Immunomodulation Pathogenesis and Treatment of Bone Nonunion.

Fractures and bone nonunion commonly require surgical intervention. Serious outcomes of non-healing in the late stages of fracture place a significant financial burden on society and families. Bone nonunion occurs when a fracture stops healing, for many reasons, and leads to a variety of bad outcomes. Numerous factors, including biomechanics and immunology, are involved in the complicated mechanisms of bone nonunion. The immune-inflammatory response plays a significant part in the emergence of bone nonunion, and the occurrence, control, and remission of inflammation in the bone healing process have a significant influence on the ultimate success of bone tissue repair. In the bone microenvironment, immune cells and associated cytokines control bone repair, which is significantly influenced by macrophages, T cells, and fibroblast growth factor. To limit acute inflammation and  balance osteogenesis and osteoblastogenesis for tissue repair and regeneration, immune cells and various cytokines in the local microenvironment must be precisely regulated. As a bad complication of late-stage fractures, bone nonunion has a significant effect on patients' quality of life and socioeconomic development. Therefore, in-depth research on its pathogenesis and treatment methods has important clinical value. To provide more precise, focused therapeutic options for the treatment of bone nonunion, we discuss the regulatory roles of the key immune cells engaged in bone healing within the microenvironment during bone healing and their effect on osteogenesis.

Changes in nail position and antirotation blade angles on the risk of femoral head varus in PFNA fixed patients: a clinical review and comprehensive biomechanical research.

BACKGROUND: Femoral head varus triggers poor clinical prognosis in intertrochanteric fracture patients with proximal femoral nail antirotation (PFNA) fixation. Studies present that changes in nail position and screw insertion angles will affect fixation stability, but the biomechanical significance of these factors on the risk of femoral head varus has yet to be identified in PFNA fixed patients. METHODS: Clinical data in PFNA fixed intertrochanteric fracture patients have been reviewed, the relative position of intermedullary nail has been judged in the instant postoperative lateral radiography. Regression analyses have been performed to identify the effect of this factor on femoral head varus. Corresponding biomechanical mechanism has been identified by numerical mechanical simulations. RESULTS: A clinical review revealed that ventral side nail insertion can trigger higher risk of femoral head varus, corresponding numerical mechanical simulations also recorded poor fixation stability in models with ventral side nail insertion, and changes in the trajectory of anti-rotation blade will not obviously affect this tendency. CONCLUSIONS: Ventral side insertion of intramedullary nail can trigger higher risk of femoral head varus in PFNA fixed patients by deteriorating the instant postoperative biomechanical environment, and changes in blade trajectory cannot change this tendency biomechanically. Therefore, this nail position should be adjusted to optimize patients' prognosis.

Helicobacter pylori Treatment and Gastric Cancer Risk Among Individuals With High Genetic Risk for Gastric Cancer.

Importance: Helicobacter pylori treatment and nutrition supplementation may protect against gastric cancer (GC), but whether the beneficial effects only apply to potential genetic subgroups and whether high genetic risk may be counteracted by these chemoprevention strategies remains unknown. Objective: To examine genetic variants associated with the progression of gastric lesions and GC risk and to assess the benefits of H pylori treatment and nutrition supplementation by levels of genetic risk. Design, Setting, and Participants: This cohort study used follow-up data of the Shandong Intervention Trial (SIT, 1989-2022) and China Kadoorie Biobank (CKB, 2004-2018) in China. Based on the SIT, a longitudinal genome-wide association study was conducted to identify genetic variants for gastric lesion progression. Significant variants were examined for incident GC in a randomly sampled set of CKB participants (set 1). Polygenic risk scores (PRSs) combining independent variants were assessed for GC risk in the remaining CKB participants (set 2) and in an independent case-control study in Linqu. Exposures: H pylori treatment and nutrition supplementation. Main Outcomes and Measures: Primary outcomes were the progression of gastric lesions (in SIT only) and the risk of GC. The associations of H pylori treatment and nutrition supplementation with GC were evaluated among SIT participants with different levels of genetic risk. Results: Our analyses included 2816 participants (mean [SD] age, 46.95 [9.12] years; 1429 [50.75%] women) in SIT and 100 228 participants (mean [SD] age, 53.69 [11.00] years; 57 357 [57.23%] women) in CKB, with 147 GC cases in SIT and 825 GC cases in CKB identified during follow-up. A PRS integrating 12 genomic loci associated with gastric lesion progression and incident GC risk was derived, which was associated with GC risk in CKB (highest vs lowest decile of PRS: hazard ratio [HR], 2.54; 95% CI, 1.80-3.57) and further validated in the analysis of 702 case participants and 692 control participants (mean [SD] age, 54.54 [7.66] years; 527 [37.80%] women; odds ratio, 1.83; 95% CI, 1.11-3.05). H pylori treatment was associated with reduced GC risk only for individuals with high genetic risk (top 25% of PRS: HR, 0.45; 95% CI, 0.25-0.82) but not for those with low genetic risk (HR, 0.81; 95% CI, 0.50-1.34; P for interaction = .03). Such effect modification was not found for vitamin (P for interaction = .93) or garlic (P for interaction = .41) supplementation. Conclusions and Relevance: The findings of this cohort study indicate that a high genetic risk of GC may be counteracted by H pylori treatment, suggesting primary prevention could be tailored to genetic risk for more effective prevention.

