Cold exposure-induced plasma exosomes impair bone mass by inhibiting autophagy.

Recently, environmental temperature has been shown to regulate bone homeostasis. However, the mechanisms by which cold exposure affects bone mass remain unclear. In our present study, we observed that exposure to cold temperature (CT) decreased bone mass and quality in mice. Furthermore, a transplant of exosomes derived from the plasma of mice exposed to cold temperature (CT-EXO) can also impair the osteogenic differentiation of BMSCs and decrease bone mass by inhibiting autophagic activity. Rapamycin, a potent inducer of autophagy, can reverse cold exposure or CT-EXO-induced bone loss. Microarray sequencing revealed that cold exposure increases the miR-25-3p level in CT-EXO. Mechanistic studies showed that miR-25-3p can inhibit the osteogenic differentiation and autophagic activity of BMSCs. It is shown that inhibition of exosomes release or downregulation of miR-25-3p level can suppress CT-induced bone loss. This study identifies that CT-EXO mediates CT-induced osteoporotic effects through miR-25-3p by inhibiting autophagy via targeting SATB2, presenting a novel mechanism underlying the effect of cold temperature on bone mass.

Assessment of causal association between the socio-economic status and osteoporosis and fractures: a bidirectional Mendelian randomization study in European population.

BACKGROUND: The relationship between socio-economic status and bone-related diseases is attracting increasing attention. Therefore, a bidirectional Mendelian randomization (MR) analysis was performed in this study. METHODS: Genetic data on factors associated with socio-economic status (average total household income before tax, years of schooling completed and Townsend Deprivation Index at recruitment), femoral neck bone mineral density (FN-BMD), heel bone mineral density (eBMD), osteoporosis, and five different sites of fracture (spine, femur, lower leg-ankle, foot, and wrist-hand fractures) were derived from genome-wide association summary statistics of European ancestry. The inverse variance weighted method was employed to obtain the causal estimates, complemented by alternative MR techniques, including MR-Egger, weighted median, and MR-pleiotropy residual sum and outlier (MR-PRESSO). Furthermore, sensitivity analyses, and multivariable MR was performed to enhance the robustness of our findings. RESULTS: A higher educational attainment was associated with an increased level of eBMD (beta:0.06, 95% CI:0.01-0.10, P = 7.24 × 10-3), and decreased risk of osteoporosis (OR:0.78, 95% CI:0.65-0.94, P = 8.49 × 10-3), spine fracture (OR:0.76, 95% CI:0.66-0.88, P = 2.94 × 10-4), femur fracture (OR:0.78, 95% CI:0.67-0.91, P = 1.33 × 10-3), lower leg-ankle fracture (OR:0.79, 95% CI:0.70-0.88, P = 2.05 × 10-5), foot fracture (OR:0.78, 95% CI:0.66-0.93, P = 5.92 × 10-3) and wrist-hand fracture (OR:0.83, 95% CI:0.73-0.95, P = 7.15 × 10-3). Further, material deprivation seemed to harm the spine fracture (OR:2.63, 95% CI:1.43-4.85, P = 1.91 × 10-3). A higher level of FN-BMD positively affected increased household income (beta:0.03, 95% CI:0.01-0.04, P = 6.78 × 10-3). All these estimates were adjusted for body mass index (BMI), type 2 diabetes, smoking initiation, and frequency of alcohol intake. CONCLUSIONS: The Mendelian randomization analyses show that higher educational levels is associated with higher eBMD, reduced risk of osteoporosis and fractures, while material deprivation is positively related to spine fracture. Enhanced FN-BMD correlates with increased household income. These findings offer valuable insights into the formulation of health guidelines and policy development.

We conducted stratified analyses to explore the causal links between socio-economic status and osteoporosis and various fractures and observed that education significantly reduced risk of osteoporosis and lower eBMD. It also lowered the risks of fractures of spine, femur, lower leg-ankle, foot, and wrist-hand, while material deprivation exhibited positive associations with spine fracture risk. Bidirectional MR analysis showed that an elevated score of FN-BMD was associated with a higher income level. Our study shows the importance of conducting routine BMD estimations and osteoporosis screening, to enhance knowledge and awareness among individuals to promote bone health and prevent fractures.

