Sympathetic innervation induces exosomal miR-125 transfer from osteoarthritic chondrocytes, disrupting subchondral bone homeostasis and aggravating cartilage damage in aging mice.

INTRODUCTION: Osteoarthritis (OA) is a progressive disease that poses a significant threat to human health, particularly in aging individuals: Although sympathetic activation has been implicated in bone metabolism, its role in the development of OA related to aging remains poorly understood. Therefore, this study aimed to investigate how sympathetic regulation impacts aging-related OA through experiments conducted both in vivo and in vitro. METHODS: To analyze the effect of sympathetic regulation on aging-related OA, we conducted experiments using various mouse models. These models included a natural aging model, a medial meniscus instability model, and a load-induced model, which were used to examine the involvement of sympathetic nerves. In order to evaluate the expression levels of ß1-adrenergic receptor (Adrß1) and sirtuin-6 (Sirt6) in chondrocytes of naturally aging OA mouse models, we performed assessments. Additionally, we investigated the influence of ß1-adrenergic receptor knockout or treatment with a ß1-adrenergic receptor blocker on the progression of OA in aging mice and detected exosome release and detected downstream signaling expression by inhibiting exosome release. Furthermore, we explored the impact of sympathetic depletion through tyrosine hydroxylase (TH) on OA progression in aging mice. Moreover, we studied the effects of norepinephrine(NE)-induced activation of the ß1-adrenergic receptor signaling pathway on the release of exosomes and miR-125 from chondrocytes, subsequently affecting osteoblast differentiation in subchondral bone. RESULTS: Our findings demonstrated a significant increase in sympathetic activity, such as NE levels, in various mouse models of OA including natural aging, medial meniscus instability, and load-induced models. Notably, we observed alterations in the expression levels of ß1-adrenergic receptor and Sirt6 in chondrocytes in OA mouse models associated with natural aging, leading to an improvement in the progression of OA. Critically, we found that the knockout of ß1-adrenergic receptor or treatment with a ß1-adrenergic receptor blocker attenuated OA progression in aging mice and the degraded cartilage explants produced more exosome than the nondegraded ones, Moreover, sympathetic depletion through TH was shown to ameliorate OA progression in aging mice. Additionally, we discovered that NE-induced activation of the ß1-adrenergic receptor signaling pathway facilitated the release of exosomes and miR-125 from chondrocytes, promoting osteoblast differentiation in subchondral bone. CONCLUSION: In conclusion, our study highlights the role of sympathetic innervation in facilitating the transfer of exosomal miR-125 from osteoarthritic chondrocytes, ultimately disrupting subchondral bone homeostasis and exacerbating cartilage damage in aging mice. These findings provide valuable insights into the potential contribution of sympathetic regulation to the pathogenesis of aging-related OA.

Estrogen deficiency induces bone loss through the gut microbiota.

Postmenopausal osteoporosis is a common bone metabolic disease, and gut microbiota (GM) imbalance plays an important role in the development of metabolic bone disease. Here, we show that ovariectomized mice had high levels of lipopolysaccharide in serum and gut microbiota dysbiosis through increases in luminal Firmicutes:Bacteroidetes ratio. We depleted the GM through antibiotic treatment and observed improvements in bone mass, bone microstructure, and bone strength in ovariectomized mice. Conversely, transplantation of GM adapted to ovariectomy induced bone loss. However, GM depletion reversed ovariectomy-induced gene expression in the tibia and increased periosteal bone formation. Furthermore, bioinformatics analysis revealed that the G-protein-coupled bile acid receptor (TGR5) and systemic inflammatory factors play key roles in bone metabolism. Silencing TGR5 expression through small interfering RNA (siRNA) in the local tibia and knockout of TGR5 attenuated the effects of GM depletion in ovariectomized mice, confirming these findings. Thus, this study highlights the critical role of the GM in inducing bone loss in ovariectomized mice and suggests that targeting TGR5 within the GM may have therapeutic potential for postmenopausal osteoporosis.

