Mapping the causal associations of cytokines with sarcopenia and aging traits: Evidence from bidirectional Mendelian randomization.

BACKGROUND: Cytokines and growth factors may serve as a bridge in studying the causal relationships between inflammaging and sarcopenia due to their roles in inflammaging. In this study, we aim to explore the causal association of cytokines with sarcopenia and aging traits and further identify the significant inflammation factors. METHODS: Bidirectional Mendelian randomization (MR) analysis was used to identify the causality. Forty-one kinds of circulation cytokines and growth factors were set as exposures, and the data were from a summary genome-wide association study (GWAS) containing three cohorts with 8293 healthy participants of European ancestry from 1983 to 2011. Hand grip strength, adjusted appendicular lean mass (AALM), usual walking pace, moderate-to-vigorous physical activity (MVPA) levels, able to walk or cycle unaided for 10 min (AWCU10) and telomere length were selected as outcomes. Data for outcomes were obtained from meta-GWAS and the UK Biobank, and sample sizes ranged from 69 537 to 472 174. Low hand grip strength was defined by the European Working Group on Sarcopenia in Older People (EWGSOP) and Foundation for the National Institutes of Health (FNIH) cut-off points, respectively. Other outcome traits were defined and measured according to the UK Biobank and raw cohorts' criteria. We set two significance thresholds for single nucleotide polymorphisms (SNPs) associated with exposures to obtain adequate SNPs (5 × 10-6 and 5 × 10-8). Inverse-variance weighted, MR-Egger and weighted median were employed to estimate the causality. RESULTS: Twenty-seven factors were identified to relate to sarcopenia and aging traits causally, and most were associated with only one outcome trait. IL16 (interleukin-16), CTACK (cutaneous T-cell attracting chemokine), MIP1b (macrophage inflammatory protein 1b) and PDGFbb (platelet-derived growth factor BB) were proven to relate causally to at least one sarcopenia and aging trait in both analyses with two significance thresholds. IL16 was causally associated with hand grip strength (0.977 [0.956-0.998] for EWGSOP and 0.933 [0.874-0.996] for FNIH), AALM (0.991 [0.984, 0.998]), MVPA (0.997 [0.995-1.000]) and AWCU10 (1.008 [1.003-1.013]). CTACK was proven to relate causally to hand grip strength (1.013 [1.007-1.019] for EWGSOP and 1.090 [1.041-1.142] for FNIH), AWCU10 (0.990 [0.986-0.994]) and telomere length (0.998 [0.983-0.994]). The results indicated that MIP1b has a causal effect on hand grip strength (1.032 [1.001-1.063] for EWGSOP), AWCU10 (0.994 [0.988-1.000] and 0.993 [0.988-0.998]) and telomere length (1.006 [1.000-1.012]). PDGFbb may causally relate to AALM (1.016 [1.001-1.030]) and telomere length (1.011 [1.007-1.015]). Reserve MR analyses also proved their unidirectional causal effects. CONCLUSIONS: Twenty-seven factors were causally related to sarcopenia and aging traits, and the causal effects of IL16, CTACK, MIP1b and PDGFbb were proven in both analyses with two significance thresholds.

Effect of inflammatory response on joint function after hip fracture in elderly patients: A clinical study.

