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BACKGROUND: Bone-derived protein osteocalcin, which has beneficial effects on brain function, may be a future research direction for neurological disorders. A growing body of evidence suggests a link between osteocalcin and neurological disorders, but the exact relationship is contradictory and unclear. SCOPE OF REVIEW: The aim of this review is to summarize the current research on the interaction between osteocalcin and the central nervous system and to propose some speculative future research directions. MAJOR CONCLUSIONS: In the normal central nervous system, osteocalcin is involved in neuronal structure, neuroprotection, and the regulation of cognition and anxiety. Studies on osteocalcin-related abnormalities in the central nervous system are divided into animal model studies and human studies, depending on the subject. In humans, the link between osteocalcin and brain function is inconsistent. These conflicting data may be due to methodological inconsistencies. By reviewing the related literature on osteocalcin, some comorbidities of the bone and nervous system and future research directions related to osteocalcin are proposed.

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OBJECTIVE: The prevalence of type 2 diabetes mellitus (T2DM) and bone metabolism disorders increase with age. Diabetic kidney disease (DKD) is one of the most serious microvascular complications of T2DM, and bone metabolism disorders are closely linked to the occurrence of DKD. The relationship between bone turnover markers(BTMs) and the kidney disease in elderly patients with T2DM remains unclear. Therefore, this study aims to investigate the association between common BTMs and DKD in a large sample of elderly patients. The goal is to provide a basis for early identification of high-risk individuals for DKD among elderly T2DM patients from a bone metabolism perspective. METHODS: In this cross-sectional study, BTMs were collected from a cohort of 2,051 hospitalized Chinese patients. The relationships between 25-hydroxyvitamin D (25-OH-D), ß-CrossLaps (ß-CTX), osteocalcin (OSTEOC), intact parathyroid hormone (iPTH), and total type I collagen N-terminal propeptide (TP1NP), and DKD, as well as urinary albumin-to-creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR) were analyzed using regression analysis and restrictive cubic spline (RCS) curves. RESULTS: Higher 25-OH-D levels were independently linked to a lower incidence of DKD and decreased UACR. The RCS curves showed a linear association of 25-OH-D and DKD, approaching the L-shape. ß-CTX was independently and positively correlated with UACR. There is an independent positive correlation between OSTEOC and UACR and a negative correlation with eGFR. iPTH is independently and positively correlated with DKD incidence and UACR, and negatively correlated with eGFR. Additionally, the RCS curves showed a non-linear association of OSTEOC and iPTH and DKD, approaching the J-shape, and the point of inflection is 10.875 ng/L and 34.15 pg/mL respectively. There is an independent positive correlation between TP1NP and UACR incidence, and a negative correlation with eGFR. Risk estimates significantly increase with higher TP1NP levels in the RCS model. CONCLUSION: BTMs are closely associated with kidney disease in elderly patients with T2DM. These discoveries potentially assist clinicians in establishing more preventive measures and targeted treatment strategies for elderly patients with T2DM.

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Despite therapy with growth hormone (GH) in children with Prader-Willi syndrome (PWS), low bone mineral density and various orthopedic deformities have been observed often. Therefore, this study aimed to analyze bone markers, with an emphasis on vitamin K-dependent proteins (VKDPs), in normal-weight children with PWS undergoing GH therapy and a low-energy dietary intervention. Twenty-four children with PWS and 30 healthy children of the same age were included. Serum concentrations of bone alkaline phosphatase (BALP), osteocalcin (OC), carboxylated-OC (Gla-OC), undercarboxylated-OC (Glu-OC), periostin, osteopontin, osteoprotegerin (OPG), sclerostin, C-terminal telopeptide of type I collagen (CTX-I), and insulin-like growth factor-I (IGF-I) were determined using immunoenzymatic methods. OC levels and the OC/CTX-I ratios were lower in children with PWS than in healthy children (p = 0.011, p = 0.006, respectively). Glu-OC concentrations were lower (p = 0.002), but Gla-OC and periostin concentrations were higher in patients with PWS compared with the controls (p = 0.005, p < 0.001, respectively). The relationships between IGF-I and OC (p = 0.013), Gla-OC (p = 0.042), and the OC/CTX-I ratio (p = 0.017) were significant after adjusting for age in children with PWS. Bone turnover disorders in children with PWS may result from impaired bone formation due to the lower concentrations of OC and the OC/CTX-I ratio. The altered profile of OC forms with elevated periostin concentrations may indicate more intensive carboxylation processes of VKDPs in these patients. The detailed relationships between the GH/IGF-I axis and bone metabolism markers, particularly VKDPs, in children with PWS requires further research.