The bone nonunion microenvironment: A place where osteogenesis struggles with osteoclastic capacity.

Bone nonunion is a common and serious orthopedic disorder, the occurrence of which is associated with a disruption of the dynamic balance between osteoblasts and osteoclasts during bone repair. However, the critical molecular mechanisms affecting this homeostasis are not well understood, and it is essential to investigate the specific components of this mechanism and to restore the balance between osteoblasts and osteoclasts to promote bone repair. First, we defined this complex local environmental factor as the "bone nonunion microenvironment" and identified the importance of the "struggle" between osteoblasts and osteoclasts, which is the most essential element in determining the process of repair. On this basis, we also explored the cellular factors that influence osteogenesis and the molecular signals that influence the balance between osteoclast and osteoblasts, which are important for restoring homeostasis. Further, we explored other factors involved in osteogenesis, such as the biomechanical environment, the nutritional environment, the acid-base environment, and the temperature environment, which are important players in osteogenesis. In conclusion, we found that the balance between osteoblasts and osteoclasts is the essence of bone healing, which is based on the "bone nonunion microenvironment". Therefore, investigating the role of the bone nonunion microenvironment in the system of osteoblast-osteoclast "struggle" provides an important basis for further understanding of the mechanism of nonunion and the development of new therapeutic approaches.

Exploration of the mode of death and potential death mechanisms of nucleus pulposus cells.

Intervertebral disc degeneration (IVDD) is a common chronic orthopaedic disease in orthopaedics that imposes a heavy economic burden on people and society. Although it is well established that IVDD is associated with genetic susceptibility, ageing and obesity, its pathogenesis remains incompletely understood. Previously, IVDD was thought to occur because of excessive mechanical loading leading to destruction of nucleus pulposus cells (NPCs), but studies have shown that IVDD is a much more complex process associated with inflammation, metabolic factors and NPCs death and can involve all parts of the disc, characterized by causing NPCs death and extracellular matrix (ECM) degradation. The damage pattern of NPCs in IVDD is like that of some programmed cell death, suggesting that IVDD is associated with programmed cell death. Although apoptosis and pyroptosis of NPCs have been studied in IVDD, the pathogenesis of intervertebral disc degeneration can still not be fully elucidated by using only traditional cell death modalities. With increasing research, some new modes of cell death, PANoptosis, ferroptosis and senescence have been found to be closely related to intervertebral disc degeneration. Among these, PANoptosis combines essential elements of pyroptosis, apoptosis and necroptosis to form a highly coordinated and dynamically balanced programmed inflammatory cell death process. Furthermore, we believe that PANoptosis may also crosstalk with pyroptosis and senescence. Therefore, we review the progress of research on multiple deaths of NPCs in IVDD to provide guidance for clinical treatment.

Bioinformatics-based discovery of intervertebral disc degeneration biomarkers and immune-inflammatory infiltrates.

