FAM19A5 in vascular aging and osteoporosis: Mechanisms and the "calcification paradox".

Aging induces a progressive decline in the vasculature's structure and function. Vascular aging is a determinant factor for vascular ailments in the elderly. FAM19A5, a recently identified adipokine, has demonstrated involvement in multiple vascular aging-related pathologies, including atherosclerosis, cardio-cerebral vascular diseases and cognitive deficits. This review summarizes the current understanding of FAM19A5' role and explores its putative regulatory mechanisms in various aging-related disorders, including cardiovascular diseases (CVDs), metabolic diseases, neurodegenerative diseases and malignancies. Importantly, we provide novel insights into the underlying therapeutic value of FAM19A5 in osteoporosis. Finally, we outline future perspectives on the diagnostic and therapeutic potential of FAM19A5 in vascular aging-related diseases.

Risk factors of primary Sjögren's syndrome combined with osteoporosis. / åŽŸå‘æ€§å¹²ç‡¥ç»¼åˆå¾åˆå¹¶éª¨è´¨ç–æ¾çš„å±é™©å› ç´ .

Primary Sjögren's syndrome (pSS) is a systemic autoimmune disease that is prevalent in middle-aged and elderly women, characterized by dry mouth, dry eyes, fatigue, and joint pain. Nearly one-third pSS patients have been suffering with osteoporosis (OP), displaying symptoms of lumbago, back pain, and even fracture, all of which severely affect their life quality. Common risk factors for pSS and OP include gender and age, persistent state of inflammation, immune disorders, intestinal flora imbalance, vitamin D deficiency, dyslipidemia and sarcopenia. Meanwhile, the comorbidities of pSS, such as renal tubular acidosis, primary biliary cholangitis, autoimmune thyroid diseases, and drugs (glucocorticoids, methotrexate, and cyclophosphamide) are unique risk factors for pSS complicated with OP. Education, guidance of healthy lifestyle, and OP screening are recommended for bone management of pSS patients. Early detection and intervention are crucial for keeping bone health and life quality in pSS patients.

Vascular endothelial cells-derived exosomes synergize with curcumin to prevent osteoporosis development.

Osteoporosis has gradually become a major public health problem. Further elucidation of the pathophysiological mechanisms that induce osteoporosis and identification of more effective therapeutic targets will have important clinical significance. Experiments in vitro on bone marrow stem cells (BMSCs) subjected to osteogenic and adipogenic differentiation and in vivo on surgical bilateral ovariectomy (OVX) mouse models revealed that exosomes of vascular endothelial cells (EC-EXOs) can promote osteogenic differentiation of BMSCs and inhibit BMSC adipogenic differentiation through miR-3p-975_4191. Both miR-3p-975_4191 and curcumin can target tumor necrosis factor (TNF) and act synergistically to regulate BMSCs fate differentiation and delay the progression of osteoporosis. Our findings suggest that EC-EXOs may exert a synergistic effect with curcumin in reversing the progression of osteoporosis by targeting TNF via miR-3p-975_4191. Our study may provide therapeutic options and potential therapeutic targets for osteoporosis and thus has important clinical implications.

Implementing mind mapping in small-group learning to promote student engagement in the medical diagnostic curriculum: a pilot study.