BACKGROUND: Excellent hip joint function facilitates limb recovery and improves the quality of survival. This study aimed to investigate the potential risk factors affecting postoperative joint functional activity and outcomes in elderly hip fractures patients and to provide evidence for patient rehabilitation and clinical management. AIM: To explore the relationship between inflammatory factors and hip function and the interaction between inflammation and health after hip fracture in elderly patients. METHODS: The elderly patients who had hip fracture surgery at our hospital between January 1, 2021, and December 31, 2022 were chosen for this retrospective clinical investigation. Patients with excellent and fair postoperative hip function had their clinical information and characteristics gathered and compared. Age, gender, fracture site, surgical technique, laboratory indices, and other variables that could have an impact on postoperative joint function were all included in a univariate study. To further identify independent risk factors affecting postoperative joint function in hip fractures, risk factors that showed statistical significance in the univariate analysis were then included in a multiple logistic regression analysis. In addition to this, we also compared other outcome variables such as visual analogue scale and length of hospital stay between the two groups. RESULTS: A total of 119 elderly patients with hip fractures were included in this study, of whom 37 were male and 82 were female. The results of univariate logistic regression analysis after excluding the interaction of various factors showed that there was a statistically significant difference in interleukin (IL)-6, IL-8, IL-10, C-reactive protein (CRP), and complement C1q (C1q) between the fair and excellent joint function groups (P < 0.05). The results of multiple logistic regression analysis showed that IL-6 > 20 pg/mL [(Odds ratio (OR) 3.070, 95%CI: 1.243-7.579], IL-8 > 21.4 pg/ mL (OR 3.827, 95%CI: 1.498-9.773), CRP > 10 mg/L (OR 2.142, 95%CI: 1.020-4.498) and C1q > 233 mg/L (OR 2.339, 95%CI: 1.094-5.004) were independent risk factors for poor joint function after hip fracture surgery (all P < 0.05). CONCLUSION: After hip fractures in older patients, inflammatory variables are risk factors for fair joint function; therefore, early intervention to address these markers is essential to enhance joint function and avoid consequences.

Biomaterials for bone defect repair: Types, mechanisms and effects.

Bone defects or bone discontinuities caused by trauma, infection, tumours and other diseases have led to an increasing demand for bone grafts and biomaterials. Autologous bone grafts, bone grafts with vascular tips, anastomosed vascular bone grafts and autologous bone marrow components are all commonly used in clinical practice, while oversized bone defects require the use of bone tissue engineering-related biomaterials to repair bone defects and promote bone regeneration. Currently, inorganic components such as polysaccharides and bioceramics, as well as a variety of bioactive proteins, metal ions and stem cells can be loaded into hydrogels or 3D printed scaffold materials to achieve better therapeutic results. In this review, we provide an overview of the types of materials, applications, potential mechanisms and current developments in the repair of bone defects.

Causal Roles of Lifestyle, Psychosocial Characteristics, and Sleep Status in Sarcopenia: A Mendelian Randomization Study.

BACKGROUND: Many studies reported that lifestyle, psychosocial characteristics, and sleep status related to sarcopenia, although few studies provided evidence of causal relationships between them. METHODS: The data used in our study were from UK Biobank, FinnGen Release 8, and large genome-wide association study meta-analyses. Two-sample Mendelian randomization was conducted to identify the causal associations of 21 traits of lifestyle, psychosocial characteristics, and sleep status with 6 traits of sarcopenia. Benjamini-Hochberg correction was performed to reduce the bias caused by multiple tests. Risk factor analyses were performed to explore the potential mechanism behind the exposures. RESULTS: Mendelian randomization analyses after adjustment proved the causal roles of coffee intake, education years, smoking, leisure screen time, and moderate-to-vigorous intensity physical activity during leisure time in sarcopenia was proven although providing no significant evidence for causal roles for carbohydrates intake, protein intake, alcohol, and sleep status in sarcopenia. CONCLUSIONS: Our results strongly support that coffee intake, education years, smoking, leisure screen time, and moderate-to-vigorous intensity physical activity during leisure time played significantly causal roles in sarcopenia, which may provide new intervention strategies for preventing the development of sarcopenia.

The prognostic value of retinol binding protein in geriatric hip fractures after surgeries: A propensity score matching and 1-year follow-up study.

BACKGROUND: We aimed to explore the predictive value of retinol binding protein (RBP) for outcomes of hip fractures. METHODS: Patients with hip fractures who underwent hip surgeries between December 2017 and February 2021 and met the inclusion criteria were analyzed. Propensity score matching was used to reduce the bias of co-factors and ROC curves based on matched populations were created to determine the optimal cutoff point of RBP. The outcomes between patients with low levels of RBP and high levels of RBP were compared. RESULTS: Four hundred eighty patients were enrolled in this study and 69 patients died within one year. After a 1:1 PSM, patients with more than 1-year survival had significantly higher RBP (p = 0.013) than those who died within one year, as well as patients divided by 6-months survival (p = 0.012). Logistics analysis showed that low RBP may be an independent risk factor for 3-month survival, 6-month survival, 1-year survival, and 3-month free walking ability. CONCLUSION: RBP may be associated with the survival and 3-month walking abilities of patients with hip fractures.

