Cytotoxic effect of celastrol alone or in combination with paclitaxel on anaplastic thyroid carcinoma cells.

The influence of celastrol alone or in combination with paclitaxel on survival of anaplastic thyroid carcinoma cells was investigated. In 8505C and SW1736 cells, after treatment of celastrol, cell viability decreased, and cytotoxic activity increased. The protein levels of heat shock protein (hsp) 90, hsp70, Bax, death receptor 5, cleaved caspase-3, cleaved poly (ADP-ribose) polymerase, phospho-extracellular signal-regulated kinase 1/2 (ERK1/2), and phospho-c-Jun N-terminal kinase (JNK) were elevated, and those of Bcl2, phospho-nuclear factor-kappaB (NF-κB), and total and phospho-Akt were reduced. The endoplasmic reticulum stress markers expression and reactive oxygen species production were enhanced. In celastrol-treated cells, N-acetylcysteine increased cell viability and phospho-NF-κB protein levels, and decreased reactive oxygen species production and cytotoxic activity. The protein levels of cyclooxygenase 2, phospho-ERK1/2, phospho-JNK and Bip were diminished. After treatment of both celastrol and paclitaxel, compared with paclitaxel alone, cell viability and the percentage of viable cells were reduced, and death rate and cytotoxic activity were elevated. The protein levels of phospho-ERK1/2, phospho-JNK, Bip, and cyclooxygenase 2, and reactive oxygen species production were enhanced. All of the Combination Index values calculated by Chou-Talalay equation were lower than 1.0, implying the synergism between celastrol and paclitaxel in induction of cell death. In conclusion, our results suggest that celastrol induces cytotoxicity through involvement of Bcl2 family proteins and death receptor, and modulation of phospho-NF-κB, Akt, and mitogen-activated protein kinase in association with endoplasmic reticulum stress and reactive oxygen species production in anaplastic thyroid carcinoma cells. Moreover, celastrol synergizes with paclitaxel in induction of cytotoxicity in anaplastic thyroid carcinoma cells.

Doxorubicin has a synergistic cytotoxicity with cucurbitacin B in anaplastic thyroid carcinoma cells.

In this study, the combined effect of doxorubicin with cucurbitacin B on survival of anaplastic thyroid carcinoma cells was evaluated. For experiments, 8505C and CAL62 human anaplastic thyroid carcinoma cells were used. Cell viability, the percentage of viable cells, and cytotoxic activity were measured using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, multiplexed cytotoxicity assay, and cytotoxicity assay, respectively. Reactive oxygen species production was measured. In experiments, doxorubicin and cucurbitacin B reduced cell viability in a dose- and time-dependent manner. Cotreatment of doxorubicin and cucurbitacin B, compared with treatment of doxorubicin alone, decreased the percentage of viable cells and increased cytotoxic activity. All of the combination index values were lower than 1.0, suggesting the synergism between doxorubicin and cucurbitacin B in induction of cytotoxicity. In cells treated with both doxorubicin and cucurbitacin B, compared with doxorubicin alone, the protein levels of cleaved poly(adenosine diphosphate-ribose) polymerase and cyclooxygenase 2 and reactive oxygen species production were enhanced. In contrast, the protein levels of B-cell chronic lymphocytic leukemia/lymphoma 2 and survivin and B-cell chronic lymphocytic leukemia/lymphoma 2/B-cell chronic lymphocytic leukemia/lymphoma 2-associated x protein ratio were diminished. The protein levels of Janus kinase 2 and signal transducer and activator of transcription 3 were reduced, while phospho-extracellular signal-regulated kinase 1/2 protein levels were elevated without change in total extracellular signal-regulated kinase 1/2 protein levels. These results suggest that doxorubicin synergizes with cucurbitacin B in induction of cytotoxicity in anaplastic thyroid carcinoma cells. Moreover, synergistic cytotoxicity of doxorubicin with cucurbitacin B is mediated by B-cell chronic lymphocytic leukemia/lymphoma 2 family proteins, survivin, and reactive oxygen species and modulated by Janus kinase 2/signal transducer and activator of transcription 3 and extracellular signal-regulated kinase 1/2 in anaplastic thyroid carcinoma cells.