Identification of kukoamine a as an anti-osteoporosis drug target using network pharmacology and experiment verification.

BACKGROUND: Osteoporosis (OP) is a major and growing public health problem characterized by decreased bone mineral density and destroyed bone microarchitecture. Previous studies found that Lycium Chinense Mill (LC) has a potent role in inhibiting bone loss. Kukoamine A (KuA), a bioactive compound extract from LC was responsible for the anti-osteoporosis effect. This study aimed to investigate the anti-osteoporosis effect of KuA isolated from LC in treating OP and its potential molecular mechanism. METHOD: In this study, network pharmacology and molecular docking were investigated firstly to find the active ingredients of LC such as KuA, and the target genes of OP by the TCMSP platform. The LC-OP-potential Target gene network was constructed by the STRING database and network maps were built by Cytoscape software. And then, the anti-osteoporotic effect of KuA in OVX-induced osteoporosis mice and MC3T3-E1 cell lines were investigated and the potential molecular mechanism including inflammation level, cell apoptosis, and oxidative stress was analyzed by dual-energy X-ray absorptiometry (DXA), micro-CT, ELISA, RT-PCR, and Western Blotting. RESULT: A total of 22 active compounds were screened, and we found KuA was identified as the highest active ingredient. Glycogen Phosphorylase (PYGM) was the target gene associated with a maximum number of active ingredients of LC and regulated KuA. In vivo, KuA treatment significantly increased the bone mineral density and improve bone microarchitecture for example increased BV/TV, Tb.N and Tb.Th but reduced Tb.Sp in tibia and lumber 4. Furthermore, KuA increased mRNA expression of osteoblastic differentiation-related genes in OVX mice and protects against OVX-induced cell apoptosis, oxidative stress level and inflammation level. In vitro, KuA significantly improves osteogenic differentiation and mineralization in cells experiment. In addition, KuA also attenuated inflammation levels, cell apoptosis, and oxidative stress level. CONCLUSION: The results suggest that KuA could protect against the development of OP in osteoblast cells and ovariectomized OP model mice and these found to provide a better understanding of the pharmacological activities of KuA again bone loss.

The gut microbiota metabolite capsiate regulate SLC2A1 expression by targeting HIF-1α to inhibit knee osteoarthritis-induced ferroptosis.

Ferroptosis is an iron-dependent cell death that has been found to aggravate the progression of osteoarthritis (OA) and gut microbiota- OA axis refers to the bidirectional information network between the gut microbiota and OA, which may provide a new way to protect the OA. However, the role of gut microbiota-derived metabolites in ferroptosis-relative osteoarthritis remains unclear. The objective of this study was to analyze the protective effect of gut microbiota and its metabolite capsiate (CAT) on ferroptosis-relative osteoarthritis in vivo and in vitro experiments. From June 2021 to February 2022, 78 patients were evaluated retrospectively and divided into two groups: The health group (n = 39) and the OA group (n = 40). Iron and oxidative stress indicators were determined in peripheral blood samples. And then in vivo and in vitro experiments, a surgically destabilized medial meniscus (DMM) mice model was established and treated with CAT or Ferric Inhibitor-1 (Fer-1). Solute Carrier Family 2 Member 1 (SLC2A1) short hairpin RNA (shRNA) was utilized to inhibit SLC2A1 expression. Serum iron was increased significantly but total iron binding capacity was decreased significantly in OA patients than healthy people (p < 0.0001). The least absolute shrinkage and selection operator clinical prediction model suggested that serum iron, total iron binding capacity, transferrin, and superoxide dismutase were all independent predictors of OA (p < 0.001). Bioinformatics results suggested that SLC2A1, Metastasis-Associated Lung Adenocarcinoma Transcript 1 (MALAT1), and HIF-1α (Hypoxia Inducible Factor 1 Alpha)-related oxidative stress signaling pathways play an important role in iron homeostasis and OA. In addition, gut microbiota 16s RNA sequencing and untargeted metabolomics were used to find that gut microbiota metabolites CAT in mice with osteoarthritis were negatively correlated with Osteoarthritis Research Society International (OARSI) scores for chondrogenic degeneration (p = 0.0017). Moreover, CAT reduced ferroptosis-dependent osteoarthritis in vivo and in vitro. However, the protective effect of CAT against ferroptosis-dependent osteoarthritis could be eliminated by silencing SLC2A1. SLC2A1 was upregulated but reduced the SLC2A1 and HIF-1α levels in the DMM group. HIF-1α, MALAT1, and apoptosis levels were increased after SLC2A1 knockout in chondrocyte cells (p = 0.0017). Finally, downregulation of SLC2A1 expression by Adeno-associated Virus (AAV) -SLC2A1 shRNA improves osteoarthritis in vivo. Our findings indicated that CAT inhibited HIF-1a expression and reduced ferroptosis-relative osteoarthritis progression by activating SLC2A1.

