Dexamethasone-induced muscle atrophy and bone loss in six genetically diverse collaborative cross founder strains demonstrates phenotypic variability by Rg3 treatment.

Background: Osteosarcopenia is a common condition characterized by the loss of both bone and muscle mass, which can lead to an increased risk of fractures and disability in older adults. The study aimed to elucidate the response of various mouse strains to treatment with Rg3, one of the leading ginsenosides, on musculoskeletal traits and immune function, and their correlation. Methods: Six Collaborative Cross (CC) founder strains induced muscle atrophy and bone loss with dexamethasone (15 mg/kg) treatment for 1 month, and half of the mice for each strain were orally administered Rg3 (20 mg/kg). Different responses were observed depending on genetic background and Rg3 treatment. Results: Rg3 significantly increased grip strength, running performance, and expression of muscle and bone health-related genes in a two-way analysis of variance considering the genetic backgrounds and Rg3 treatment. Significant improvements in grip strength, running performance, bone area, and muscle mass, and the increased gene expression were observed in specific strains of PWK/PhJ. For traits related to muscle, bone, and immune functions, significant correlations between traits were confirmed following Rg3 administration compared with control mice. The phenotyping analysis was compiled into a public web resource called Rg3-OsteoSarco. Conclusion: This highlights the complex interplay between genetic determinants, pathogenesis of muscle atrophy and bone loss, and phytochemical bioactivity and the need to move away from single inbred mouse models to improve their translatability to genetically diverse humans. Rg3-OsteoSarco highlights the use of CC founder strains as a valuable tool in the field of personalized nutrition.

Osteogenic Effects of the Diospyros lotus L. Leaf Extract on MC3T3-E1 Pre-Osteoblasts and Ovariectomized Mice via BMP2/4 and TGF ß Pathways.

Osteoporosis, a disease defined by the primary bone strength due to a low bone mineral density, is a bone disorder associated with increased mortality in the older adult population. Osteoporosis is mainly treated via hormone replacement therapy, bisphosphates, and anti-bone resorption agents. However, these agents exert severe side effects, necessitating the development of novel therapeutic agents. Many studies are focusing on osteogenic agents as they increase the bone density, which is essential for osteoporosis treatment. Here, we aimed to investigate the effects of Diospyros lotus L. leaf extract (DLE) and its components on osteoporosis in MC3T3-E1 pre-osteoblasts and ovariectomized mice and to elucidate the underlying related pathways. DLE enhanced the differentiation of MC3T3-E1 pre-osteoblasts, with a 1.5-fold elevation in ALP activity, and increased the levels of osteogenic molecules, RUNX family transcription factor 2, and osterix. This alteration resulted from the activation of bone morphogenic protein 2/4 (BMP2/4) and transformation of growth factor ß (TGF ß) pathways. In ovariectomized mice, DLE suppressed the decrease in bone mineral density by 50% and improved the expression of other bone markers, which was confirmed by the 3~40-fold increase in osteogenic proteins and mRNA expression levels in bone marrow cells. The three major compounds identified in DLE exhibited osteogenic and estrogenic activities with their aglycones, as previously reported. Among the major compounds, myricitrin alone was not as strong as whole DLE with all its constituents. The osteogenic activity of DLE was partially suppressed by the inhibitor of estrogen signaling, indicating that the estrogenic activity of DLE participated in its osteogenic activity. Overall, DLE suppresses osteoporosis by inducing osteoblast differentiation.

OsMYB58 Negatively Regulates Plant Growth and Development by Regulating Phosphate Homeostasis.

Phosphate (Pi) starvation is a critical factor limiting crop growth, development, and productivity. Rice (Oryza sativa) R2R3-MYB transcription factors function in the transcriptional regulation of plant responses to various abiotic stresses and micronutrient deprivation, but little is known about their roles in Pi starvation signaling and Pi homeostasis. Here, we identified the R2R3-MYB transcription factor gene OsMYB58, which shares high sequence similarity with AtMYB58. OsMYB58 expression was induced more strongly by Pi starvation than by other micronutrient deficiencies. Overexpressing OsMYB58 in Arabidopsis thaliana and rice inhibited plant growth and development under Pi-deficient conditions. In addition, the overexpression of OsMYB58 in plants exposed to Pi deficiency strongly affected root development, including seminal root, lateral root, and root hair formation. Overexpressing OsMYB58 strongly decreased the expression of the rice microRNAs OsmiR399a and OsmiR399j. By contrast, overexpressing OsMYB58 strongly increased the expression of rice PHOSPHATE 2 (OsPHO2), whose expression is repressed by miR399 during Pi starvation signaling. OsMYB58 functions as a transcriptional repressor of the expression of its target genes, as determined by a transcriptional activity assay. These results demonstrate that OsMYB58 negatively regulates OsmiR399-dependent Pi starvation signaling by enhancing OsmiR399s expression.