The dipeptidyl peptidase-IV inhibitor gemigliptin alone or in combination with NVP-AUY922 has a cytotoxic activity in thyroid carcinoma cells.

The effect of the dipeptidyl peptidase-IV inhibitor gemigliptin alone or in combination with the heat shock protein 90 inhibitor NVP-AUY922 (AUY922) on survival of thyroid carcinoma cells was elucidated. The SW1736 and TPC-1 human thyroid carcinoma cells were used. Cell viability, the percentage of viable cells, cytotoxic activity, the percentage of apoptotic cells, and mitochondrial membrane potential were measured. To evaluate the combined effect of gemigliptin with AUY922, the interactions were estimated by calculating combination index. Gemigliptin led to cell death in conjunction with overexpression of the phosphorylated protein levels of Akt, extracellular signal-regulated kinase 1/2, and adenosine monophosphate-activated protein kinase. In gemigliptin-treated cells, wortmannin augmented cell death, whereas AZD6244 and compound C did not affect cell survival. Wortmannin decreased phosphorylated adenosine monophosphate-activated protein kinase protein levels, and AZD6244 increased phosphorylated Akt protein levels. Meanwhile, cotreatment of both gemigliptin and AUY922, compared with treatment of AUY922 alone, potentiated cell death. All the combination index values were lower than 1.0, suggesting synergistic cytotoxicity of gemigliptin with AUY922. In treatment of both gemigliptin and AUY922, compared with AUY922 alone, the protein levels of total and phosphorylated Akt, phosphorylated extracellular signal-regulated kinase 1/2, and phosphorylated adenosine monophosphate-activated protein kinase increased without alteration in those of total extracellular signal-regulated kinase 1/2 and total adenosine monophosphate-activated protein kinase. The percentage of apoptotic cells increased. The protein levels of Bax and cleaved poly (ADP-ribose) polymerase increased, whereas Bcl2 protein levels were unchanged, resulting in increment of Bax/Bcl2 ratio. Transfection of Bax small interfering RNA did not cause any variation in cell viability, the percentage of viable cells and cytotoxic activity. Our results demonstrate that gemigliptin exerts a cytotoxic activity with concomitant alterations in expression of Akt, extracellular signal-regulated kinase 1/2, and adenosine monophosphate-activated protein kinase in thyroid carcinoma cells. Furthermore, gemigliptin synergizes with AUY922 in induction of cytotoxicity via regulation of Akt, extracellular signal-regulated kinase 1/2, and adenosine monophosphate-activated protein kinase as well as involvement of Bcl2 family proteins in thyroid carcinoma cells.

Number of osteoporotic sites as a modifying factor for bone mineral density.

Discordance has been proposed as a new predictor of fracture risk that may affect fracture risk via bone mineral density (BMD). With an emphasis on better understanding the relationship between discordance and BMD, the aim of this study was to determine the effect of the number of osteoporotic sites, as an indicator of discordance, on BMD and to explore the clinical significance of BMD modification by this factor. This study was based on data obtained from the Korea National Health and Nutrition Examination Survey 2008-2011, which is a nationwide cross-sectional study. Among postmenopausal women aged 50 years or older, 3,849 women whose BMD was measured at three sites (lumbar spine, femoral neck, and total hip) were included in the study. The diagnosis was consistent across sites in only 39.2-59.0 % of cases. Lumbar spine T-score was reduced by 0.163 for two osteoporotic sites and by 0.462 for three osteoporotic sites, compared with having one osteoporotic site at the lumbar spine only. Femoral neck T-score was reduced by 0.609 for three osteoporotic sites compared with one or two osteoporotic sites. Using BMD adjusted for discordance, we found fracture risk probability changed significantly. Our results confirmed that BMD discordance was considerably high among Korean women in their 50s and older owing to site-dependent differences in the pattern of BMD reduction with age. Mean BMD decreased with increasing number of osteoporotic sites. Using a modified BMD adjusted for the number of osteoporotic sites may offer more accurate fracture risk assessment.

