrinkles in the nose, forehead, and cheek from 434 polarized images. The measurement results were analyzed according to site, age, and sex. Relationship between enlarged pore counts and wrinkle severity was also analyzed. The study was conducted by using DermaVision,™ which can take cross-polarization, parallel polarization, and ultraviolet light images. RESULTS: The enlarged pores of the nose and forehead were more prominent than in the cheeks. Pore counts were increased with age, and the increment was significant between the 30's and 40's. There was no significant difference by gender. Enlarged pore counts were related to wrinkle severity. CONCLUSIONS: The number of enlarged pores differs depending on body site and increased with age. The enlarged pore counts correlate with wrinkle severity and the correlation varies depending on the body site.

Electronic Band Alignment at Complex Oxide Interfaces Measured by Scanning Photocurrent Microscopy.

The band alignment at an Al2O3/SrTiO3 heterointerface forming a two-dimensional electron gas (2DEG) was investigated using scanning photocurrent microscopy (SPCM) in an electrolyte-gated environment. We used a focused UV laser source for above-the-bandgap illumination on the SrTiO3 layer, creating electron-hole pairs that contributed to the photocurrent through migration towards the metal electrodes. The polarity of the SPCM signals of a bare SrTiO3 device shows typical p-type behavior at zero gate bias, in which the photogenerated electrons are collected by the electrodes. In contrast, the SPCM polarity of 2DEG device indicates that the hole carriers were collected by the metal electrodes. Careful transport measurements revealed that the gate-dependent conductance of the 2DEG devices exhibits n-type switching behavior. More importantly, the SPCM signals in 2DEG devices demonstrated very unique gate-responses that cannot be found in conventional semiconducting devices, based on which we were able to perform detailed investigation into the electronic band alignment of the 2DEG devices and obtain the valence band offset at the heterointerface.

Undifferentiated embryonic cell transcription factor 1 (UTF1) and deleted in azoospermia-like (DAZL) expression in the testes of donkeys.

Putative markers for each specific germ cell stage can be a useful tool to study the fate and functions of these cells. Undifferentiated embryonic cell transcription factor 1 (UTF1) is a putative marker for undifferentiated spermatogonia in humans, rats and horses. The deleted in azoospermia-like (DAZL) protein is also expressed by differentiated spermatogonia and primary spermatocytes in several species. However, whether the expression patterns of these molecular markers are identical and applicable to donkeys remains to be elucidated. The objective of this study was to investigate the expression patterns of UTF1 and DAZL in donkey testicular tissue, using immunohistochemistry (IHC). Testicular samples were collected from routine field castration of donkeys in Korea. The reproductive stages (pre- or post-puberty) of the testes were determined from the morphological characteristics of cross-sections of the seminiferous tubules. For IHC, the UTF1 and DAZL primary antibodies were diluted at 1:100 and 1:200, respectively. The immunolabelling revealed that UTF1 was expressed in approximately 50% of spermatogonia in the pre-pubertal stage, whereas its expression was limited to an early subset of spermatogonia in the post-pubertal stage. DAZL was expressed in some, but not all, spermatogonia in the pre-pubertal spermatogonia, and interestingly, its expression was also observed in spermatogonia and primary spermatocytes in the post-pubertal stage. Co-immunolabelling of the germ cells with both UTF1 and DAZL revealed three types of protein expression patterns at both reproductive stages, namely UTF1 only, DAZL only and both UTF1 and DAZL. These protein molecules were not expressed in Sertoli and Leydig cells. In conclusion, a co-immunolabelling system with UTF1 and DAZL antibodies may be used to identify undifferentiated (UTF1 only), differentiating (UTF1 and DAZL), and differentiated spermatogonia (DAZL only) in donkey testes.

The use of continuous negative pressure after open debridement for septic arthritis of the shoulder.