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Aim: This study was intended to establish the reference intervals of bone turnover markers (BTMs) for healthy populations. Methods: According to the Clinical Laboratory Standards Institute (CLSI) EP28-A3c, we recruited 774 healthy Chinese and investigated their clinical characteristics and relationships among gender, age, season and BTMs. The reference intervals of BTMs for healthy populations in Hebei of China were established through defining the central 95% range of all observations. Results: We found that gender were associated with 25(OH)D, OC, ß-CTX, and P1NP (P < 0.05), but not PTH1-84 (P=0.138). All serum BTMs showed differences among different age groups (P < 0.01). The level of 25 (OH) D in winter showed statistical differences with spring, summer, and autumn (P<0.05). The OC level showed statistical difference between summer and winter (P=0.000). The P1NP levels showed statistical difference between spring and winter (P=0.019), summer and winter (P=0.000), and summer and autumn (P=0.012), respectively. The PTH1-84 levels in winter showed statistical differences with spring, and summer (all P=0.000), while there was no statistically significant difference in ß- CTX levels between seasons. Conclusion: We have established the reference intervals of several BTMs for healthy individuals in Hebei of China, which have statistical significance across different age groups and genders, and there are also significant differences between different seasons. Therefore, the Chinese medical laboratories in different locations should group individuals according to gender and age groups in different seasons, and establish corresponding biological reference intervals.

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Despite their diverse physiologies and roles, the heart, skeletal muscles, and smooth muscles all derive from a common embryonic source as bones. Moreover, bone tissue, skeletal and smooth muscles, and the heart share conserved signaling pathways. The maintenance of skeletal health is precisely regulated by osteocytes, osteoblasts, and osteoclasts through coordinated secretion of bone-derived factors known as osteokines. Increasing evidence suggests the involvement of osteokines in regulating atherosclerotic vascular disease. Therefore, this review aims to examine the evidence for the role of osteokines in atherosclerosis development and progression comprehensively. Specifically discussed are extensively studied osteokines in atherosclerosis such as osteocalcin, osteopontin, osteoprotegerin, and fibroblast growth factor 23. Additionally, we highlighted the effects of exercise on modulating these key regulators derived from bone tissue metabolism. We believe that gaining an enhanced understanding of how osteocalcin contributes to the process of atherosclerosis will enable us to develop targeted and comprehensive therapeutic strategies against diseases associated with its progression.

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OBJECTIVE: The research aimed to determine the importance of vitamin D and markers of bone metabolism in the overall assessment of bone mineralization during a child's first year of life. METHODS: The 198 children were selected by screening all infants seen at our pediatric clinic over a 2-year period from 2020-2022 and including those who met the eligibility criteria of being aged 0 to 1 year, healthy with no chronic conditions, and not on vitamin D supplementation. Children were divided into 3 groups depending on the content of vitamin D in the blood serum: sufficient, insufficient, and deficient. The markers of bone tissue status included: markers of mineral metabolism (calcium, phosphorus, parathyroid hormone, calcitonin), a marker of bone formation (osteocalcin), resorption marker (deoxypyridinoline). Laboratory values were obtained at the time of study enrollment during the initial study visit. Labs were not repeated during the course of the study. RESULTS: A quarter of the infants exhibited vitamin D deficiency at enrollment with serum 25OHD concentrations below 20 ng/mL, which showed a positive correlation with serum calcium and phosphorus -concentrations and a negative correlation with PTH, while osteocalcin and deoxypyridinoline concentrations remained consistent regardless of vitamin D status. CONCLUSIONS: The study's practical significance allows for the recommendation of using vitamin D -concentrations as a marker to detect bone formation and mineral metabolism disorders in children during their first year of life. By identifying and addressing these issues early on, the health care system aims to ensure better musculoskeletal health for children.