The effects of the Korean reference value on the prevalence of osteoporosis and the prediction of fracture risk.

BACKGROUND: Since the reference value is the core factor of the T-score calculation, it has a significant impact on the prevalence of osteoporosis. The purpose of this study was to determine the effects of using the Korean reference value on the prevalence of osteoporosis and on the prediction of fracture risk. METHODS: We used femoral neck bone mineral density (BMD) data from the Korea National Health and Nutrition Examination Survey (KNHANES) 2008-2011. The Korean reference was identified by the mean and standard deviation of men and women aged 20-29 years. We compared the prevalence and the fracture risk assessment tool (FRAX™) probability obtained from the Korean reference and the NHANES III reference. RESULTS: In men, the prevalence of osteoporosis increased when using the Korean men's reference, and the difference increased up to 9% for those in their 80s. In women, the prevalence increased when using the NHANES III reference, and the difference increased up to 17% for those in their 80s. The reference value also affected the fracture risk probability, and the difference from changing the reference value increased in women and in subjects with more clinical fracture risk factors. In major osteoporotic fractures, the difference of the risk probability was up to 6% in women aged 70-79 years with two clinical risk factors. For femoral neck fractures, the difference was up to 7% in women aged 50-59 years with two clinical risk factors. CONCLUSIONS: We confirmed that the reference value had significant effects on the prevalence of osteoporosis and on the fracture risk probability. The KNHANES 2008-2011 BMD data reflected the characteristics of the Korean BMD status well with regard to data size and study design; therefore, these data can be used as reference values.

The hsp70 inhibitor VER155008 induces paraptosis requiring de novo protein synthesis in anaplastic thyroid carcinoma cells.

In this study, we evaluated the effect of the hsp70 inhibitor VER155008 on survival of anaplastic thyroid carcinoma (ATC) cells. In ATC cells, VER155008 increased the percentages of dead cells and vacuolated cells. VER155008 did not lead to the cleavage of caspase-3 protein regardless of pretreatment with z-VAD-fmk. VER155008 increased LC3-II protein levels but the protein levels were not changed by autophagy inhibitors. VER155008 caused the dilatation of endoplasmic reticulum (ER), and the increased mRNA levels of Bip and CHOP, suggesting paraptosis. VER155008-induced paraptosis was attenuated by pretreatment with cycloheximide. In conclusion, VER155008 induces paraptosis characterized by cytoplasmic vacuolation, independence of caspase, dilatation of ER and induction of ER stress markers in ATC cells. Moreover, VER155008-induced paraptosis requires de novo protein synthesis in ATC cells.

Herbimycin A inhibits cell growth with reversal of epithelial-mesenchymal transition in anaplastic thyroid carcinoma cells.

We aimed to elucidate the effect of herbimycin A (HMA), a heat shock protein 90 inhibitor, on cell growth and epithelial-mesenchymal transition (EMT) in anaplastic thyroid carcinoma (ATC) cells. HMA inhibited cell growth and migration concomitantly with increase of E-cadherin as well as decrease of N-cadherin and vimentin. Moreover, HMA upregulated p21 and p27, while it downregulated p53 and Akt. In HMA-treated condition, knockdown of E-cadherin and overexpression of p53 increased N-cadherin and vimentin, and mitigated the inhibitory effects of HMA on cell growth and migration. Furthermore, knockdown of p21 and p27 ameliorated inhibition of cell growth and reversal of EMT. In addition, the activation of Akt attenuated growth inhibition, cell death and EMT reversal. Therefore, we propose that HMA suppresses cell growth, and reverses EMT in conjunction with the activation of E-cadherin, p21 and p27 and the inactivation of p53 and PI3K/Akt signaling in ATC cells.

