VDR promotes pancreatic cancer progression in vivo by activating CCL20-mediated M2 polarization of tumor associated macrophage.

BACKGROUND: Activation of VDR pathway was a promising anti-tumor therapy strategy. However, numerous clinical studies have demonstrated the effect of activating VDR is limited, which indicates that VDR plays a complex role in vivos. METHODS: We analyzed the TCGA database to examine the association between VDR expression and immune cell infiltration in pancreatic adenocarcinoma (PAAD). Western blot, ELISA, ChIP, and dual-luciferase reporter assays were performed to determine the mechanism of VDR regulating CCL20. Migration assay and immunofluorescence were used to investigate the role of CCL20 in M2 macrophage polarization and recruitment. We employed multiplexed immunohistochemical staining and mouse models to validate the correlation of VDR on macrophages infiltration in PAAD. Flow cytometry analysis of M2/M1 ratio in subcutaneous graft tumors. RESULTS: VDR is extensively expressed in PAAD, and patients with elevated VDR levels exhibited a significantly reduced overall survival. VDR expression in PAAD tissues was associated with increased M2 macrophages infiltration. PAAD cells overexpressing VDR promote macrophages polarization towards M2 phenotype and recruitment in vitro and vivo. Mechanistically, VDR binds to the CCL20 promoter and up-regulates its transcription. The effects of polarization and recruitment on macrophages can be rescued by blocking CCL20. Finally, the relationship between VDR and M2 macrophages infiltration was evaluated using clinical cohort and subcutaneous graft tumors. A positive correlation was demonstrated between VDR/CCL20/CD163 in PAAD tissues and mouse models. CONCLUSION: High expression of VDR in PAAD promotes M2 macrophage polarization and recruitment through the secretion of CCL20, which activates tumor progression. This finding suggests that the combination of anti-macrophage therapy may improve the efficacy of VDR activation therapy in PAAD.

The efficacy of extracorporeal shock wave therapy for knee osteoarthritis : an umbrella review.

BACKGROUND: An umbrella review was conducted to compare the effectiveness of extracorporeal shock wave therapy (ESWT) versus non-ESWT in the treatment of knee osteoarthritis (KOA). MATERIALS AND METHODS: Three databases including PubMed, Embase and Web of science were searched up to September 2023. Literature screening, quality evaluation, and data extraction were performed according to inclusion and exclusion criteria. Meta-analysis of outcome indicators was performed using Revman 5.4 software. RESULTS: A total of eight meta-analysis were included in this umbrella review. All meta-analysis were graded against a Measurement Tool to Assess Systematic Reviews 2 (AMSTAR 2) and scored between 8 and 11. Compared to the sham group, the ESWT group showed better results in WOMAC (Western Ontario and McMaster Universities Arthritis Index) [mean difference (MD)=-2.94, 95% CI: -5.52, -0.37, P=0.03, I²=60%], Visual Analog Scale (VAS) (MD=-2.0, 95% CI: -2.5, -1.5, P<0.01, I²=0%), range of motion (ROM) (MD=17.55, 95% CI: 13.49, 21.61, P<0.00001, I²=0%), and Lequesne index (MD=-2.85, 95% CI: -3.64, -2.07, P<0.00001, I²=48%). CONCLUSION: Based on the results of our analysis, ESWT is now an effective therapy for improving pain and function in patients with KOA.

Trends and hotspots of publications on ferroptosis: A 10 Year overview.

