Flos magnoliae constituent fargesin has an anti-allergic effect via ORAI1 channel inhibition

Flos magnoliae (FM), the dry flower buds of Magnolia officinalis or its related species, is a traditional herbal medicine commonly used in Asia for symptomatic relief of and treating allergic rhinitis, headache, and sinusitis. Although several studies have reported the effects of FM on store-operated calcium entry (SOCE) via the ORAI1 channel, which is essential during intracellular calcium signaling cascade generation for T cell activation and mast cell degranulation, the effects of its isolated constituents on SOCE remain unidentified. Therefore, we investigated which of the five major constituents of 30% ethanoic FM (vanillic acid, tiliroside, eudesmin, magnolin, and fargesin) inhibit SOCE and their physiological effects on immune cells. The conventional whole-cell patch clamp results showed that fargesin, magnolin, and eudesmin significantly inhibited SOCE and thus human primary CD4 + T lymphocyte proliferation, as well as allergen-induced histamine release in mast cells. Among them, fargesin demonstrated the most potent inhibitory effects not only on ORAI1 (IC 50 = 12.46 ± 1.300 μM) but also on T-cell proliferation (by 87.74% ± 1.835%) and mast cell degranulation (by 20.11% ± 5.366%) at 100 μM. Our findings suggest that fargesin can be a promising candidate for the development of therapeutic drugs to treat allergic diseases.

Nootkatol prevents ultraviolet radiation-induced photoaging via ORAI1 and TRPV1 inhibition in melanocytes and keratinocytes

Skin photoaging occurs due to chronic exposure to solar ultraviolet radiation (UV), the main factor contributing to extrinsic skin aging. Clinical signs of photoaging include the formation of deep, coarse skin wrinkles and hyperpigmentation.Although melanogenesis and skin wrinkling occur in different skin cells and have different underlying mechanisms, their initiation involves intracellular calcium signaling via calcium ion channels. The ORAI1 channel initiates melanogenesis in melanocytes, and the TRPV1 channel initiates MMP-1 production in keratinocytes in response to UV stimulation. We aimed to develop a drug that may simultaneously inhibit ORAI1 and TRPV1 activity to help prevent photoaging. We synthesized nootkatol, a chemical derivative of valencene. TRPV1 and ORAI1 activities were measured using the whole-cell patch-clamp technique. Intracellular calcium concentration [Ca2+ ] i was measured using calcium-sensitive fluorescent dye (Fura-2 AM). UV-induced melanin formation and MMP-1 production were quantified in B16F10 melanoma cells and HaCaT cells, respectively. Our results indicate that nootkatol (90 μM) reduced TRPV1 current by 94% ± 2% at –60 mV and ORAI1 current by 97% ± 1% at –120 mV. Intracellular calcium signaling was significantly inhibited by nootkatol in response to ORAI1 activation in human primary melanocytes (51.6% ± 0.98% at 100 μM). Additionally, UV-induced melanin synthesis was reduced by 76.38% ± 5.90% in B16F10 melanoma cells, and UV-induced MMP-1 production was reduced by 59.33% ± 1.49% in HaCaT cells. In conclusion, nootkatol inhibits both TRPV1 and ORAI1 to prevent photoaging, and targeting ion channels may be a promising strategy for preventing photoaging.

Flos magnoliae constituent fargesin has an anti-allergic effect via ORAI1 channel inhibition

