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.

Macrophage Polarization Modulated by NF-κB in Polylactide Membranes-Treated Peritendinous Adhesion.

Foreign body reactions (FBR) to implants seriously impair tissue-implant integration and postoperative adhesion. The macrophage, owing to its phenotypic plasticity, is a major regulator in the formation of the inflammatory microenvironment; NF-κB signaling also plays a vital role in the process. It is hypothesized that NF-κB phosphorylation exerts a proinflammatory regulator in FBR to polylactide membranes (PLA-M) and adhesion. First, in vitro and in vivo experiments show that PLA-M induces NF-κB phosphorylation in macrophages, leading to M1 polarization and release of inflammatory factors. The inflammatory microenvironment formed due to PLA-M accelerates myofibroblast differentiation and release of collagen III and MMP2, jointly resulting in peritendinous adhesion. Therefore, JSH-23 (a selective NF-κB inhibitor)-loaded PLA membrane (JSH-23/PLA-M) is fabricated by blend electrospinning to regulate the associated M1 polarization for peritendinous anti-adhesion. JSH-23/PLA-M specifically inhibits NF-κB phosphorylation in macrophages and exhibits anti-inflammatory and anti-adhesion properties. The findings demonstrate that NF-κB phosphorylation has a critical role in PLA-induced M1 polarization and aggravating FBR to PLA-M. Additionally, JSH-23/PLA-M precisely targets modulation of NF-κB phosphorylation in FBR to break the vicious cycle in peritendinous adhesion therapy.

Metal-organic framework based in-syringe solid-phase extraction for the on-site sampling of polycyclic aromatic hydrocarbons from environmental water samples.

In-syringe solid-phase extraction is a promising sample pretreatment method for the on-site sampling of water samples because of its outstanding advantages of portability, simple operation, short extraction time, and low cost. In this work, a novel in-syringe solid-phase extraction device using metal-organic frameworks as the adsorbent was fabricated for the on-site sampling of polycyclic aromatic hydrocarbons from environmental waters. Trace polycyclic aromatic hydrocarbons were effectively extracted through the self-made device followed by gas chromatography with mass spectrometry analysis. Owing to the excellent adsorption performance of metal-organic frameworks, the analytes could be completely adsorbed during one adsorption cycle, thus effectively shortening the extraction time. Moreover, the adsorbed analytes could remain stable on the device for at least 7 days, revealing the potential of the self-made device for on-site sampling of degradable compounds in remote regions. The limit of detection ranged from 0.20 to 1.9 ng/L under the optimum conditions. Satisfactory recoveries varying from 84.4 to 104.5% and relative standard deviations below 9.7% were obtained in real samples analysis. The results of this study promote the application of metal-organic frameworks in sample preparation and demonstrate the great potential of in-syringe solid-phase extraction for the on-site sampling of trace contaminants in environmental waters.

A Micro-Scale Investigation on the Behaviors of Asphalt Mixtures under Freeze-Thaw Cycles Using Entropy Theory and a Computerized Tomography Scanning Technique.

The thermodynamic behavior of asphalt mixtures is critical to the engineers since it directly relates to the damage in asphalt mixtures. However, most of the current research of the freeze-thaw damage of asphalt mixtures is focused on the bulk body from the macroscale and lacks a fundamental understanding of the thermodynamic behaviors of asphalt mixtures from the microscale perspective. In this paper, to identify the important thermodynamic behaviors of asphalt mixtures under freeze-thaw loading cycle, the information entropy theory, an X-ray computerized tomography (CT) scanner and digital image processing technology are employed. The voids, the average size of the voids, the connected porosity, and the void number are extracted according to the scanned images. Based on the experiments and the CT scanned images, the information entropy evolution of the asphalt mixtures under different freeze-thaw cycles is calculated and the relationship between the change of information entropy and the pore structure characteristics is established. Then, the influences of different freezing and thawing conditions on the thermodynamic behaviors of asphalt mixtures are compared. The combination of information entropy theory and CT scanning technique proposed in this paper provides an innovative approach to investigate the thermodynamics behaviors of asphalt mixtures and a new way to analyze the freeze-thaw damage in asphalt mixtures.

Characteristics of micro-nano bubbles and potential application in groundwater bioremediation.

Content of oxygen in water is a critical factor in increasing bioremediation efficiency for contaminated groundwater. Micro-nano bubbles (MNBs) injection seems to be an effective technique for increasing oxygen in water compared with traditional air sparging technology with macrobubbles. Micro-nano bubbles have larger interfacial area, higher inner pressure and density, and lower rising velocity in water, superior to that of macrobubbles. In this paper, MNBs with diameters ranging from 500 nm to 100 microm are investigated, with a specific focus on the oxygen mass transfer coefficient from inner bubbles to surrounding water. The influence of surfactant on the bubbles formation and dissolution is studied as well. The stability of MNBs is further investigated by means of zeta potential measurements and rising velocity analysis. The results show that MNBs can greatly increase oxygen content in water. Higher surfactant concentration in water will decrease the bubbles size, reduce the dissolution rate, and increase the zeta potential. Moreover, MNBs with greater zeta potential value tend to be more stable. Besides, the low rising velocity of MNBs contributes to the long stagnation in water. It is suggested that micro-nano bubble aeration, a potential in groundwater remediation technology, can largely enhance the bioremediation effect.

Pharmacological effects of bioactive agents in earthworm extract: A comprehensive review.

