Hashimoto Thyroiditis and Mortality in Patients with Differentiated Thyroid Cancer: The National Epidemiologic Survey of Thyroid Cancer in Korea and Meta-Analysis.

BACKGRUOUND: Many studies have shown that Hashimoto's thyroiditis (HT) acts as a protective factor in differentiated thyroid cancer (DTC), but little is known about its effects on mortality. Therefore, this study was performed to reveal the prognosis of HT on mortality in patients with DTC. METHODS: This study included two types of research. RESULTS: retrospective cohort study using the National Epidemiologic Survey of Thyroid cancer (NEST) in Korea and meta-analysis study with the NEST data and eight selected studies. RESULTS: Of the 4,398 patients with DTC in NEST, 341 patients (7.8%) died during the median follow-up period of 15 years (interquartile range, 12.3 to 15.6). Of these, 91 deaths (2.1%) were related to DTC. HT was associated with a smaller tumor size and less aggressive DTC. In Cox regression analysis after adjusting for age and sex, patients with HT showed a significantly lower risk of all-cause death (hazard ratio [HR], 0.71; 95% confidence interval [CI], 0.52 to 0.96) and DTC-related death (HR, 0.33; 95% CI, 0.14 to 0.77). The analysis with inverse probability of treatment weight data adjusted for age, sex, and year of thyroid cancer registration showed similar association. The meta-analysis showed that patients with HT showed a lower risk of all-cause mortality (risk ratio [RR], 0.24; 95% CI, 0.13 to 0.47) and thyroid cancer-related mortality (RR, 0.23; 95% CI, 0.13 to 0.40) in comparison with patients without HT. CONCLUSION: This study showed that DTC co-presenting with HT is associated with a low risk of advanced DTC and presents a low risk for all-cause and DTC-related death.

Switchable Design of Redox-Enhanced Nonaromatic Quinones Enabled by Conjugation Recovery.

An innovative switchable design strategy for modulating the electronic structures of quinones is proposed herein, leading to remarkably enhanced intrinsic redox potentials by restoring conjugated but nonaromatic backbone architectures. Computational validation of two fundamental hypotheses confirms the recovery of backbone conjugation and optimal utilization of the inductive effect in switched quinones, which affords significantly improved redox chemistry and overall performance compared to reference quinones. Geometric and electronic analyses provide strong evidence for the restored backbone conjugation and nonaromaticity in the switched quinones, while highlighting the reinforcement of the inductive effect and suppression of the resonance effect. This strategic approach facilitates the development of an exceptional quinone, viz. 2,6-naphthoquinone, with outstanding performance parameters (338.9 mAh g-1 and 912.9 mWh g-1). Furthermore, 2,6-anthraquinone with superior cyclic stability, demonstrates comparable performance (257.4 mAh g-1 and 702.8 mWh g-1). These findings offer valuable insights into the design of organic cathode materials with favorable redox chemistry in secondary batteries.

Association between body composition and the risk of mortality in the obese population in the United States.

Background: Recent studies have presented the concept of the obesity paradox, suggesting that individuals with obesity have a lower risk of death than those without obesity. This paradox may arise because body mass index (BMI) alone is insufficient to understand body composition accurately. This study investigated the relationship between fat and muscle mass and the risk of mortality in individuals with overweight/obesity. Methods: We used data from the National Health and Nutrition Examination Survey (NHANES) from 1999 to 2006 and 2011 to 2018, which were linked to mortality information obtained from the National Death Index. Multiple Cox regression analyses were performed to estimate mortality risk. Subgroup analysis was conducted using propensity score-matched (PSM) data for age, sex, and race/ethnicity. Results: This study included 16,555 participants who were overweight/obese (BMI≥25 kg/m2). An increase in appendicular skeletal muscle mass index was associated with a lower mortality risk (hazard ratio [HR]: 0.856; 95% confidence interval [CI]: 0.802-0.915). This finding was consistent with the subgroup analysis of the PSM data. Contrastingly, a high fat mass index was associated with an increased risk of mortality. Sarcopenic overweight/obesity was significantly associated with high mortality compared to obesity without sarcopenia (HR: 1.612, 95%CI: 1.328-1.957). This elevated risk was significant in both age- and sex-based subgroups. This finding was consistent with the subgroup analysis using PSM data. Conclusion: In contrast to the obesity paradox, a simple increase in BMI does not protect against mortality. Instead, low body fat and high muscle mass reduce mortality risk.