BACKGROUND: Medical diagnostics is a pivotal bridge curriculum that receives much less attention from undergraduates in non-clinical medicine health profession programs with less student engagement and poor performance. Mind mapping is an active learning strategy for graphically presenting radiant thinking to culture clinical reasoning. The purpose of this study was to explore whether students' comprehensive diagnostic skills are enhanced through increased student engagement by employing mind mapping. METHODS: We implemented mind mapping in small-grouped workshops with 86 junior undergraduates from preventive medicine program, for physical diagnostic sessions including physical examination (PE) maneuver, electrocardiogram (ECG) interpretation and medical history collection. We also conducted assessments of the above skills, as well as online surveys regarding their expectation on this course, self-evaluation of mind mapping in teaching and the learning process of all the modules. RESULTS: Group members employing mind mapping in all PE sessions obtained higher scores in the heart and lung systems during the PE maneuver exam. Similarly, groups that made more in-depth mind maps achieved higher scores on the ECG quiz. In addition, groups displaying mind maps for history taking from normal classes and reformed class exhibited greater completeness of medical history with both standardized patients and real patients, which was consistent with increased collection of accompanying symptoms. Mind mapping was valued by the majority of students for its benefits in terms of acquiring PE maneuver, theoretical knowledge, medical history collection and medical records writing, clinical reasoning, communication skills, sense of teamwork and cooperation, professionalism and humanistic literacy. DISCUSSION: The visual feature of mind mapping evoked extensive behavioral engagement in all groups, as did cognitive and emotional engagement, as the majority of students expressed their willingness and affective reactions. In the short term, the positive feedbacks encourage growing engagement. The continuous benefits of mind mapping require long-term observation.

Exosome-derived miR-5p-72106_14 in vascular endothelial cells regulates fate determination of BMSCs.

Vascular endothelial cells have recently been shown to be associated with osteogenic activity. However, the mechanism of vascular endothelial cells promoting osteogenesis is unclear. Here, we found that exosomes secreted from human microvascular endothelial cells (HMEC-1) promoted osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) and inhibited adipogenic differentiation. Aged and ovariectomy mice treated with exosomes showed increased bone formation and decreased lipid accumulation in the bone marrow cavity. Additionally, we screened out novel exosomal miR-5p-72106_14 by miRNA-seq and confirmed that miR-5p-72106_14 promoted osteogenic differentiation and inhibited adipogenic differentiation of BMSCs by inhibiting STAT1. Our results suggest that vascular endothelial cell-derived exosomes are involved in BMSC differentiation and exosomal miR-5p-72106_14 is a major factor in regulating fate determination of BMSCs.

Reply to Mahat, R.K.; Rathore, V. Comment on "Xiang et al. Association between the Triglyceride-Glucose Index and Vitamin D Status in Type 2 Diabetes Mellitus. Nutrients 2023, 15, 639".

We are pleased to see that Mahat and Rathore [...].

Utilizing biochar to decorate nanoscale FeS for the highly effective decontamination of Se(IV) from simulated wastewater.

Selenium (Se) as an essential nutrient for human beings at trace concentrations, the allowable concentration for the human is only 40 µg/L. Iron sulfide (FeS) nanoparticles have been applied for excessive of selenium (Se) remediation in surface water and groundwater. In this study, FeS nanoparticles were anchored onto biochar (BC) to reduce agglomeration of FeS and prepared into the composite of FeS-BC by pyrolysis to economically and efficiently remove Se(IV) from simulated wastewater based on the excellent performance of FeS and the low cost of BC. Characterizations presented the uniform anchorage of FeS on the BC surface to prevent agglomeration. The results of batch experiments revealed that the removal of Se(IV) by FeS-BC nanomaterials significantly depended on the pH value, with the maximum removal of ∼174.96 mg/g at pH 3.0. A pseudo-second-order kinetic model well reflected the kinetic removal of Se(IV) in pure Se(IV) solution with different concentration, as well as the coexistence of K+, Ca2+, Cl-, and SO42- ions. The presence of K+ ions significantly inhibited the removal of Se(IV) with the increase of K+ ion concentration compared with the effect of the other three ions. SEM-EDS and XPS analyses indicated that the removal process was achieved through adsorption by surface complexation, and reductive precipitation of Se(IV) into Se0 with the electron donor of Fe(II) and S(-II) ions. The FeS-BC nanomaterial exhibited an excellent application prospect in the remediation of Se(IV).

Vertical sleeve gastrectomy-derived gut metabolite licoricidin activates beige fat thermogenesis to combat obesity.