Background: Intervertebral disc degeneration (IVDD) is a common chronic disease in orthopedics, and its molecular mechanisms are still not well explained. Aim: This study's objective was to bioinformatics-based discovery of IVDD biomarkers and immune-inflammatory infiltrates. Materials and Methods: The IVDD illness gene collection was gathered from GeneCards, DisGeNet, and gene expression profiles were chosen from the extensive Gene Expression Omnibus database (GSE124272, GSE150408, and GSE153761). The STRING database was used to create a network of protein-protein interactions, while the Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) databases were used for functional enrichment analysis. Using hub genes, the immune cell infiltration between IVDD patient samples and control tissues was examined. Finally, quantitative polymerase chain reaction and Western blot experiments were used to verify the expression of hub genes. Results: A total of 27 differentially expressed hub genes were identified by bioinformatics. According to GO and KEGG analyses, hub genes were prominent in immunological responses, chemokine-mediated signaling pathways, and inflammatory responses, with the key signaling pathways engaged in cellular senescence, apoptosis, Th1 and Th2 cell differentiation, and Th17 cell differentiation. Immune cell infiltration research revealed that T cells, lymphocytes, B cells, and NK cells were decreased in IVDD patients while monocytes, neutrophils, and CD8 T cells were increased. The expression levels of the senescence hub genes SP1, VEGFA, IL-6, and the apoptosis key gene CASP3 were considerably greater in the IVDD model group than in the control group, according to in vitro validation. Conclusion: In conclusion, the cellular senescence signaling pathway, the apoptosis signaling pathway, and associated hub genes play significant roles in the development and progression of IVDD, this finding may help direct future research on the senescence signaling route in IVDD.

Mitochondrial dysfunction: a new molecular mechanism of intervertebral disc degeneration.

OBJECTIVE: Intervertebral disc degeneration (IVDD) is a chronic degenerative orthopedic illness that causes lower back pain as a typical clinical symptom, severely reducing patients' quality of life and work efficiency, and imposing a significant economic burden on society. IVDD is defined by rapid extracellular matrix breakdown, nucleus pulposus cell loss, and an inflammatory response. It is intimately related to the malfunction or loss of myeloid cells among them. Many mechanisms have been implicated in the development of IVDD, including inflammatory factors, oxidative stress, apoptosis, cellular autophagy, and mitochondrial dysfunction. In recent years, mitochondrial dysfunction has become a hot research topic in age-related diseases. As the main source of adenosine triphosphate (ATP) in myeloid cells, mitochondria are essential for maintaining myeloid cell survival and physiological functions. METHODS: We searched the PUBMED database with the search term "intervertebral disc degeneration and mitochondrial dysfunction" and obtained 82 articles, and after reading the abstracts and eliminating 30 irrelevant articles, we finally obtained 52 usable articles. RESULTS: Through a review of the literature, it was discovered that IVDD and cellular mitochondrial dysfunction are also linked. Mitochondrial dysfunction contributes to the advancement of IVDD by influencing a number of pathophysiologic processes such as mitochondrial fission/fusion, mitochondrial autophagy, cellular senescence, and cell death. CONCLUSION: We examine the molecular mechanisms of IVDD-associated mitochondrial dysfunction and present novel directions for quality management of mitochondrial dysfunction as a treatment approach to IVDD.

Mechanism of Liuwei Dihuang Pills in treating osteoporosis based on network pharmacology.

Osteoporosis is a prevalent age-related disease that poses a significant public health concern as the population continues to age. While current treatments have shown some therapeutic benefits, their long-term clinical efficacy is limited by a lack of stable curative effects and significant adverse effects. Traditional Chinese Medicine has gained attention due to its positive curative effects and fewer side effects. Liuwei Dihuang Pill has been found to enhance bone mineral density in patients with osteoporosis and rats, but the underlying mechanism is not yet clear. To shed more light on this problem, this study aims to explore the pharmacological mechanism of Liuwei Dihuang Pill in treating osteoporosis using network pharmacology and molecular docking. The findings indicate that Liuwei Dihuang Pills treat osteoporosis through various targets and channels. Specifically, it mainly involves TNF, IL17, and HIF-1 signaling pathways and helps regulate biological processes such as angiogenesis, apoptosis, hypoxia, and gene expression. Furthermore, molecular docking demonstrates excellent binding properties between the drug components and key targets. Therefore, this study offers a theoretical foundation for understanding the pharmacological mechanism and clinical application of Liuwei Dihuang Pills in treating osteoporosis more comprehensively.

