BACKGROUND:Many recent studies have shown a close relationship between inflammatory cytokines and osteoporosis and bone mineral density(BMD).However,the causal relationship between inflammatory cytokines and BMD has not been fully revealed. OBJECTIVE:To explore the potential causal relationship between inflammatory cytokines and BMD using a two-sample Mendelian randomization analysis. METHODS:The single nucleotide polymorphisms associated with 41 circulating inflammatory cytokines were selected from the open database of genome-wide association studies(GWAS)as instrumental variables.The GWAS data about BMD were from the Genetic Factors for Osteoporosis Consortium,involving a total of 32 735 individuals of European ancestry.Inverse variance weighting was used as the primary analysis to evaluate the causal effect.Weighted median,MR Egger regression,simple mode,and weighted mode methods were used to supplement the explanation.We used the MR-Egger intercept and MR-PRESSO method to conduct a pleiotropy test,the Cochran's Q test was used to determine whether there was heterogeneity in the results,and the leave-one-out method was used to evaluate the stability of the results.In addition,to more accurately assess the causality,the Bonferroni-corrected test was used to identify inflammatory cytokines that have a strong causal relationship with BMD. RESULTS AND CONCLUSION:(1)According to the results of the inverse variance weighting method,we found a positive causal relationship between interleukin-8 and lumbar spine BMD[β=0.075,95%confidence interval(CI):0.033-0.117,P=0.000 5),while a negative causal relationship between interleukin-17 and lumbar spine BMD(β=-0.083,95%CI:-0.152 to-0.014,P=0.018).There might be a negative causal relationship between tumor necrosis factor b and femoral neck BMD(β=-0.053,95%CI:-0.088 to-0.018,P=0.003),while a positive causal relationship between basic fibroblast growth factor and femoral neck BMD(β=0.085,95%CI:0.016-0.154,P=0.015).There might be a negative causal relationship between macrophage inflammatory protein-1a and total body BMD(β=-0.056,95%CI:-0.105 to-0.007,P=0.025).There was a negative causal relationship between interleukin-5(β=-0.019,95%CI:-0.031 to-0.006,P=0.004),stromal cell-derived factor-1a(β=-0.022,95%CI:-0.038 to-0.005,P=0.010),hepatocyte growth factor(β=-0.021,95%CI:-0.041 to-0.002,P=0.030),interleukin-4(β=-0.016,95%CI:-0.032 to-0.001,P=0.034)and heel BMD,while a positive causal relationship between nerve growth factor(β=0.019,95%CI:0.002-0.036,P=0.033),granulocyte colony-stimulating factor(β=0.011,95%CI:0.000-0.022,P=0.050),and heel BMD.Meanwhile,after the Bonferroni-corrected test,there was a strong positive causal effect between interleukin-8 and lumbar spine BMD(P=0.000 5).And consistent directional effects for all analyses were observed in MR Egger,weighted median,simple mode,and weighted mode methods.(2)Sensitivity analyses revealed no heterogeneity,pleiotropy,or outliers for the causal effect of circulating inflammatory cytokines on BMD.