Destruction of Vowel Space Area in Patients with Dysphagia after Stroke.

Dysphagia is associated with dysarthria in stroke patients. Vowel space decreases in stroke patients with dysarthria; destruction of the vowel space is often observed. We determined the correlation of destruction of acoustic vowel space with dysphagia in stroke patients. Seventy-four individuals with dysphagia and dysarthria who had experienced stroke were enrolled. For /a/, /ae/, /i/, and /u/ vowels, we determined formant parameter (it reflects vocal tract resonance frequency as a two-dimensional coordinate point), formant centralization ratio (FCR), and quadrilateral vowel space area (VSA). Swallowing function was assessed using the videofluoroscopic dysphagia scale (VDS) during videofluoroscopic swallowing studies. Pearson's correlation and linear regression were used to determine the correlation between VSA, FCR, and VDS. Subgroups were created based on VSA; vowel space destruction groups were compared using ANOVA and Scheffe's test. VSA and FCR were negatively and positively correlated with VDS, respectively. Groups were separated based on mean and standard deviation of VSA. One-way ANOVA revealed significant differences in VDS, FCR, and age between the VSA groups and no significant differences in VDS between mild and moderate VSA reduction and vowel space destruction groups. VSA and FCR values correlated with swallowing function. Vowel space destruction has characteristics similar to VSA reduction at a moderate-to-severe degree and has utility as an indicator of dysphagia severity.

Elastic Dynamic Sling on Subluxation of Hemiplegic Shoulder in Patients with Subacute Stroke: A Multicenter Randomized Controlled Trial.

Background: Shoulder subluxation occurs in 17−64% of hemiplegic patients after stroke and develops mostly during the first three weeks of hemiplegia. A range of shoulder orthoses has been used in rehabilitation to prevent subluxation. However, there is little evidence of their efficacy. AIM: This study aimed to investigate whether there is a difference in the subluxation distance, pain, and functional level of the hemiplegic upper extremity among patients with two different shoulder orthoses. Design: This is a prospective, randomized controlled trial with intention-to-treat analysis. SETTING: Multicenter, rehabilitation medicine department of two university hospitals in South Korea. Population: Forty-one patients with subacute stroke with shoulder subluxation with greater than 0.5 finger width within 4 weeks of stroke were recruited between January 2016 and October 2021. Methods: The experimental group used an elastic dynamic sling while sitting and standing to support the affected arm for eight weeks. The control group used a Bobath sling while sitting and standing. The primary outcome was to assess the distance of the shoulder subluxation on radiography. The secondary outcomes were upper-extremity function, muscle power, activities of daily living, pain and spasticity. Result: The horizontal distance showed significant improvement in the elastic dynamic sling group, but there were no significant differences in the vertical distance between the elastic dynamic and Bobath sling groups. Both groups showed improvements in upper-extremity movements and independence in daily living after 4 and 8 weeks of using shoulder orthoses, and the differences within the groups were significant (p < 0.05). However, there were no significant differences in upper-extremity movements and independence in daily living between the two groups. Conclusions: The subluxation distance showed better results in the elastic dynamic sling, which has both proximal and distal parts, than in the Bobath sling, which holds only the proximal part. Both shoulder orthoses showed improvements in the modified Barthel index, upper-extremity function, and manual muscle testing.

Association between body shape index and risk of mortality in the United States.