Background: Ferroptosis was proposed to be a type of programmed cell death in 2012. Ferroptosis plays a significant role in a variety of illnesses. Objective: To better understand the direction of future research, we performed a bibliometric analysis to identify research hotspots with a focus on ferroptosis. Methods: The search terms [TI = "ferroptosis" OR ("GSH" AND "GPX4") OR "lipid peroxidation" OR "iron homeostasis" OR "iron metabolism"] AND [PY = "2012-2022"] AND [DT = "Article OR Review"] AND [LA = "English"] were used to retrieve publications related to ferroptosis for a bibliometric analysis. We utilized Microsoft Excel to calculate the frequency and proportion of the published articles, VOSviewer to perform a co-occurrence analysis and for visualizing the data, CiteSpace to obtain a timeline of keywords and institutions, and RStudio to calculate citation metrics. As indicated by the analysis, indicators such as the number of publications, the most productive authors and coauthorship status, the distribution of publications by country, favoured journals, the most influential institutions and the most frequently cited documents are reported in this article. Results: A total of 8009 publications were retrieved from the WOS core collection, and 197 papers published in 2023 were removed from this analysis. The remaining 7812 papers, which included 118 in the WOS collection, were incorporated into the bibliometric study. Conclusion: The number of annual scientific publications on ferroptosis have been increasing each year. The academic communities represented by Tang, Daolin, Stockwell, Brent R., Wang, Fudi, and Conrad, Marcus were the most authoritative. China, USA, and Germany were the front-runners in the field of ferroptosis. Free Radical Biology and Medicine was the largest contributor of ferroptosis-related research, and Cell and Nature were the most influential journals to publish articles on ferroptosis. Columbia Univ and Univ Pittsburgh were the institutions that received the most attention. Recent research on ferroptosis has been focused on molecular mechanisms, particularly those in the contexts of various diseases, which will be a hotspot of future research. In addition, interdisciplinary ferroptosis and big-data research is expected to be a new frontier.

Design and development of high precision four roll CNC roll bending machine and automatic control model.

In recent years, advancements in industries such as aerospace, military weaponry, automobiles, locomotives, and shipbuilding have led to a surge in the demand for bent and rolled components, along with increasingly stringent requirements for rolling precision. However, the traditional hydraulic cylinder feeding solution has hindered further enhancements in the accuracy of rolled profile contours. Additionally, owing to variations in profile specifications, material properties, and an assortment of random factors during the forming process, the applicability of existing forming formulas remains limited, rendering them suitable only for profile processing under specific circumstances. To address these challenges, servo electric cylinders have been introduced as a replacement for traditional hydraulic cylinders, and the mechanical structure of a four-roll bending machine has been re-engineered. This innovation has demonstrated the feasibility of employing servo electric cylinders in four-roll CNC bending machines for profile bending, resulting in higher control precision and faster response times, ultimately providing a comprehensive design solution for four-roll CNC bending machines. In response to the limited universality of existing forming formulas, the actual R (profile forming curvature) and d (servo electric cylinder feed) values from the four-roll CNC bending machine have been utilized, and curve fitting methods have been implemented as the foundation for the automatic control model. This approach offers a high degree of universality, making it suitable for a wide range of applications. Moreover, as the number of trials increased, forming precision progressively improved.

The p65-LOC727924-miR-26a/KPNA3-p65 regulatory loop mediates vasoactive intestinal peptide effects on osteoarthritis chondrocytes.

Loss and dysfunction of articular chondrocytes, which disrupt the homeostasis of extracellular matrix formation and breakdown, promote the onset of osteoarthritis (OA). Targeting inflammatory pathways is an important therapeutic strategy for OA. Vasoactive intestinal peptide (VIP) is an immunosuppressive neuropeptide with potent anti-inflammatory effects; however, its role and mechanism in OA remain unclear. In this study, microarray expression profiling from the Gene Expression Omnibus database and integrative bioinformatics analyses were performed to identify differentially expressed lncRNAs in OA samples. qRT-PCR validation of the top ten different expressed lncRNAs indicated that the expression level of intergenic non-protein coding RNA 2203 (LINC02203, also named LOC727924) was the highest in OA cartilage compared to normal cartilage. Hence, the LOC727924 function was further investigated. LOC727924 was upregulated in OA chondrocytes, with a dominant sub-localization in the cytoplasm. In OA chondrocytes, LOC727924 knockdown boosted cell viability, suppressed cell apoptosis, reactive oxygen species (ROS) accumulation, increased aggrecan and collagen II, decreased matrix metallopeptidase (MMP)-3/13 and ADAM metallopeptidase with thrombospondin type 1 motif (ADAMTS)-4/5 levels, and reduced the levels of tumor necrosis factor alpha (TNF-α), interleukin 1 beta (IL-1ß), and interleukin 6 (IL-6). LOC727924 could interact with the microRNA 26a (miR-26a)/ karyopherin subunit alpha 3 (KPNA3) axis by competitively targeting miR-26a for KPNA3 binding, therefore down-regulating miR-26a and upregulating KPNA3; in OA chondrocytes, miR-26a inhibition partially abolished LOC727924 knockdown effects on chondrocytes. miR-26a inhibited the nuclear translocation of p65 through targeting KPNA3 and p65 transcriptionally activated LOC727924, forming a p65-LOC727924-miR-26a/KPNA3-p65 regulatory loop to modulate OA chondrocyte phenotypes. In vitro, VIP improved OA chondrocyte proliferation and functions, down-regulated LOC727924, KPNA3, and p65 expression, and upregulated miR-26a expression; in vivo, VIP ameliorated destabilization of the medial meniscus (DMM)-induced damages on the mouse knee joint, down-regulated KPNA3, inhibited the nuclear translocation of p65. In conclusion, the p65-LOC727924-miR-26a/KPNA3-p65 regulatory loop modulates OA chondrocyte apoptosis, ROS accumulation, extracellular matrix (ECM) deposition, and inflammatory response in vitro and OA development in vivo, being one of the mechanisms mediating VIP ameliorating OA.