OBJECTIVE: To assess the efficacy and safety of Erzhu Jiedu Decoction (EZJDD) Granules in treating mid-advanced hepatitis B virus-associated primary liver cancer (HBV-PLC) patients with Pi (Spleen)-deficiency and dampness-heat syndrome. METHODS: From January 2021 to June 2023, a cohort of 132 patients were enrolled and randomly assigned to a control group or a EZJDD group according to the random numbers, with 66 patients in each group. The patients in the control group received conventional treatment for 3 months, followed by a 3-month follow-up. In addition to the conventional treatment, patients in the EZJDD group were administered EZJDD Granules (10.9 g/pack, 2 packs twice per day) orally for same duration. Progression-free survival (PFS) as primary outcome was evaluated by Kaplan Meier method. Karnofsky performance status (KPS) scores were used to assess the quality of life in two groups before and after treatment, and survival rates were determined as well. The efficacy of Chinese medicine syndrome was calculated with Nimodipine method. Liver function, tumor indicators and T lymphocyte subsets were measured, respectively. Safety indicators were recorded and assessed. RESULTS: Of the 116 patients who completed the study, 57 were in the control group and 59 in the EZJDD group. The median PFS was 3.53 months (106 days) in the EZJDD group compared to 2.33 months (70 days) in the control group (P=0.005). Six-month survival rate was 52.63% (30/57) in the control group and 69.49% (41/59) in the EZJDD group (P=0.039). The median KPS score in the EZJDD group [70(63, 90)] was higher than that in the control group [70(60, 80)] (P=0.013). The total effective rate of CM syndrome was 52.63% (30/57) in the control group and 77.97% (46/59) in the EZJDD group (P=0.005). The levels of alpha fetoprotein, alpha fetoprotein-L3, alpha-L-fucosidase and protein induced by Vitamin K absence or antagonist- II in the EZJDD group increased less than the control group (P>0.05). CD8⁺ levels were decreased, while CD3⁺ and CD4⁺ levels, as well as CD4⁺/CD8⁺ ratio were significantly increased in the EZZJD group (P<0.05). No treatment-related adverse reactions were observed during the study. CONCLUSION EZJDD Granules significantly prolonged the median PFS and improved 6-month survival rate in patients with mid-advanced HBV-PLC (Registration No. ChiCTR2200056922).
Humans ; Drugs, Chinese Herbal/adverse effects* ; Male ; Female ; Middle Aged ; Liver Neoplasms/complications* ; Hepatitis B virus/physiology* ; Hepatitis B/complications* ; Treatment Outcome ; Adult ; Spleen/drug effects* ; Quality of Life ; Medicine, Chinese Traditional ; Aged ; Syndrome

OBJECTIVE: To investigate the effect of zedoarondiol on neovascularization of atherosclerotic (AS) plaque by exosomes experiment. METHODS: ApoE^-/- mice were fed with high-fat diet to establish AS model and treated with high- and low-dose (10, 5 mg/kg daily) of zedoarondiol, respectively. After 14 weeks, the expressions of anti-angiogenic protein thrombospondin 1 (THBS-1) and its receptor CD36 in plaques, as well as platelet activation rate and exosome-derived miR-let-7a were detected. Then, zedoarondiol was used to intervene in platelets in vitro, and miR-let-7a was detected in platelet-derived exosomes (Pexo). Finally, human umbilical vein endothelial cells (HUVECs) were transfected with miR-let-7a mimics and treated with Pexo to observe the effect of miR-let-7a in Pexo on tube formation. RESULTS: Animal experiments showed that after treating with zedoarondiol, the neovascularization density in plaques of AS mice was significantly reduced, THBS-1 and CD36 increased, the platelet activation rate was markedly reduced, and the miR-let-7a level in Pexo was reduced (P<0.01). In vitro experiments, the platelet activation rate and miR-let-7a levels in Pexo were significantly reduced after zedoarondiol's intervention. Cell experiments showed that after Pexo's intervention, the tube length increased, and the transfection of miR-let-7a minics further increased the tube length of cells, while reducing the expressions of THBS-1 and CD36. CONCLUSION Zedoarondiol has the effect of inhibiting neovascularization within plaque in AS mice, and its mechanism may be potentially related to inhibiting platelet activation and reducing the Pexo-derived miRNA-let-7a level.
Animals ; MicroRNAs/genetics* ; Exosomes/drug effects* ; Plaque, Atherosclerotic/genetics* ; Neovascularization, Pathologic/genetics* ; Human Umbilical Vein Endothelial Cells/metabolism* ; Humans ; Blood Platelets/drug effects* ; Apolipoproteins E/deficiency* ; Thrombospondin 1/metabolism* ; CD36 Antigens/metabolism* ; Platelet Activation/drug effects* ; Male ; Mice ; Mice, Inbred C57BL