The body mass index (BMI) neither differentiates fat from lean mass nor does it consider adipose tissue distribution. In contrast, the recently introduced z-score of the log-transformed A Body Shape Index (LBSIZ) can be applied to measure obesity using waist circumference (WC), height, and weight. We aimed to investigate the association between LBSIZ and mortality. We used data from the National Health and Nutrition Examination Survey 1999-2014 and linked the primary dataset to death certificate data from the National Death Index with mortality follow-up through December 31, 2015. A multiple Cox regression analysis was performed to evaluate the hazard ratio (HR) of all-cause and cardiovascular disease (CVD) mortalities with adjustment for baseline characteristics. LBSIZ, WC, and BMI showed positive association with total fat percentage (P < 0.001); however, only WC and BMI were positively associated with appendicular skeletal mass index (ASMI) (P < 0.001). In the multiple Cox regression analysis, only LBSIZ showed a significant HR for all-cause and CVD mortalities. Under restricted cubic spline regression, mortality risk increased with LBSIZ. However, BMI and WC showed a U-shape association. In conclusion, LBSIZ is strongly associated with all-cause and CVD mortalities. Since LBSIZ is independent of BMI, LBSIZ complements BMI to identify high-risk groups for mortality even in individuals with low or normal BMI.

Quantitative Measurement of Dysphonia Severity in Patients With Stroke With Unilateral Vocal Cord Palsy.

Unilateral vocal cord palsy (UVCP) is frequently observed in patients with stroke. This study aimed to evaluate the association between objective dysphonia severity and the classification of UVCP in patients with stroke by objectively and quantitatively measuring their phonetic function. We recruited patients with UVCP diagnosed using laryngoscopy after stroke. Subgroups were divided according to UVCP type, and the dysphonia severity index (DSI) and maximum phonation time (MPT) were measured to objectively evaluate dysphonia. The DSI and MPT were compared between subgroups using analysis of variance with Tukey's honest significant difference post hoc test. In total, 103 patients with stroke and UVCP were recruited. We found that a higher UVCP severity possibly had to do with lower DSI and MPT values. We objectively confirmed that phonetic function was worse in patients with stroke with higher UVCP severity, and the DSI and MPT tests can be helpful in determining the severity and need for additional evaluation.

Association between Serum Selenium Level and the Presence of Diabetes Mellitus: A Meta-Analysis of Observational Studies.

BACKGROUND: Epidemiological studies have suggested an association between selenium (Se) and diabetes mellitus (DM). However, different studies have reported conflicting results. Therefore, we performed a comprehensive meta-analysis to clarify the impact of Se on DM. METHODS: We searched the PubMed database for studies on the association between Se and DM from inception to June 2018. RESULTS: Twenty articles evaluating 47,930 participants were included in the analysis. The meta-analysis found that high levels of Se were significantly associated with the presence of DM (pooled odds ratios [ORs], 1.88; 95% confidence interval [CI], 1.44 to 2.45). However, significant heterogeneity was found (I²=82%). Subgroup analyses were performed based on the Se measurement methods used in each study. A significant association was found between high Se levels and the presence of DM in the studies that used blood (OR, 2.17; 95% CI, 1.60 to 2.93; I²=77%), diet (OR, 1.61; 95% CI, 1.10 to 2.36; I²=0%), and urine (OR, 1.49; 95% CI, 1.02 to 2.17; I²=0%) as samples to estimate Se levels, but not in studies on nails (OR, 1.24; 95% CI, 0.52 to 2.98; I²=91%). Because of significant heterogeneity in the studies with blood, we conducted a sensitivity analysis and tested the publication bias. The results were consistent after adjustment based on the sensitivity analysis as well as the trim and fill analysis for publication bias. CONCLUSION: This meta-analysis demonstrates that high levels of Se are associated with the presence of DM. Further prospective and randomized controlled trials are warranted to elucidate the link better.

Association between Body Fat and Bone Mineral Density in Normal-Weight Middle-Aged Koreans.

