The CH25H-CYP7B1-RORα axis of cholesterol metabolism regulates osteoarthritis.

Osteoarthritis-the most common form of age-related degenerative whole-joint disease1-is primarily characterized by cartilage destruction, as well as by synovial inflammation, osteophyte formation and subchondral bone remodelling2,3. However, the molecular mechanisms that underlie the pathogenesis of osteoarthritis are largely unknown. Although osteoarthritis is currently considered to be associated with metabolic disorders, direct evidence for this is lacking, and the role of cholesterol metabolism in the pathogenesis of osteoarthritis has not been fully investigated4-6. Various types of cholesterol hydroxylases contribute to cholesterol metabolism in extrahepatic tissues by converting cellular cholesterol to circulating oxysterols, which regulate diverse biological processes7,8. Here we show that the CH25H-CYP7B1-RORα axis of cholesterol metabolism in chondrocytes is a crucial catabolic regulator of the pathogenesis of osteoarthritis. Osteoarthritic chondrocytes had increased levels of cholesterol because of enhanced uptake, upregulation of cholesterol hydroxylases (CH25H and CYP7B1) and increased production of oxysterol metabolites. Adenoviral overexpression of CH25H or CYP7B1 in mouse joint tissues caused experimental osteoarthritis, whereas knockout or knockdown of these hydroxylases abrogated the pathogenesis of osteoarthritis. Moreover, retinoic acid-related orphan receptor alpha (RORα) was found to mediate the induction of osteoarthritis by alterations in cholesterol metabolism. These results indicate that osteoarthritis is a disease associated with metabolic disorders and suggest that targeting the CH25H-CYP7B1-RORα axis of cholesterol metabolism may provide a therapeutic avenue for treating osteoarthritis.

A Successful Live Birth From a Vitrified Oocyte for Fertility Preservation of a Patient With Borderline Ovarian Tumor Undergoing Bilateral Ovarian Surgery: A Case Report.

This article reports the live birth of a healthy newborn using vitrified-warmed oocytes from fertility preservation before ovarian surgery. The patient in our case underwent two cycles of controlled ovarian stimulation before laparoscopic bilateral ovarian cystectomy for endometriosis, and a total of 23 mature oocytes were vitrified. After surgery, her pathologic reports revealed a serous borderline tumor and endometrioma. Fifteen months after her second surgery of laparoscopic right salpingo-oophorectomy and left ovarian cystectomy owing to recurrence, she had been married by then, and three of the frozen oocytes were thawed for intracytoplasmic sperm injection. These oocytes were cryopreserved for 2.5 years. All three were fertilized, and two grade-A cleavage-stage embryos were transferred. A singleton pregnancy was achieved, resulting in the delivery of a healthy baby boy at 39.3 weeks of gestation. Oocyte cryopreservation is an effective method for fertility preservation prior to ovarian surgery when ovarian function decline is predictable.

Ultrasonographic images and correspondence with real color sectioned images of the upper limb.

PURPOSE: For basic training in ultrasonography (US), medical students and residents must learn cross-sectional anatomy. However, the present educational material is not sufficient to learn the sectional anatomy for US. This study aimed to provide a criterion for reading ambiguous structures on US images of upper limb through the sectioned images of Visible Korean. METHODS: US images of the right arm of a volunteer were scanned (28 planes). For comparison with US images, the sectioned images of the right upper limb (24 bits color, 0.5 mm intervals, 0.06 mm × 0.06 mm sized pixel) were used. After the volume model was constructed from the sectioned images using MRIcroGL, new sectioned images of 28 planes corresponding to the US images of 28 planes were created by adjusting the slope of the volume model. In all images, the anatomical terms of 59 structures from the shoulder to the fingers were annotated. RESULTS: In the atlas, which consists of 28 sets of US images and sectioned images of various slope planes, 59 structures of the shoulder, arm, elbow, wrist, palm, and fingers were observed in detail. CONCLUSION: We were able to interpret the ambiguous structures on the US images using the sectioned images with high resolution and actual color. Therefore, to learn the cross-sectional anatomy for US, the sectioned images from the Visible Korean project were deemed to be the suitable data because they contained all human gross anatomical information.