A quasi-experimental study on the effectiveness of a standardized comprehensive sexuality education curriculum for primary school students.

INTRODUCTION: Although the importance of sexuality education has been recognized, Chinese rural students have limited access to sexual and reproductive information. This study aims to evaluate the effectiveness of a standardized comprehensive sexuality education curriculum package featuring cartoon animation on sexuality-related knowledge and skills, attitudes, and practices of primary school students. METHODS: This quasi-experimental study recruited 1725 students in grades 4-6 (aged 9-13) from eight primary schools sampled as school clusters in 2020 in China. Internet-based questionnaires from three intervention schools' participants were collected after trained schoolteachers had conducted six 45-min sexuality education sessions. We performed optimal full matching and treatment effects were estimated in the matched sample by outcome regression models that further adjusted the covariates. RESULTS: Compared with the control group, intervention group students achieved significantly higher scores by 3.35 out of 38 and 2.02 out of 34 in knowledge- and skill-based tests and attitudinal tests, respectively. For the five self-reported practices on genital care, the experimental group showed significantly better performance than the control group in genital hygiene, by 6.92%, 22.45%, and 30.66% higher rates in the overall prevalence of three proper practices of genital hygiene, with effect sizes larger for boys than girls. CONCLUSIONS: Our sexuality education package effectively improved primary school students' sexuality-related knowledge, skills, attitudes, and hygiene practices. Our study suggests that the standardized curriculum package could be a promising approach to improving the quality and accessibility of sexuality education in underdeveloped rural China.

Mechanisms of inhibition of nucleus pulposus cells pyroptosis through SDF1/CXCR4-NFkB-NLRP3 axis in the treatment of intervertebral disc degeneration by Duhuo Jisheng Decoction.

Intervertebral disc degeneration (IVDD) is one of the leading causes of lower back pain and the most common health problem in the world. Inflammasomes, which is mainly caused by NLRP3, mediated nucleus pulposus pyroptosis has been discovered to be strongly related to IVDD. In addition, Duhuo Jisheng Decoction (DHJSD) has anti-inflammatory and regulatory effects on NLRP3 inflammasome, but the molecular mechanism of whether DHJSD can regulate pyroptosis through NLRP3 to treat IVDD is unclear. In this study, we used a bioinformatics way to discover the molecular mechanism of DHJSD regulation of pyroptosis in IVDD, and validated our predictions through vitro and vivo experiments. Through bioinformatics, we found that NLRP3, GSDMD, IL-1ßand other hub proteins of pyroptosis were highly expressed in IVDD SD rats, and network pharmacology discovered that DHJSD may control cellular senescence, apoptosis, and pyroptosis in order to treat IVDD. Additional findings demonstrated that DHJSD could successfully treat IVDD brought on by imaging and histomorphological analysis. Western blot showed that NLRP3, a key protein of pyroptosis, was elevated in rat degenerated nucleus pulposus tissue and lipopolysaccharide-treated Nucleus pulposus Cells (NPCs), and that DHJSD intervention was effective in reducing LPS-induced inflammatory responses and further suppressing the expression of pyroptosis related proteins to improve IVDD. The specific mechanism is that DHJSD inhibits NPCs pyroptosis via the SDF-1/CXCR4-NF-kB-NLRP3 axis. In conclusion, we revealed the intrinsic mechanism of DHJSD regulation of NPCs pyroptosis to improve IVDD and its intrinsic value for IVDD treatment.

A review of Duhuo Jisheng decoction mechanisms in intervertebral disc degeneration in vitro and animal studies.