This review compiles information from the literature on the chemical composition, pharmacological effects, and molecular mechanisms of earthworm extract (EE) and suggests possibilities for clinical translation of EE. We also consider future trends and concerns in this domain. We summarize the bioactive components of EE, including G-90, lysenin, lumbrokinase, antimicrobial peptides, earthworm serine protease (ESP), and polyphenols, and detail the antitumor, antithrombotic, antiviral, antibacterial, anti-inflammatory, analgesic, antioxidant, wound-healing, antifibrotic, and hypoglycemic activities and mechanisms of action of EE based on existing in vitro and in vivo studies. We further propose the potential of EE for clinical translation in anticancer and lipid-modifying therapies, and its promise as source of a novel agent for wound healing and resistance to antibiotic tolerance. The earthworm enzyme lumbrokinase embodies highly effective anticoagulant and thrombolytic properties and has the advantage of not causing bleeding phenomena due to hyperfibrinolysis. Its antifibrotic properties can reduce the excessive accumulation of extracellular matrix. The glycolipoprotein extract G-90 can effectively scavenge reactive oxygen groups and protect cellular tissues from oxidative damage. Earthworms have evolved a well-developed defense mechanism to fight against microbial infections, and the bioactive agents in EE have shown good antibacterial, fungal, and viral properties in in vitro and in vivo experiments and can alleviate inflammatory responses caused by infections, effectively reducing pain. Recent studies have also highlighted the role of EE in lowering blood glucose. EE shows high medicinal value and is expected to be a source of many bioactive compounds.

Role of signaling pathways in age-related orthopedic diseases: focus on the fibroblast growth factor family.

Fibroblast growth factor (FGF) signaling encompasses a multitude of functions, including regulation of cell proliferation, differentiation, morphogenesis, and patterning. FGFs and their receptors (FGFR) are crucial for adult tissue repair processes. Aberrant FGF signal transduction is associated with various pathological conditions such as cartilage damage, bone loss, muscle reduction, and other core pathological changes observed in orthopedic degenerative diseases like osteoarthritis (OA), intervertebral disc degeneration (IVDD), osteoporosis (OP), and sarcopenia. In OA and IVDD pathologies specifically, FGF1, FGF2, FGF8, FGF9, FGF18, FGF21, and FGF23 regulate the synthesis, catabolism, and ossification of cartilage tissue. Additionally, the dysregulation of FGFR expression (FGFR1 and FGFR3) promotes the pathological process of cartilage degradation. In OP and sarcopenia, endocrine-derived FGFs (FGF19, FGF21, and FGF23) modulate bone mineral synthesis and decomposition as well as muscle tissues. FGF2 and other FGFs also exert regulatory roles. A growing body of research has focused on understanding the implications of FGF signaling in orthopedic degeneration. Moreover, an increasing number of potential targets within the FGF signaling have been identified, such as FGF9, FGF18, and FGF23. However, it should be noted that most of these discoveries are still in the experimental stage, and further studies are needed before clinical application can be considered. Presently, this review aims to document the association between the FGF signaling pathway and the development and progression of orthopedic diseases. Besides, current therapeutic strategies targeting the FGF signaling pathway to prevent and treat orthopedic degeneration will be evaluated.

SIRT1 signaling pathways in sarcopenia: Novel mechanisms and potential therapeutic targets.

Sarcopenia is an aging-related skeletal disease characterized by decreased muscle mass, strength, and physical function, severely affecting the quality of life (QoL) of the elderly population. Sirtuin 1 (SIRT1), as a nicotinamide adenine dinucleotide (NAD+)-dependent histone deacetylases, has been reported to participate in various aging-related signaling pathways and exert protective effect on many human diseases. SIRT1 functioned as an important role in the occurrence and progression of sarcopenia through regulating key pathways related to protein homeostasis, apoptosis, mitochondrial dysfunction, insulin resistance and autophagy in skeletal muscle, including SIRT1/Forkhead Box O (FoxO), AMP-activated protein kinase (AMPK)/SIRT1/nuclear factor κB (NF-κB), SIRT1/p53, AMPK/SIRT1/peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α), and SIRT1/live kinase B1 (LKB1)/AMPK pathways. However, the specific mechanisms of these processes have not been fully illuminated. Currently, several SIRT1-mediated interventions on sarcopenia have been preliminarily developed, such as SIRT1 activator polyphenolic compounds, exercising and calorie restriction. In this review, we summarized the predominant mechanisms of SIRT1 involved in sarcopenia and therapeutic modalities targeting the SIRT1 signaling pathways for the prevention and prognosis of sarcopenia.

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.

Smoking and osteoimmunology: Understanding the interplay between bone metabolism and immune homeostasis.

Smoking continues to pose a global threat to morbidity and mortality in populations. The detrimental impact of smoking on health and disease includes bone destruction and immune disruption in various diseases. Osteoimmunology, which explores the communication between bone metabolism and immune homeostasis, aims to reveal the interaction between the osteoimmune systems in disease development. Smoking impairs the differentiation of mesenchymal stem cells and osteoblasts in bone formation while promoting osteoclast differentiation in bone resorption. Furthermore, smoking stimulates the Th17 response to increase inflammatory and osteoclastogenic cytokines that promote the receptor activator of NF-κB ligand (RANKL) signaling in osteoclasts, thus exacerbating bone destruction in periodontitis and rheumatoid arthritis. The pro-inflammatory role of smoking is also evident in delayed bone fracture healing and osteoarthritis development. The osteoimmunological therapies are promising in treating periodontitis and rheumatoid arthritis, but further research is still required to block the smoking-induced aggravation in these diseases. Translational potential: This review summarizes the adverse effect of smoking on mesenchymal stem cells, osteoblasts, and osteoclasts and elucidates the smoking-induced exacerbation of periodontitis, rheumatoid arthritis, bone fracture healing, and osteoarthritis from an osteoimmune perspective. We also propose the therapeutic potential of osteoimmunological therapies for bone destruction aggravated by smoking.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.