Effects of magnetic resonance imaging (MRI)-detected extramural vascular invasion (mrEMVI) and tumor deposits (TDs) on distant metastasis and long-term survival after surgery for stage III rectal cancer: a retrospective study grouped based on the relationship between the bottom of the tumor and peritoneal reflection.

Background: To evaluate the effect of magnetic resonance imaging (MRI)-detected extramural vascular invasion (mrEMVI) and tumor deposits (TDs) on distant metastasis and long-term survival after surgery for stage III rectal cancer based on the relationship between the bottom of the tumor and peritoneal reflection. Methods: A retrospective study was performed on 694 patients who underwent radical resection for rectal cancer at the Harbin Medical University Tumor Hospital from October 2016 to October 2021. According to the surgical records, a new group was established based on the relationship between the lower end of the tumor and peritoneal reflection. On the peritoneal reflection group: the tumors are all located on the peritoneal reflection. Across the peritoneal reflection group: the tumors recurred across the peritoneal reflection. Under the peritoneal reflection group: the tumors are all located under the peritoneal reflection. We evaluated the effects of mrEMVI and TDs on postoperative distant metastasis and long-term survival of stage III rectal cancer by combining mrEMVI with TDs. Results: In the whole study population, neoadjuvant therapy (P=0.003) was negatively correlated with distant metastasis after rectal cancer surgery. Also, mesorectal fascia (MRF) (P=0.024), postoperative distant metastasis (P<0.001), and TDs (P<0.001) were independent risk factors for long-term survival after rectal cancer surgery. Lymph node metastasis (P<0.001) and neoadjuvant therapy (P=0.023) were independent risk factors for the presence or absence of TDs of rectal cancer. In the non-neoassisted subgroup, postoperative distant metastasis (P<0.001) was considered to be an independent risk factor for long-term survival after rectal cancer surgery. Conclusions: In the under the peritoneal reflection group, the combination of mrEMVI and TDs seems to play a certain guiding role in predicting distant metastasis and long-term survival after rectal cancer surgery.

The effect of hamstring donor-site block for functional outcomes and rehabilitation after anterior cruciate ligament reconstruction.

Purpose: To determine the effect of local infiltration anesthesia (LIA) at the donor site combined with a femoral nerve block (FNB) on short-term postoperative pain, functional outcomes, and rehabilitation after arthroscopic hamstring tendon autograft anterior cruciate ligament reconstruction (ACLR). Methods: This study was a single center, randomized controlled trial. Seventy-three subjects with ACL rupture were enrolled. Participants were randomly allocated to two groups, 47 in the experimental group (Group A) and 26 in the control group (Group B). All operations were performed under FNB. In Group A, 10 ml of 1% ropivacaine was injected precisely at the hamstring donor site. Patients in Group B were treated with the same amount of saline. Preoperatively and postoperatively, pain scores based on the numerical rating scale (NRS) and consumption of opioids were recorded. In addition, knee functions were assessed by the International Knee Documentation Committee Subjective Knee Form (IKDC), the Lysholm score, and the Knee injury and Osteoarthritis Outcome Score (KOOS) preoperatively and postoperatively at 1 and 3 months. In addition, we applied the KNEELAX3 arthrometer to evaluate the stability of the knee preoperatively and postoperatively so that subjective and objective knee conditions were obtained to help us assess knee recovery in a comprehensive manner. Results: The hamstring donor-site block reduced pain within the first 12 postoperative hours. There were no significant differences between two groups in pain intensity preoperatively and equal to or greater than 24 hours postoperatively. Furthermore, there were no differences between the groups concerning knee functions preoperatively or in the short-term follow-up at 1 and 3 months. Conclusion: LIA at the donor site can effectively improve the early postoperative pain of patients after ACLR and reduce the use of opioids without affecting the functional outcomes of the surgery.