AIMS: The treatment of septic arthritis of the shoulder is challenging. The infection frequently recurs and the clinical outcome can be very poor. We aimed to review the outcomes following the use of continuous negative pressure after open debridement with a large diameter drain in patients with septic arthritis of the shoulder. PATIENTS AND METHODS: A total of 68 consecutive patients with septic arthritis of the shoulder underwent arthrotomy, irrigation and debridement. A small diameter suction drain was placed in the glenohumeral joint and a large diameter drain was placed in the subacromial space with continuous negative pressure of 15 cm H2O. All patients received a standardised protocol of antibiotics for a mean of 5.1 weeks (two to 11.1). RESULTS: Negative pressure was maintained for a mean of 24 days (14 to 32). A total of 67 patients (98.5%) were cured without further treatment being required. At a mean follow-up of 14 months (three to 72), the mean forward flexion was 123° (80° to 140°) and the mean external rotation was 28°(10° to 40°) in those with a rotator cuff tear, and 125° (85° to 145°) and 35° (15° to 45°) in those without a rotator cuff tear. CONCLUSION: Continuous negative pressure, following open arthrotomy, irrigation and debridement, was effective in treating septic arthritis of the shoulder. The rate of recurrence was significantly lower than with conventional treatment involving arthroscopic or open debridement reported in the literature. Functional outcomes, even in patients with rotator cuff tears, were excellent. TAKE HOME MESSAGE: Continuous negative pressure is effective in treating septic arthritis of the shoulder. Cite this article: Bone Joint J 2016;98-B:660-5.

Essential role of insulin-like growth factor 2 in resistance to histone deacetylase inhibitors.

Histone deacetylase (HDAC) inhibitors (HDIs) are promising anticancer therapies and have been clinically used for the treatment of hematological malignancy. However, their efficacy in solid tumors is marginal and drug resistance hampers their further clinical utility. To develop novel strategies for the HDI-based anticancer therapeutics in non-small cell lung cancer (NSCLC), in the present study, we investigated the mechanisms underlying resistance to HDI treatment in NSCLC cells. We show the STAT3-mediated IGF2/IGF-1R signaling cascade as a key modulator for both acquired and primary HDI resistance. The treatment with HDI upregulated IGF2 transcription in NSCLC cells carrying intrinsic or acquired drug resistance via direct binding of STAT3 in IGF2 P3 and P4 promoters. Acetylated STAT3 emerged upon HDAC inhibition was protected from the proteasome-mediated degradation of STAT3 and functioned as a direct transcription factor for IGF2 expression. Genomic or pharmacological strategies targeting STAT3 diminished the HDI-induced IGF2 mRNA expression and overcame the resistance to HDI treatment in HDI-resistant NSCLC- or patient-derived tumor xenograft models. These findings provide new insights into the role of acetylated STAT3-mediated activation of IGF2 transcription in HDI resistance, suggesting IGF2 or STAT3 as novel targets to overcome HDI resistance in NSCLC.

The anticancer effect of chaetocin is enhanced by inhibition of autophagy.

Chaetocin is a fungal metabolite that possesses a potent antiproliferative activity in solid tumors by inducing cell death. Although recent studies have extended the role of chaetocin in tumors, the underlying molecular mechanisms such as the downstream cascade that induces cell death has not clearly been elucidated. In this study, we show that chaetocin is able to induce both apoptosis and autophagy in several hepatoma cell lines including HepG2, Hep3B and Huh7 cell lines. Moreover, we found that the inhibition of caspase-3/7 activity by z-VAD-fmk treatment was able to block chaetocin-mediated cell death, whereas blocking autophagy by Bafilomycin A1 or the knockdown of autophagy protein 5 enhanced cell death mediated by chaetocin. These findings suggest that chaetocin has a potent anticancer effect against hepatoma. Inhibition of autophagy may potentiate anticancer effects of chaetocin thus providing evidence that combined treatment with chaetocin and autophagy inhibitors will be an effective strategy for treating cancer.

The nutrition contribution of dietary supplements on total nutrient intake in children and adolescents.

BACKGROUND/OBJECTIVES: The use of dietary supplements (DSs) by children and adolescents is increasing. The aim of this study was to identify the characteristics of DS users and examine the nutritional contributions of DSs to total nutrient intakes in children and adolescents, using data obtained from a national survey. SUBJECTS/METHODS: In total, 3134 subjects aged 9-18 years who participated in the 4th Korea National Health and Nutrition Examination Survey (2007-2009) were selected; the survey included 24-h recall questions on food intake and questions on DS use over the past year. Nutrient intakes from DSs were calculated using the aid of a label-based database on such supplements, and individual total nutrient intakes were derived by combining information on the foods and DSs consumed by each subject. RESULTS: There were 895 DS users (28.5%), 85.2% of whom (n=577) had complete DS nutrient information and were therefore defined as identified-DS users. Identified-DS users were slightly younger and had a greater household income and better nutritional knowledge than did non-users. The most frequently consumed type of supplement was a 'multivitamin and minerals' complex. For total nutrient intake, identified-DS users had a significantly higher intake of most of the nutrients, except for macronutrient and sodium than non-users. In all identified-DS users, the contribution of vitamins and minerals from DSs to total nutrient intake was higher than energy and macronutrients. CONCLUSIONS: DS use by children and adolescents can improve micronutrient status, but it also increases the risk of excessive intake of certain vitamins and minerals.