Intervertebral disc degeneration (IVDD) has become a serious public health problem, placing a heavy burden on society and the healthcare system. Its pathogenesis is not completely clear and may be closely related to mechanical damage, inflammatory factors, oxidative stress and death of nucleus pulposus cells (NPCs). The treatment of IVDD mainly includes conservative treatment and surgery. Conservative treatment is based on hormonal and anti-inflammatory drugs and massage techniques, which can relieve the pain symptoms to a certain extent, but cannot solve the problem from the root cause. Surgical treatment is mainly by removing the herniated nucleus pulposus, but it is more traumatic for IVDD patients, expensive and not suitable for all patients. Therefore, it is extremely important to clarify the pathogenesis of IVDD, to find an effective and convenient treatment and to further elaborate its mechanism of action. The effectiveness of traditional Chinese medicine in the treatment of IVDD has been well demonstrated in clinical medical research. We have been working on the Chinese herbal formula Duhuo Jisheng Decoction, which is a common formula for the treatment of degenerative disc disease. Not only does it have significant clinical effects, but it also has few adverse effects. At present, we found that its mechanism of action mainly involves regulation of inflammatory factors, reduction of apoptosis and pyroptosis of NPCs, inhibition of extracellular matrix degradation, improvement of intestinal flora, etc. However, a few relevant articles have yet comprehensively and systematically summarized the mechanisms by which they exert their effect. Therefore, this paper will comprehensively and systematically explain on it. This is of great clinical significance and social value for elucidating the pathogenesis of IVDD and improving the symptoms of patients, and will provide a theoretical basis and scientific basis for the treatment of IVDD with traditional Chinese medicine.

Exploring the pharmacological mechanism of Duhuo Jisheng Decoction in treating intervertebral disc degeneration based on network pharmacology.

BACKGROUND: The purpose of this study was to examine the mechanism of Duhuo Jisheng Decoction (DHJSD) in the treatment of intervertebral disc degeneration (IVDD). METHODS: The active compounds of DHJSD and their corresponding targets were obtained from the TCMSP database. "Intervertebral disc degeneration" was used as a search term in the DisGeNET, GeneCards, Comparative Toxicogenomics Database, and MalaCards database to obtain disease-related targets. Following the discovery of overlapping DHJSD and IVDD targets, enrichment analyses for Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, Reactome, and WikiPathways were performed. Cytoscape 3.9.1 was used to build the "DHJSD-Active Ingredients-Target Genes-IVDD" network and protein-protein interaction network, and CytoHubba was used to screen the pivotal genes. Molecular docking confirmed the binding activity of hub genes and key components. RESULTS: The bioinformatic analysis of DHJSD in the treatment of IVDD revealed 209 potential therapeutic gene targets, including 36 important gene targets and 10 of these crucial gene targets. Enrichment analysis of 36 key therapeutic targets showed that the biological processes involved in the Gene Ontology analysis of DHJSD in treating IVDD were mainly cytokine-mediated signaling pathway, inflammatory response, negative regulation of apoptotic process, and vascular endothelial growth factor production. The Kyoto Encyclopedia of Genes and Genomes signaling pathway is mainly involved in TNF signaling pathway, Th17 cell differentiation, IL-17 signaling pathway, and HIF-1 signaling pathway. The Recactome signaling pathway is mainly involved in cytokine signaling in immune system, cellular responses to stress, immune system, cytokines, and inflammatory response. HIF1A and PPARG regulation of glycolysis are mostly involved in the WikiPathways signaling system. The findings demonstrated that to cure IVDD, DHJSD affects the pathogenic processes of inflammation, extracellular matrix, cellular senescence, autophagy, apoptosis, focal death, and proliferation through the aforementioned targets and signaling pathways. The results of molecular docking demonstrated that the protein can be effectively bound by the DHJSD active component. Further evidence was provided for the molecular mechanism through which DHJSD works to treat IVDD. CONCLUSION: This study uncovers the multi-component, multi-target, and multi-pathway characteristics of DHJSD for the treatment of IVDD, offering fresh perspectives to further investigate the mechanism of DHJSD for the treatment of IVDD.

Metabolite Alterations and Interactions with Microbiota in Helicobacter pylori-Associated Gastric Lesions.