Comparison of a novel hand-held retractor-assisted transforaminal lumbar interbody fusion by the wiltse approach and posterior TLIF: a one-year prospective controlled study.

BACKGROUND: This study aims to compare the clinical outcomes and safety of a novel hand-held retractor system-assisted Wiltse TLIF with that P-TLIF and assess whether this hand-held retractor system assisted Wiltse TLIF can yield less paraspinal muscle injury. METHODS: 56 patients (P-TLIF: 26, Wiltse TLIF: 30) were included in this one year prospective controlled study. The operation time, intraoperative blood loss, postoperative drainage, mobilization time, and discharge time were recorded. The clinical outcomes were evaluated by ODI, VAS, JOA, and SF-36 scores (7 days, 3, 6, and 12 months after surgery). Paraspinal muscle injury was assessed by postoperative MRI (6 months after surgery). CK and C-reaction protein were measured pre and postoperatively, and CT or X-ray (one year postoperatively) was used to assess bony union/non-union. RESULTS: The Wiltse (study) group was associated with significantly less estimated blood loss (79.67 ± 28.59 ml vs 192.31 ± 59.48 ml, P = 0.000*), postoperative drainage (43.33 ± 27.89 ml vs 285.57 ± 123.05 ml, P = 0.000*), and shorter mobilization (4.1 ± 1.2 d vs. 3.0 ± 0.9 d, P < 0.05) and discharge times (7.7 ± 1.9 d vs. 6.1 ± 1.2 d, P = 0.002*) than the P-TLIF (control) group. Serum CK activity at 24 h postoperatively in the study group was significantly lower than in the control group (384.10 ± 141.99 U/L vs 532.76 ± 225.76 U/L, P = 0.018*). At 7 days after surgery, VAS (2.3 ± 0.6 vs 3.2 ± 0.7, P = 0.000*)and ODI scores (43.9 ± 11.9 vs 55.2 ± 12.9, P = 0.001*) were lower, while the JOA scores (18.4 ± 3.4 vs 16.3 ± 4.2, P = 0.041*) was higher in the control group than in the study group. Results observed at 3 months of follow-up were consistent with those at 7 days. After six months postoperatively, paraspinal muscle degeneration in the control group was more significant than in the study group (P = 0.008*). CONCLUSION: Our study showed that this novel hand-held retractor system assisted Wiltse approach TLIF can significantly reduce paraspinal muscle injury, postoperative drainage, and intraoperative blood loss, mobilization and discharge time, as well as yield better short-term outcomes compared to P-TLIF. TRIAL REGISTRATION: 25/09/2023 NCT06052579.

Vascular wall microenvironment: exosomes secreted by adventitial fibroblasts induced vascular calcification.

Vascular calcification often occurs in patients with chronic renal failure (CRF), which significantly increases the incidence of cardiovascular events in CRF patients. Our previous studies identified the crosstalk between the endothelial cells (ECs) and vascular smooth muscle cells (VSMCs), and the paracrine effect of VSMCs, which regulate the calcification of VSMCs. Herein, we aim to investigate the effects of exosomes secreted by high phosphorus (HPi) -induced adventitial fibroblasts (AFs) on the calcification of VSMCs and the underlying mechanism, which will further elucidate the important role of AFs in high phosphorus vascular wall microenvironment. The conditioned medium of HPi-induced AFs promotes the calcification of VSMCs, which is partially abrogated by GW4869, a blocker of exosomes biogenesis or release. Exosomes secreted by high phosphorus-induced AFs (AFsHPi-Exos) show similar effects on VSMCs. miR-21-5p is enriched in AFsHPi-Exos, and miR-21-5p enhances osteoblast-like differentiation of VSMCs by downregulating cysteine-rich motor neuron 1 (Crim1) expression. AFsHPi-Exos and exosomes secreted by AFs with overexpression of miR-21-5p (AFsmiR21M-Exos) significantly accelerate vascular calcification in CRF mice. In general, AFsHPi-Exos promote the calcification of VSMCs and vascular calcification by delivering miR-21-5p to VSMCs and subsequently inhibiting the expression of Crim1. Combined with our previous studies, the present experiment supports the theory of vascular wall microenvironment.