Prealbumin as a nutrition status indicator may be associated with outcomes of geriatric hip fractures: a propensity score matching and 1-year follow-up study.

AIM: Nutrition status may affect bone metabolism and regeneration in the elderly. However, few studies reported a sensitive nutrition indicator or evaluation tool for geriatric hip fractures. This study aimed to explore if prealbumin (PAB), a critical nutrition-related protein, is related to the prognosis of hip fractures. METHODS: Patients with hip fractures who met the inclusion criteria were included in our study. Geriatric nutritional risk index (GNRI) and prognostic nutritional index (PNI) were calculated. Propensity score matching (PSM) was used to reduce the influence of confounding factors and ROC curves were conducted to explore the optimal cutoff points of PAB and to compare the prognostic value between GNRI, PNI, and PAB. Then Cox and Logistics analyses were performed to identify the relation between PAB and outcomes of hip fractures. RESULTS: Out of the 546 patients enrolled in this study, 91 patients died within one year. After a 1:1 PSM, the patients with less than 1-year survival had significantly lower PAB (p < 0.001) than those who were still alive at one year. ROC curves showed that the PAB may sensitively predict 6-month survival (AUROC: 0.695), 1-year survival (AUROC: 0.696), and 1-year-free walking ability (AUROC: 0.642). Logistics analysis showed that low PAB may be an independent risk factor for survival and 1-year-free walking ability. CONCLUSION: Low levels of PAB may be associated with poor survival and walking abilities of older patients after surgery for hip fracture.

Dual-modality imaging of atherosclerotic plaques using ultrasmall superparamagnetic iron oxide labeled with rhodamine.

Aim: The diagnosis of vulnerable atherosclerotic plaques remains challenging. This study labeled ultrasmall superparamagnetic iron oxide with rhodamine (USPIO-R) and evaluated USPIO-R for imaging atherosclerotic plaques. Methods: Apolipoprotein E-deficient mice were fed a high-fat diet and underwent MRI before and after an intravenous injection of USPIO-R. Subsequently, an aortic specimen from the mice was removed and sliced for fluorescence imaging and Prussian blue and immunofluorescent staining. Results: T2 signal loss appeared and persisted in the aortic plaque postinjection, and spontaneous fluorescence from the plaque was observed. The accumulated mechanism of USPIO-R by plaque was the macrophage internalization by Prussian blue and immunofluorescence. Conclusion: USPIO-R is a promising dual-modality probe for diagnosing and monitoring vulnerable atherosclerotic plaques.

Baicalin inhibits C2C12 myoblast apoptosis and prevents against skeletal muscle injury.

Anti­apoptotic and anti­inflammatory treatments are imperative for skeletal muscle regeneration following injury. Baicalin is well known and has previously been investigated for its role in the treatment of injury and inflammatory diseases. Therefore, the present study aimed to investigate the effects of baicalin in inhibiting apoptosis of C2C12 myoblasts and preventing skeletal muscle injury. A cell counting kit­8 (CCK­8) assay and Annexin V/PI staining were initially performed to measure cell viability and apoptosis under conditions of H2O2 exposure with or without baicalin. Subsequently, oxidative activity, mitochondrial function, mitochondrial apoptogenic factors and caspase proteins were analyzed to examine the mechanism underlying the effect of baicalin on inhibiting apoptosis in C2C12 myoblasts. Furthermore, BALB/C mice with skeletal muscle injuries were established, and the potential application of baicalin for anti­apoptotic and anti­inflammatory effects was examined via small animal ß­2­[18F]­fluoro­2­deoxy­D­glucose (18F­FDG) positron emission tomography (PET) imaging and pathological examination. The CCK­8 assay and Annexin V/PI staining revealed cell death in the C2C12 myoblasts induced by H2O2, which was apoptotic, and this was effectively reversed by treatment with baicalin. H2O2 increased the reactive oxygen species and malondialdehyde levels in C2C12 myoblasts, which was caused by mitochondrial dysfunction, decreased expression of cytochrome c and apoptosis­inducing factor from cytosolic and mitochondrial fractions, and activated expression of caspase­3 and caspase­9; however, treatment with baicalin reversed these effects. In addition, small animal PET imaging revealed that treatment with baicalin decreased the accumulation of FDG by ~65.9% in the injured skeletal muscle induced by H2O2. These pathological results also confirmed the protective effect of baicalin on injured skeletal muscle. Taken together, the results of the present study indicated that baicalin effectively inhibited the apoptosis of C2C12 myoblasts and protected skeletal muscle from injury, which may have potential therapeutic benefits for patients in a clinical setting.