Flos magnoliae (FM), the dry flower buds of Magnolia officinalis or its related species, is a traditional herbal medicine commonly used in Asia for symptomatic relief of and treating allergic rhinitis, headache, and sinusitis. Although several studies have reported the effects of FM on store-operated calcium entry (SOCE) via the ORAI1 channel, which is essential during intracellular calcium signaling cascade generation for T cell activation and mast cell degranulation, the effects of its isolated constituents on SOCE remain unidentified. Therefore, we investigated which of the five major constituents of 30% ethanoic FM (vanillic acid, tiliroside, eudesmin, magnolin, and fargesin) inhibit SOCE and their physiological effects on immune cells. The conventional whole-cell patch clamp results showed that fargesin, magnolin, and eudesmin significantly inhibited SOCE and thus human primary CD4 + T lymphocyte proliferation, as well as allergen-induced histamine release in mast cells. Among them, fargesin demonstrated the most potent inhibitory effects not only on ORAI1 (IC 50 = 12.46 ± 1.300 μM) but also on T-cell proliferation (by 87.74% ± 1.835%) and mast cell degranulation (by 20.11% ± 5.366%) at 100 μM. Our findings suggest that fargesin can be a promising candidate for the development of therapeutic drugs to treat allergic diseases.

Nootkatol prevents ultraviolet radiation-induced photoaging via ORAI1 and TRPV1 inhibition in melanocytes and keratinocytes

Skin photoaging occurs due to chronic exposure to solar ultraviolet radiation (UV), the main factor contributing to extrinsic skin aging. Clinical signs of photoaging include the formation of deep, coarse skin wrinkles and hyperpigmentation.Although melanogenesis and skin wrinkling occur in different skin cells and have different underlying mechanisms, their initiation involves intracellular calcium signaling via calcium ion channels. The ORAI1 channel initiates melanogenesis in melanocytes, and the TRPV1 channel initiates MMP-1 production in keratinocytes in response to UV stimulation. We aimed to develop a drug that may simultaneously inhibit ORAI1 and TRPV1 activity to help prevent photoaging. We synthesized nootkatol, a chemical derivative of valencene. TRPV1 and ORAI1 activities were measured using the whole-cell patch-clamp technique. Intracellular calcium concentration [Ca2+ ] i was measured using calcium-sensitive fluorescent dye (Fura-2 AM). UV-induced melanin formation and MMP-1 production were quantified in B16F10 melanoma cells and HaCaT cells, respectively. Our results indicate that nootkatol (90 μM) reduced TRPV1 current by 94% ± 2% at –60 mV and ORAI1 current by 97% ± 1% at –120 mV. Intracellular calcium signaling was significantly inhibited by nootkatol in response to ORAI1 activation in human primary melanocytes (51.6% ± 0.98% at 100 μM). Additionally, UV-induced melanin synthesis was reduced by 76.38% ± 5.90% in B16F10 melanoma cells, and UV-induced MMP-1 production was reduced by 59.33% ± 1.49% in HaCaT cells. In conclusion, nootkatol inhibits both TRPV1 and ORAI1 to prevent photoaging, and targeting ion channels may be a promising strategy for preventing photoaging.

Luteolin reduces fluid hypersecretion by inhibiting TMEM16A in interleukin-4 treated Calu-3 airway epithelial cells

Rhinorrhea in allergic rhinitis (AR) is characterized by the secretion of electrolytes in the nasal discharge. The secretion of Cl– and HCO3 – is mainly regulated by cystic fibrosis transmembrane conductance regulator (CFTR) or via the calciumactivated Cl– channel anoctamin-1 (ANO1) in nasal gland serous cells. Interleukin-4 (IL-4), which is crucial in the development of allergic inflammation, increases the expression and activity of ANO1 by stimulating histamine receptors. In this study, we investigated ANO1 as a potential therapeutic target for rhinorrhea in AR using an ANO1 inhibitor derived from a natural herb. Ethanolic extracts (30%) of Spirodela polyrhiza (SPEtOH) and its five major flavonoids constituents were prepared. To elucidate whether the activity of human ANO1 (hANO1) was modulated by SPEtOH and its chemical constituents, a patch clamp experiment was performed in hANO1-HEK293T cells. Luteolin, one of the major chemical constituents in SPEtOH, significantly inhibited hANO1 activity in hANO1-HEK293T cells. Further, SPEtOH and luteolin specifically inhibited the calcium-activated chloride current, but not CFTR current in human airway epithelial Calu-3 cells. Calu-3 cells were cultured to confluency on transwell inserts in the presence of IL-4 to measure the electrolyte transport by Ussing chamber. Luteolin also significantly inhibited the ATP-induced increase in electrolyte transport, which was increased in IL-4 sensitized Calu-3 cells. Our findings indicate that SPEtOH and luteolin may be suitable candidates for the prevention and treatment of allergic rhinitis. SPEtOH- and luteolin-mediated ANO1 regulation provides a basis for the development of novel approaches for the treatment of allergic rhinitis-induced rhinorrhea.