Unprotected daily sun exposure is differently associated with central adiposity and ß-cell dysfunction by gender: the Korean National Health and Nutrition Examination Survey (KNHANES) V.

BACKGROUND: Ultraviolet irradiation by sun exposure has been associated with both harms and benefits to metabolic health. OBJECTIVE: The objective of this study was to determine whether unprotected daily sun exposure is associated with the prevalence of diabetes and explore the underlying mechanism. METHODS: We analyzed the Korean National Health and Nutrition Survey V from 2010 to 2011. Participants 19-60 years of age were asked about the average amount of time they had been exposed to direct sunlight per day since the age of 19. We categorized participants into three groups with different levels of lifetime daily sun exposure and explored the association of sun exposure with the prevalence of diabetes. RESULTS: The risk of diabetes was higher in subjects with more than 5h of unprotected sun exposure per day, with an odds ratio of 2.39 (95% CI 1.75-3.25), compared to those with less than 2h of sun exposure, and the association remained significant after adjusting for diabetes risk factors. Long-term sun exposure was associated with increased central obesity and the possibility of an increase in visceral adiposity, especially among women, and with decrease in beta cell function and peripheral adiposity or percent body fat in men. CONCLUSIONS: Our study provides a cutoff for upper limit of sun exposure and suggests unprotected daily sun exposure for more than 5h should be avoided to prevent diabetes. Increased central adiposity and decreased beta cell function were observed in women and men, respectively, who had long-term unprotected daily sun exposure.

Seasonal variations in glycemic control of type 2 diabetes in Korean women.

BACKGROUND AND AIMS: Seasonal variations in lifestyle, such as food intake and physical activity, have been reported. Glycemic control in type 2 diabetes mellitus (T2DM) may be affected by such changes. We investigated seasonal variations in glycemic control, food intake, and physical activity in type 2 diabetic patients. METHODS: This prospective observational study included 37 Korean female patients who had <8.0 % hemoglobin A1c (HbA1c) and managed diabetes by oral anti-diabetic drugs or lifestyle modification only. Participants underwent four or five assessments, including total physical activity (household, leisure-time, and occupational activity) (metabolic equivalent of test-h/day), food intake (kcal/day), HbA1c, and anthropometry every 3 months (August, November, February, May, and August in the Northern Hemisphere) over 1 year. When anti-diabetic drugs were changed, we analyzed the data just before the changes. RESULTS: The mean HbA1c levels (%) of August and November in 2008, and February, May, and August in 2009 were 7.0 ± 0.1, 6.9 ± 0.1, 7.2 ± 0.2, 7.4 ± 0.2, and 7.2 ± 0.2, respectively (P = 0.018). The change of HbA1c was nearly 0.5 % for the 1-year period. From August to May of the following year, there were also seasonal variations in food intake (1,872 ± 143, 1,739 ± 97, 1,673 ± 86, 1,561 ± 132, respectively; P = 0.013), and total physical activity [7.7 (3.7-14.6), 6.3 (2.8-10.4), 5.1 (2.7-12.6), and 11.2 (4.7-20.5), respectively; P = 0.048]. However, the seasonal variations of HbA1c and total physical activity became non-significant when farmers were excluded. CONCLUSIONS: These data suggested that glycemic control, total physical activity, and food intake varied seasonally in Korean T2DM patients. These seasonal variations should be considered in education for glycemic control.

A prospective randomized controlled trial of the effects of vitamin D supplementation on long-term glycemic control in type 2 diabetes mellitus of Korea.