Baicalin prevents the apoptosis of endplate chondrocytes by inhibiting the oxidative stress induced by H2O2.

Osteoarthritis (OA) is a degenerative disease of articular cartilage. The pathogenesis of OA remains to be fully elucidated, and several studies have found that oxidative stress is important in its pathogenesis. Baicalin is well known and has already been investigated for its role of inhibiting the oxidative stress pathway. Thus, the present study aimed to investigate the role of baicalin on the inhibition of oxidative stress in endplate chondrocytes induced by hydrogen peroxide (H2O2). Following treatment of endplate chondrocytes with different doses of H2O2 with or without baicalin for different incubation durations, a CCK­8 assay and Annexin V/PI staining were used to measure the cell proliferation and apoptotic rates to identify the optimal experimental conditions. Subsequently, for examining the effects and underlying mechanism of baicalin on oxidative stress, the protein expression levels of cleaved­poly (ADP­ribose) polymerase (PARP), B­cell lymphoma­2­associated X protein (Bax) and pro­caspase­3 were analyzed using western blot analysis, intracellular anti­oxidant activities, including those of malondialdehyde (MDA), superoxide dismutase (SOD) and nitric oxide (NO), were quantified, and the levels of endothelial nitric oxide synthase (eNOS) were examined using reverse transcription­polymerase chain reaction analysis. The results revealed that the oxidative stress of endplate chondrocytes induced by 0.5 mM H2O2 for 4 h were the most appropriate conditions for experiments, and pretreatment with 100 µmol/l baicalin for 1 h effectively reversed the effect of H2O2 on the endplate chondrocytes. In addition, Annexin V/PI staining demonstrated that the cell death induced by H2O2 was apoptotic, and baicalin reversed the apoptosis induced by oxidative stress. H2O2 activated PARP cleavage, and the expression of Bax and pro­caspase­3; however, baicalin inhibited the expression of these apoptotic signaling indicators. Baicalin also reduced the levels of MDA, and increased the levels of SOD and NO. Baicalin also significantly elevated the mRNA levels of eNOS in endplate chondrocytes. Therefore, the results of the present study showed that baicalin significantly inhibited the oxidative stress in endplate chondrocytes induced by H2O2, and decreased cell apoptosis.

Inhibition of ERK1/2 Signaling Pathway is Involved in Melatonin's Antiproliferative Effect on Human MG-63 Osteosarcoma Cells.

BACKGROUND: In a previous study, we found that melatonin inhibits MG-63 osteosarcoma cell proliferation; however, the underlying mechanisms remain elusive. Mitogen-activated protein kinase (MAPK) and Akt signaling pathways play key roles in the anticancer effects of melatonin. AIMS: The present study investigated whether MAPK and Akt signaling pathways are involved in melatonin's antiproliferative actions on the human MG-63 osteosarcoma cells. METHODS/RESULTS: Western blot analysis confirmed that melatonin significantly inhibited phosphorylation of ERK1/2 but not p38, JNK, or Akt. The expression of ERK1/2, p38, JNK, and Akt was not altered by melatonin. PD98059 and melatonin alone, and especially in combination, significantly inhibited cell proliferation. The changes included G1 and G2/M phase arrest of the cell cycle, and a downregulation of the expression at both the protein and mRNA levels of cyclin D1 and CDK4 (related to the G1 phase) and of cyclin B1 and CDK1 (related to the G2/M phase) as measured by flow cytometry after propidium iodide staining, and both western blot and real-time PCR, respectively. Furthermore, the combination of PD98059 and melatonin synergistically and markedly augmented the action of either agent alone. Co-immunoprecipitation further confirmed that there was an interaction between p-ERK1/2 and cyclin D1, CDK4, cyclin B1, or CDK1, which was blunted in the presence of melatonin or PD98059. CONCLUSION: These findings suggest that melatonin's antiproliferative action is mediated by inhibition of the ERK1/2 signaling pathway rather than the p38, JNK, or Akt pathways.