Obesity is a chronic metabolic disease, affecting individuals throughout the world. Bariatric surgery such as vertical sleeve gastrectomy (VSG) provides sustained weight loss and improves glucose homeostasis in obese mice and humans. However, the precise underlying mechanisms remain elusive. In this study, we investigated the potential roles and the mechanisms of action of gut metabolites in VSG-induced anti-obesity effect and metabolic improvement. Methods: High-fat diet (HFD)-fed C57BL/6J mice were subjected to VSG. Energy dissipation in mice was monitored using metabolic cage experiments. The effects of VSG on gut microbiota and metabolites were determined by 16S rRNA sequencing and metabolomics, respectively. The metabolic beneficial effects of the identified gut metabolites were examined in mice by both oral administration and fat pad injection of the metabolites. Results: VSG in mice greatly increased thermogenic gene expression in beige fat, which was correlated with increased energy expenditure. VSG reshaped gut microbiota composition, resulting in elevated levels of gut metabolites including licoricidin. Licoricidin treatment promoted thermogenic gene expression in beige fat by activating the Adrb3-cAMP-PKA signaling pathway, leading to reduced body weight gain in HFD-fed mice. Conclusions: We identify licoricidin, which mediates the crosstalk between gut and adipose tissue in mice, as a VSG-provoked anti-obesity metabolite. Identification of anti-obesity small molecules should provide new insights into treatment options for obesity and its associated metabolic diseases.

Novel insights into the multifaceted roles of m6A-modified LncRNAs in cancers: biological functions and therapeutic applications.

N6-methyladenosine (m6A) is considered as the most common and important internal transcript modification in several diseases like type 2 diabetes, schizophrenia and especially cancer. As a main target of m6A methylation, long non-coding RNAs (lncRNAs) have been proved to regulate cellular processes at various levels, including epigenetic modification, transcriptional, post-transcriptional, translational and post-translational regulation. Recently, accumulating evidence suggests that m6A-modified lncRNAs greatly participate in the tumorigenesis of cancers. In this review, we systematically summarized the biogenesis of m6A-modified lncRNAs and the identified m6A-lncRNAs in a variety of cancers, as well as their potential diagnostic and therapeutic applications as biomarkers and therapeutic targets, hoping to shed light on the novel strategies for cancer treatment.

Evaluation of graphical models for multi-group metabolomics data.

Gaussian graphical model is a strong tool for identifying interactions from metabolomics data based on conditional correlation. However, data may be collected from different stages or subgroups of subjects with heterogeneity or hierarchical structure. There are different integrating strategies of graphical models for multi-group data proposed by data scientists. It is challenging to select the methods for metabolism data analysis. This study aimed to evaluate the performance of several different integrating graphical models for multi-group data and provide support for the choice of strategy for similar characteristic data. We compared the performance of seven methods in estimating graph structures through simulation study. We also applied all the methods in breast cancer metabolomics data grouped by stages to illustrate the real data application. The method of Shaddox et al. achieved the highest average area under the receiver operating characteristic curve and area under the precision-recall curve across most scenarios, and it was the only approach with all indicators ranked at the top. Nevertheless, it also cost the most time in all settings. Stochastic search structure learning tends to result in estimates that focus on the precision of identified edges, while BEAM, hierarchical Bayesian approach and birth-death Markov chain Monte Carlo may identify more potential edges. In the real metabolomics data analysis from three stages of breast cancer patients, results were in line with that in simulation study.

Association between the Triglyceride-Glucose Index and Vitamin D Status in Type 2 Diabetes Mellitus.

BACKGROUND: Vitamin D deficiency (VDD) increases the risk for type 2 diabetes mellitus (T2DM), which might be related to insulin resistance (IR). We aimed to explore the association between the triglyceride-glucose (TyG) index, a reliable indicator of IR, and VDD in patients with T2DM. METHODS: There were 1034 participants with T2DM enrolled in the Second Xiangya Hospital of Central South University. The TyG index was calculated as ln (fasting triglyceride (TG, mg/dL) × fasting blood glucose (mg/dL)/2). VDD was defined as 25-hydroxyvitamin D [25(OH)D] level <50 nmol/L. RESULTS: Correlation analysis showed a negative association between the TyG index and 25(OH)D level. After adjustments for clinical and laboratory parameters, it was revealed that when taking the Q1 quartile of TyG index as a reference, an increasing trend of VDD prevalence was presented in the other three groups divided by TyG index quartiles, where the OR (95% CI) was 1.708 (1.132-2.576) for Q2, 2.041 (1.315-3.169) for Q3, and 2.543 (1.520-4.253) for Q4 (all p < 0.05). CONCLUSIONS: Patients with higher TyG index were more likely to have an increased risk of VDD in T2DM population, which may be related to IR.