Metabolites and their interactions with microbiota may be involved in Helicobacter pylori-associated gastric lesion development. This study aimed to explore metabolite alterations upon H. pylori eradication and possible roles of microbiota-metabolite interactions in progression of precancerous lesions. Targeted metabolomics assays and 16S rRNA gene sequencing were conducted to investigate metabolic and microbial alterations of paired gastric biopsy specimens in 58 subjects with successful and 57 subjects with failed anti-H. pylori treatment. Integrative analyses were performed by combining the metabolomics and microbiome profiles from the same intervention participants. A total of 81 metabolites were significantly altered after successful eradication compared to failed treatment, including acylcarnitines, ceramides, triacylglycerol, cholesterol esters, fatty acid, sphingolipids, glycerophospholipids, and glycosylceramides, with P values of <0.05 for all. The differential metabolites showed significant correlations with microbiota in baseline biopsy specimens, such as negative correlations between Helicobacter and glycerophospholipids, glycosylceramide, and triacylglycerol (P < 0.05 for all), which were altered by eradication. The characteristic negative correlations between glycosylceramides and Fusobacterium, Streptococcus, and Gemella in H. pylori-positive baseline biopsy specimens were further noticed in active gastritis and intestinal metaplasia (P < 0.05 for all). A panel including differential metabolites, genera, and their interactions may help to discriminate high-risk subjects who progressed from mild to advanced precancerous lesions in short-term and long-term follow-up periods with areas under the curve (AUC) of 0.914 and 0.801, respectively. Therefore, our findings provide new insights into the metabolites and microbiota interactions in H. pylori-associated gastric lesion progression. IMPORTANCE In this study, a panel was established including differential metabolites, genera, and their interactions, which may help to discriminate high-risk subjects for progression from mild lesions to advanced precancerous lesions in short-term and long-term follow-up.

Cellular senescence - Molecular mechanisms of intervertebral disc degeneration from an immune perspective.

Intervertebral disc degeneration (IVDD) is a frequent and intractable chronic condition in orthopedics that causes enormous discomfort in patients' lives and thoughts, as well as a significant economic burden on society and the nation. As a result, understanding the pathophysiology of IVDD is critical. The pathophysiology of IVDD has been linked to numerous variables, including oxidative stress, apoptosis, matrix metalloproteinases, and inflammatory factors. Cellular senescence has recently attracted a lot of attention in the study of age-related diseases. It has been discovered that IVDD is intimately linked to human senescence, in which nucleus pulposus cell senescence may play a significant role. Previously, our group did a comprehensive and systematic clarification of the pathogenesis of IVDD from an immune perspective and discovered that the fundamental pathogenesis of IVDD is inflammatory upregulation and nucleus pulposus cell death caused by an imbalance in the immune microenvironment. In this review, we will treat nucleus pulposus cell senescence as a novelty point to clarify the pathophysiology of IVDD and further explore the probable relationship between senescence and immunity along with the dysregulation of the immunological microenvironment to propose new therapeutic approaches for IVDD.

Resveratrol induces proliferation and differentiation of mouse pre-osteoblast MC3T3-E1 by promoting autophagy.

BACKGROUND: In mouse, it was discovered that resveratrol (Res) enhanced osteoporosis (OP) by boosting osteogenesis. Besides, Res can also have an impact on MC3T3-E1 cells, which are crucial for the control of osteogenesis and thus increase osteogenesis. Although some articles have discovered that Res enhanced autophagy to promote the value-added differentiation of MC3T3, it is unclear exactly how this affects the process of osteogenesis in mouse. Therefore, we will show that Res encourages MC3T3-E1 proliferation and differentiation in mouse pre-osteoblasts and further investigate the autophagy-related mechanism for this impact. METHODS: (1) MC3T3-E1 cells were separated into blank control group and various concentrations (0.01, 0.1, 1, 10, 100µmol/L) of group in order to determine the ideal Res concentration. In the Res group, Cell Counting Kit-8 (CCK-8) was used to measure the proliferation activity of pre-osteoblasts in mice in each group after resveratrol intervention. Alkaline Phosphatase (ALP) and alizarin red staining were used to gauge the degree of osteogenic differentiation, and RT-qPCR was used to measure the expression levels of Runx2 and OCN in the osteogenic differentiation ability of the cells. (2) In the experiment, four groups were set up: the control group, 3MA group, Res group, and Res + 3MA group. To examine cell mineralization, ALP and alizarin red staining were utilized. RT-qPCR and Western blot detection of cell autophagy activity levels and osteogenic differentiation capacity in each group following intervention. RESULTS: (1) Resveratrol might increase the number of mice pre-osteoblast, with the impact being most pronounced at 10µmol/L (P < 0.05). The nodules developed substantially more often than in the blank control group, and Runx2 and OCN expressions significantly increased (P < 0.05). (2) In contrast to the Res group, after 3MA purine blocked autophagy, the Res + 3MA group's alkaline phosphatase staining and the development of mineralized nodules were reduced. Runx2, OCN, LC3II / LC3I expression decreased, p62 expression increased (P < 0.05). CONCLUSION: The present study partially or indirectly demonstrated that Res may, through increased autophagy, induce osteogenic differentiation of MC3T3-E1 cells.