Bone mass loss in chronic heart failure is associated with sympathetic nerve activation.

PURPOSE: Chronic heart failure causes osteoporosis, but the mechanism remains unclear. The sympathetic nerve plays an important role in both bone metabolism and cardiovascular function. METHODS: Thirty-six adult male SD rats were randomly divided into the following four groups: sham surgery (Sham) group, guanethidine (GD) group, abdominal transverse aorta coarctation-induced heart failure + normal saline (TAC) group, and TAC + guanethidine (TAC + GD) group. Normal saline (0.9 % NaCl) or guanethidine (40 mg/kg/ml) was intraperitoneally injected daily for 5 weeks. Then, DXA, micro-CT, ELISA and RT-PCR analyses were performed 12 weeks after treatment. RESULTS: The bone loss in rats subjected to TAC-induced chronic heart failure and chemical sympathectomy with guanethidine was increased. Serum norepinephrine levels were increased in rats with TAC-induced heart failure but were decreased in TAC-induced heart failure rats treated with guanethidine. The expression of α2A adrenergic receptor, α2C adrenergic receptor, osteoprotegerin (OPG), and osteocalcin in the tibia decreased in the TAC-induced heart failure group, and the expression of ß1 adrenergic receptor, ß2 adrenergic receptor, receptor activator of nuclear factor-κ B ligand (RANKL), and RANKL/OPG in the tibia increased in the heart failure group. In addition, these changes in gene expression levels were rescued by chemical sympathectomy with guanethidine. CONCLUSIONS: TAC-induced chronic heart failure is associated with bone mass loss, and the sympathetic nerve plays a significant role in heart failure-related bone mass loss. MINI ABSTRACT: The present study supports the hypothesis that heart failure is related to bone loss, and the excessive activation of sympathetic nerves participates in this pathophysiological process. The present study suggests a potential pathological mechanism of osteoporosis associated with heart failure and new perspectives for developing strategies for heart failure-related bone loss.

The role of TGR5 as an onco-immunological biomarker in tumor staging and prognosis by encompassing the tumor microenvironment.

The relationship between G protein-coupled bile acid receptor 1 (TGR5, GPBAR1) and, specifically, cancer has been studied in in vivo and in vitro experiments, but there is still a lack of pan-cancer analysis to understand the prognostic significance and functioning mechanism of TGR5 in different cancer-driving oncogenic processes. Here, we used Gene Expression Integration, Human Protein Atlas, and The Cancer Genome Atlas (TCGA) to perform a pan-cancer analysis of the role of TGR5 in all 33 tumors. In all TCGA tumors, the TGR5 gene expression has been assessed, and we found that the high TGR5 gene expression in most cancers is associated with poor prognosis of overall survival for cancers such as glioblastoma multiforme (p = 0.0048), kidney renal papillary cell carcinoma (p = 0.033), lower grade glioma (p = 0.0028), thymoma (p = 0.048), and uveal melanoma (p = 0.004), and then the lower expression of TGR5 was linked with poor prognosis in cervical squamous cell carcinoma and endocervical adenocarcinoma (p = 0.014), malignant mesothelioma (MESO) (p = 0.048), sarcoma (p = 0.018), and skin cutaneous melanoma (p = 0.0085). The TGR5 expression was linked with the immune infiltration level of the macrophage M2_TIDE and was also associated with DNA methylation in ovarian and breast cancers. The regulation of hormone secretion, Rap1 pathway, osteoclast differentiation, and bile acid pathway was involved in the functional mechanism of TGR5. Besides, gene expressions were different in different tumors detected by RT-PCR, and cell activity experiments have also found that TGR5 can increase the activity of renal cell carcinoma and reduce the activity of skin cancer and osteosarcoma cells. In this investigation, the aim was to assess the comprehensive overview of the oncogenic roles of TGR5 in all TCGA tumors using pan-analysis.