Gardenia jasminoides extract and its constituent, genipin, inhibit activation of CD3/CD28 co-stimulated CD4+ T cells via ORAI1 channel

Gardenia jasminoides (GJ) is a widely used herbal medicine with antiinflammatory properties, but its effects on the ORAI1 channel, which is important in generating intracellular calcium signaling for T cell activation, remain unknown. In this study, we investigated whether 70% ethanolic GJ extract (GJEtOH) and its subsequent fractions inhibit ORAI1 and determined which constituents contributed to this effect. Whole-cell patch clamp analysis revealed that GJEtOH (64.7% ± 3.83% inhibition at 0.1 mg/ml) and all its fractions showed inhibitory effects on the ORAI1 channel. Among the GJ fractions, the hexane fraction (GJHEX, 66.8% ± 9.95% at 0.1 mg/ml) had the most potent inhibitory effects in hORAI1-hSTIM1 co-transfected HEK293T cells. Chemical constituent analysis revealed that the strong ORAI1 inhibitory effect of GJHEX was due to linoleic acid, and in other fractions, we found that genipin inhibited ORAI1. Genipin significantly inhibited IORAI1 and interleukin-2 production in CD3/ CD28-stimulated Jurkat T lymphocytes by 35.9% ± 3.02% and 54.7% ± 1.32% at 30 μM, respectively. Furthermore, the same genipin concentration inhibited the proliferation of human primary CD4+ T lymphocytes stimulated with CD3/CD28 antibodies by 54.9% ± 8.22%, as evaluated by carboxyfluorescein succinimidyl ester assay. Our findings suggest that genipin may be one of the active components of GJ responsible for T cell suppression, which is partially mediated by activation of the ORAI1 channel. This study helps us understand the mechanisms of GJ in the treatment of inflammatory diseases.

Luteolin reduces fluid hypersecretion by inhibiting TMEM16A in interleukin-4 treated Calu-3 airway epithelial cells

Rhinorrhea in allergic rhinitis (AR) is characterized by the secretion of electrolytes in the nasal discharge. The secretion of Cl– and HCO3 – is mainly regulated by cystic fibrosis transmembrane conductance regulator (CFTR) or via the calciumactivated Cl– channel anoctamin-1 (ANO1) in nasal gland serous cells. Interleukin-4 (IL-4), which is crucial in the development of allergic inflammation, increases the expression and activity of ANO1 by stimulating histamine receptors. In this study, we investigated ANO1 as a potential therapeutic target for rhinorrhea in AR using an ANO1 inhibitor derived from a natural herb. Ethanolic extracts (30%) of Spirodela polyrhiza (SPEtOH) and its five major flavonoids constituents were prepared. To elucidate whether the activity of human ANO1 (hANO1) was modulated by SPEtOH and its chemical constituents, a patch clamp experiment was performed in hANO1-HEK293T cells. Luteolin, one of the major chemical constituents in SPEtOH, significantly inhibited hANO1 activity in hANO1-HEK293T cells. Further, SPEtOH and luteolin specifically inhibited the calcium-activated chloride current, but not CFTR current in human airway epithelial Calu-3 cells. Calu-3 cells were cultured to confluency on transwell inserts in the presence of IL-4 to measure the electrolyte transport by Ussing chamber. Luteolin also significantly inhibited the ATP-induced increase in electrolyte transport, which was increased in IL-4 sensitized Calu-3 cells. Our findings indicate that SPEtOH and luteolin may be suitable candidates for the prevention and treatment of allergic rhinitis. SPEtOH- and luteolin-mediated ANO1 regulation provides a basis for the development of novel approaches for the treatment of allergic rhinitis-induced rhinorrhea.