Astrocytic FoxO1 in the hypothalamus regulates metabolic homeostasis by coordinating neuropeptide Y neuron activity.

The forkhead box transcription factor O1 (FoxO1) is expressed ubiquitously throughout the central nervous system, including in astrocytes, the most prevalent glial cell type in the brain. While the role of FoxO1 in hypothalamic neurons in controlling food intake and energy balance is well-established, the contribution of astrocytic FoxO1 in regulating energy homeostasis has not yet been determined. In the current study, we demonstrate the essential role of hypothalamic astrocytic FoxO1 in maintaining normal neuronal activity in the hypothalamus and whole-body glucose metabolism. Inhibition of FoxO1 function in hypothalamic astrocytes shifts the cellular metabolism from glycolysis to oxidative phosphorylation, enhancing astrocyte ATP production and release meanwhile decreasing astrocytic export of lactate. As a result, specific deletion of astrocytic FoxO1, particularly in the hypothalamus, causes a hyperactivation of hypothalamic neuropeptide Y neurons, which leads to an increase in acute feeding and impaired glucose regulation and ultimately results in diet-induced obesity and systemic glucose dyshomeostasis.

Anti-obesity effects of Lactiplantibacillus plantarum SKO-001 in high-fat diet-induced obese mice.

PURPOSE: Previous reports showed that some probiotics provide beneficial effects on various diseases including metabolic disorders. This study aimed to investigate the anti-obesity effects of Lactiplantibacillus (L.) plantarum SKO-001 (SKO-001), a probiotic strain newly isolated from Angelica gigas. METHODS: C57BL/6J mice were fed with high-fat diet (HFD, 60% fat) for four weeks, and then different doses of SKO-001 (n = 10 each group) were orally given for 12 weeks. Following treatment, body weight, fat weight, serum parameters and adipose and liver tissues were analyzed. RESULTS: SKO-001 (2 × 1010 CFU/day, per os) reduced body weight gain after 10th week of administration, accompanied by a reduction in body fat mass of mice. In the SKO-001-fed group, increased serum adiponectin, decreased leptin, insulin, total cholesterol, low-density lipoprotein cholesterol, free fatty acids, and triglyceride levels were observed. Hematoxylin and eosin staining of various fat depots showed that increased adipocyte size caused by HFD intake was markedly reduced and correlated with reduced mRNA levels of lipogenesis genes, including sterol regulatory element-binding protein-1c, peroxisome proliferator-activated receptor gamma, and CCAAT/enhancer binding protein alpha, and increased uncoupling protein 1 levels. Similarly, SKO-001 reduced lipid accumulation, decreased the mRNA levels of lipogenic genes, and reduced α-smooth muscle actin and collagen type 1 alpha 1 levels in the liver. CONCLUSIONS: SKO-001 ameliorates obesity and related metabolic abnormalities in adipose and liver tissues, possibly via the regulation of lipid metabolism. Based on the results of the present study, SKO-001 may be applicable as an anti-obesity therapeutic or functional food.

Impact of BRCA mutations and hormone receptor status on reproductive potential in breast cancer patients undergoing fertility preservation.