Icariin attenuates the calcification of vascular smooth muscle cells through ERα - p38MAPK pathway.

Objective: To investigate the relationship between icariin and the osteoblastic differentiation of vascular smooth muscle cells (VSMCs) and the signal pathway involved. Methods: We applied a universally accepted calcification model of VSMCs induced by ß glycerophosphate. Then the VSMCs calcification was observed by treatment with icariin and/or inhibitors of estrogen receptors (ERs) and p38-mitogen-activated protein kinase (MAPK) signaling. Results: Icariin inhibited osteoblastic differentiation and mineralization of VSMCs due to decreased ALP activity and Runx2 expression. Further study demonstrated that icariin exerted this suppression effect through activating p38-MAPK but not extracellular-regulated kinase, JNK or Akt. An inhibitor of p38-MAPK partially reversed the inhibitory effects of icariin on osteoblastic differentiation. Interestingly, treatment of VSMCs with an ER antagonist ICI182780 and a selective ERα receptor antagonist PPT attenuated icariin-mediated inhibition effect of VSMCs calcification, associated with suppression of p38-MAPK phosphorylation. Conclusions: Icariin inhibited the osteoblastic differentiation of VSMCs, and that the inhibitory effects were mediated by p38-MAPK pathways through ERα.

The regulatory role and therapeutic application of pyroptosis in musculoskeletal diseases.

Pyroptosis is a controlled form of inflammatory cell death characterized by inflammasome activation, pore formation, and cell lysis. According to different caspases, pyroptosis can be divided into canonical, non-canonical, and other pathways. The role of pyroptosis in disease development has been paid more attention in recent years. The trigger factors of pyroptosis are often related to oxidative stress and proinflammatory substances, which coincide with the pathological mechanism of some diseases. Pyroptosis directly leads to cell lysis and death, and the release of cytosolic components and proinflammatory cytokines affects cell activity and amplifies the inflammatory response. All the above are involved in a series of basic pathological processes, such as matrix degradation, fibrosis, and angiogenesis. Since these pathological changes are also common in musculoskeletal diseases (MSDs), emerging studies have focused on the correlations between pyroptosis and MSDs in recent years. In this review, we first summarized the molecular mechanism of pyroptosis and extensively discussed the differences and crosstalk between pyroptosis, apoptosis, and necrosis. Next, we elaborated on the role of pyroptosis in some MSDs, including osteoarthritis, rheumatoid arthritis, osteoporosis, gout arthritis, ankylosing spondylitis, intervertebral disc degeneration, and several muscle disorders. The regulation of pyroptosis could offer potential therapeutic targets in MSDs treatment. Herein, the existing drugs and therapeutic strategies that directly or indirectly target pyroptosis pathway components have been discussed in order to shed light on the novel treatment for MSDs.

The emerging role of pyroptosis in pediatric cancers: from mechanism to therapy.

Pediatric cancers are the driving cause of death for children and adolescents. Due to safety requirements and considerations, treatment strategies and drugs for pediatric cancers have been so far scarcely studied. It is well known that tumor cells tend to progressively evade cell death pathways, which is known as apoptosis resistance, one of the hallmarks of cancer, dominating tumor drug resistance. Recently, treatments targeting nonapoptotic cell death have drawn great attention. Pyroptosis, a newly specialized form of cell death, acts as a critical physiological regulator in inflammatory reaction, cell development, tissue homeostasis and stress response. The action in different forms of pyroptosis is of great significance in the therapy of pediatric cancers. Pyroptosis could be induced and consequently modulate tumorigenesis, progression, and metastasis if treated with local or systemic therapies. However, excessive or uncontrolled cell death might lead to tissue damage, acute inflammation, or even cytokine release syndrome, which facilitates tumor progression or recurrence. Herein, we aimed to describe the molecular mechanisms of pyroptosis, to highlight and discuss the challenges and opportunities for activating pyroptosis pathways through various oncologic therapies in multiple pediatric neoplasms, including osteosarcoma, neuroblastoma, leukemia, lymphoma, and brain tumors.