BACKGROUND: Osteoporosis and osteopenia are characterized by reduced bone mineral density (BMD) and increased fracture risk. Although the risk of fractures is higher in underweight people than in overweight people, the accumulation of body fat (especially abdominal fat) can increase the risk of bone loss. This study aimed to evaluate the association between body fat percentage and BMD in normal-weight middle-aged Koreans. METHODS: This study included 1,992 adults (mean age, 48.7 years; 52.9% women). BMD and body fat were measured using dual-energy X-ray absorptiometry. Multiple linear regression analyses and analysis of covariance were used to assess the association between BMD and body fat. Body fat percentage was grouped by cut-off values. The cut-off values were 20.6% and 25.7% for men with a body mass index of 18.5-22.9 kg/m2 , while the cut-off values were 33.4% and 36% for women. RESULTS: Body fat percentage tended to be negatively associated with BMD. Increased body fat percentage was associated with reduced BMD in normal-weight middle-aged adults. The effects of body fat percentage on BMD in normal-weight individuals were more pronounced in men than in women. CONCLUSION: There was a negative correlation between BMD and body fat percentage in middle-aged Korean men and women with normal body weight. This association was stronger in men than in women.

Cardiovascular disease risk factor clustering in children and adolescents: a prospective cohort study.

OBJECTIVE: The early identification of predictors related to cardiovascular disease risk factor clustering (CVD-RFC) can help prevent chronic disease. We aimed to identify the risk factors for CVD-RFC in adolescents. METHODS: A prospective longitudinal cohort study design was used to obtain data included in these analyses from school-aged children who participated in the Korean Child-Adolescent Study 2008-2014. A total of 1309 children aged 6-15 years were enrolled. We compared the participants based on the presence or absence of CVD-RFC and examined the cumulative incidence of CVD-RFC. RESULTS: Of the total 1309 children, 410 (31.32%) had CVD-RFC in adolescence. A higher average household income ≥3 million Korean Republic won (KRW)/month (3-5 million KRW/month: HR 0.75 (95% CI 0.58 to 0.97); ≥5 million KRW/month: HR 0.58 (95% CI 0.44 to 0.77)) was associated with a lower CVD-RFC incidence, while the presence of parental CVD history (HR 1.28 (95% CI 1.04 to 1.57)), overweight or obesity (HR 3.83 (95% CI 3.05 to 4.80)) and shorter sleep duration of 8-9 hour/day (HR 1.80 (95% CI 1.05 to 3.07)) and <8 hour/day (HR 1.93 (95% CI 1.11 to 3.34)) had higher CVD-RFC incidences. CONCLUSIONS: Obesity in childhood, short sleep duration and parental factors such as low socioeconomic status and parental history of CVD are significant risk factors for the development of CVD-RFC in adolescents. Efforts to create awareness regarding sufficient sleep duration in children via intervention programmes targeting cardiometabolic health in children and special attention to lifestyle modifications and socioeconomic components of the family should be considered.

Gender Differences in the relationship between carbonated sugar-sweetened beverage intake and the likelihood of hypertension according to obesity.

OBJECTIVES: The aim of the present study was to investigate the association between hypertension and carbonated sugar-sweetened beverages (SSB) intake according to gender and obesity. METHODS: The study used data from 2007, 2008 and 2009 Korea National Health and Nutrition Examination Surveys. A total of 9869 subjects (men = 3845 and women = 6024) were included. SSB intakes were calculated from food frequency questionnaires. Odds ratios (ORs) and 95 % confidence interval (CI) for hypertension were assessed using survey logistic regression and multivariable adjusted models. RESULTS: A total of 14.5 % of individuals were classified as having hypertension. The likelihood of hypertension in the third, fourth and fifth quintiles for SSB intake increased to OR 1.00, 1.20 and 1.42 respectively, after adjusting for confounding factors. Compared to the participants in the lowest tertile for SSB intake, participants in the third tertile showed an increased likelihood of hypertension with ORs (CI) of 2.00 (1.21-3.31) and 1.75 (1.23-2.49) for obese women and non-obese men, respectively. CONCLUSIONS: The present study showed gender differences in the relationship between carbonated SSB intake and the hypertension according to obesity.

Association of dietary patterns with the fecal microbiota in Korean adolescents.