Epidemiologic studies have shown that low vitamin D levels are associated with reduced insulin sensitivity and increased risk of developing type 2 diabetes mellitus (T2DM). However, there is little evidence that vitamin D supplementation improves glucose intolerance. We evaluated the glucose-lowering effect of vitamin D in Korean T2DM subjects. We enrolled 158 T2DM patients who had stable glycemic control [hemoglobin A1c (HbA1c) <8.5%] and vitamin D levels less than 20 ng/mL. The participants were randomized into two groups: Placebo (100 mg daily of elemental calcium administered twice a day) or Vitamin D (1000 IU daily of cholecalciferol combined with 100 mg of elemental calcium administered twice a day). We compared outdoor physical activity, glycemic control, homeostasis model of assessment - insulin resistance (HOMA-IR), and parathyroid hormone (PTH), during the 24-week intervention. We analyzed the data of 129 participants (placebo =65, vitamin D =64) who completely followed the protocol. Outdoor physical activity and oral anti-diabetic drugs did not differ between the groups. While there were significant differences in the vitamin D levels (15.6 ± 7.1 ng/mL vs 30.2 ± 10.8 ng/mL, P<0.001) and change in PTH levels (1.4 ± 15.3 pg/mL vs -5.5 ± 9.8 pg/mL, P=0.003) between the placebo and vitamin D groups, there were no differences in HbA1c (7.27 ± 0.87% vs 7.40 ± 0.90%) (P=0.415) and HOMA-IR. Serum calcium and kidney function results showed that the vitamin D supplementation was safe. While vitamin D supplementation is safe and effective in the attainment of vitamin D sufficiency, it had no effect on long-term glycemic control for T2DM in our study.

Sleep disturbances and glucoregulation in patients with type 2 diabetes.

We investigated the frequency of sleep disturbances and the association between sleep disturbances and glucoregulation in type 2 diabetic patients. The frequency of sleep disturbances in 614 type 2 diabetic patients was investigated using validated sleep questionnaires. There were 381 male and 233 female patients. The mean age was 59.7 ± 11.1 yr; the mean body mass index was 24.9 ± 4.4 kg/m(2); the mean HbA1c was 7.8% ± 1.5%; and the mean duration of diabetes was 10.3 ± 8.4 yr. The questionnaires revealed insomnia in 48.2% of the patients while 8.5% reported excessive daytime sleepiness. A total of 49% of the patients was poor sleepers, while 28.5% had depression. Multivariate logistic regression analysis showed that there was no significant association between HbA1c and other sleep disturbances, such as poor sleep, insomnia, and short duration of sleep. Sleep disturbances were very common in patients with type 2 diabetes mellitus, whereas there was no association between poor or short sleep and glucoregulation. Awareness and identifying sleep complaints in such patients are necessary to improve their quality of daily life.

The modulatory role of spinally located histamine receptors in the regulation of the blood glucose level in d-glucose-fed mice.

The possible roles of spinal histamine receptors in the regulation of the blood glucose level were studied in ICR mice. Mice were intrathecally (i.t.) treated with histamine 1 (H1) receptor agonist (2-pyridylethylamine) or antagonist (cetirizine), histamine 2 (H2) receptor agonist (dimaprit) or antagonist (ranitidine), histamine 3 (H3) receptor agonist (α-methylhistamine) or antagonist (carcinine) and histamine 4 (H4) receptor agonist (VUF 8430) or antagonist (JNJ 7777120), and the blood glucose level was measured at 30, 60 and 120 min after i.t. administration. The i.t. injection with α-methylhistamine, but not carcinine slightly caused an elevation of the blood glucose level. In addition, histamine H1, H2, and H4 receptor agonists and antagonists did not affect the blood glucose level. In D-glucose-fed model, i.t. pretreatment with cetirizine enhanced the blood glucose level, whereas 2-pyridylethylamine did not affect. The i.t. pretreatment with dimaprit, but not ranitidine, enhanced the blood glucose level in D-glucose-fed model. In addition, α-methylhistamine, but not carcinine, slightly but significantly enhanced the blood glucose level D-glucose-fed model. Finally, i.t. pretreatment with JNJ 7777120, but not VUF 8430, slightly but significantly increased the blood glucose level. Although histamine receptors themselves located at the spinal cord do not exert any effect on the regulation of the blood glucose level, our results suggest that the activation of spinal histamine H2 receptors and the blockade of spinal histamine H1 or H3 receptors may play modulatory roles for up-regulation and down-regulation, respectively, of the blood glucose level in D-glucose fed model.