Allium vegetable intake associated with the risk of incident gastric cancer: a continuous follow-up study of a randomized intervention trial.

BACKGROUND: Allium vegetable components have antibacterial, antioxidative, and immune modulation properties, thus potentially exhibiting antitumor effects. Despite evidence from case-control studies, prospective studies linking allium vegetables with gastric cancer (GC) have been sparse. OBJECTIVE: In a prospective study, we examined whether allium vegetable intake would change the risk of GC occurrence and whether the associations would be modified by vitamin supplementation, garlic supplementation, and Helicobacter pylori (H. pylori) treatment. METHODS: The study was conducted on the basis of the Shandong Intervention Trial, a randomized, placebo-controlled, factorial-designed trial (1995-2003) in a well-recognized high-risk area for GC in China. Participants were continuously followed up to December 2017 for 22.3 y (1995-2017). A total of 3229 subjects were included, with information on the intake of allium vegetables (garlic vegetables and scallions), collected by structured questionnaires in 1994. The associations of total and individual allium vegetable intake with the risk of GC were examined, respectively. RESULTS: During the follow-up, 144 incident cases of GC were identified. Garlic vegetable intake was associated with a decreased risk of incident GC (P-trend = 0.02; OR: 0.83; 95% CI: 0.70, 0.98, per 1 kg/y increment), whereas scallion intake showed no association (P-trend = 0.80). An inverse association of the risk of GC with total allium vegetable and garlic vegetable intake was particularly stronger among those receiving the placebo for vitamin supplementation or garlic supplementation, indicating potential effect modifications by nutritional supplementation on allium vegetable intake and the risk of developing GC. Similar findings were found for analyses of the combined prevalence of dysplasia or GC. CONCLUSIONS: We found a significant reduction in the risk of developing GC with increasing dietary intake of allium vegetables, particularly garlic vegetables. The findings add to the literature on the potential inverse association of garlic vegetable intake with the risk of GC, therefore holding public health implications for dietary recommendations. This trial was registered at clinicaltrials.gov as NCT00339768.

Health economic evaluation on population-based Helicobacter pylori eradication and endoscopic screening for gastric cancer prevention.

Gastric cancer is a global public health burden, nearly one million new cases are diagnosed per year worldwide, of which 44% of cases occur in China. The prognosis of gastric cancer varies remarkably by the stage of cancer, and most of the patients in China are diagnosed at advanced stages, resulting in poor prognoses. Effective strategies to reduce the burden of gastric cancer include primary prevention through testing and treatment of Helicobacter pylori (H. pylori) and secondary prevention by screening and early detection. Although many countries have issued management guidelines and consensus reports concerning these strategies, the limited availability of healthcare resources often precludes their widespread implementation. Therefore, assessing the costs, benefits, and harms of population-based intervention measures through health economic evaluation is necessary for informed health policy decisions. Accordingly, we synthesize management approaches from different countries on H. pylori eradication and endoscopic screening, and also summarize recent advancements in health economic evaluations on population-based preventive strategies. The goal of the review is to provide empirical evidence supporting optimal resource allocation, maximizing benefits for the population, and ultimately reducing the burden of gastric cancer.

Urine proteomic signatures predicting the progression from premalignancy to malignant gastric cancer.