A combination of excimer laser treatment and topical tacrolimus is more effective in treating vitiligo than either therapy alone for the initial 6 months, but not thereafter.

BACKGROUND: There are insufficient data on the long-term outcome of a combination therapy that comprises phototherapy and topical administration of tacrolimus. AIM: To evaluate the clinical efficacy according to the duration of treatment and in vitro results of a combination therapy involving topical tacrolimus and an excimer laser in the treatment of vitiligo. METHODS: In total, 276 patients with nonsegmental vitiligo were treated with an excimer laser twice weekly, or with tacrolimus ointment twice daily, or both. The melanin contents and levels of melanogenic enzymes were measured in cultured human melanocytes treated with tacrolimus and/or excimer laser. RESULTS: After adjusting for potential confounders, the combination of tacrolimus plus excimer laser was significantly more effective than either tacrolimus or excimer laser alone (P < 0.001 and P < 0.01, respectively) for the first 6 months. However, this superiority was not observed after the initial 6 months of treatment. In vitro, the combination of tacrolimus plus excimer laser led to a higher level of melanogenesis than with either treatment alone. CONCLUSIONS: A combination treatment with topical tacrolimus and an excimer laser may be useful as an induction therapy for up to 6 months, but continuation of this therapy for > 6 months might not provide a better final outcome than monotherapy.

Acrosin-binding protein (ACRBP) in the testes of stallions.

Acrosin Binding Protein (ACRBP) is specifically localized in the acrosome of germ cells of several species, including mice, pigs, guinea pigs, and humans. The main objective of this study was to investigate ACRBP patterns in the germ cells of stallions at different reproductive stages and seminiferous tubule stages using Western blot, immunohistochemistry, and immunocytochemistry techniques. The stallion reproductive stages were classified as follows: pre-pubertal and post-pubertal stages based on the presence/absence of lumen opening in the seminiferous tubules and full spermatogenesis. The protein band associated with the presence of ACRBP appeared at approximately 35-kDa position, indicating that the antibody used in this study recognizes the mature form of ACRBP. During the pre-pubertal stages, immunolabeling did not detect the presence of ACRBP in the germ cells. However, during the post-pubertal stage, immunolabeling of the ACRBP was observed in the pachytene spermatocyte as well as for round, elongating, and elongated spermatids, and in some spermatozoa. In conclusion, the ACRBP can be used as a molecular marker for pachytene spermatocytes, and for round, elongating, and elongated spermatids. The ACRBP can be used to monitor either normal spermatogenesis in the testicular tissues, or germ cell development in vitro. Because the ACRBP is present in the germ cells of stallions that have undergone puberty, it can be used as an indicator for the sexual maturation of stallions.

VASA (DDX4) is a Putative Marker for Spermatogonia, Spermatocytes and Round Spermatids in Stallions.

Expression of the protein DDX4/MVH, or VASA, has been reported in germ cells of several species. The main objectives of this study were to (i) investigate VASA expression patterns in testicular cells of stallions at two different reproductive stages (pre-pubertal and post-pubertal) and (ii) evaluate the use of VASA antibody as a molecular marker for single germ cells from stallions. Testicular tissues were obtained from stallions and categorized as pre-pubertal and post-pubertal based on the formation of lumen and status of spermatogenesis on the cross section of seminiferous tubules. The results of Western blot showed a VASA protein band located at 76 kDa, indicating that the rabbit antibody has a cross-reactivity with horse testicular tissues. The result of immunolabelling showed that VASA was expressed in the cytoplasm of spermatogonia at both reproductive stages and in spermatocytes and round spermatids at the post-pubertal stage. GATA4-positive Sertoli cells and Leydig cells located in the interstitial space were not immunolabelled with VASA. These results suggest that VASA can be utilized as a molecular marker for germ cells of stallions at pre-pubertal and post-pubertal stages. Interestingly, immunolabelling intensity was significantly higher in pachytene spermatocytes compared to spermatogonia and round spermatid. VASA antibody was also effective for staining of single germ cell preparations. In conclusion, VASA protein expression can be used as a marker for identification of spermatogonia, spermatocytes and round spermatids in testicular tissues of stallions.