Gardenia jasminoides extract and its constituent, genipin, inhibit activation of CD3/CD28 co-stimulated CD4+ T cells via ORAI1 channel

Gardenia jasminoides (GJ) is a widely used herbal medicine with antiinflammatory properties, but its effects on the ORAI1 channel, which is important in generating intracellular calcium signaling for T cell activation, remain unknown. In this study, we investigated whether 70% ethanolic GJ extract (GJEtOH) and its subsequent fractions inhibit ORAI1 and determined which constituents contributed to this effect. Whole-cell patch clamp analysis revealed that GJEtOH (64.7% ± 3.83% inhibition at 0.1 mg/ml) and all its fractions showed inhibitory effects on the ORAI1 channel. Among the GJ fractions, the hexane fraction (GJHEX, 66.8% ± 9.95% at 0.1 mg/ml) had the most potent inhibitory effects in hORAI1-hSTIM1 co-transfected HEK293T cells. Chemical constituent analysis revealed that the strong ORAI1 inhibitory effect of GJHEX was due to linoleic acid, and in other fractions, we found that genipin inhibited ORAI1. Genipin significantly inhibited IORAI1 and interleukin-2 production in CD3/ CD28-stimulated Jurkat T lymphocytes by 35.9% ± 3.02% and 54.7% ± 1.32% at 30 μM, respectively. Furthermore, the same genipin concentration inhibited the proliferation of human primary CD4+ T lymphocytes stimulated with CD3/CD28 antibodies by 54.9% ± 8.22%, as evaluated by carboxyfluorescein succinimidyl ester assay. Our findings suggest that genipin may be one of the active components of GJ responsible for T cell suppression, which is partially mediated by activation of the ORAI1 channel. This study helps us understand the mechanisms of GJ in the treatment of inflammatory diseases.

Accuracy of frozen section diagnosis and factors associated with final pathological diagnosis upgrade of mucinous ovarian tumors / 부인종양

OBJECTIVE: To determine the accuracy of frozen section diagnosis and factors associated with final pathological diagnosis upgrade in patients with mucinous ovarian tumors. METHODS: This study included 1,032 patients with mucinous ovarian tumors who underwent frozen section diagnosis during surgery. Sensitivity, specificity, and diagnostic accuracy of frozen section diagnosis was calculated. Univariate and multivariate regression analyses were performed to determine factors associated with diagnosis upgrade in the final pathology report. RESULTS: The sensitivity and specificity of frozen section diagnosis were 99.1% (95% confidence interval [CI]=98%–99.6%) and 82.2% (95% CI=77.9%–85.7%), respectively, for benign mucinous tumors; 74.6% (95% CI=69.1%–79.4%) and 96.7% (95% CI=95.2%–97.8%), respectively, for mucinous borderline ovarian tumors; and 72.5% (95% CI=62.9%–80.3%) and 98.8% (95% CI=97.9%–99.3%), respectively, for invasive mucinous carcinomas. The multivariate analysis revealed that mixed tumor histology (odds ratio [OR]=2.8; 95% CI=1.3–6.3; p=0.012), tumor size >12 cm (OR=2.5; 95% CI=1.5–4.3; p=0.001), multilocular tumor (OR=2.9; 95% CI=1.4–6.0; p=0.006), and presence of a solid component in the tumor (OR=3.1; 95% CI=1.8–5.1; p12 cm, multilocular tumor, and presence of a solid component in the tumor were independent risk factors for final pathological diagnosis upgrade based on frozen section diagnosis.