Identifying Liver Metastasis-Related Genes Through a Coexpression Network to Construct a 5-Gene Model for Predicting Pancreatic Ductal Adenocarcinoma Patient Prognosis.

OBJECTIVES: This study aimed to develop a liver metastasis-related gene prognostic index (LMPI) for pancreatic ductal adenocarcinoma prognosis and therapy. METHODS: The Cancer Genome Atlas data set was used to identify liver metastasis-related hub genes via weighted gene coexpression network analysis. The core genes were identified to construct an LMPI by using the Cox regression method. An immune cell abundance identifier was applied to determine the immune cell abundance. RESULTS: A total of 78 hub liver metastasis-related genes in the black module were significantly enriched in complement and coagulation cascades, fat digestion and absorption, and the PPAR signaling pathway. Then, an LMPI was constructed on the basis of the 5 prognostic genes (MOGAT3, ASGR1, TRPM8, SGSM1, and LOC101927851). Patients with higher LMPI scores had poor overall survival, more co-occurring or mutually exclusive pairs of driver gene mutations, and less benefit from immunotherapy than patients with lower LMPI scores. In addition, a high correlation was also found between LMPI scores and immune infiltration, such as CD4 naive, CD8 T, cytotoxic T, T helper 2, follicular helper T, and natural killer cells. CONCLUSIONS: The core genes of the LMPI developed may be independent factors for predicting prognosis, immune characteristics, and immunotherapy efficacy in pancreatic ductal adenocarcinoma.

Global publication trends and research trends of necroptosis application in tumor: A bibliometric analysis.

Introduction: Necroptosis is an alternative, caspase-independent programmed cell death that appears when apoptosis is inhibited. A gowing number of studies have reflected the link between necroptosis and tumors. However, only some systematical bibliometric analyses were focused on this field. In this study, we aimed to identify and visualize the cooperation between countries, institutions, authors, and journals through a bibliometric analysis to help understand the hotspot trends and emerging topics regarding necroptosis and cancer research. Methods: The articles and reviews on necroptosis and cancer were obtained from the Web of Science Core Collection on 16 September 2022. Countries, institutions, authors, references, and keywords in this field were visually analyzed by CtieSpace 5.8.R3, VOSviewer 1.6.18, and R package "bibliometrix." Results: From 2006 to 2022, 2,216 qualified original articles and reviews on necroptosis in tumors were published in 685 academic journals by 13,009 authors in 789 institutions from 75 countries/regions. Publications focusing on necroptosis and cancer have increased violently in the past 16 years, while the citation number peaked around 2008-2011. Most publications were from China, while the United States maintained the dominant position as a "knowledge bridge" in necroptosis and cancer research; meanwhile, Ghent University and the Chinese Academy of Sciences were the most productive institutions. Moreover, only a tiny portion of the articles were multiple-country publications. Peter Vandenabeele had the most significant publications, while Alexei Degterev was most often co-cited. Peter Vandenabeele also gets the highest h-index and g-index in this research field. Cell Death and Disease was the journal with the most publications on necroptosis and cancer, which was confirmed to be the top core source by Bradford's Law. At the same time, Cell was the leading co-cited journal, and the focus area of these papers was molecular, biology, and immunology. High-frequency keywords mainly contained those that are molecularly related (MLKL, NF-kB, TNF, RIPK3, RIPK1), pathological process related (necroptosis, apoptosis, cell-death, necrosis, autophagy), and mechanism related (activation, expression, mechanisms, and inhibition). Conclusion: This study comprehensively overviews necroptosis and cancer research using bibliometric and visual methods. Research related to necroptosis and cancer is flourishing. Cooperation and communication between countries and institutions must be further strengthened. The information in our paper would provide valuable references for scholars focusing on necroptosis and cancer.

Identifying key genes of classic papillary thyroid cancer in women aged more than 55 years old using bioinformatics analysis.