Prediction scores of postoperative liver metastasis and long-term survival of pancreatic head cancer based on the distance between the mesenteric vessels and tumor, preoperative serum carbohydrate antigen 19-9 level, and lymph node metastasis rate.

BACKGROUND: The shortest distance between the superior mesenteric artery (SMA) or superior mesenteric vein (SMV) and the tumor margin was combined with preoperative serum carbohydrate antigen (CA) 19-9 and lymph node ratio (LNR) to evaluate joint effects on long-term survival and liver metastasis in patients with pancreatic head cancer after radical surgery. METHODS: This retrospective study included 149 patients who underwent pancreaticoduodenectomy for pancreatic head cancer at Harbin Medical University Tumor Hospital from May 2011 to March 2021. The preoperative serum CA 19-9 level and LNR were combined with the SMA or SMV distance. The joint association between long-term survival and postoperative liver metastasis was evaluated. RESULTS: Based on the receiver operating characteristic curve of postoperative liver metastasis or long-term survival, the optimal cut-off values of SMV distance were 3.1 and 0.7 mm, respectively, whereas the optimal cut-off value of SMA distance was 10.25 mm. The univariate model identified the liver metastasis score (p < 0.001) as a negative factor for postoperative liver metastasis of pancreatic head carcinoma. The SMV distance (p = 0.003), SMA distance (p < 0.001), LNR score (p < 0.001), and survival score (p < 0.001) were negatively correlated with long-term survival after pancreatic head cancer. The multivariate model highlighted SMA distance (p < 0.001), survival score (p = 0.001), and LNR score (p < 0.001) as independent risk factors for long-term survival in pancreatic head cancer. CONCLUSION: Liver metastasis score may be an independent predictor of postoperative liver metastasis in patients with pancreatic head cancer. Survival and LNR scores may be independent predictors of long-term postoperative survival in patients with pancreatic head cancer. However, the LNR score appears to improve long-term survival.

A Retrospective Study of the Perioperative Period Management of Joint Arthroplasty in Patients with Chronic Kidney Disease.

OBJECTIVE: With the rising prevalence of chronic kidney disease (CKD) and the increasing demand for joint arthroplasty, the management of CKD patients in the perioperative period of joint arthroplasty has become an issue worthy of attention for orthopedic surgeons. This study aimed to explore comprehensive perioperative period management strategies for CKD patients. METHODS: From March 2017 to August 2022, 62 patients who underwent joint arthroplasty in our hospital were included in a retrospective study, including 31 CKD patients (mean age 69.8 ± 13.4 years old) and 31 non-CKD patients (mean age 69.4 ± 14.2 years old). The outcome indicators were analyzed, including serum urea, serum creatinine, blood uric acid, hematocrit, and hemoglobin. RESULTS: All patients included in the retrospective study had an average preoperative preparation time of 4.3 ± 2.6 days and an average hospitalization time of 11.0 ± 7.3 days. There were no significant differences in the changes in the serum urea values between the preoperative and postoperative measurements in the CKD patients or in the serum creatinine values and blood uric acid values (P > 0.05). The hemoglobin value in postoperative measurements was lower than in preoperative measurements in the CKD patients (P < 0.05). The hematocrit value in postoperative measurements was lower than in preoperative measurements in the CKD patients (P < 0.001). CONCLUSION: Patients with CKD have distinct characteristics compared to non-CKD patients, and they generally have a higher risk for postoperative complications and adverse events. Recognition of risk factors, suitable timing of surgery, the undertaking of protective strategies, and proper management of complications are vital for managing CKD patients in the perioperative period of joint arthroplasty.

Perlecan: Roles in osteoarthritis and potential treating target.