Prognostic value of post-treatment ¹⁸F-fluorodeoxyglucose positron emission tomography in uterine cervical cancer patients treated with radiotherapy: a systematic review and meta-analysis / 부인종양

OBJECTIVES: To perform a systematic review and meta-analysis of the prognostic value of post-treatment 18F-fluorodeoxyglucose positron emission tomography (¹⁸F-FDG PET) in uterine cervical cancer patients treated with radiotherapy (RT) with or without chemotherapy. METHODS: PubMed and Embase databases were searched up to July 22, 2018, for studies which evaluated the response outcomes of ¹⁸F-FDG PET following RT, and their prognostic significance in uterine cervical cancer was assessed with overall survival (OS) or progression-free survival (PFS) as endpoints. Hazard ratios (HRs) were meta-analytically pooled using the random-effects model. RESULTS: Eleven studies with 12 patient cohorts including 1,104 patients were included. For a quantitative synthesis of OS, 7 cohorts were included. Two cohorts which reported disease-specific survival instead of OS were also included with flexibility. Pooled HR of complete metabolic response (CMR) compared to partial metabolic response (PMR) was 0.19 (95% confidence interval [CI]=0.11–0.31). Pooled HR of CMR compared to progressive metabolic disease (PMD) was more evident at 0.07 (95% CI=0.04–0.12), and that of CMR compared to both PMR and PMD was 0.20 (95% CI=0.12–0.34). Quantitative synthesis for PFS was performed with a total of 8 cohorts. Pooled HR of CMR was 0.17 (95% CI=0.10–0.29) compared to PMR, 0.02 (95% CI=0.01–0.06) compared to PMD and 0.12 (95% CI=0.07–0.19) compared to both PMR and PMD. CONCLUSION: Response results of post-RT ¹⁸F-FDG PET were significant prognostic factors in patients with uterine cervical cancer, and ¹⁸F-FDG PET could be a reasonable follow-up imaging modality.

Six months response rate of combined oral medroxyprogesterone/levonorgestrel-intrauterine system for early-stage endometrial cancer in young women: a Korean Gynecologic-Oncology Group Study / 부인종양

OBJECTIVE: To evaluate the efficacy of combined oral medroxyprogesterone acetate (MPA)/levonorgestrel-intrauterine system (LNG-IUS) treatment and to compare the diagnostic accuracy of endometrial aspiration biopsy with dilatation & curettage (D&C) in young women with early-stage endometrial cancer (EC) who wished to preserve their fertility. METHODS: A prospective phase II multicenter study was conducted from January 2012 to January 2017. Patients with grade 1 endometrioid adenocarcinoma confined to the endometrium were treated with combined oral MPA (500 mg/day)/LNG-IUS. At 3 and 6 months of treatment, the histologic change of the endometrial tissue was assessed. The regression rate at 6 months treatment and the consistency of the histologic results between the aspiration biopsy and the D&C were evaluated. RESULTS: Forty-four patients were enrolled. Nine voluntarily withdrew and 35 patients completed the protocol treatment. The complete regression (CR) rate at 6 months was 37.1% (13/35). Partial response was shown in 25.7% of cases (9/35). There were no cases of progressive disease and no treatment-related complications. A comparison of the pathologic results from aspiration biopsy and D&C was carried out for 33 cases. Fifteen cases were diagnosed as “EC” by D&C. Among these, only 8 were diagnosed with EC from aspiration biopsy, yielding a diagnostic concordance of 53.3% (ĸ=0.55). CONCLUSION: Combined oral MPA/LNG-IUS treatment for EC showed 37.1% of CR rate at 6 months. Considering the short treatment periods, CR rate may be much higher if the treatment continued to 9 or 12 months. So, this treatment is still a viable treatment option for young women of early-stage EC. Endometrial aspiration biopsy with the LNG-IUS in place is less accurate than D&C for follow-up evaluation of patients undergoing this treatment. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01594879

Diagnostic value of integrated ¹⁸F-fluoro-2-deoxyglucose positron emission tomography/computed tomography in recurrent epithelial ovarian cancer: accuracy of patient selection for secondary cytoreduction in 134 patients / 부인종양