Integration of multi-omics data reveals cis-regulatory variants that are associated with phenotypic differentiation of eastern from western pigs.

BACKGROUND: The genetic mechanisms that underlie phenotypic differentiation in breeding animals have important implications in evolutionary biology and agriculture. However, the contribution of cis-regulatory variants to pig phenotypes is poorly understood. Therefore, our aim was to elucidate the molecular mechanisms by which non-coding variants cause phenotypic differences in pigs by combining evolutionary biology analyses and functional genomics. RESULTS: We obtained a high-resolution phased chromosome-scale reference genome with a contig N50 of 18.03 Mb for the Luchuan pig breed (a representative eastern breed) and profiled potential selective sweeps in eastern and western pigs by resequencing the genomes of 234 pigs. Multi-tissue transcriptome and chromatin accessibility analyses of these regions suggest that tissue-specific selection pressure is mediated by promoters and distal cis-regulatory elements. Promoter variants that are associated with increased expression of the lysozyme (LYZ) gene in the small intestine might enhance the immunity of the gastrointestinal tract and roughage tolerance in pigs. In skeletal muscle, an enhancer-modulating single-nucleotide polymorphism that is associated with up-regulation of the expression of the troponin C1, slow skeletal and cardiac type (TNNC1) gene might increase the proportion of slow muscle fibers and affect meat quality. CONCLUSIONS: Our work sheds light on the molecular mechanisms by which non-coding variants shape phenotypic differences in pigs and provides valuable resources and novel perspectives to dissect the role of gene regulatory evolution in animal domestication and breeding.

A novel multi-layer perceptron model for assessing the diagnostic value of non-invasive imaging instruments for rosacea.

Background: Reflectance confocal microscopy (RCM), VISIA, and dermoscopy have emerged as promising tools for objective diagnosis and assessment of rosacea. However, little is known about the diagnostic value of these imaging systems for rosacea. Objectives: To assess the diagnostic value of RCM, VISIA, and dermoscopy for rosacea by establishing a novel multilayer perceptron (MLP) model. Methods: A total of 520 patients with rosacea and other facial diseases were included in this study. A total of 474 samples of dermoscopy data, 374 samples of RCM data, 434 samples of VISIA data, and 291 samples containing three data sources were collected. An MLP model was built with the total data to explore the association between the imageological features of each instrument and the probability of rosacea. Results: Our MLP model revealed that the area under the receiver operating characteristic curve (AUROC) values of RCM, VISIA and dermoscopy for diagnosing rosacea were 0.5233, 0.5646 and 0.7971, respectively. The integration of these three tools with clinical data could further improve the accuracy of the predictive diagnosis to 0.8385. For the imageological features of each tool, abnormalities (hyperkeratosis or parakeratosis) in the stratum corneum were effective variables for excluding rosacea (odds ratio [OR], 0.4333) under RCM. The indicators of rosacea under VISIA included overall severity of erythema, erythema involving the cheek or superciliary arch, visible red blood vessels, and papules (OR = 2.2745, 3.1592, 1.8365, 2.8647, and 1.4260, respectively). The candidate variables of dermoscopy included yellow background, white background, uniform distribution of vessels, branched vessels, and reticular blood vessels (OR = 0.4259, 0.4949, 2.2858, 3.7444, and 2.4576, respectively). Conclusions: RCM, dermoscopy, and VISIA each can present several imageological features and were of certain value for assisting rosacea diagnosis. The combined analysis of these three tools using our MLP model may be useful for improving the accuracy of diagnosing rosacea.