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Nonalcoholic fatty liver disease (NAFLD) is a common chronic liver disease worldwide. Osteocalcin plays an important role in energy metabolism. In this study, we investigated the mechanism of action of chemically synthesized osteocalcin (csOCN) in ameliorating NAFLD. We demonstrated for the first time that csOCN attenuates lipid accumulation in the liver and hepatocytes by modulating CD36 protein expression. In addition, we found that the expression of p-AMPK, FOXO1 and BCL6 decreased and the expression of CD36 increased after OA/PA induction compared to the control group, and these effects were reversed by the addition of csOCN. In contrast, the therapeutic effect of csOCN was inhibited by the addition of AMPK inhibitors and BCL6 inhibitors. This finding suggested that csOCN regulates CD36 expression via the AMPK-FOXO1/BCL6 axis. In NAFLD mice, oral administration of csOCN also activated the AMPK pathway and reduced CD36 expression. Molecular docking revealed that osteocalcin has a docking site with CD36. Compared to oleic acid and palmitic acid, osteocalcin bound more strongly to CD36. Laser confocal microscopy results showed that osteocalcin colocalized with CD36 at the cell membrane. In conclusion, we demonstrated the regulatory role of csOCN in fatty acid uptake pathways for the first time; it regulates CD36 expression via the AMPK-FOXO1/BCL6 axis to reduce fatty acid uptake, and it affects fatty acid transport by may directly binding to CD36. There are indications that csOCN has potential as a CD36-targeted drug for the treatment of NAFLD.

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This study aimed to explore the role of histone methyltransferase SET and MYND domain containing 3 (SMYD3) in bone metabolism of osteoblasts exposed to fluoride. The levels of urine fluoride, BALP, and OC and the mRNA expression of SMYD3 were determined in patients with skeletal fluorosis and non-fluoride-exposed people on informed consent. The expression of SMYD3 protein, OC contents, and BALP activities were detected in human osteoblast-like MG63 cells and rat primary osteoblasts treated with sodium fluoride (NaF) for 48 h. The autophagosomes were observed by transmission electron microscopy. Then, we knocked down SMYD3 to confirm whether it was involved in the regulation of bone formation and related to autophagy and Wnt/ß-catenin pathway. We observed that OC and BALP levels in patients with skeletal fluorosis significantly increased, while the mRNA expression of SMYD3 significantly decreased in the skeletal fluorosis groups. In vitro, the OC contents, BALP activities, and expression of SMYD3 significantly increased, and many autophagosomes were observed in NaF treated osteoblasts. The downregulation of SMYD3 significantly inhibited OC contents, BALP activities, and expression of autophagy-related proteins, but with no significant changes in the Wnt/ß-catenin pathway. Our results demonstrated that fluoride exposure with coal-burning pollution caused orthopedic injuries and abnormalities in the levels of OC and BALP and hindered normal bone metabolism. Silencing the SMYD3 gene could significantly reduce OC and BALP levels via inhibiting the increase in autophagy induced by fluoride.