OBJECTIVE: The aim of this study was to evaluate the diagnostic value of integrated 18F-fluoro-2-deoxyglucose-positron emission tomography/computed tomography (18F-FDG-PET/CT) for suspected recurrence of epithelial ovarian cancer (EOC) with non-disseminated lesions. METHODS: We retrospectively reviewed the medical records of recurrent EOC patients who underwent secondary cytoreduction from January 2000 to December 2013. A total of 134 patients underwent secondary cytoreduction after imaging with either 18F-FDG-PET/CT or contrast-enhanced computed tomography (CECT). RESULTS: In a patient-based analysis of 134 patients, 124 (92.5%) were confirmed to be positive for malignancy. Among 72 patients with suspected non-disseminated recurrence on 18F-FDG-PET/CT, 65 (89.0%) were confirmed to have recurrence, giving 98.5% sensitivity, 87.7% accuracy, and 88.9% positive predictive value (PPV). In the 65 patients with recurrence, residual tumor remained in 14 patients, giving an accuracy of patient selection for secondary cytoreduction of 69.4% (50/72) and it is higher than that of CECT (64.0%). In 169 lesions removed from patients who underwent preoperative 18F-FDG-PET/CT, 135 (79.9%) were confirmed to be positive for malignancy and 124 were accurately detected by 18F-FDG-PET/CT, giving 91.9% sensitivity, 81.1% accuracy, and 85.5% PPV. Foreign body granuloma was found in 33.3% of 21 lesions with false-positive 18F-FDG-PET/CT findings (7/21). The mean preoperative cancer antigen 125 (CA-125) level in false-positive patients was 28.8 U/mL. CONCLUSION: Compared with CECT, 18F-FDG-PET/CT shows higher sensitivity in lesion-based analysis and better accuracy of patient selection for secondary cytoreduction. However, there is still a need for integration of the results of 18F-FDG-PET/CT, CECT, and CA-125 levels to aid treatment planning.

Androgen receptor as a prognostic biomarker and therapeutic target in uterine leiomyosarcoma / 부인종양

OBJECTIVE: To investigate the expression of androgen receptor (AR) and its correlation with disease status and survival outcome in uterine leiomyosarcoma with other hormone receptors. METHODS: The medical records and paraffin blocks of 42 patients were reviewed. The immunohistochemical expression of AR, estrogen receptor (ER), progesterone receptor (PR), gonadotropin releasing hormone (GnRH), and cytochrome P450, family 19, subfamily A, polypeptide 1 (CYP19A1) were assessed using tissue microarray. RESULTS: In total, AR expression was observed in 11 patients (26.2%). International Federation of Gynecology and Obstetrics (FIGO) stage and AR were independent factors for disease-free survival (DFS) in multivariate regression analysis (odds ratio [OR]=5.8; 95% confidence interval [CI]=1.2–28.4 and OR=0.2; 95% CI=0.05–0.90; p=0.029 and 0.032, respectively). There were no deaths in the AR expression group, whereas the 5-year overall survival (OS) was 54.8% in the no expression group (p=0.014). Co-expression of ER and/or PR with AR was associated with significantly better 5-year DFS and OS than those with negative AR (72.7% vs. 28.6% and 100% vs. 64.3%; p=0.020 and 0.036, respectively). AR may be an independent prognostic marker regardless of ER/PR. CONCLUSION: AR can be a potential prognostic biomarker in uterine leiomyosarcoma.

How should gynecologic oncologists react to the unexpected results of LACC trial? / 부인종양

No abstract available.