Effects of Palonosetron on Perioperative Cardiovascular Complications in Patients Undergoing Noncardiac Surgery With General Anesthesia: A Retrospective Cohort Study.

We retrospectively investigated whether palonosetron administered during the induction of general anesthesia is associated with an increased risk of perioperative cardiovascular complications in a single tertiary center cohort consisting of 4,517 palonosetron-exposed patients and 4,517 propensity score-matched patients without palonosetron exposure. The primary endpoint was a composite of perioperative cardiovascular complications, including intraoperative cardiac arrhythmia, intraoperative cardiac death, and myocardial injury within the first postoperative week, and there was no significant difference between the groups (odds ratio [OR] = 1.04; 95% confidence interval [CI] = 0.92-1.19). As secondary endpoints, intraoperative cardioversion, cardiac compression, use of cardiovascular drugs, postoperative hospital stay, and in-hospital mortality showed no differences between the groups. However, the palonosetron group showed decreased intraoperative hypotension (OR = 0.88; 95% CI = 0.79-0.97) and length of postoperative intensive care unit (ICU) stay (4.26 ± 9.86 vs. 6.14 ± 16.75; P = 0.026). Palonosetron did not increase the rate of perioperative cardiovascular complications, and can therefore be used safely during anesthetic induction.

Estimating retrospective exposure of household humidifier disinfectants.

UNLABELLED: We conducted a comprehensive humidifier disinfectant exposure characterization for 374 subjects with lung disease who presumed their disease was related to humidifier disinfectant use (patient group) and for 303 of their family members (family group) for an ongoing epidemiological study. We visited the homes of the registered patients to investigate disinfectant use characteristics. Probability of exposure to disinfectants was determined from the questionnaire and supporting evidence from photographs demonstrating the use of humidifier disinfectant, disinfectant purchase receipts, any residual disinfectant, and the consistency of their statements. Exposure duration was estimated as cumulative disinfectant use hours from the questionnaire. Airborne disinfectant exposure intensity (µg/m(3)) was estimated based on the disinfectant volume (ml) and frequency added to the humidifier per day, disinfectant bulk level (µg/ml), the volume of the room (m(3)) with humidifier disinfectant, and the degree of ventilation. Overall, the distribution patterns of the intensity, duration, and cumulative exposure to humidifier disinfectants for the patient group were higher than those of the family group, especially for pregnant women and patients ≤6 years old. Further study is underway to evaluate the association between the disinfectant exposures estimated here with clinically diagnosed lung disease. PRACTICAL IMPLICATIONS: Retrospective exposure to household humidifier disinfectant as estimated here can be used to evaluate associations with clinically diagnosed lung disease due to the use of humidifier disinfectant in Korea. The framework, with modifications to account for dispersion and use patterns, can also be potentially adapted to assessment of other household chemical exposures.

PKCδ phosphorylation is an upstream event of GSK3 inactivation-mediated ROS generation in TGF-ß1-induced senescence.

Transforming growth factor ß1 (TGF-ß1) induces Mv1Lu cell senescence through inactivating glycogen synthase kinase 3 (GSK3), thereby inactivating complex IV and increasing intracellular ROS. In the present study, we identified protein kinase C delta (PKCδ) as an upstream regulator of GSK3 inactivation in this mechanism of TGF-ß1-induced senescence. When Mv1Lu cells were exposed to TGF-ß1, PKCδ phosphorylation simultaneously increased with GSK3 phosphorylation, and then AKT and ERK were phosphorylated. AKT phosphorylation and Smad signaling were independent of GSK3 phosphorylation, but ERK phosphorylation was downstream of GSK3 inactivation. TGF-ß1-triggered GSK3 phosphorylation was blocked by inhibition of PKCδ, using its pharmacological inhibitor, Rottlerin, or overexpression of a dominant negative PKCδ mutant, but GSK3 inhibition with SB415286 did not alter PKCδ phosphorylation. Activation of PKCδ by PMA delayed cell growth and increased intracellular ROS level, but did not induce senescent phenotypes. In addition, overexpression of wild type or a constitutively active PKCδ mutant was enough to delay cell growth and decrease the mitochondrial oxygen consumption rate and complex IV activity, but weakly induce senescence. However, PMA treatment on Mv1Lu cells, which overexpress wild type and constitutively active PKCδ mutants, effectively induced senescence. These results indicate that PKCδ plays a key role in TGF-ß1-induced senescence of Mv1Lu cells through the phosphorylation of GSK3, thereby triggering mitochondrial complex IV dysfunction and intracellular ROS generation.