Osteoarthritis (OA) is the most common joint disease, affecting hundreds of millions of people globally, which leads to a high cost of treatment and further medical care and an apparent decrease in patient prognosis. The recent view of OA pathogenesis is that increased vascularity, bone remodeling, and disordered turnover are influenced by multivariate risk factors, such as age, obesity, and overloading. The view also reveals the gap between the development of these processes and early stage risk factors. This review presents the latest research on OA-related signaling pathways and analyzes the potential roles of perlecan, a typical component of the well-known protective structure against osteoarthritic pericellular matrix (PCM). Based on the experimental results observed in end-stage OA models, we summarized and analyzed the role of perlecan in the development of OA. In normal cartilage, it plays a protective role by maintaining the integrin of PCM and sequesters growth factors. Second, perlecan in cartilage is required to not only activate vascular epithelium growth factor receptor (VEGFR) signaling of endothelial cells for vascular invasion and catabolic autophagy, but also for different signaling pathways for the catabolic and anabolic actions of chondrocytes. Finally, perlecan may participate in pain sensitization pathways.

Investigation of transverse crack spacing in an asphalt pavement with a semi-rigid base.

Transverse cracking is a serious problem for semi-rigid base asphalt pavement. The shrinkage of the base course and the surface course, as well as reflective cracks, are key factors for transverse cracking in asphalt pavement. Crack spacing can directly reflect the degree of transverse cracking in pavements. Therefore, this study aims to calculate the transverse crack spacing and discuss its affecting factors. To this end, a calculation model of transverse crack spacing for the semi-rigid base asphalt pavement was first established. Then, the transverse crack spacings of different composite structures were calculated, and the influences of the shrinkage coefficient, the structural layer thickness, and the pavement tensile strength on transverse crack spacing were expounded. Finally, the transverse crack spacing of the pavement after the appearance of the reflective was calculated. The results show that the lower lime and fly ash content and skeleton gap gradation can be adopted during the design of the base course. Meanwhile, the lower lime and fly ash content in the macadam base, the skeleton gap gradation and asphalt concrete with a larger particle size in the surface layer can be used during the design of surface layer. In addition, the transverse crack spacing of the semi-rigid base asphalt pavement could be increased by reducing the shrinkage coefficient, increasing the thicknesses of the surface course and the base course, and improving the tensile strength of the pavement. After the appearance of reflective cracks, the transverse crack spacing of the surface layer ranged between 32.8 m and 66.5 m. 15fp-AC25, 15fp-AC20, 15df-AC25, and 17fp-AC25 were found to be the best semi-rigid base asphalt pavement structures to reduce transverse cracking. Finally, transverse cracking in pavement composite structures under different bonding conditions needs to be analyzed in the follow-up work.

Identification of Significant Genes and Pathways for the Chronic and Subacute Cutaneous Lupus Erythematosus via Bioinformatics Analysis.

Background: Chronic cutaneous lupus erythematosus (CCLE) and subacute cutaneous lupus erythematosus (SCLE) are both common variants of cutaneous lupus erythematosus (CLE) that mainly involve the skin and mucous membrane. Oral mucosal involvement is frequently observed in patients of CLE. Despite that they have different clinicopathological features, whether there is a significant difference in pathogenesis between them remains unclear. Herein, we investigated specific genes and pathways of SCLE and CCLE via bioinformatics analysis. Methods: Microarray expression datasets of GSE109248 and GSE112943 were both retrieved from the GEO database. Differentially expressed genes (DEGs) between CCLE or SCLE skin tissues and health controls were selected by GEO2R. Common DEGs were picked out via the Venn diagram software. Then, functional enrichment and PPI network analysis were conducted, and the top 10 key genes were identified via Cytohubba. Results: Totally, 176 DEGs of SCLE and 287 DEGs of CCLE were identified. The GO enrichment and KEGG analysis of DEGs of SCLE is significantly enriched in the response to virus, defense response to virus, response to IFN-gamma, cellular response to IFN-γ, type I IFN signaling pathway, chemokine activity, chemokine receptor binding, NOD-like receptor signaling pathway, etc. The GO enrichment and KEGG analysis of DEGs of CCLE is significantly enriched in the response to virus, regulation of multiorganism process, negative regulation of viral process, regulation of lymphocyte activation, chemokine receptor binding, CCR chemokine receptor binding, NOD-like receptor signaling pathway, etc. The top 10 hub genes of SCLE and CCLE, respectively, include STAT1, CXCL10, IRF7, ISG15, and RSAD2 and CXCL10, IRF7, IFIT3, CTLA4, and ISG15. Conclusion: Our finding suggests that SCLE and CCLE have the similar potential key genes and pathways and majority of them belong to IFN signatures and IFN signaling pathway. Besides, the NOD-like receptor signaling pathway might also have an essential role in the pathogenesis of SCLE and CCLE. Together, the identified genes and signaling pathways have enhanced our understanding of the mechanism underlying the occurrence and development of both SCLE and CCLE.