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OBJECTIVES: To evaluate the value of fractional exhaled nitric oxide (FeNO) combined with impulse oscillometry (IOS) in the diagnosis of asthma in preschool children, and to establish the optimal predictive model. METHODS: A retrospective analysis was performed on 156 children with wheezing, aged 3-5 years, who were admitted from September 2019 to December 2020. These children were divided into an asthma group with 52 children and a non-asthma group with 104 children. The two groups were compared in terms of IOS parameters, FeNO, and clinical data. The multivariate logistic regression analysis was used to establish the optimal predictive model. RESULTS: Compared with the non-asthma group, the asthma group had significantly higher total respiratory system impedance at 5 Hz (Z5), resistance of respiratory system at 5 Hz and 20 Hz (R5 and R20, respectively), resonance frequency, reactance area (AX), and FeNO and a significantly lower reactance difference at 5 Hz (P<0.05). The receiver operating characteristic (ROC) curve analysis showed that Z5, R5, R20, and FeNO had a certain value in the diagnosis of asthma (P<0.05). The multivariate logistic regression analysis established the optimal predictive model of R20+AX+FeNO, with an area under the ROC curve of 0.858 (P<0.05), a sensitivity of 78.8%, and a specificity of 76.9%. CONCLUSIONS: FeNO combined with IOS is helpful for the diagnosis of asthma in preschool children, and the model of R20+AX+FeNO has a certain value in the diagnosis of asthma in these children.

Single-intraosseous simvastatin injection suppresses cancers via activating CD8+ T cells.

Immunotherapies provide effective strategies for cancer treatment. Cholesterol induces CD8+ T cell exhaustion, which inhibits antitumor immunity. CD8+ T cells are derived from bone marrow and transport and function in bone marrow, where provides more porous cavities for drugs to access the circulation than other solid organs. We previously found that single-dose intraosseous (i.o.) injection of simvastatin suppresses breast cancer development and prolongs survival, but the exact mechanism remains unclear. In this study, we found the antitumor activity of simvastatin i.o. mainly depended on CD8+ T cells. Simvastatin i.o. increased the percentage and cytotoxicity of CD8+ T cells and downregulated the expression of PD-1, TIM3 and CTLA4 in CD8+ T cells in vivo. Simvastatin promoted the activation, proliferation and cytotoxicity of tumor antigen-specific CD8+ T cells in vitro. Furthermore, Simvastatin i.o. suppressed cancers by activating the T-cell antigen receptor signaling pathway. Taken together, simvastatin i.o. effectively suppresses cancer progression, which would be a potential strategy for cancer treatment.

Evaluating the Lower Urinary Tract Syndrome with a Telemedicine Application: An Exploration of the Electronic Audiovisual Prostate Symptom Score.