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Understanding the mechanisms involved in whole body glucose regulation is key for the discovery of new treatments for type 2 diabetes (T2D). Historically, glucose regulation was largely focused on responses to insulin and glucagon. Impacts of incretin-based therapies, and importance of muscle mass, are also highly relevant. Recently, bone was recognized as an endocrine organ, with several bone proteins, known as osteokines, implicated in glucose metabolism through their effects on the liver, skeletal muscle, and adipose tissue. Research efforts mostly focused on osteocalcin (OC) as a leading example. This review will provide an overview on this role of bone by discussing bone turnover markers (BTMs), the receptor activator of nuclear factor kB ligand (RANKL), osteoprotegerin (OPG), sclerostin (SCL) and lipocalin 2 (LCN2), with a focus on OC. Since 2007, some, but not all, research using mostly OC genetically modified animal models suggested undercarboxylated (uc) OC acts as a hormone involved in energy metabolism. Most data generated from in vivo, ex vivo and in vitro models, indicate that exogenous ucOC administration improves whole-body and skeletal muscle glucose metabolism. Although data in humans are generally supportive, findings are often discordant likely due to methodological differences and observational nature of that research. Overall, evidence supports the concept that bone-derived factors are involved in energy metabolism, some having beneficial effects (ucOC, OPG) others negative (RANKL, SCL), with the role of some (LCN2, other BTMs) remaining unclear. Whether the effect of osteokines on glucose regulation is clinically significant and of therapeutic value for people with insulin resistance and T2D remains to be confirmed.

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Uncarboxylated osteocalcin (ucOC) is a hormone secreted by osteoblasts that strengthens bone during mineralization and is a biomarker for ongoing bone formation. It also regulates glucose homeostasis by stimulating insulin secretion from pancreatic ß-cells. However, its effect on ß-cells under hyperglycemic diabetic conditions is unclear. The objective of this study was to investigate ucOC's effect on insulin secretion in ß-cells maintained under high glucose conditions. We hypothesized that hyperglycemia potentiates insulin secretion in response to ucOC stimulation. Using INS-1 cells, we performed insulin secretion experiments, intracellular calcium recordings, and RT-qPCR to determine ucOC's effect on glucose-stimulated insulin secretion (GSIS)-related genes. The results reveal that ucOC significantly increased insulin secretion under hyperglycemic conditions compared to lower glucose levels. High glucose conditions also potentiated the effect of ucOC on calcium signals, which enhanced insulin secretion. The increase in intracellular calcium was due to an influx from the extracellular space via voltage-dependent calcium channels (VDCCs). Interestingly, the treatment of cells with NPS-2143, a GPRC6A blocker, failed to abolish the calcium signals. Uncarboxylated osteocalcin upregulated the expression of GSIS-related genes under high glucose conditions (450 mg/dL) compared to cells under standard culture conditions (200 mg/dL). In conclusion, hyperglycemia potentiates ucOC-induced insulin secretion in ß-cells by opening VDCCs and upregulating GSIS genes. These findings provide a better understanding of ucOC's mechanism in the diabetic state and could lead to alternative treatments to stimulate insulin secretion.

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The aim of the present review is to discuss the roles of vitamin K (phylloquinone or menaquinones) and vitamin K-dependent proteins, and the combined action of the vitamins K and D, for the maintenance of bone health. The most relevant vitamin K-dependent proteins in this respect are osteocalcin and matrix Gla-protein (MGP). When carboxylated, these proteins appear to have the ability to chelate and import calcium from the blood to the bone, thereby reducing the risk of osteoporosis. Carboxylated osteocalcin appears to contribute directly to bone quality and strength. An adequate vitamin K status is required for the carboxylation of MGP and osteocalcin. In addition, vitamin K acts on bone metabolism by other mechanisms, such as menaquinone 4 acting as a ligand for the nuclear steroid and xenobiotic receptor (SXR). In this narrative review, we examine the evidence for increased bone mineralization through the dietary adequacy of vitamin K. Summarizing the evidence for a synergistic effect of vitamin K and vitamin D3, we find that an adequate supply of vitamin K, on top of an optimal vitamin D status, seems to add to the benefit of maintaining bone health. More research related to synergism and the possible mechanisms of vitamins D3 and K interaction in bone health is needed.