Arthroscopic therapy of rotator cuff diseases: A bibliometric study of the past 2 decades (2002-2021).

Purpose: Rotator cuff diseases, as a common cause of shoulder pain and disability, have seriously affected the patients' daily life. Rotator cuff repair techniques have been a hot topic in the arthroscopic therapy field. Our study was to use bibliometrics analysis to clarify the current status and research trends in the field of arthroscopic therapy of rotator cuff diseases. Methods: The publications relating to arthroscopic therapy of rotator cuff diseases published from 2001 to 2021 were obtained from the Web of Science Core Collection (WoSCC) database. The R software and VOSviewer software were used for the cross-sectional bibliometric and scientometric analysis. Results: A total of 4,567 publications about arthroscopic therapy of rotator cuff diseases published between 2002 and 2021 retrieved from the WoSCC database were analyzed in our study. The results showed that the United States made the largest contribution to this field. The most relevant institutions were Seoul National University, Rush University, and Hospital for Special Surgery. Stephen S Burkhart was the most relevant researcher in this field with the largest number of publications, as well as the highest H-index and G-index. The journal ARTHROSCOPY contributed the largest number of publications in the past 2 decades. Considering the H-index and G-index, ARTHROSCOPY was also the journal with the largest impact in this field. Conclusions: Arthroscopic Therapy of Rotator Cuff Diseases Related research presented a rising trend in the past 2 decades. The United States can be regarded as the leader because of its huge contributions to this field. The journal ARTHROSCOPY published the largest number of publications in this field. It can be predicted that research about advanced arthroscopic techniques and postoperative pain management of patients with rotator cuff diseases will be the next research hotspots in the following years.

Inhibition of PGE2 in Subchondral Bone Attenuates Osteoarthritis.

Aberrant subchondral bone architecture is a crucial driver of the pathological progression of osteoarthritis, coupled with increased sensory innervation. The sensory PGE2/EP4 pathway is involved in the regulation of bone mass accrual by the induction of differentiation of mesenchymal stromal cells. This study aimed to clarify whether the sensory PGE2/EP4 pathway induces aberrant structural alteration of subchondral bone in osteoarthritis. Destabilization of the medial meniscus (DMM) using a mouse model was combined with three approaches: the treatment of celecoxib, capsaicin, and sensory nerve-specific prostaglandin E2 receptor 4 (EP4)-knockout mice. Cartilage degeneration, subchondral bone architecture, PGE2 levels, distribution of sensory nerves, the number of osteoprogenitors, and pain-related behavior in DMM mice were assessed. Serum and tissue PGE2 levels and subchondral bone architecture in a human sample were measured. Increased PGE2 is closely related to subchondral bone's abnormal microstructure in humans and mice. Elevated PGE2 concentration in subchondral bone that is mainly derived from osteoblasts occurs in early-stage osteoarthritis, preceding articular cartilage degeneration in mice. The decreased PGE2 levels by the celecoxib or sensory denervation by capsaicin attenuate the aberrant alteration of subchondral bone architecture, joint degeneration, and pain. Selective EP4 receptor knockout of the sensory nerve attenuates the aberrant formation of subchondral bone and facilitates the prevention of cartilage degeneration in DMM mice. Excessive PGE2 in subchondral bone caused a pathological alteration to subchondral bone in osteoarthritis and maintaining the physiological level of PGE2 could potentially be used as an osteoarthritis treatment.

OPN inhibits autophagy through CD44, integrin and the MAPK pathway in osteoarthritic chondrocytes.