OBJECTIVE: To identify whether the BRCA mutations and hormone receptor status affect the ovarian reserve and ovarian stimulation outcomes in breast cancer patients undergoing fertility preservation. METHODS: A total of 117 women diagnosed with breast cancer who were referred to the fertility preservation clinics at Seoul National University Bundang Hospital and Seoul National University Hospital between September 2012 and July 2019 undergone ovarian stimulation for oocyte retrieval. Basal characteristics including age, BMI, basal AMH, basal FSH, and fertility preservation outcomes such as the number of retrieved oocytes and mature oocytes were compared retrospectively. RESULTS: BRCA1 mutation was noted in 25 women, and BRCA2 mutation was observed in 35 women. Positive estrogen receptor status was noted in 87 women, and positive progesterone receptor status was noted in 69 women. HER2 was positive in 55 women, and 19 women were diagnosed with triple-negative breast cancers. The number of total oocytes retrieved was lower in patients with BRCA mutation (8.3 ± 5.4 vs. 15.3 ± 8.7, p = .002). The number of mature oocytes retrieved was also lower in BRCA carriers (4.7 ± 4.2 vs. 8.7 ± 7.9, p = .025). Triple-negative breast cancer (TNBC) patients were younger than non-TNBC patients (30.3 ± 4.8 vs. 33.9 ± 5.0, p = .007). The rate of mature oocyte rate was higher in TNBC patients (68.6%±20.6 vs. 52.5%±29.7, p = .037). CONCLUSIONS: Our study demonstrated that BRCA carriers with breast cancer had comparable ovarian reserve to non-carriers but the response to ovarian stimulation was lower. We also observed that oocyte maturity was higher in TNBC patients, however age might be a confounding factor of this result.

Advanced-sectioned images obtained by microsectioning of the entire male body.

Realistic two-dimensional (2D) and three-dimensional (3D) applications for anatomical studies are being developed from true-colored sectioned images. We generated advanced-sectioned images of the entire male body and verified that anatomical structures of both normal and abnormal shapes could be visualized in them. The cadaver was serially sectioned at constant intervals using a cryomacrotome. The sectioned surfaces were photographed using a digital camera to generate horizontal advanced-sectioned images in which normal and abnormal structures were classified. Advanced-sectioned images of the entire male body were generated. The image resolution was 3.3 × 3.3 fold better than that of the first sectioned images obtained in 2002. In the advanced-sectioned images, normal and abnormal structures ranging from microscopic (≥0.06 mm × 0.06 mm; pixel size) to macroscopic (≤473.1 mm × 202 mm; body size) could be identified. Furthermore, the real shapes and actual sites of lung cancer and lymph node enlargement were ascertained in them. Such images will be useful because of their true color and high resolution in digital 2D and 3D applications for gross anatomy and clinical anatomy. In future, we plan to generate new advanced-sectioned images of abnormal cadavers with different diseases for clinical anatomy studies.

Microbiome-Based Metabolic Therapeutic Approaches in Alcoholic Liver Disease.

Alcohol consumption is a global healthcare problem. Chronic alcohol consumption generates a wide spectrum of hepatic lesions, the most characteristic of which are steatosis, hepatitis, fibrosis, and cirrhosis. Alcoholic liver diseases (ALD) refer to liver damage and metabolomic changes caused by excessive alcohol intake. ALD present several clinical stages of severity found in liver metabolisms. With increased alcohol consumption, the gut microbiome promotes a leaky gut, metabolic dysfunction, oxidative stress, liver inflammation, and hepatocellular injury. Much attention has focused on ALD, such as alcoholic fatty liver (AFL), alcoholic steatohepatitis (ASH), alcoholic cirrhosis (AC), hepatocellular carcinoma (HCC), a partnership that reflects the metabolomic significance. Here, we report on the global function of inflammation, inhibition, oxidative stress, and reactive oxygen species (ROS) mechanisms in the liver biology framework. In this tutorial review, we hypothetically revisit therapeutic gut microbiota-derived alcoholic oxidative stress, liver inflammation, inflammatory cytokines, and metabolic regulation. We summarize the perspective of microbial therapy of genes, gut microbes, and metabolic role in ALD. The end stage is liver transplantation or death. This review may inspire a summary of the gut microbial genes, critical inflammatory molecules, oxidative stress, and metabolic routes, which will offer future promising therapeutic compounds in ALD.