Analysis of differentially expressed genes between rheumatoid arthritis and osteoarthritis based on the gene co-expression network.

The aim of the current study was to investigate disease-associated genes and related molecular mechanisms of osteoarthritis (OA) and rheumatoid arthritis (RA). Using GSE7669 datasets downloaded from Gene Expression Omnibus databases, the differentially expressed genes (DEGs) between RA and OA synovial fibroblasts (SFBs) (n=6 each) were screened. DEG-associated co-expression and topological properties were analyzed to determine the rank of disease-associated genes. Specifically, the fold change of differentially expressed genes, the clustering coefficient and the degree of differential gene co-expression were integrated to determine the disease-associated gene ranking. The underlying molecular mechanisms of these crucial disease-associated genes were investigated by gene ontology (GO) enrichment analysis. A total of 1313 DEGs, including 1068 upregulated genes and 245 downregulated genes were observed. The top 20 disease-associated genes were identified, including proteoglycan 4, inhibin ß B, carboxypeptidase M, alcohol dehydrogenase 1C and integrin ß2. The major GO biological processes of these top 20 disease-associated genes were highly involved in the immune system, such as responses to stimuli, immune responses and inflammatory responses. This large-scale gene expression study observed disease-associated genes and their associated GO function in RA and OA, which may provide opportunities for biomarker development and novel insights into the molecular mechanisms of these two diseases.

[Selection of surgical methods for lumbar disc herniation with degenerative endplates changes].

OBJECTIVE: To analyze the selection of surgical methods for lumbar disc herniation with low back and leg pain and degenerative lumbar Modic endplate changes and their different postoperative therapeutic effects. METHODS: All 30 cases of single segment lumbar disc herniation accompanied by Modic endplate changes operated at our hospital using simple discectomy or decompressions with interbody fusion from January 2005 to January 2008 were retrospectively identified. There were 18 males and 12 females with an average age of 38.5 years old (26-53 years old) and an average follow-up of 21 months (4-40 months). RESULTS: Discectomy alone group included 15 cases. The average score of Japanese Orthopedics Association (JOA) and visual analysis scale (VAS) of low back pain and lower extremity radicular pain at the preoperative and final follow-up time was 13.2 (5-17), 6.8 (4-10), 4.8 (1-8) and 19.8 (14 -24), 4.8 (2-10), 1.2 (0-6) respectively. The average improvement rate of JOA was 41.9%. The difference of VAS of lower extremity radicular pain between pre and post-operation was 3.7 on average. Among these 15 cases, Modic I, II and I/II mixed-type was 5, 9, and 1 respectively. Decompression with interbody fusion group included 15 cases. VAS of low back pain and lower extremity radicular pain at the preoperative and final follow-up time was 12.9 (5-17), 7.0 (4-10), 4.9 (1-8) and 22.6 (19-28), 2.8 (2-8) and 1.3 (0-6) respectively. The average improvement rate of JOA was 63.4%. The differences of VAS of lower extremity radicular pain and low back pain between pre and post-operation were 4.3 and 3.6 on average respectively. Among these cases, Modic I, II and I/II mixed-type was 6, 8, and 1 respectively. Comparing the VAS of low back pain, JOA average score and the improvement rate of JOA score of two groups at pre-operation and post-operation, statistical analysis showed that decompression with interbody fusion group was superior to simple discectomy group. CONCLUSION: For lumbar disc herniation with degenerative Modic endplate changes, who suffered more from low back pain than lower extremity radicular pain, discectomy alone and decompression with interbody fusion could both improve the degree of lower extremity radicular pain, but discectomy alone is less likely to improve the degree of low back pain and function score than the latter. So the maneuver of lumbar decompression with fusion is a better choice.