Cinnamic acid suppresses bone loss via induction of osteoblast differentiation with alteration of gut microbiota.

Osteoporosis, a disease characterized by low bone density that poses a high risk of bone fractures, is associated with aging, diet, and menopause. Despite the various known therapeutic methods for osteoporosis treatment, the development of a new therapeutic agent without side effects in long-term use is required. Cinnamic acid (CA) is a phytochemical found in cinnamon. In this study, we evaluated the effect of CA on osteoporosis and demonstrated its mechanism in MC3T3E1 preosteoblasts and ovariectomized mice. CA treatment induced osteoblast differentiation with elevation of osteogenic markers both in vitro and in vivo. CA treatment ameliorated bone loss resulting in better bone indices, increased gut microbial diversity, and recovered changes in the gut microbial composition induced by ovariectomy. These changes were accompanied by an increase in BMP/TGFß/Smad signaling. Therefore, CA has the potential to suppress the progress of bone loss via the enhancement of bone density through the regulation of gut microbiota.

Agastache rugosa ethanol extract suppresses bone loss via induction of osteoblast differentiation with alteration of gut microbiota.

PURPOSE: Osteoporosis is a metabolic skeletal disease characterized by bone loss and an increased risk of fractures. This study aimed to investigate the therapeutic effect of Agastache rugosa on postmenopausal osteoporosis and elucidate its mechanisms in modulating the bone status. METHODS AND RESULTS: In the osteoblast differentiation process with MC3T3-E1 pre-osteoblasts, ethanol extract of Agastache rugosa (EEAR) and its compounds increased the expression of the proteins and genes of the osteoblast differentiation-related markers such as Runt-related transcription factor 2 (RUNX2) and ß-catenin along with the elevation of calcium deposits. An ovariectomized mouse model was utilized to determine the impact of EEAR extract on postmenopausal osteoporosis. Twelve weeks of AR treatment suppressed the loss of bone strength, which was observed through micro-computed tomography. AR elevated osteogenic markers in the bone marrow cells, and collagen type 1 alpha 1 in the distal femoral bone. The results of the 16S rRNA gene sequencing analysis of cecal gut microbiomes demonstrated that AR reversed the ovariectomy-induced changes in the gut microbiomes. CONCLUSION: Ethanol extract of Agastache rugosa has a therapeutic effect on postmenopausal osteoporosis via bone morphogenic protein, transforming growth factor ß, and Wnt signaling pathway. It also increases the diversity of gut microbiota. Therefore, these data suggest that EEAR could be a potential candidate to treat postmenopausal osteoporosis.

Characterization of dwarf and narrow leaf (dnl-4) mutant in rice.

Height and leaf morphology are important agronomic traits of the major crop plant rice (Oryza sativa). In previous studies, the dwarf and narrow leaf genes (dnl1, dnl2 and dnl3) have identified in rice. Using the Ac/Ds knockout system, we found a new dwarf and narrow leaf (dnl) mutant and identified mutated gene. The dnl-4 mutant showed reduced plant height and leaf blade width compared to the wild type, and increased leaf inclination. The morphological defects of the mutant were caused by the suppressed expression of the DNL-4 gene, which encodes a pfkB carbohydrate kinase protein. These results suggest that DNL-4 expression is involved in modulating plant height and leaf growth. Furthermore, DNL-4 expression also affects productivity in rice: the dnl-4 mutant exhibited reduced panicle length and grain width compared with the wild type. To understand DNL-4 function in rice, we analyzed the expression levels of leaf growth-related genes, such as NAL1, NAL7, and CSLD4, in the dnl-4 mutant. Expression of NAL1 and NAL7 was downregulated in the dnl-4 mutant compared to the wild type. The observation that DNL-4 expression corresponded with that of NAL1 and NAL7 is consistent with the narrow leaf phenotype of the dnl-4 mutant. These results suggest that DNL-4 regulates plant height and leaf structure in rice.

The anti-Mullerian hormone as a predictor of early pregnancy loss in subfertile women.