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AIM: To evaluate the suitability of serum osteocalcin (OC) as a marker to distinguish between rapidly and non-rapidly progressive central precocious puberty (RP-CPP and NRP-CPP), as well as its potential to assess growth rates following treatment with gonadotropin-releasing hormone agonist (GnRHa). METHODS: Serum levels of OC were measured using enzyme-linked immunosorbent assays in girls diagnosed with either RP-CPP or NRP-CPP as well as in normal control subjects. Receiver operating characteristic (ROC) curve analysis was performed to determine the cut-off value for OC. Multivariate linear regression analysis was used to analyse the main influencing factors associated with OC. RESULTS: Serum OC levels were higher in the CPP girls when compared to normal controls (110.76 ± 43.69 vs 55.97 ± 20.96 ng/mL, P < 0.001). The level in the RP-CPP group was higher than the NRP-CPP group (153.28 ± 33.89 vs 88.33 ± 29.26 ng/mL, P < 0.001). The cut-off value of OC levels for distinguishing between RP-CPP and NRP-CPP was 107.05 ng/mL, the sensitivity was 94.7% and the specificity was 77.8%, which was superior to using the basal luteinising hormone (B-LH) levels, and the area under ROC curve (AUC) were 0.933 versus 0.695, respectively. Following 1-2 years of treatment with GnRHa for girls with CPP, both OC levels and the growth rates decreased to pre-pubertal values. B-LH levels, bone age and body weight were also significant factors, which affected OC levels. CONCLUSIONS: Serum OC levels may be a useful marker for distinguishing RP-CPP from NRP-CPP. In addition, it was also found to be a useful predictor for growth rate during GnRHa treatment.

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Background and Objectives: Enhanced osteoblast differentiation may be leveraged to prevent and treat bone-related diseases such as osteoporosis. No-ozone cold plasma (NCP) treatment is a promising and safe strategy to enhance osteoblast differentiation. Therefore, this study aimed to determine the effectiveness of direct and indirect NCP treatment methods on osteoblast differentiation. Mouse osteoblastic cells (MC3T3-E1) were treated with NCP using different methods, i.e., no NCP treatment (NT group; control), direct NCP treatment (DT group), direct NCP treatment followed by media replacement (MC group), and indirect treatment with NCP-treated media only (PAM group). Materials and Methods: The MC3T3-E1 cells were subsequently assessed for cell proliferation, alkaline phosphatase (ALP) activity, calcium deposition, and ALP and osteocalcin mRNA expression using real-time polymerase chain reaction. Results: Cell proliferation significantly increased in the NCP-treated groups (DT and PAM; MC and PAM) compared to the NT group after 24 h (p < 0.038) and 48 h (p < 0.000). ALP activity was increased in the DT and PAM groups at 1 week (p < 0.115) and in the DT, MC, and PAM groups at 2 weeks (p < 0.000) compared to the NT group. Calcium deposition was higher in the NCP-treated groups than in NT group at 2 and 3 weeks (p < 0.000). ALP mRNA expression peaked in the MC group at 2 weeks compared to the NP group (p < 0.014). Osteocalcin mRNA expression increased in the MC group at 2 weeks (p < 0.000) and was the highest in the PAM group at 3 weeks (p < 0.000). Thus, the effects of direct (DT and MC) and indirect (PAM) treatment varied, with MC direct treatment showing the most significant impact on osteoblast activity. Conclusions: The MC group exhibited enhanced osteoblast differentiation, indicating that direct NCP treatment followed by media replacement is the most effective method for promoting bone formation.