BACKGROUND: Early detection of gastric cancer (GC) remains challenging. We aimed to examine urine proteomic signatures and identify protein biomarkers that predict the progression of gastric lesions and risk of GC. METHODS: A case-control study was initially designed, covering subjects with GC and gastric lesions of different stages. Subjects were aged 40-69 years, without prior diagnosis of renal or urological diseases. We enrolled a total of 255 subjects, with 123 in the discovery stage from Linqu, China, a high-risk area for GC and 132 in the validation stage from Linqu and Beijing. A prospective study was further designed for a subset of 60 subjects with gastric lesions, which were followed for 297-857 days. FINDINGS: We identified 43 differentially expressed urine proteins in subjects with GC vs. mild or advanced gastric lesions. Baseline urinary levels of ANXA11, CDC42, NAPA and SLC25A4 were further positively associated with risk of gastric lesion progression. Three of them, except for SLC25A4, also had higher expression in GC than non-GC tissues. Integrating these four proteins showed outstanding performance in predicting the progression of gastric lesions (AUC (95% CI): 0.92 (0.83-1.00)) and risk of GC (AUC (95% CI): 0.81 (0.73-0.89) and 0.84 (0.77-0.92) for GC vs. mild or advanced gastric lesions respectively). INTERPRETATION: This study revealed distinct urine proteomic profiles and a panel of proteins that may predict the progression of gastric lesions and risk of GC. These biomarkers in a non-invasive approach may have translational significance for defining high-risk populations of GC and its early detection. FUNDING: Funders are listed in the Acknowledgement.

Shared mechanisms and crosstalk of COVID-19 and osteoporosis via vitamin D.

Recently accumulated evidence implicates a close association of vitamin D (VitD) insufficiency to the incidence and clinical manifestations of the COVID-19 caused by severe acute respiratory syndrome coronavirus-2 (SARS-COV-2). Populations with insufficient VitD including patients with osteoporosis are more susceptible to SARS-COV-2 infection and patients with COVID-19 worsened or developed osteoporosis. It is currently unknown, however, whether osteoporosis and COVID-19 are linked by VitD insufficiency. In this study, 42 common targets for VitD on both COVID-19 and osteoporosis were identified among a total of 243 VitD targets. Further bioinformatic analysis revealed 8 core targets (EGFR, AR, ESR1, MAPK8, MDM2, EZH2, ERBB2 and MAPT) in the VitD-COVID-19-osteoporosis network. These targets are involved in the ErbB and MAPK signaling pathways critical for lung fibrosis, bone structural integrity, and cytokines through a crosstalk between COVID-19 and osteoporosis via the VitD-mediated conventional immune and osteoimmune mechanisms. Molecular docking confirmed that VitD binds tightly to the predicted targets. These findings support that VitD may target common signaling pathways in the integrated network of lung fibrosis and bone structural integrity as well as the immune systems. Therefore, VitD may serve as a preventive and therapeutic agent for both COVID-19 and osteoporosis.

M6A Modifier-Mediated Methylation Characterized by Diverse Prognosis, Tumor Microenvironment, and Immunotherapy Response in Hepatocellular Carcinoma.

Objective: Emerging evidence highlights the clinical implications of N6-methyladenosine (m6A) modification in HCC. Yet, the roles of m6A modification in modulating cancer immunity and shaping tumor microenvironment (TME) are undefined in hepatocellular carcinoma (HCC). Methods: Here, m6A modification classification was determined for HCC through 23 m6A modifier levels by employing consensus clustering approach. Prognosis analysis was presented for comparing the differences in survival outcomes. The ssGSEA and ESTIMATE approaches were adopted for evaluating the abundances of tumor-infiltrating immune cell populations. The m6A scoring system was computed for reflecting m6A modification classification via PCA algorithm. Results: Three m6A modifier-mediated modification patterns were established among HCC specimens, which were characterized by different prognosis, signaling pathways, and TME features. After extracting m6A phenotype-associated DEGs, we determined m6A scores in individual HCC and stratified patients into high- and low-score groups. Patients with low m6A score displayed the survival advantage and higher sensitivity to gemcitabine. Moreover, those with low m6A score possessed the better anti-PD-1/PD-L1 therapeutic response in the IMvigor210 immunotherapy cohort. Conclusion: Our findings highlighted that m6A modification exerted a nonnegligible role in remodeling diverse and complex TME. Quantification of the m6A modification patterns of individual HCC may enhance the comprehension of TME features and facilitate immunotherapeutic plans.