Background: The Visual Prostate Symptom Score (VPSS) is used for the assessment of lower urinary tract symptoms (LUTS). It is usually administered by general practitioners (GPs), but in these cases, outcomes do not seem to be reflecting the real conditions of a patient well, with consequent risks of misestimations and misinterpretations. We developed an electronic audiovisual version of VPSS (EPSS), a new symptom scale based on a telemedicine mobile light-based app. The aim of this study is to test and evaluate its reliability. Methods: We enrolled male patients aged between 50 and 80 years across 24 community-based healthcare facilities in Guangzhou, China. Patients were asked to complete the Chinese version of VPSS and EPSS before consultation with the urology specialists. Patients were divided into two groups based on age. First, we analyzed the rate of full understanding of EPSS using a chi-square test. Then, we analyzed the difference between each score of EPSS, VPSS, and outcomes measured by specialists, used as the reference score (RS). Finally, the outcomes were analyzed with the Spearman test and Bartlett test separately. Results: Seventy-nine male patients were included (mean age 70.42 years). Patients were divided into two groups: group 1 (>70 years, n = 40) and group 2 (<70 years, n = 39). The full-understanding rates in groups 1 and 2 were 50% and 64.1%, respectively. No significant differences were noted between groups (p = 0.206). A t-test was presented between each question of VPSS, EPSS, and RS. All questions did not display significant differences (p > 0.05); total scores from the three scales had no significant differences in the evaluation of LUTS. We further explored the variations of choices made by patients in different scales. Spearman's test among VPSS, EPSS, and RS showed positive correlations, and coefficients of the total score were 0.92, 0.91, and 0.93 (p < 0.05). Conclusion: EPSS can be easily used in a significant number of patients and showed correlation with the VPSS and RS. Moreover, certain items resulted in better performance than VPSS. The results showed that EPSS could be a valuable option for both patients and GPs monitoring LUTS and particularly helpful when teleconsultations are considered, especially during the COVID-19 pandemic.

Secreted Protein Acidic and Rich in Cysteine Mediates the Development and Progression of Diabetic Retinopathy.

Backgrounds: Diabetic retinopathy (DR) is one of the most severe microvascular complications of diabetes mellitus (DM). Secreted protein acidic and rich in cysteine (SPARC) has been found to play an important role in many diseases, but its role and mechanism in DR remain unknown. Methods: We studied the role of SPARC and integrin ß1 in vascular pathophysiology and identified potential therapeutic translation. The SPARC levels were tested in human serum and vitreous by ELISA assay, and then the Gene Expression Omnibus (GEO) dataset was used to understand the key role of the target gene in DR. In human retinal capillary endothelial cells (HRCECs), we analyzed the mRNA and protein level by RT-PCR, immunohistochemistry, and Western blotting. The cell apoptosis, cell viability, and angiogenesis were analyzed by flow cytometry, CCK-8, and tube formation. Results: In this study, we investigated the role of SPARC in the development and progression of human DR and high glucose-induced HRCEC cells and found that the SPARC-ITGB1 signaling pathway mimics early molecular and advanced neurovascular pathophysiology complications of DR. The result revealed that DR patients have a high-level SPARC expression in serum and vitreous. Knockdown of SPARC could decrease the expressions of inflammatory factors and VEGFR, inhibit cell apoptosis and angiogenesis, and increase cell viability by regulating integrin ß1 in HRCECs. Conclusion: SPARC promotes diabetic retinopathy via the regulation of integrin ß1. The results of this study can provide a potential therapeutic application for the treatment of DR.

The Role of Depletion of Gut Microbiota in Osteoporosis and Osteoarthritis: A Narrative Review.

Osteoporosis and osteoarthritis are common diseases in an aging society, are considered metabolic diseases, and affect the quality of life of older adults. In addition, the gut microbiome is considered an additional organ to regulate bone metabolism. In the past decade, people have been studying the relationship between gut microbiota and bone metabolism. The role and mechanism of the gut microbiota in regulating bone metabolism is very important to improve the development of osteoporosis and osteoarthritis. Depletion of the gut microbiota as a method of studying the role of the gut microbiota was provided strategies to enhance the role of the gut microbiota in regulating osteoporosis and osteoarthritis. In this review, we discuss how depletion of the gut microbiota affects osteoporosis and osteoarthritis.

Identification of Ferroptosis-Related Genes as Biomarkers for Sarcoma.