Background: The incidence rate of thyroid carcinoma (THCA) markedly increased in the recent few decades and has been likely over-diagnosed, especially papillary thyroid cancer (PTC) in women. However, the incidence of advanced-stage papillary thyroid cancer is also rising. According to earlier studies, tumors with identical pathology might have different clinical outcomes, which implies some variances in papillary thyroid cancer. Although the mortality of thyroid cancer has remained stable or declined, there is still an important problem in estimating whether it is benign or needs surgery for patients with papillary thyroid cancer. Methods: After obtaining data from The Cancer Genome Atlas (TCGA) Project-THCA database by R package TCGA bio links, 18 samples (11 at stage IV as high-risk group and 7 at stage I as low-risk group) were obtained using survival package and edgeR to ensure differential expression; ClusterProfiler package was used to carry on gene set enrichment analysis and searched the possible pathways in the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. STRING and Cytoscape were used to construct and modify the protein-protein interaction (PPI) network to get hub genes of differentially expressed genes. Next, the pROC package was used to get the receiver operating characteristic (ROC) curves of hub genes' disease-free survival (DFS). Then, transcription factors (TFs) and miRNAs of key genes were predicted by ENCORI and AnimalTFDB. In the end, TF-target genes-miRNA regulatory network was also constructed by Cytoscape. Results: Our research obtained the top 9 candidate genes from the whole network (IFNA1, MRC1, LGALS3, LOX, POSTN, TIMP1, CD276, SDC4, and TLR2). According to the ROC results, TIMP1, LOX, CD276, IFNA1, TLR2, and POSTN were considered to play a more critical role in malignant papillary thyroid cancer or immature cancer of papillary thyroid cancer. Our analysis concludes that TIMP1, LOX, CD276, IFNA1, TLR2, and POSTN are identified as thyroid cancer biomarkers, which lead to the different clinical courses of a woman older than 55 years old with papillary thyroid cancer. Especially CD276, POSTN, and IFNA1 may be considered as new biomarkers associated with the prognosis of thyroid cancer. Conclusions: TIMP1, LOX, CD276, IFNA1, TLR2, and POSTN have different expressions in PTCs, which lead to the various clinical courses of a woman older than 55 years old with papillary thyroid cancer. Especially CD276, POSTN, and IFNA1 may be considered as new potential biomarkers associated with the prognosis of thyroid cancer. In addition, TF-miRNA-target gene regulatory network may help further reach for PTC.

The Multi-Therapeutic Role of MSCs in Diabetic Nephropathy.

Diabetic nephropathy (DN) is one of the most common diabetes mellitus (DM) microvascular complications, which always ends with end-stage renal disease (ESRD). Up to now, as the treatment of DN in clinic is still complicated, ESRD has become the main cause of death in diabetic patients. Mesenchymal stem cells (MSCs), with multi-differentiation potential and paracrine function, have attracted considerable attention in cell therapy recently. Increasing studies concerning the mechanisms and therapeutic effect of MSCs in DN emerged. This review summarizes several mechanisms of MSCs, especially MSCs derived exosomes in DN therapy, including hyperglycemia regulation, anti-inflammatory, anti-fibrosis, pro-angiogenesis, and renal function protection. We also emphasize the limitation of MSCs application in the clinic and the enhanced therapeutic role of pre-treated MSCs in the DN therapy. This review provides balanced and impartial views for MSC therapy as a promising strategy in diabetic kidney disease amelioration.

Clinical cure and liver fibrosis reversal after postoperative antiviral combination therapy in hepatitis B-associated non-cirrhotic hepatocellular carcinoma: A case report.