BACKGROUND: The gut microbiota has emerged as an important environmental factor associated with obesity, type 2 diabetes, and cardiovascular disease, through its interactions with dietary factors. Therefore, we analyzed the composition of the fecal microbiota and levels of biochemical markers related to metabolic disease according to dietary pattern in Korean adolescents. METHODS: We collected fecal samples from 112 student subjects aged 13-16 years with sufficient information available regarding clinical biomarkers and diet, and performed 16S rRNA targeted gene sequencing. RESULTS: Regarding bacterial composition according to taxonomic rank, we found that traditional dietary patterns enriched in plant-based and fermented foods were associated with higher proportions of Bacteroides (Bacteroidaceae) and Bifidobacterium (Bifidobacteriaceae-Actinobacteria) and a lower proportion of Prevotella (Prevotellaceae) relative to modified Western dietary patterns (a greater proportion of animal-based foods). Specifically, the proportion of Bacteroides (Bacteroidaceae) was associated with intake of plant-based nutrients such as fiber; however, that of Prevotella (Prevotellaceae) was negatively associated with these factors. Additionally, we observed that the increase of prevotella (Prevotellaceae) and decrease of Bacteroides (Bacteroidaceae) and Ruminococcaceae had a higher risk of obesity. We also found that the traditional dietary pattern was negatively associated with general and central adiposity and levels of clinical biomarkers, including AST, ALT, total cholesterol, triglyceride, hs-CRP, insulin, and HOMA-IR, whereas the positive associations were found for a modified Western dietary pattern. CONCLUSIONS: These findings suggest that the gut microbiota composition differs markedly according to dietary intake and suggest a role for diet in promoting a gut microbiome associated with the pathogenesis of metabolic disease.

Efficacy and safety of fermented garlic extract on hepatic function in adults with elevated serum gamma-glutamyl transpeptidase levels: a double-blind, randomized, placebo-controlled trial.

PURPOSE: Alcoholic liver disease or non-alcoholic fatty liver disease/non-alcoholic steatohepatitis are well-known risk factors for liver fibrosis or cirrhosis and hepatocellular carcinoma; it is a major global health concern, but there are few effective and safe management options. Therefore, we aimed to investigate the effects of fermented garlic extracts (FGEs) on hepatic function in adults with mild hepatic dysfunction without underlying hepatic disease. METHODS: In this double-blind, randomized, placebo-controlled study, seventy-five adults with elevated serum gamma-glutamyl transpeptidase (GGT) levels were included in a FGE-administered group (n = 36) or a placebo group (n = 39), and received either two sachets/day containing FGEs or placebo over a 12-week period. Primary endpoint was the change in serum GGT levels. Data were analysed using a generalized linear mixed effects model. RESULTS: Significant group × time interactions for serum levels of GGT (F = 3.98, P = 0.022) and alanine aminotransferase (ALT; F = 3.28, P = 0.043) were observed with an improvement in levels of GGT (P = 0.066) and ALT (P = 0.014) in the FGE group compared to that reported for the placebo group at the 12-week visits. There was no intergroup difference in the prevalence of adverse events. CONCLUSIONS: Intake of FGEs improved serum GGT and ALT levels in adults with mildly elevated serum GGT level without reported adverse side effects. FGEs might be effective and safe management options for mild hepatic dysfunction.

Ethanolic extract of Schizonepeta tenuifolia attenuates osteoclast formation and activation in vitro and protects against lipopolysaccharide-induced bone loss in vivo.

BACKGROUND: Excessive osteoclast activity is a major cause of metabolic bone disorders, such as osteopenia, rheumatoid arthritis, and osteoporosis. Thus, discovery of agents targeting osteoclast differentiation and bone resorption is important for development of novel treatments for bone diseases. It has been demonstrated that ethanolic extract of schizonepeta tenuifolia (EEST) has potent anti-oxidant and anti-inflammatory activities. However, the beneficial effects of EEST on bone metabolism have not been studied. Therefore, we intend to investigate the effects of EEST on osteoclast differentiation. METHODS: We examined the effects and mechanisms of action of the EEST on osteoclastogenesis in vitro in bone marrow macrophages (BMMs) stimulated with receptor activator of nuclear factor kappa-B ligand (RANKL) and in vivo using a mouse model of lipopolysaccharide (LPS)-induced bone destruction. RESULTS: We found that EEST inhibited phosphorylation of Akt and IkB at early stages of RANKL-induced osteoclastogenesis. Furthermore, EEST negatively controlled the transcription and translation levels of nuclear factor of activated T cells c1 (NFATc1) and the translation level of c-Fos at the final stage of osteoclast differentiation. Reflecting these effects, EEST blocked both filamentous actin (F-actin) ring formation and bone resorbing activity of mature osteoclasts in vitro. The inhibitory effects of EEST on osteoclast formation and activity were observed in an LPS-mediated bone erosion mouse model using micro-CT and histological analysis. CONCLUSIONS: EEST is a potential agent that is able to treat osteoclast-related bone diseases, such as osteoporosis.