Sarcomas are seen as mixed-up nature with genetic and transcriptional heterogeneity and poor prognosis. Although the genes involved in ferroptosis are still unclear, iron loss is considered to be the core of glioblastoma, tumor progression, and tumor microenvironment. Here, we developed and tested the prognosis of SARC, which is a genetic marker associated with iron residues. The ferroptosis-related gene expression, one-way Cox analysis, and least-selection absolute regression algorithm (LASSO) are used to track prognostic-related genes and create risk assessment models. Finally, immune system infiltration and immune control point analysis are used to study the characteristics of the tumor microenvironment related to risk assessment. Moreover, LncRNA-miRNA-mRNA network was contributed in our studies. We determined the biomarker characteristics associated with iron degradation in gene 32 and developed a risk assessment model. ROC analysis showed that its model was accurately predicted, with 1, 2, 3, 4, and 5 years of overall survival in TCGA cohort of SARC patients. A comparative analysis of settings found that overall survival (OS) was lower in the high-risk than that in the low-risk group. The nomogram survival prediction model also helped to predict the OS of SARC patients. The nomogram survival prediction model has strong predictive power for the overall survival of SARC patients in TCGA dataset. GSEA analysis shows that high-risk groups are rich in inflammation, cancer-related symptoms, and pathological processes. High risk is related to immune cell infiltration and immune checkpoint. Our prediction model is based on SARC ferritin-related genes, which may support SARC prediction and provide potential attack points.

The effects of metformin and alendronate in attenuating bone loss and improving glucose metabolism in diabetes mellitus mice.

BACKGROUND: To explore the anti-osteoporosis and anti-diabetes effects and potential underlying mechanisms of treatment with metformin and alendronate in diabetes mellitus mice. METHODS: Eight-week-old C57 BL/KS db/db and db/+ female mice were evaluated according to the following treatment group for 12 weeks: control group, diabetes mellitus group, diabetes mellitus with metformin group, diabetes mellitus with Alendronate group, diabetes mellitus with metformin plus alendronate group. Glucose level, glucose tolerance test, bone mineral density, bone microarchitecture, bone histomorphometry, serum biomarkers, and qPCR analysis. RESULTS: Combined metformin and alendronate can improve progression in glucose metabolism and bone metabolism, including blood glucose levels, blood glucose levels after 4 and 16 hours fasting, glucose tolerance test results, insulin sensitivity and reduces bone loss than the diabetes group. The use of alendronate alone can increase significantly serum glucagon-like peptide-1 levels than the diabetes group. The use of metformin alone can improve bone microstructure such as Tb.Sp and Tb.N of spine in diabetic mice. CONCLUSION: The combined use of alendronate and metformin has an anti-diabetes and anti-osteoporotic effect compared with diabetic mice, but they appear to act no obvious synergistically between alendronate and metformin.

The effect of whole-body vibration in osteopenic patients after total knee arthroplasty: a randomized controlled trial.

BACKGROUND: Total knee arthroplasty (TKA) is an important treatment for knee osteoarthritis, but the result of whole-body vibration (WBV) in knee function rehabilitation and bone loss with osteopenia was unknown. Therefore, the purpose of this study is to study whether low-frequency, low-amplitude WBV can improve the clinical outcome of knee osteoarthritis. METHODS: This study was randomized and included 67 osteopenic patients (55-90 years, 85% women) for TKA surgery (control group N = 32, WBV group N = 35). All selected patients after TKA surgery tested clinical results, such as knee function and bone mass in baseline, 3 months after surgery, and 6 months after surgery. RESULTS: Compared to the control group, the WBV group improved pain scores, thigh circumference, lower limb muscle strength, joint activity, and joint function in 6 months after surgery. WBV intervention also improves bone density in the spine, the microstructure of the radius and tibia, and the bone turnover marker. At 3 months after TKA surgery, the WBV group had no significant effect on knee function and bone loss. CONCLUSIONS: Whole-body vibration for osteopenic patients with knee arthroplasty showed good therapeutic results in 6 months after TKA surgery, but the long-term therapeutic effect still needs to be further observed.