BACKGROUND: The incidence of hepatocellular carcinoma (HCC) is high in China, and approximately 15%-20% of HCC cases occur in the absence of cirrhosis. Compared with patients with cirrhotic HCC, those with non-cirrhotic HCC have longer postoperative tumor-free survival. However, the overall survival time is not significantly increased, and the risk of postoperative recurrence remains. Strategies to improve the postoperative survival rate in these patients are currently required. CASE SUMMARY: A 47-year-old man with a family history of HCC was found to have hepatitis B virus (HBV) infection 25 years ago. In 2000, he was administered lamivudine for 2 years, and entecavir (ETV 0.5 mg) was administered in 2006. In October 2016, magnetic resonance imaging revealed a tumor in the liver (5.3 cm × 5 cm × 5 cm); no intraoperative hepatic and portal vein and bile duct tumor thrombi were found; and postoperative pathological examination confirmed a grade II HCC with no nodular cirrhosis (G1S3). ETV was continued, and no significant changes were observed on imaging. After receiving pegylated interferon alfa-2b (PEG IFNα-2b) (180 µg) + ETV in February 2019, the HBsAg titer decreased significantly within 12 wk. After receiving hepatitis B vaccine (60 µg) in 12 wk, HBsAg serological conversion was realized at 48 wk. During the treatment, no obvious adverse reactions were observed, except for early alanine aminotransferase flares. The reexamination results of liver pathology were G2S1, and reversal of liver fibrosis was achieved. CONCLUSION: The therapeutic regimen of ETV+ PEG IFNα-2b + hepatitis B vaccine for patients with HBV-associated non-cirrhotic HCC following hepatectomy can achieve an HBV clinical cure and prolong the recurrence-free survival.

The Role of Mesenchymal Stromal Cells-Derived Small Extracellular Vesicles in Diabetes and Its Chronic Complications.

Mesenchymal stromal cells (MSCs) are applied in regenerative medicine of several tissues and organs nowadays by virtue of their self-renewal capabilities, multiple differentiation capacity, potent immunomodulatory properties, and their ability to be favourably cultured and manipulated. With the continuous development of "cell-free therapy" research, MSC-derived small extracellular vesicles (MSC-sEVs) have increasingly become a research hotspot in the treatment of various diseases. Small extracellular vesicles (SEVs) are membrane vesicles with diameters of 30 to 150 nm that mediate signal transduction between adjacent or distal cells or organs by delivering non-coding RNA, protein, and DNA. The contents and effects of sEVs vary depending on the properties of the originating cell. In recent years, MSC-sEVs have been found to play an important role in the occurrence and development of diabetes mellitus as a new way of communication between cells. Diabetes mellitus is a common metabolic disease in clinic. Its complications of the heart, brain, kidney, eyes, and peripheral nerves are a serious threat to human health and has been a hot issue for clinicians. MSC-sEVs could be applied to repair or prevent damage from the complications of diabetes mellitus through anti-inflammatory effects, reduction of endoplasmic reticulum-related protein stress, polarization of M2 macrophages, and increasing autophagy. Therefore, we highly recommend that MSC-sEVs-based therapies to treat diabetes mellitus and its chronic complication be further explored. The analysis of the role and molecular mechanisms of MSC-sEVs in diabetes and its related complications will provide new idea and insights for the prevention and treatment of diabetes.

The Suppression of miR-199a-3p by Promoter Methylation Contributes to Papillary Thyroid Carcinoma Aggressiveness by Targeting RAP2a and DNMT3a.