Analysis of the relationship between serum alanine aminotransferase and body composition in Chinese women.

Objective: To investigate the relationships between serum alanine aminotransferase (ALT) and body composition among postmenopausal women in China. Methods: A cross-sectional study was conducted with 776 postmenopausal women in China from May to July 2008. Clinical information was collected using a standardized questionnaire. Measures of body composition were obtained using dual X-ray absorptiometry. Body lean mass and fat mass indices were calculated by dividing total body lean/fat weight (kg) by body height squared (kg/m2). Blood samples were collected to assess liver and renal functions and lipid profiles. Analysis of variance, Pearson correlations, and multiple regression were used to analyze the associations between serum ALT and body composition. Results: We found negative relationships of serum ALT with age, menopause duration, and serum HDL-C levels. Serum ALT was positively correlated with BMI, serum TG levels, and the lean mass index and fat mass index. In a multivariate model adjusted for age, menopause duration, serum TG, and HDL-C levels, a 1-unit increase in the fat mass index was associated with a 0.176 U/L increase in ALT (95% CI 0.020 to 0.050, P < 0.001). Conclusion: Serum ALT was positively associated with the body fat mass index of postmenopausal women in China.

Exosomal MiRNAs in Osteosarcoma: Biogenesis and Biological Functions.

MiRNAs are a group of non-coding RNA molecules that function in mRNA translational inhibition via base-pairing with complementary sequences in target mRNA. In oncology, miRNAs have raised great attention due to their aberrant expression and pivotal roles in the pathogenesis of multiple malignancies including osteosarcoma. MiRNAs can be transported by exosome, the nano-extracellular vesicle with a diameter of 30-150 nm. Recently, a growing number of studies have demonstrated that exosomal miRNAs play a critical role in tumor initiation and progression, by exerting multiple biological functions including metastasis, angiogenesis, drug resistance and immunosuppression. In this review, we aim to depict the biogenesis of exosomal miRNAs and summarize the potential diagnostic and therapeutic functions of exosomal miRNAs in osteosarcoma.

Roles and mechanisms of exosomal non-coding RNAs in human health and diseases.

Exosomes play a role as mediators of cell-to-cell communication, thus exhibiting pleiotropic activities to homeostasis regulation. Exosomal non-coding RNAs (ncRNAs), mainly microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), are closely related to a variety of biological and functional aspects of human health. When the exosomal ncRNAs undergo tissue-specific changes due to diverse internal or external disorders, they can cause tissue dysfunction, aging, and diseases. In this review, we comprehensively discuss the underlying regulatory mechanisms of exosomes in human diseases. In addition, we explore the current knowledge on the roles of exosomal miRNAs, lncRNAs, and circRNAs in human health and diseases, including cancers, metabolic diseases, neurodegenerative diseases, cardiovascular diseases, autoimmune diseases, and infectious diseases, to determine their potential implication in biomarker identification and therapeutic exploration.

Simultaneously Enhanced Thermal Conductivity and Dielectric Breakdown Strength in Sandwich AlN/Epoxy Composites.

Polymer-based composites with high thermal conductivity and dielectric breakdown strength have gained increasing attention due to their significant application potential in both power electronic devices and power equipment. In this study, we successfully prepared novel sandwich AlN/epoxy composites with various layer thicknesses, showing simultaneously and remarkably enhanced dielectric breakdown strength and thermal conductivity. The most optimized sandwich composite, with an outer layer thickness of 120 µm and an inner layer thickness of 60 µm (abbreviated as 120-60) exhibits a high through-plane thermal conductivity of 0.754 W/(m·K) (4.1 times of epoxy) and has a dielectric breakdown strength of 69.7 kV/mm, 8.1% higher compared to that of epoxy. The sandwich composites also have higher in-plane thermal conductivity (1.88 W/(m·K) for 120-60) based on the novel parallel models. The sandwich composites with desirable thermal and electrical properties are very promising for application in power electronic devices and power equipment.