Background: To investigate whether osteopontin (OPN) affects autophagy in human osteoarthritic chondrocytes and determine the roles of CD44, αvß3 integrin and the Mitogen-activated protein kinase (MAPK) pathway in this progress. Methods: First, we compared the autophagy levels in the human osteoarthritis (OA) and normal cartilage, then, we cultured human OA chondrocytes in vitro and treated cells with recombinant human OPN (rhOPN) to determine autophagy changes. Next, the anti-CD44 and anti-CD51/61 monoclonal antibodies (Abs) or isotype IgG were used to determine the possible role of CD44 and αvß3 integrin; subsequently, an inhibitor of the ERK MAPK pathway was used to investigate the role of ERK MAPK. Western blotting was used to measure the Beclin1, LC3 II and MAPK proteins expressions, mRFP-GFP-LC3 confocal imaging and transmission electron microscopy were also used to detect the autophagy levels. Cell Counting Kit-8 (CCK-8) was used to assay the proliferation and activity of chondrocytes. Results: The LC3 protein was greatly decreased in OA cartilage compared to normal cartilage, and OPN suppressed the autophagy activity in chondrocytes in vitro. Blocking experiments with anti-CD44 and anti-CD51/61 Abs indicated that OPN could suppress the expression of LC3II and Beclin1 through αvß3 integrin and CD44. Our results also indicated that the ratio of p-ERK/ERK but not p-P38/P38 and p-JNK/JNK was increased after the rhOPN treatment. The ERK inhibitor inhibited the activity of OPN in the suppression of autophagy, and the CCK-8 results showed that rhOPN could promote chondrocyte proliferation. Conclusion: OPN inhibited chondrocyte autophagy through CD44 and αvß3 integrin receptors and via the ERK MAPK signaling pathway.

The miR-548d-5p/SP1 signaling axis regulates chondrocyte proliferation and inflammatory responses in osteoarthritis.

Chondrocyte apoptosis and dysfunction play an important role in osteoarthritis (OA), a chronic progressive arthropathy. Non-coding RNAs have been implicated in OA pathogenesis. In this study, microRNA (miR)-548d-5p was found to be downregulated in OA samples and IL-1ß-stimulated chondrocytes. miR-548d-5p overexpression partially reversed IL-1ß-induced chondrocyte damage in vitro, evidenced by the promotion of cell growth, the inhibition of apoptosis and inflammatory cytokine release, and the improvement in extracellular matrix (ECM) deposition. Furthermore, miR-548d-5p overexpression partially reversed papain-induced damages on OA rat's knee articular cartilage. Specificity protein 1 (SP1) was inhibited by miR-548d-5p and identified as its direct downstream target. In IL-1ß-stimulated chondrocytes, SP1 overexpression significantly attenuated the protective effects of miR-548d-5p overexpression against chondrocyte damage. In conclusion, miR-548d-5p was abnormally downregulated in OA samples and IL-1ß-stimulated chondrocytes. miR-548d-5p protects against IL-1ß-induced chondrocyte damage via direct inhibition of SP1.

Resistance training and Urtica dioica increase neurotrophin levels and improve cognitive function by increasing age in the hippocampus of rats.

INTRODUCTION: Inflammation and oxidative stress are two major factors in accelerating brain aging. Consumption of some traditional herbs with antioxidant and anti-inflammatory properties such as Urtica dioica extract (Ud) and resistance training (RT) may be effective in controlling premature aging and memory impairment. Therefore, we hypothesized that the combined effect of RT and Ud might play an essential role in preventing memory disorders and hippocampal tissue changes caused by increasing age in rats. METHODS: 28 male Wistar rats (24-week) were divided into 4-groups (n = 7): control (C), Ud, RT, and Ud+RT. RT groups were trained for five weeks, and Ud extract in the 0.0166 w/v concentration (50 mg/kg, oral/daily) was administered. We also examined the effects of RT and Ud on the behavioral (memory and learning), histological (the morphological changes in the dentate gyrus), and transcript aspects of hippocampal tissue. RESULTS: Aging led to karyopyknosis in the hippocampal tissue, which was alleviated by RT and Ud supplementation. RT and Ud were accompanied by increased GPx, GSH, GAP-43, and decreased CAP-1 levels in the hippocampus. Moreover, RT and Ud led to increased NGF, BDNF, and GAP-43 levels, decreased MDA, and protection of hippocampal tissue from karyopyknosis, which was associated with cognitive improvement. However, these interventions had no significant effect on the hippocampal levels of IL-1ß, SOD, and CAT. CONCLUSIONS: These findings suggest that increasing age decreases hippocampal NGF, BDNF, and GAP-43 levels and impairs cognition, which may be reversed by regular RT and Ud extract.