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Introduction. Type 1 diabetes mellitus is considered one of the most common chronic diseases of childhood. It is a high-risk factor for developing early cardiovascular disease and it also affects bone health. Objective. To describe demographic characteristics and biochemical parameters of a population of children with type 1 diabetes, evaluated in the pediatric diabetes unit of a tertiary Spanish hospital. Materials and methods. In this retrospective study, we determined metabolic, lipid, and bone parameters in 124 children with type 1 diabetes who were monitored in the pediatric diabetes unit of the Hospital Universitario Miguel Servet in Zaragoza (Spain) from May 2020 to July 2021. Results. Children with type 1 diabetes have worse metabolic control of the disease at puberty, but their lipid control is considered acceptable. We found an inverse correlation between bone formation markers and disease duration, as well as with metabolic control. Conclusion. Bone formation markers are inversely correlated with the percentage of glycated hemoglobin and diabetes evolution time. Patients' lipid and bone profiles are more favorable when metabolic control of the disease is achieved.

Introducción. La diabetes mellitus de tipo 1 se considera una de las enfermedades crónicas más frecuentes de la infancia. Es un factor de gran riesgo de desarrollar enfermedad cardiovascular temprana y afecta también la salud ósea. Objetivo. Describir las características demográficas y los parámetros bioquímicos de una población de niños con diabetes de tipo 1, supervisados en la unidad pediátrica de diabetes de un hospital español de tercer nivel. Materiales y métodos. En este estudio retrospectivo, se determinaron los parámetros de control metabólico, lipídico y óseo en 124 niños con diabetes de tipo 1, a los que se hizo seguimiento en la Unidad Pediátrica de Diabetes del Hospital Universitario Miguel Servet de Zaragoza, desde mayo del 2020 hasta julio del 2021. Resultados. Los niños con diabetes de tipo 1 presentan peor control metabólico de la enfermedad en la pubertad, pero su control lipídico se puede considerar aceptable. Existe una correlación inversa de los marcadores de formación ósea con el tiempo de evolución de la enfermedad, así como con el control metabólico. Conclusión. Los marcadores de formación ósea se encuentran correlacionados de forma inversa con el porcentaje de hemoglobina glicosilada y con el tiempo de evolución de la diabetes. En estos pacientes, el perfil lipídico y el óseo son más favorables cuando existe un buen control metabólico de la enfermedad.

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Metabolic dysfunctions are among the best documented hallmarks of ageing. Cardiovascular disease, Alzheimer's disease, cancer, type 2 diabetes mellitus, metabolic-dysfunction-associated steatosis liver disease, and fragility fractures are diseases of hyperinsulinaemia that reduce life and healthspan. We studied the effect of suppressing ketosis in 10 lean (BMI 20.5 kg/m2 ± 1.4), metabolically healthy, pre-menopausal women (age 32.3 ± 8.9 years) maintaining nutritional ketosis (NK) for an average of 3.9 years (± 2.3) who underwent three 21-day phases: nutritional ketosis (NK; P1), suppressed ketosis (SuK; P2), and returned to NK (P3). Ketosis suppression significantly increased insulin, 1.83-fold (p = 0.0006); glucose, 1.17-fold (p = 0.0088); homeostasis model assessment for insulin resistance (HOMA-IR), 2.13-fold (p = 0.0008); leptin, 3.35-fold (p = 0.0010); total osteocalcin, 1.63-fold (p = 0.0138); and uncarboxylated osteocalcin, 1.98-fold (p = 0.0417) and significantly decreased beta-hydroxybutyrate, 13.50-fold (p = 0.0012) and glucagon-like peptide-1 (GLP-1), 2.40-fold (p = 0.0209). Sustained NK showed no adverse health effects and may mitigate hyperinsulinemia. All biomarkers returned to basal P1 levels after removing the intervention for SuK, indicating that metabolic flexibility was maintained with long-term euketonaemia.