Dendrobium moniliforme Exerts Inhibitory Effects on Both Receptor Activator of Nuclear Factor Kappa-B Ligand-Mediated Osteoclast Differentiation in Vitro and Lipopolysaccharide-Induced Bone Erosion in Vivo.

Dendrobium moniliforme (DM) is a well-known plant-derived extract that is widely used in Oriental medicine. DM and its chemical constituents have been reported to have a variety of pharmacological effects, including anti-oxidative, anti-inflammatory, and anti-tumor activities; however, no reports discuss the beneficial effects of DM on bone diseases such as osteoporosis. Thus, we investigated the relationship between DM and osteoclasts, cells that function in bone resorption. We found that DM significantly reduced receptor activator of nuclear factor kappa-B ligand (RANKL)-induced tartrate-resistant acid phosphatase (TRAP)-positive osteoclast formation; DM directly induced the down-regulation of c-Fos and nuclear factor of activated T cells c1 (NFATc1) without affecting other RANKL-dependent transduction pathways. In the later stages of osteoclast maturation, DM negatively regulated the organization of filamentous actin (F-actin), resulting in impaired bone-resorbing activity by the mature osteoclasts. In addition, micro-computed tomography (µ-CT) analysis of the murine model revealed that DM had a beneficial effect on lipopolysaccharide (LPS)-mediated bone erosion. Histological analysis showed that DM attenuated the degradation of trabecular bone matrix and formation of TRAP-positive osteoclasts in bone tissues. These results suggest that DM is a potential candidate for the treatment of metabolic bone disorders such as osteoporosis.

Obesity Alters the Microbial Community Profile in Korean Adolescents.

Obesity is an increasing public health concern worldwide. According to the latest Organization for Economic Co-operation and Development (OECD) report (2014), the incidence of child obesity in Korea has exceeded the OECD average. To better understand and control this condition, the present study examined the composition of the gut microbial community in normal and obese adolescents. Fecal samples were collected from 67 obese (body mass index [BMI] ≥ 30 kg/m2, or ≥ 99th BMI percentile) and 67 normal (BMI < 25 kg/m2 or < 85th BMI percentile) Korean adolescents aged 13-16 years and subjected to 16S rRNA gene sequencing. Analysis of bacterial composition according to taxonomic rank (genus, family, and phylum) revealed marked differences in the Bacteroides and Prevotella populations in normal and obese samples (p < 0.005) at the genus and family levels; however, there was no difference in the Firmicutes-to-Bacteroidetes (F/B) ratio between normal and obese adolescents samples at the phylum level (F/B normal = 0.50 ± 0.53; F/B obese = 0.56 ± 0.86; p = 0.384). Statistical analysis revealed a significant association between the compositions of several bacterial taxa and child obesity. Among these, Bacteroides and Prevotella showed the most significant association with BMI (p < 0.0001 and 0.0001, respectively). We also found that the composition of Bacteroides was negatively associated with triglycerides (TG), total cholesterol, and high-sensitive C-reactive protein (hs-crp) (p = 0.0049, 0.0023, and 0.0038, respectively) levels, whereas that of Prevotella was positively associated with TG and hs-crp levels (p = 0.0394 and 0.0150, respectively). We then applied the association rule mining algorithm to generate "rules" to identify the association between the populations of multiple bacterial taxa and obesity; these rules were able to discriminate obese from normal states. Therefore, the present study describes a systemic approach to identify the association between bacterial populations in the gut and childhood obesity.