Modified minimally invasive technique for decompression and reduction of thoracolumbar burst fracture with neurological symptoms: Technical Note.

PURPOSE: There are few reports about minimally invasive decompression and fixation for patients with thoracolumbar fracture and neurological symptoms. The previously reported method requires complete laminectomy, and removal of the medial part of the pedicle to expose the spinal canal for reduction. Thus, some approach-related damage to the bony structure and soft tissue still occurs. This study was performed to describe a modified minimally invasive tube technique for decompression and reduction of thoracolumbar fracture with neurological symptoms. This modified technique preserves most of the posterior structures of the spine as well as the muscle. METHODS: Percutaneous pedicle screws were placed on the vertebrae superior and inferior to the fracture and at the fracture segment on the side with less severe symptoms. After retraction, the tube for decompression was placed on the facet joint where the decompression was needed. Under microscopic vision, part of the lamina and ligamentum flavum were removed to expose the spinal canal, and an L-shaped probe was used to reduce the bone fragment. RESULTS: The modified method was successfully used in eight patients. Complete decompression was achieved and the bone fragment was safely reduced through the tube under microscopy in all cases. Fluoroscopy confirmed that the positioning of the percutaneous pedicle screw was good and the bone fragment was reduced. The neurological status was improved in all patients at last follow up. CONCLUSION: The modified method of minimally invasive decompression and fusion is effective in treating thoracolumbar fractures with neurological symptoms and preserves most of the ligaments and bone structure.

Blood-Brain Barrier, Cell Junctions, and Tumor Microenvironment in Brain Metastases, the Biological Prospects and Dilemma in Therapies.

Brain metastasis is the most commonly seen brain malignancy, frequently originating from lung cancer, breast cancer, and melanoma. Brain tumor has its unique cell types, anatomical structures, metabolic constraints, and immune environment, which namely the tumor microenvironment (TME). It has been discovered that the tumor microenvironment can regulate the progression, metastasis of primary tumors, and response to the treatment through the particular cellular and non-cellular components. Brain metastasis tumor cells that penetrate the brain-blood barrier and blood-cerebrospinal fluid barrier to alter the function of cell junctions would lead to different tumor microenvironments. Emerging evidence implies that these tumor microenvironment components would be involved in mechanisms of immune activation, tumor hypoxia, antiangiogenesis, etc. Researchers have applied various therapeutic strategies to inhibit brain metastasis, such as the combination of brain radiotherapy, immune checkpoint inhibitors, and monoclonal antibodies. Unfortunately, they hardly access effective treatment. Meanwhile, most clinical trials of target therapy patients with brain metastasis are always excluded. In this review, we summarized the clinical treatment of brain metastasis in recent years, as well as their influence and mechanisms underlying the differences between the composition of tumor microenvironments in the primary tumor and brain metastasis. We also look forward into the feasibility and superiority of tumor microenvironment-targeted therapies in the future, which may help to improve the strategy of brain metastasis treatment.

Reversal of alopecia areata, osteoporosis follow treatment with activation of Tgr5 in mice.

BACKGROUND: Alopecia areata is an autoimmune hair loss disease with infiltration of pro-inflammatory cells into hair follicles. The role of Tgr5 in dermatitis has attracted considerable attention. The present study aimed to investigate the effect of Tgr5 in the development of Alopecia areata. METHODS: The study utilized a comparison control group design with four groups of wild-type group, wild-type+INT777 group, Tgr5-/- group, and Tgr5-/-+INT777 group. The mice were treated with INT777 (30 mg/kg/day) or the carrier solution (DMSO) intraperitoneally for 7 weeks, and the back skin was collected and analyzed by histology and immunohistochemistry staining. The lumbar vertebrae 4 has also been analyzed by DXA and Micro-CT. RESULTS: Tgr5-/- mice displayed the decreasingly significant in hair area and length, skin thickness, and the ratio of anagen and telogen, collagen, and mast cell number and loss the bone mass than WT group. After treating with INT777, the appearance of alopecia areata and bone microstructure has improved. Immunohistochemistry and qPCR analysis showed that activation of Tgr5 can down-regulate the express of JAK1, STAT3, IL-6, TNF-α, and VEGF. CONCLUSION: These findings indicate that activation of Tgr5 mediated amelioration of alopecia areata and osteoporosis by down-regulated JAK1-STAT3 signaling pathway.