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Osteocalcin is a bone-derived hormone implicated in the acute stress response and recently linked to adult depression. Yet it is unclear whether osteocalcin is a biomarker of other forms of psychopathology and whether osteocalcin-psychopathology associations emerge during developmentally sensitive periods earlier in life. Thus, in the current pilot study we examined salivary osteocalcin and psychiatric symptoms and disorders among 48 early adolescents during a period of stress. A logistic regression indicated lower osteocalcin was associated with meeting criteria for a psychiatric disorder, OR = 0.43, 95 % CI [.002,.924], and showed moderate-to-large cross-sectional associations with a range of elevated psychopathology symptoms, Bs ≥ |-3.44|, ps ≤.034. Multilevel linear growth models indicated that low osteocalcin prospectively predicted an even greater range of psychopathology symptoms at one-year follow-up as well as increases in some symptoms over time, Bs ≥ |-1.83|, ps ≤.021. Findings introduce osteocalcin as a biomarker of diverse forms of psychopathology in youth. Osteocalcin is a potential transdiagnostic mechanism through which dysregulated responses to stress could cause or exacerbate various types of psychopathology, highlighting a promising target for clinical assessment and early intervention.

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Inadequate management and control of hyperglycemia predisposes diabetic patients to a wide range of complications. Thus, this opens new windows for exploring and scrutinizing novel candidate biomarkers. This study was designed to scrutinize the relationship between HbA1c, osteocalcin, calcium, phosphorus, and expression levels of miR-143 and miR-145 in individuals with T1DM and explore their correlations and diagnostic potential for T1DM. 120 unrelated participants were included (i.e., 90 participants with type 1 diabetes mellitus and 30 healthy controls) and were allocated into two groups. Participants with T1DM were allocated into three subgroups (i.e., below 1 year, 1-8 years, and over 8 years) based on diabetic duration. Participants with T1DM experienced noticeable HbA1c elevation. However, osteocalcin, phosphorus, and calcium profiles notably declined in participants with diabetes compared with those in healthy controls. Moreover, the expression levels of miR-143 and miR-145 decreased in participants with diabetes with a significant difference between participants with diabetes and healthy controls. Additionally, significant alterations in HbA1c, osteocalcin, phosphorus, and calcium profiles and expression levels of miR-143 and miR-145 were observed with increasing diabetic duration (T1DM > 8 years compared with those with a diabetes duration of less than 1 year). This study suggests that miR-143 and miR-145 are prospective biomarkers of diabetes mellitus, which may help predict the progression of complications.

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Bone has traditionally been viewed in the context of its structural contribution to the human body. Foremost providing necessary support for mobility, its roles in supporting calcium homeostasis and blood cell production are often afterthoughts. Recent research has further shed light on the ever-multifaceted role of bone and its importance not only for structure, but also as a complex endocrine organ producing hormones responsible for the autoregulation of bone metabolism. Osteocalcin is one of the most important substances produced in bone tissue. Osteocalcin in circulation increases insulin secretion and sensitivity, lowers blood glucose, and decreases visceral adipose tissue. In males, it has also been shown to enhance testosterone production by the testes. Neuropeptide Y is produced by various cell types including osteocytes and osteoblasts, and there is evidence suggesting that peripheral NPY is important for regulation of bone formation. Hormonal disorders are often associated with abnormal levels of bone turnover markers. These include commonly used bone formation markers (bone alkaline phosphatase, osteocalcin, and procollagen I N-propeptide) and commonly used resorption markers (serum C-telopeptides of type I collagen, urinary N-telopeptides of type I collagen, and tartrate-resistant acid phosphatase type 5b). Bone, however, is not exclusively comprised of osseous tissue. Bone marrow adipose tissue, an endocrine organ often compared to visceral adipose tissue, is found between trabecula in the bone cortex. It secretes a diverse range of hormones, lipid species, cytokines, and other factors to exert diverse local and systemic effects.