BACKGROUND: It was previously demonstrated that miR-199a-3p plays an important role in tumor progression; especially, its down-regulation in papillary thyroid cancer (PTC) is associated with cancer cell invasion and proliferation. In the present report, we investigated the mechanism involved in the down-regulation of miR-199a-3p in PTC and how miR-199a-3p regulates PTC invasion both in vivo and in vitro. METHODS: qRT-PCR and Western blot assays were used to determine the expression of the investigated genes. Bisulfite sequencing PCR was used to investigate miR-199a-3p methylation. The functions of miR-199a-3p were investigated by a series of in vitro and in vivo experiments. RESULTS: Our results showed hypermethylation of the miR-199a-3p promoter, which resulted in decreased miR-199a-3p expression both in PTC cell lines and PTC tissues. DNA-methyltransferase 3a (DNMT3a), a target gene of miR-199a-3p, was increased both in PTC cell lines and PTC tissues, while 5-aza-2'-deoxycytidine (methyltransferase-specific inhibitor) or knock-down using DNMT3a Small-Interfering RNA could restore the expression of miR-199a-3p, and the over-expression of miR-199a-3p could decrease the expression of DNMT3a; this suggests that miR-199a-3p/DNMT3a constructs a regulatory circuit in regulating miR-199a-3p/DNMT3a expression. Moreover, gain- and loss-of-function studies revealed that miR-199a-3p is involved in cancer cell migration, invasion, and growth. Meanwhile, we found that RAP2a was also a direct target of miR-199a-3p, which might mediate the tumor-growth-inhibiting effect of miR-199a-3p. To further confirm the tumor-suppressive properties of miR-199a-3p, stable overexpression of miR-199a-3p in a PTC cell line (BCPAP cells) was xenografted to athymic BALB/c nude mice, resulting in delayed tumor growth in vivo. In clinical PTC samples, the expression of RAP2a and DNMT3a was increased significantly, and the expression of RAP2a was inversely correlated with that of miR-199a-3p. CONCLUSION: Our studies demonstrate that an epigenetic change in the promoter region of miR-199a contributes to the aggressive behavior of PTC via the miR-199a-3p/DNMT3a regulatory circuit and directly targets RAP2a.

New Insights Into Implications of CTRP3 in Obesity, Metabolic Dysfunction, and Cardiovascular Diseases: Potential of Therapeutic Interventions.

Adipose tissue, as the largest endocrine organ, secretes many biologically active molecules circulating in the bloodstream, collectively termed adipocytokines, which not only regulate the metabolism but also play a role in pathophysiological processes. C1q tumor necrosis factor (TNF)-related protein 3 (CTRP3) is a member of C1q tumor necrosis factor-related proteins (CTRPs), which is a paralog of adiponectin. CTRP3 has a wide range of effects on glucose/lipid metabolism, inflammation, and contributes to cardiovascular protection. In this review, we comprehensively discussed the latest research on CTRP3 in obesity, diabetes, metabolic syndrome, and cardiovascular diseases.

Exosomes as Mediators of Cell-to-Cell Communication in Thyroid Disease.

Exosomes are a type of extracellular vehicle, formed by budding cell membranes, containing proteins, DNA, and RNA. Concentrated cargoes from parent cells are enveloped in exosomes, which are cell specific and may have functions in the recipient cell, reflecting a novel physiological and pathological mechanism in disease development. As a transmitter, exosomes shuttle to different cells or tissues and mediate communications among these organelles. To date, several studies have demonstrated that exosomes play crucial roles in disease pathogenesis and development, such as breast and prostate cancer. However, studies investigating connections between exosomes and thyroid disease are limited. In this review, recent research advances on exosomes in thyroid cancer and Graves' disease are reviewed. These studies suggest that exosomes are involved in thyroid disease and appear as impressive potentials in thyroid therapeutic areas.

Brenneria populi subsp. brevivirga subsp. nov. isolated from symptomatic bark of Populus × euramericana canker, and description of Brenneria populi subsp. populi subsp. nov.

Two Gram-stain-negative, facultatively anaerobic, motile bacterial strains isolated from symptomatic bark of Populus × euramericana canker in China were investigated using a polyphasic approach, including 16S rRNA gene sequencing, multilocus sequence analysis, and biochemical and physiological assays. 16S rRNA gene sequencing indicated that these strains belonged to the genus Brenneria, family Pectobacteriaceae, and had the highest sequence similarity with Brenneria populi CFCC 11963T (98 %). DNA-DNA hybridization experiments revealed DNA-DNA relatedness values of 72.1-78.2 % between the new isolates and strains of B. populi, revealing that these strains belonged to the same species. The 16S rRNA gene sequencing and multilocus sequence analysis suggested that the two novel strains and those of B. populi are phylogenetically closely related but form two clearly separated subgroups. Based on the data, the two novel isolates represent a subspecies of B. populi for which the name B. populi subsp. brevivirga subsp. nov. is proposed with D8-10-4-5T (=CFCC 11935T=KCTC 42841T) as the type strain, with the automatic creation of B. populi subsp. populi subsp. nov. (type strain D9-5T=CFCC 11963T=KCTC 42088T).