Clinical efficacy of dual trigger with human chorionic gonadotropin and a gonadotropin-releasing hormone agonist for women undergoing fertility preservation.

Purpose: To determine the optimal maturation method to increase the yield of mature oocytes, especially for cancer patients with fewer chances of fertility preservation (FP) before gonadotoxic therapy. Methods: A total of 373 cycles in 293 patients undergoing controlled ovarian stimulation (COS) for FP using a gonadotropin-releasing hormone (GnRH) antagonist protocol were enrolled. The control group (n = 225) received 250 µg of recombinant human chorionic gonadotropin (rhCG) while the study group (n = 148) received 250 µg of rhCG and 0.2 mg of triptorelin for triggering. Subgroup analyses were performed for stimulation cycles with diminished ovarian reserve (DOR; anti-Müllerian hormone (AMH) levels <1.1 ng/ml, n = 86), with endometrioma (n = 104), or with breast cancer and endometrial cancer using 5 mg of letrozole during the COS cycles (n = 84). Results: There was no significant difference in the baseline characteristics or the number of total and mature oocytes between the two groups. Subgroup analyses for women with endometrioma or DOR showed similar results. However, the dual trigger group had a significantly higher number of mature oocytes than the rhCG trigger group in breast and endometrial cancer patients using letrozole during the COS cycles (6.9 ± 6.0 vs. 4.6 ± 3.6, p = 0.034). The maturation rate was higher in the dual trigger group, although the difference was not statistically significant (59.3 ± 26.7 vs. 50.0 ± 28.0, p = 0.124). Conclusions: Dual triggering can be an efficient maturation method to maximize the yield of mature oocytes in breast or endometrial cancer patients using letrozole-combined GnRH antagonist protocol for FP.

Operative and Obstetric Outcomes after Single-port Laparoscopic Myomectomy: A Retrospective Single-center Analysis of 504 Cases.

STUDY OBJECTIVE: To analyze the obstetric and operative outcomes of 504 cases of single-port laparoscopic myomectomy (SPLM). DESIGN: Single-center retrospective study. SETTING: A tertiary university hospital. PATIENTS: A total of 502 patients (504 SPLM procedures) who underwent SPLM for symptom relief or growing myomas between October 2009 and April 2020. INTERVENTIONS: Data on patient demographics, operative variables (estimated blood loss, hemoglobin decrease, operation time, perioperative complications, and postoperative hospital stay), and obstetric outcomes (the surgery-to-pregnancy interval and birth-related outcomes) were obtained from medical records and analyzed. MEASUREMENTS AND MAIN RESULTS: The mean age of the patients was 40.6 ± 6.6 years. The patients had had an average of 2.3 ± 2.2 myomas removed; the largest myoma size was 6.8 ± 2.4 cm. The mean operation time, postoperative hemoglobin decrease, and postoperative hospital stay duration were 112.9 ± 45.3 minutes, 1.7 ± 1.1 g/dL, and 2.2 ± 1.4 days, respectively. The overall rate of postoperative complications was 7.7% (39/504), and the common complications were transfusions (16/504, 3.1%) or wound problems (15/504, 3.0%). Conversion to multiport or open myomectomy was required in 0.8% of the cases (4/504). A total of 376 women were of child-bearing age, and 56 attempted to become pregnant after surgery. The mean interval from surgery to pregnancy was 15.6 ± 12.2 months. The obstetric outcomes were pregnancy (42/56, 75.0%), live birth (39/56, 69.6%), and miscarriage (2/56, 3.6%). One pregnant woman was lost to follow-up. The 39 live births predominantly involved full-term delivery (36/39, 92.3%), mostly through cesarean section (36/39, 92.3%). No postpartum complications were reported. The 2 most common obstetric complications were preterm labor (7.6%) and gestational diabetes (5.1%). CONCLUSION: SPLM seems to be an effective procedure with good operative and postoperative obstetric outcomes for women with myomas who require surgery and may wish to subsequently become pregnant.