Interleukin-1ß (IL-1ß) increases pain behavior and the blood glucose level: possible involvement of glucocorticoid system.

The possible involvement of glucocorticoid system in interleukin-1ß (IL-1ß)-induced nociception and the blood glucose level was studied in ICR mice. In the first experiment, mice were treated intrathecally (i.t.) with IL-1ß (100 pg). Corticotrophin releasing hormone (CRH) mRNA (hypothalamus) and c-Fos mRNA (pituitary gland, spinal cord, and the adrenal gland) levels were measured at 30, 60 and 120 min after IL-1ß administration. We found that i.t. injection with IL-1ß increased CRH mRNA level in the hypothalamus. The IL-1ß administered i.t. elevated c-Fos mRNA levels in the spinal cord, pituitary and adrenal glands. Furthermore, i.t. administration of IL-1ß significantly increased the plasma corticosterone level up to 60 min. In addition, the adrenalectomy caused the reductions of the blood glucose level and pain behavior induced by IL-1ß injected i.t. in normal and D-glucose-fed groups. Furthermore, intraperitoneal (i.p.) pretreatment with RU486 (100mg/kg) attenuated the blood glucose level and pain behavior induced by IL-1ß administered i.t. in normal and D-glucose-fed groups. Our results suggest that IL-1ß administered i.t. increases the blood glucose level and pain behavior via an activation of the glucocorticoid system.

Effect of GABA receptor agonists or antagonists injected spinally on the blood glucose level in mice.

The possible roles of gamma-amino butyric acid (GABA) receptors located in the spinal cord for the regulation of the blood glucose level were studied in ICR mice. We found in the present study that intrathecal (i.t.) injection with baclofen (a GABAB receptor agonist; 1-10 µg/5 µl) or bicuculline (a GABAA receptor antagonist; 1-10 µg/5 µl) caused an elevation of the blood glucose level in a dose-dependent manner. The hyperglycemic effect induced by baclofen was more pronounced than that induced by bicuculline. However, muscimol (a GABAA receptor agonist; 1-5 µg/5 µl) or phaclofen (a GABAB receptor antagonist; 5-10 µg/5 µl) administered i.t. did not affect the blood glucose level. Baclofen-induced elevation of the blood glucose was dose-dependently attenuated by phaclofen. Furthermore, i.t. pretreatment with pertussis toxin (PTX; 0.05 or 0.1 µg/5 µl) for 6 days dose-dependently reduced the hyperglycemic effect induced by baclofen. Our results suggest that GABAB receptors located in the spinal cord play important roles for the elevation of the blood glucose level. Spinally located PTX-sensitive G-proteins appear to be involved in hyperglycemic effect induced by baclofen. Furthermore, inactivation of GABAA receptors located in the spinal cord appears to be responsible for tonic up-regulation of the blood glucose level.

Repaglinide, but not nateglinide administered supraspinally and spinally exerts an anti-diabetic action in d-glucose fed and streptozotocin-treated mouse models.