Survival impact of low anterior resection in patients with epithelial ovarian cancer grossly confined to the pelvic cavity: a Korean multicenter study / 부인종양

OBJECTIVE: To evaluate survival impact of low anterior resection (LAR) in patients with epithelial ovarian cancer (EOC) grossly confined to the pelvis. METHODS: We retrospectively reviewed 397 patients who underwent primary staging surgery for treatment of 2014 International Federation of Gynecology and Obstetrics (FIGO) stage II–IIIA EOC: 116 (29.2%) IIA, 212 (53.4%) IIB, and 69 (17.4%) IIIA. Patients with grossly enlarged retroperitoneal lymph nodes positive for metastatic carcinoma were excluded. Of 92 patients (23.2%) with gross tumors at the rectosigmoid colon, 68 (73.9%) underwent tumorectomy and 24 (26.1%), LAR for rectosigmoid lesions. Survival outcomes between patients who underwent tumorectomy and LAR were compared using Kaplan-Meier curves. RESULTS: During the median follow-up of 55 months (range, 1–260), 141 (35.5%) recurrences and 81 (20.4%) deaths occurred. Age (52.8 vs. 54.5 years, p=0.552), optimal debulking (98.5% vs. 95.0%, p=0.405), histologic type (serous, 52.9% vs. 50.0%, p=0.804), FIGO stage (p=0.057), and platinum-based adjuvant chemotherapy ≥6 cycles (85.3% vs. 79.2%, p=0.485) were not different between groups. No significant difference in 5-year progression-free survival (PFS; 57.9% vs. 62.5%, p=0.767) and overall survival (OS; 84.7% vs. 63.8%, p=0.087), respectively, was noted between groups. Postoperative ileus was more frequent in patients subjected to LAR than those who were not (4/24 [16.7%] vs. 11/373 [2.9%], p=0.001). The 5-year PFS (60.3% vs. 57.9%, p=0.523) and OS (81.8% vs. 87.7%, p=0.912) between patients who underwent tumorectomy and those who did not were also similar. CONCLUSION: Survival benefit of LAR did not appear to be significant in EOC patients with grossly pelvis-confined tumors.

Mitochondrial dysfunction reduces the activity of KIR2.1 K⁺ channel in myoblasts via impaired oxidative phosphorylation

Myoblast fusion depends on mitochondrial integrity and intracellular Ca²⁺ signaling regulated by various ion channels. In this study, we investigated the ionic currents associated with [Ca²⁺]i regulation in normal and mitochondrial DNA-depleted (ρ0) L6 myoblasts. The ρ0 myoblasts showed impaired myotube formation. The inwardly rectifying K⁺ current (I(Kir)) was largely decreased with reduced expression of KIR2.1, whereas the voltage-operated Ca²⁺ channel and Ca²⁺-activated K⁺ channel currents were intact. Sustained inhibition of mitochondrial electron transport by antimycin A treatment (24 h) also decreased the I(Kir). The ρ0 myoblasts showed depolarized resting membrane potential and higher basal [Ca²⁺]ᵢ. Our results demonstrated the specific downregulation of I(Kir) by dysfunctional mitochondria. The resultant depolarization and altered Ca²⁺ signaling might be associated with impaired myoblast fusion in ρ0 myoblasts.

Prognostic value of metabolic parameters determined by preoperative ¹⁸F-FDG PET/CT in patients with uterine carcinosarcoma / 부인종양

OBJECTIVE: To evaluate the prognostic value of metabolic parameters measured by preoperative ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) positron emission tomography (PET)/computed tomography (CT) in patients with uterine carcinosarcoma (UCS). METHODS: Data of 55 eligible patients with UCS who underwent preoperative ¹⁸F-FDG PET/CT and surgical staging were analyzed retrospectively. Maximum standardized uptake value (SUVmax), metabolic tumor volume (MTV₂.₅), and total lesion glycolysis (TLG₂.₅) of the primary tumors were measured using a SUV threshold of 2.5. The optimal cutoff value of each parameter was determined by time-dependent receiver operating characteristic curve, and its impact on progression-free survival and overall survival was evaluated by Cox proportional hazards model. RESULTS: During a median follow-up period of 29 (range, 1.5–109.4) months, 47.3% (26/55) of the patients experienced disease progression, and the disease-associated mortality rate was 43.6% (24/55). Univariate analysis determined that hazard ratios (HRs) for disease progression for SUVmax (≥8.33), MTV₂.₅ (≥63.92 mL), and TLG₂.₅ (≥396.16) were 1.930 (95% confidence interval [CI]=0.793–4.701), 3.264 (95% CI=1.466–7.268), and 2.692 (95% CI=1.224–5.924), respectively. And, HRs for death were 1.979 (95% CI=0.774–5.060), 2.764 (95% CI=1.217–6.274), and 2.721 (95% CI=1.198–6.182), respectively. While peritoneal cytology, histology, and tumor diameter were independent prognostic factors in multivariate analysis, MTV and TLG were not. CONCLUSION: Though MTV and TLG of primary UCS were not independent predictors compared to surgically obtained data, MTV and TLG of primary UCS may provide useful information on prognosis especially in patients who are not able to undergo surgical staging.