Long-term pretreatment with alendronate inhibits calvarial defect healing in an osteoporotic rat model.

INTRODUCTION: This study aimed to observe the effects of long-term alendronate pretreatment on the healing of osteoporotic calvarial defects, and further investigate the effect of alendronate combined with once-weekly parathyroid hormone following 12 weeks of alendronate treatment in ovariectomized rats. MATERIALS AND METHODS: Thirty 3-month-old female rats were ovariectomized, and 24 rats received alendronate for 12 weeks. Then, a critical defect was created in the calvaria of all animals. Immediately after osteotomy, the animals received one of five treatments for 8 weeks: (1) continuation of vehicle (group E), (2) alendronate followed by vehicle (group A), (3) continuation of alendronate (group B), (4) alendronate followed by once-weekly parathyroid hormone alone (group C), or (5) continuation of alendronate combined with once-weekly parathyroid hormone (group D). Calvarial defect healing was assessed using dual-energy X-ray absorptiometry, micro-computed tomography, histology, and sequential fluorescence labeling. RESULTS: Group E showed a significantly higher volume of newly formed bone than groups A, B, C, and D. Evidence of new dense bone formation in group E was observed histologically. In addition, the immunohistochemical expression of runt-related transcription factor 2 was increased in group E but inhibited in groups A, B, C, and D. Sequential immunofluorescence also showed inhibited mineral apposition in groups A, B, C, and D compared with group E. CONCLUSION: The present study shows that long-term pretreatment with alendronate inhibited calvarial defect healing in osteoporotic rats, and this effect could not be reversed by stopping alendronate, switching to parathyroid hormone, or combining with once-weekly parathyroid hormone.

Computational numerical analysis of different cannulation methods during cardiopulmonary bypass of type A aortic dissection model based on computational fluid dynamics.

BACKGROUND: The aim of the present study was to use a numerical simulation based on computational fluid dynamics (CFD) to analyze the difference of different cannulation methods on hemodynamics characteristic in a type A aortic dissection (TAAD) model. METHODS: A finite-element analysis based on the CFD model of a TAAD patient was used, and axillary artery cannulation (AAC), innominate artery cannulation (IAC), and femoral artery cannulation (FAC) were analyzed under different situations, including a cardiac output (CO) of 2.5 L/min and cardiopulmonary bypass (CPB) of 2.5 L/min (partial CPB before cross-clamping aorta, defined as condition A), and a CO of 0 L/min and CPB of 5 L/min (aortic cross-clamping phase, defined as condition B). The insertion of an 8-mm cannula into the different models was simulated. Hemodynamic characteristics, including wall shear stress, wall stress, blood flow, and velocity were analyzed. RESULTS: In condition A, the total flow of branches of the aortic arch was 2,009.5 mL/min (AAC), 1,855.47 mL/min (IAC), and 1,648.03 mL/min (FAC). All cannulation methods improved left renal blood perfusion. However, in relation to blood flow in the right renal artery, FAC showed the highest blood flow (105 mL/min). The results in condition B were similar to those of condition A. The velocity, shear stress, and stress of entry tear via AAC and IAC decreased in condition B compared with condition A. The velocity, shear stress, stress of tear via AAC was lower than that of IAC. CONCLUSIONS: Different cannulation modes have an effect on the hemodynamic characteristic of the tear, but this effect is related to different states of CPB. AAC was found to superior to IAC, especially in reducing velocity, stress, and shear stress of site of tear. However, IAC and AAC are more conductive to blood supply than FAC in branch vessels of the aortic arch without being affected by the CPB state.