CTRP3 acts as a negative regulator of osteoclastogenesis through AMPK-c-Fos-NFATc1 signaling in vitro and RANKL-induced calvarial bone destruction in vivo.

Adipokines derived from adipocytes are important factors that act as circulating regulators of bone metabolism. C1q/tumor necrosis factor (TNF)-related Protein-3 (CTRP3) is a novel adipokine with multiple effects such as lowering glucose levels, inhibiting gluconeogenesis in the liver, and increasing angiogenesis and anti-inflammation. However, the effects and the mechanisms of CTRP3 on bone metabolism, which is regulated by osteoblasts and osteoclasts, have not been investigated. Here, we found that CTRP3 inhibited osteoclast differentiation induced by osteoclastogenic factors in bone marrow cell-osteoblast co-cultures, but did not affect the ratio of receptor activator of nuclear factor κB (NF-κB) ligand (RANKL) to osteoprotegerin (OPG) induced by osteoclastogenic factors in osteoblasts. We also found that CTRP3 inhibited osteoclast differentiation from mouse bone marrow macrophages (BMMs) induced by RANKL in a dose-dependent manner without cytotoxicity. Functionally, CTRP3 inhibited the F-actin formation and bone resorbing activity of mature osteoclasts. Pretreatment with CTRP3 significantly inhibited RANKL-induced expression of c-Fos and nuclear factor of activated T-cells (NFATc1), essential transcription factors for osteoclast development. Surprisingly, the activation of AMP-activated protein kinase (AMPK) was considerably increased by pretreatment with CTRP3 for 1h. The CTRP3-stimulated AMPK activation was also maintained during RANKL-induced osteoclastogenesis. CTRP3 did not affect RANKL-induced p38, ERK, JNK, Akt, IκB, CREB, and calcium signaling (Btk and PLCγ2). These results suggest that CTRP3 plays an important role as a negative regulator of RANKL-mediated osteoclast differentiation by acting as an inhibitor of NFATc1 activation through the AMPK signaling pathway. Furthermore, CTRP3 treatment reduced RANKL-induced osteoclast formation and bone destruction in mouse calvarial bone in vivo based on micro-CT and histologic analysis. In conclusion, these findings strongly suggest that CTRP3 deserves new evaluation as a potential treatment target in various bone diseases associated with excessive osteoclast differentiation and bone destruction.

Mollugin from Rubea cordifolia suppresses receptor activator of nuclear factor-κB ligand-induced osteoclastogenesis and bone resorbing activity in vitro and prevents lipopolysaccharide-induced bone loss in vivo.

Osteopenic diseases, such as osteoporosis, are characterized by progressive and excessive bone resorption mediated by enhanced receptor activator of nuclear factor-κB ligand (RANKL) signaling. Therefore, downregulation of RANKL downstream signals may be a valuable approach for the treatment of bone loss-associated disorders. In this study, we investigated the effects of the naphthohydroquinone mollugin on osteoclastogenesis and its function in vitro and in vivo. Mollugin efficiently suppressed RANKL-induced osteoclast differentiation of bone marrow macrophages (BMMs) and bone resorbing activity of mature osteoclasts by inhibiting RANKL-induced c-Fos and NFATc1 expression. Mollugin reduced the phosphorylation of signaling pathways activated in the early stages of osteoclast differentiation, including the MAP kinase, Akt, and GSK3ß and inhibited the expression of different genes associated with osteoclastogenesis, such as OSCAR, TRAP, DC-STAMP, OC-STAMP, integrin αν, integrin ß3, cathepsin K, and ICAM-1. Furthermore, mice treated with mollugin showed significant restoration of lipopolysaccharide (LPS)-induced bone loss as indicated by micro-CT and histological analysis of femurs. Consequently, these results suggested that mollugin could be a novel therapeutic candidate for bone loss-associated disorders including osteoporosis, rheumatoid arthritis, and periodontitis.