We have recently demonstrated that some anti-diabetic drugs such as biguanide and thizolidinediones administered centrally modulate the blood glucose level, suggesting that orally administered anti-diabetic drugs may modulate the blood glucose level by acting on central nervous system. The present study was designed to explore the possible action of another class of anti-diabetic drugs, glinidies, administered centrally on the blood glucose level in ICR mice. Mice were administered intracerebroventricularly (i.c.v.) or intrathecally (i.t.) with 5 to 30 µg of repaglinide or nateglinide in D-glucose-fed and streptozotocin (STZ)-treated models. We found that i.c.v. or i.t. injection with repaglinide dose-dependently attenuated the blood glucose level in D-glucose-fed model, whereas i.c.v. or i.t. injection with nateglinide showed no modulatory action on the blood glucose level in D-glucose-fed model. Furthermore, the effect of repaglinide administered i.c.v. or i.t. on the blood glucose level in STZ-treated model was studied. We found that repaglinide administered i.c.v. slightly enhanced the blood glucose level in STZ-treated model. On the other hand, i.t. injection with repaglinide attenuated the blood glucose level in STZ-treated model. The plasma insulin level was enhanced by repaglinide in D-glucose-fed model, but repaglinide did not affect the plasma insulin level in STZ-treated model. In addition, nateglinide did not alter the plasma insulin level in both D-glucose-fed and STZ-treated models. These results suggest that the anti-diabetic action of repaglinide appears to be, at least, mediated via the brain and the spinal cord as revealed in both D-glucose fed and STZ-treated models.

Effect of cholera toxin administered supraspinally or spinally on the blood glucose level in pain and d-glucose fed animal models.

In the present study, the effect of intrathecal (i.t.) or intracerebroventricular (i.c.v.) administration with cholera toxin (CTX) on the blood glucose level was examined in ICR mice. The i.t. treatment with CTX alone for 24 h dose-dependently increased the blood glucose level. However, i.c.v. treatment with CTX for 24 h did not affect the blood glucose level. When mice were orally fed with D-glucose (2 g/kg), the blood glucose level reached to a maximum level at 30 min and almost returned to the control level at 120 min after D-glucose feeding. I.c.v. pretreatment with CTX increased the blood glucose level in a potentiative manner, whereas i.t. pretreatment with CTX increased the blood glucose level in an additive manner in a D-glucose fed group. In addition, the blood glucose level was increased in formalin-induced pain animal model. I.c.v. pretreatment with CTX enhanced the blood glucose level in a potentiative manner in formalin-induced pain animal model. On the other hand, i.t. pretreatment with CTX increased the blood glucose level in an additive manner in formalin-induced pain animal model. Our results suggest that CTX administered supraspinally or spinally differentially modulates the regulation of the blood glucose level in D-glucose fed model as well as in formalin-induced pain model.

Sinus lifts in the presence of pseudoantral and mucous retention cysts.

Objectives: Mucous retention cysts and pseudoantral cysts are mainly located within the floor of the maxillary sinus. Most of these maxillary cysts are asymptomatic and often only require observation. However, the presence of these benign maxillary cysts may create problems when maxillary sinus all types of implants are needed. Various treatment methods have been introduced. The selected treatment option depends on the type, size, and location of the cyst and its symptoms. Patients and. Methods: The case reports of four patients with maxillary cysts were reviewed retrospectively. These patients received a sinus lift between January 2016 and October 2021 at the Wonkwang University Dental Hospital. Results: To reduce unnecessary operations and the duration of treatment, a conservative treatment method is required. A sinus lift in the presence of maxillary cyst will not typically cause sinus problems if the lifted sinus membrane does not interfere with ventilation of the maxillary sinus. Conclusion: When proper treatment is provided, sinus perforation during a sinus lift performed in the presence of maxillary cyst and contamination of bone graft materials by cystic fluid does not necessarily result in adverse outcomes.

Temporomandibular joint reconstruction with costochondral graft: case series study.

Various techniques have been used to reconstruct the temporomandibular joints, including autogenous transplants and alloplastic implants. Among autogenous grafts, costochondral grafts have mainly been used. A costochondral graft has many advantages over other autogenous grafts and alloplastic implants. Harvest is easy and has minimal impact on patients. The graft can bear functional load well and biocompatibility is excellent. A costochondral graft obviates foreign body reactions and further surgery for revision of alloplastic replacements if the graft takes well. Although long-term prognosis remains unclear, it appears that for autogenous condylar reconstruction, costochondral grafts can be used with few complications and acceptable results. This article describes cases and discusses surgical techniques and considerations related to costochondral grafts.