The aim of this study was to evaluate the predictive value of the anti-Mullerian hormone (AMH) level for early pregnancy loss and to compare the significance of AMH level to age as prognostic factors of pregnancy loss in subfertile women. The outcome of 848 subfertile patients confirmed with intrauterine pregnancies by ultrasound within 1 year of measuring serum AMH level were retrospectively analyzed. Among 848 patients, 206 women were diagnosed with early pregnancy loss. The mean age of the 848 patients was 35.66 ± 3.61 years (range: 26-46 years), and the mean AMH level was 2.95 ± 1.89 (range: 0.14-8.82 ng/mL). There were no significant differences in gravidity, parity, body mass index (BMI), and previous abortion history depending on early pregnancy loss. However, multivariable logistic regression analysis confirmed that the probability of early pregnancy loss is significantly affected by age (odd ratio, 1.079: 1.025-1.135, P = 0.004) and AMH (odd ratio, 0.885: 0.797-0.982, p = 0.022). According to this study, AMH level and age are both powerful predictors of early pregnancy loss. While chronological age is already well known as a factor related to early pregnancy loss, AMH was also considered when individualizing risk prediction for early pregnancy loss.

Robotic-assisted laparoscopic myomectomy: the feasibility in single-site system.

OBJECTIVE: To evaluate the feasibility of robotic single-site myomectomy (RSSM). METHODS: Medical records of 355 consecutive women who underwent robotic-assisted laparoscopic myomectomy were retrospectively reviewed. Clinical characteristics were compared between multi-site and single-site systems. After 1:1 propensity score matching for the total myoma number, largest myoma size, and total tumor weight (105 women in each group), surgical outcomes were also compared between the 2 systems. RESULTS: A total of 105 (29.6%) and 250 (70.4%) women underwent RSSM and robotic multi-site myomectomy (RMSM), respectively. RSSM was more commonly performed in women with lower body mass index (21.6 vs. 22.5 kg/m2, P=0.014), without peritoneal adhesions (7.6% vs. 24.8%, P<0.001), and less (2.6 vs. 4.6, P<0.001) and smaller (6.3 vs. 7.7 cm, P<0.001) myomas compared to RMSM. After propensity score matching, the largest myoma size (P=0.143), total myoma number (P=0.671), and tumor weight (P=0.510) were not significantly different between the 2 groups. Although the docking time was significantly longer in the RSSM group (5.1 vs. 3.8 minutes, P=0.005), total operation time was similar between RSSM and RMSM groups (145.9 vs. 147.3 minutes, P=0.856). Additionally, hemoglobin decrement was lower in the RSSM group than in the RMSM group (1.4 vs. 1.8 g/dL, P=0.009). No surgical complication was observed after RSSM, while 1 ileus and 2 febrile complications occurred in women that underwent RMSM (0% vs. 2.9%, P=0.246). CONCLUSION: Although RMSM is preferred for women with multiple large myomas in real clinical practice, RSSM seems to be a feasible surgical method for less complicated cases, and is associated with minimal surgical morbidity.

Activation of RhoA and FAK induces ERK-mediated osteopontin expression in mechanical force-subjected periodontal ligament fibroblasts.

The precise mechanism by which Rho kinase translates the mechanical signals into OPN up-regulation in force-exposed fibroblasts has not been elucidated. Human periodontal ligament fibroblasts (hPLFs) were exposed to mechanical force by centrifuging the culture plates at a magnitude of 50 g/cm(2) for 60 min. At various times of the force application, they were processed for analyzing cell viability, trypan blue exclusion, and OPN expression at protein and RNA levels. Cellular mechanism(s) of the force-induced OPN up-regulation was also examined using various kinase inhibitors or antisense oligonucleotides specific to mechanosensitive factors. Centrifugal force up-regulated OPN expression and induced a rapid and transient increase in the phosphorylation of focal adhesion kinase (FAK), extracellular signal-regulated kinase (ERK), and Elk1. Pharmacological blockade of RhoA/Rho-associated coiled coil-containing kinase (ROCK) signaling markedly reduced force-induced FAK and ERK1/2 phosphorylation. Transfecting hPLFs with FAK antisense oligonucleotide diminished ERK1/2 activation and force-induced OPN expression. Further, ERK inhibitor inhibited significantly OPN expression, Elk1 phosphorylation, and activator protein-1 (AP-1)-DNA binding activation, but not FAK phosphorylation, in the force-applied cells. These results demonstrate that FAK signaling plays critical roles in force-induced OPN expression in hPLFs through interaction with Rho/ROCK as upstream effectors and ERK-Elk1/ERK-c-Fos as downstream effectors.