Comparing and evaluating the efficacy of methotrexate and actinomycin D as first-line single chemotherapy agents in low risk gestational trophoblastic disease / 부인종양

OBJECTIVE: The aim of this study was to compare responses to single-agent chemotherapies and evaluate the predictive factors of resistance in low risk (LR) gestational trophoblastic disease (GTD). The chemotherapy agents included methotrexate (MTX) and actinomycin D (ACT-D). METHODS: We conducted a retrospective study of 126 patients with GTD who were treated between 2000 and 2013. A total of 71 patients with LR GTD were treated with MTX (8-day regimen or weekly regimen, n=53) or ACT-D (bi-weekly pulsed regimen or 5-day regimen, n=18). The successful treatment group and the failed treatment group were compared and analyzed to identify prognostic factors. RESULTS: The complete response rates were 83.3% for ACT-D and 62.2% for MTX, with no statistically significant difference. There was no severe adverse effect reported for either group. Longer interval durations from the index pregnancy (>2 months, p=0.040) and larger tumor size (>3 cm, p=0.020) were more common in non-responders than in responders; these results were statistically significant. CONCLUSION: Based on our results, ACT-D may be a better option than MTX as a first-line single chemotherapy agent for LR GTD. The bi-weekly pulsed ACT-D regimen had minimal, or at least the same, toxicities compared with MTX. However, due to the lack of strong supporting evidence, it cannot be conclusively stated that this is the best single agent for first-line chemotherapy in LR GTD patients. Further larger controlled trials will be necessary to establish the best guidelines for GTD treatment.

Activation of transient receptor potential vanilloid 3 by the methanolic extract of Schisandra chinensis fruit and its chemical constituent γ-schisandrin

Transient receptor potential vanilloid 3 (TRPV3) is a non-selective cation channel with modest permeability to calcium ions. It is involved in intracellular calcium signaling and is therefore important in processes such as thermal sensation, skin barrier formation, and wound healing. TRPV3 was initially proposed as a warm temperature sensor. It is activated by synthetic small-molecule chemicals and plant-derived natural compounds such as camphor and eugenol. Schisandra chinensis (Turcz.) Baill (SC) has diverse pharmacological properties including antiallergic, anti-inflammatory, and wound healing activities. It is extensively used as an oriental herbal medicine for the treatment of various diseases. In this study, we investigated whether SC fruit extracts and seed oil, as well as four compounds isolated from the fruit can activate the TRPV3 channel. By performing whole-cell patch clamp recording in HEK293T cells overexpressing TRPV3, we found that the methanolic extract of SC fruit has an agonistic effect on the TRPV3 channel. Furthermore, electrophysiological analysis revealed that γ-schisandrin, one of the isolated compounds, activated TRPV3 at a concentration of 30 µM. In addition, γ-schisandrin (~100 µM) increased cytoplasmic Ca²⁺ concentrations by approximately 20% in response to TRPV3 activation. This is the first report to indicate that SC extract and γ-schisandrin can modulate the TRPV3 channel. This report also suggests a mechanism by which γ-schisandrin acts as a therapeutic agent against TRPV3-related diseases.

Erratum: Author correction

The Editorial Office of Obstet Gynecol Sci would like to correct the author list.