Efficacy and Safety of Switching to Teneligliptin in Patients with Type 2 Diabetes Inadequately Controlled with Dipeptidyl Peptidase-4 Inhibitors: 52-Week Results from a Prospective Observational Study.

INTRODUCTION: The aim of this study was to assess the efficacy and safety of switching to teneligliptin from other dipeptidyl peptidase-4 (DPP-4) inhibitors in patients with type 2 diabetes mellitus (T2DM) inadequately controlled despite treatment with a stable dose of other DPP-4 inhibitors. METHODS: Patients with glycosylated hemoglobin (HbA1c) ≥ 7% despite taking DPP-4 inhibitors other than teneligliptin, with or without other antidiabetic agents, for at least 3 months were enrolled in this study. Patients on DPP-4 inhibitors administered prior to participation in this study were switched to 20 mg teneligliptin once daily and the dose was maintained for the 52-week study period. The primary endpoint was the change in HbA1c at week 12. Fasting plasma glucose (FPG) and the blood lipid profile were also evaluated. Adverse events were monitored for safety assessment. RESULTS: At weeks 12, 24, and 52, the HbA1c values significantly decreased by - 0.39, - 0.44, and - 0.52%, respectively, compared to the baseline value (p < 0.0001); in addition, 56.3, 60.3, and 62.3% of patients, respectively, achieved decreases in HbA1c of at least 0.3%, and 40.1, 46.5, and 52.4% of patients, respectively, achieved decreases in HbA1c of at least 0.5%. The proportion of the patient population achieving HbA1c < 7.0% increased throughout the study period, reaching 30.4, 35.4, and 36.9% at weeks 12, 24, and 52, respectively; at these same time points, the percentage of patients achieving HbA1c < 6.5% increased to 9.5, 11.9, and 13.2% of the total study population. FPG levels and lipid parameters were also significantly decreased after teneligliptin treatment. There were no significant safety concerns. CONCLUSION: Our results suggest the significant glucose-lowering effect of teneligliptin after switching from other DPP-4 inhibitors in patients with T2DM. The improvement in glycemic control was maintained for up to 52 weeks without safety concerns.

Heat Shock Protein 90 Inhibitors AUY922, BIIB021 and SNX5422 Induce Bim-mediated Death of Thyroid Carcinoma Cells.

BACKGROUND/AIM: Heat shock protein 90 (HSP90) controls maturation of oncogenic client proteins of cancer cells, and thus we studied the effect of HSP 90 inhibitors on cell survival and survival-related mediators in thyroid carcinoma cells. MATERIALS AND METHODS: Human TPC-1 and SW1736 thyroid carcinoma cells were utilized. Cell viability, cytotoxic activity and apoptosis were estimated using CCK-8 assay, cytotoxicity assay and FACS analysis, respectively. RESULTS: AUY922, BIIB021 and SNX5422 decreased cell viability, and increased cytotoxic activity and the proportion of apoptotic cells. The protein levels of cleaved PARP, cleaved caspase-3, Bax and Bim were elevated, and Bcl2 protein levels were reduced. Knockdown of Bax did not change cell viability, cytotoxic activity, the proportion of apoptotic cells and cleaved caspase-3 protein levels. Meanwhile, knockdown of Bim enhanced cell viability, and diminished cytotoxic activity, the proportion of apoptotic cells and cleaved caspase-3 protein levels. AUY922, BIIB021 and SNX5422 increased the protein levels of phospho-AMPK, and decreased those of phospho-ERK1/2, and total and phospho-AKT. CONCLUSION: AUY922, BIIB021 and SNX5422 induce cytotoxicity by modulating Bim and ERK1/2, AKT and AMPK signaling in thyroid carcinoma cells.