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INTRODUCTION: Eucommia ulmoides is a unique monophyletic and tertiary relict in China and is listed as a national second-class precious protected tree species. Eucommia ulmoides, recognized as a traditional Chinese medicine, can tonify the liver and kidneys and strengthen bones and muscles. Modern pharmacological research has proved that Eucommia ulmoides has multiple osteoprotective effects, including prohibiting the occurrence of osteoporosis and arthritis and enhancing the healing of bone fractures and bone defects. AIM: To check its osteotropic effects, which may provide ideas for its potential use for the development of novel drugs to treat osteoporosis, this study evaluated the effect of total flavonoids from Eucommia ulmoides leaves (TFEL) on the acquisition of Peak Bone Mass (PBM) in young female rats. MATERIALS AND METHODS: TFEL was isolated, and its purity was confirmed by using a UV spectrophotometer. TFEL with a purity of 85.09% was administered to 6-week-old female rats by oral gavage at a low (50), mid (100), or high (200 mg/kg/d) dose, and the control group was administrated only with the same volume of water. After 13 weeks of treatment, the rats were sacrificed, and serum, different organs, and limb bones (femurs and tibias) were harvested, and the bone turnover markers, organ index, Bone Mineral Density (BMD), biomechanical property, and microstructure parameters were assayed. Furthermore, molecular targets were screened, and network pharmacology analyses were conducted to reveal the potential mechanisms of action of TFEL. RESULTS: Oral administration of TFEL for 13 weeks decreased the serum level of bone resorption marker TRACP-5b. As revealed by micro-computer tomography analysis, it elevated BMD even at a low dose (50 mg/kg/d) and improved the microstructural parameters, which were also confirmed by H&E histological staining. However, TFEL showed no effects on body weights, organ index, and micromorphology in the uterus. In our network pharmacology study, an intersection analysis screened out 64 shared targets, with quercetin, kaempferol, naringenin, and apigenin regulating the greatest number of targets associated with osteoporosis. Flavonoids in Eucommia ulmoides inhibited the occurrence of osteoporosis potentially through targeting signaling pathways for calcium, VEGF, IL-17, and NF-κB. Furthermore, AKT1, EGFR, PTGS2, VEGFA, and CALM were found to be potentially important target genes for the osteoprotective effects of flavonoids in Eucommia ulmoides. CONCLUSION: The above results suggested that TFEL can be used to elevate the peak bone mass in adolescence in female individuals, which may prevent the occurrence of postmenopausal osteoporosis, and the good safety of TFEL also suggests that it can be used as a food additive for daily life to improve the bone health.

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BACKGROUND: Triple negative breast cancer (TNBC) is a type of breast cancer that is negative for oestrogen receptor, progesterone receptor and human epidermal growth factor receptor 2, is highly malignant and aggressive, lacks of corresponding targeted therapy, and has a relatively poor prognosis. Therefore, understanding the mechanism of TNBC development and formulating effective treatment strategies for inducing cell death are still urgent tasks in the treatment of TNBC. Research has shown that uncarboxylated osteocalcin can promote the proliferation of prostate cancer, lung adenocarcinoma and TNBC cells, but the mechanism by which GluOC affects TNBC growth and metastasis needs further study. METHODS: MDA-MB-231 breast cancer cells were used for in vitro cell analysis. Key target molecules or pathways were identified by RNA sequencing, and migration ability was detected by scratch assays, Transwell assays, cell adhesion assays and western blot analysis. Fluorescence staining, colony detection, qRT‒PCR and flow cytometry were used to detect apoptosis, oxidative stress, the cell cycle and the stemness of cancer cells, and a xenotransplantation model in BALB/C nude mice was used for in vivo analysis. RESULTS: This study demonstrated that GluOC facilitates the migration of MDA-MB-231 breast cancer cells through the ROCK1/MYPT1/MLC2 signalling pathway and promotes the proliferation of TNBC cells via the ROCK1/JAK2/PIK3CA/AKT signalling pathway. Experiments in nude mice demonstrated that GluOC promoted tumour cell proliferation and metastasis in tumour-bearing mice, which further clarified the molecular mechanism of TNBC growth and invasion. CONCLUSION: Our findings highlight the importance of GluOC in driving TNBC progression and its association with poor patient outcomes. This study clarifies the functional effects of GluOC on TNBC growth, providing insight into the molecular basis of TNBC and potentially providing new ideas for developing targeted therapies to improve patient outcomes.