Immune system and sarcopenia: Presented relationship and future perspective.

Sarcopenia, a geriatric syndrome that is characterized by a progressive and generalized skeletal muscle disorder, can be associated with many comorbidities, including obesity, diabetes, and fracture. Currently, the importance and urgency of sarcopenia have gained more consensus. Discovering the mechanisms of sarcopenia has been more and more important. It has been previously suggested that immune system during ageing plays an important role in the progression of sarcopenia. Immune ageing, which is often highlighted in elder individuals, may be an important contributor in sarcopenia. Immune ageing can occur in different aspects. The alteration in immune organs can affect both the innate immunity and adaptive immunity, affecting the whole condition of the body through circulation. Several kinds of immune cells, including lymphocytes, macrophages, neutrophils and other immune cells, together alters the situation of muscle fiber, causing muscle weakness, loss of muscle strength and muscle mass. Synergistic and cumulative effect of cytokines, such as TNF-α and IFN-γ, interrelates with obesity and diabetes, impairing the condition of skeletal muscle tissue and leading to deterioration of sarcopenia. Studying the relationship of sarcopenia and immune system offers great potential in future studies. Thoroughly studying these mechanisms can help to better determine an ideal scheme and better management of sarcopenia and its associated comorbidities, which tends to offer deeper insight and guidance in treating sarcopenia through alterations of food intake, exercise and medical intervention.

Pyroptosis and Sarcopenia: Frontier Perspective of Disease Mechanism.

With global ageing, sarcopenia, as an age-related disease, has brought a heavy burden to individuals and society. Increasing attention has been given to further exploring the morbidity mechanism and intervention measures for sarcopenia. Pyroptosis, also known as cellular inflammatory necrosis, is a kind of regulated cell death that plays a role in the ageing progress at the cellular level. It is closely related to age-related diseases such as cardiovascular diseases, Alzheimer's disease, osteoarthritis, and sarcopenia. In the process of ageing, aggravated oxidative stress and poor skeletal muscle perfusion in ageing muscle tissues can activate the nod-like receptor (NLRP) family to trigger pyroptosis. Chronic inflammation is a representative characteristic of ageing. The levels of inflammatory factors such as TNF-α may activate the signaling pathways of pyroptosis by the NF-κB-GSDMD axis, which remains to be further studied. Autophagy is a protective mechanism in maintaining the integrity of intracellular organelles and the survival of cells in adverse conditions. The autophagy of skeletal muscle cells can inhibit the activation of the pyroptosis pathway to some extent. A profound understanding of the mechanism of pyroptosis in sarcopenia may help to identify new therapeutic targets in the future. This review article focuses on the role of pyroptosis in the development and progression of sarcopenia.

HOXB9 blocks cell cycle progression to inhibit pancreatic cancer cell proliferation through the DNMT1/RBL2/c-Myc axis.

Homeobox B9 (HOXB9) is involved in the occurrence and development of malignant tumors. However, the functions and underlying molecular mechanisms of HOXB9 in pancreatic cancer have yet to be identified. In this study, we find that both HOXB9 mRNA and protein levels are down-regulated in pancreatic cancer tissues and cell lines. Kaplan-Meier survival plots of 150 pancreatic cancer cases show that higher expression of HOXB9 in pancreatic cancer patients is associated with higher survival rates. We also find that over-expression of HOXB9 inhibits pancreatic cancer cell proliferation both in cell lines and the nude mouse xenograft as well as PDX models. Applying cell cycle PCR array analysis, Flow CytoMetry, ChIP-qPCR, and luciferase experiments, we observe that HOXB9 blocks cell cycle progression in the G0/G1 phase via up-regulating RBL2 and inhibiting c-Myc, and we further find that DNMT1 inhibits the expression of HOXB9 in pancreatic cancer by promoting the methylation of its promoter. Our findings highlight a novel mechanism of the DNMT1/HOXB9/RBL2/c-Myc pathway in regulating the cell cycle and proliferation of pancreatic cancer cells and provide a research basis for the prognosis and therapeutic application of HOXB9 in pancreatic cancer.