Ischemia-reperfusion (I/R) injury following skin flap transplantation is a critical factor leading to flap necrosis and transplant failure. Antagonizing inflammatory responses and oxidative stress are regarded as crucial targets for mitigating reperfusion injury and enhancing flap survival. In this study, caffeic acid-vanadium metal polyphenol nanoparticles (CA-V NPs) were prepared for the treatment of skin flap ischemia and reperfusion. This study was conducted using a one-step method to prepare new types of CA-V NPs with uniform sizes and stable structures. In vitro, the CA-V NPs exhibited CAT-like and SOD-like activities and could effectively scavenge ROS, generate oxygen, and alleviate oxidative stress. In the H₂O₂-induced cellular oxidative stress model, CA-V NPs effectively reduced ROS levels and inhibited apoptosis through the XIAP/Caspase-3 pathway. In the cellular inflammation model induced by LPS combined with IFN-γ, CA-V NPs reprogrammed macrophage polarization toward the M2 phenotype and reduced inflammatory responses by reducing the expression of the chemokines CCL4 and CXCL2. In addition, animal experiments have shown that CA-V NPs can alleviate oxidative stress in skin flap tissues, inhibit apoptosis, promote angiogenesis, and ultimately improve the survival rate of skin flaps. CA-V NPs provide a new target and strategy for the treatment of flap I/R injury.

Ovarian tumor (OT) is the most lethal form of gynecologic malignancy, with minimal improvements in patient outcomes over the past several decades. Metastasis is the leading cause of ovarian cancer-related deaths, yet the underlying mechanisms remain poorly understood. Psychological stress is known to activate the glucocorticoid receptor (NR3C1), a factor associated with poor prognosis in OT patients. However, the precise mechanisms linking NR3C1 signaling and metastasis have yet to be fully elucidated. In this study, we demonstrate that chronic restraint stress accelerates epithelial-mesenchymal transition (EMT) and metastasis in OT through an NR3C1-dependent mechanism involving nuclear protein 1 (NUPR1). Mechanistically, NR3C1 directly regulates the transcription of NUPR1, which in turn increases the expression of snail family transcriptional repressor 2 (SNAI2), a key driver of EMT. Clinically, elevated NR3C1 positively correlates with NUPR1 expression in OT patients, and both are positively associated with poorer prognosis. Overall, our study identified the NR3C1/NUPR1 axis as a critical regulatory pathway in psychological stress-induced OT metastasis, suggesting a potential therapeutic target for intervention in OT metastasis.

Poly(ADP-ribosyl)ation (PARylation) is a specific form of post-translational modification (PTM) predominantly triggered by the activation of poly-ADP-ribose polymerase 1 (PARP1). However, the role and mechanism of PARylation in the advancement of acute kidney injury (AKI) remain undetermined. Here, we demonstrated the significant upregulation of PARP1 and its associated PARylation in murine models of AKI, consistent with renal biopsy findings in patients with AKI. This elevation in PARP1 expression might be attributed to trimethylation of histone H3 lysine 4 (H3K4me3). Furthermore, a reduction in PARylation levels mitigated renal dysfunction in the AKI mouse models. Mechanistically, liquid chromatography-mass spectrometry indicated that PARylation mainly occurred in receptor for activated C kinase 1 (RACK1), thereby facilitating its subsequent phosphorylation. Moreover, the phosphorylation of RACK1 enhanced its dimerization and accelerated the ubiquitination-mediated hypoxia inducible factor-1α (HIF-1α) degradation, thereby exacerbating kidney injury. Additionally, we identified a PARP1 proteolysis-targeting chimera (PROTAC), A19, as a PARP1 degrader that demonstrated superior protective effects against renal injury compared with PJ34, a previously identified PARP1 inhibitor. Collectively, both genetic and drug-based inhibition of PARylation mitigated kidney injury, indicating that the PARylated RACK1/HIF-1α axis could be a promising therapeutic target for AKI treatment.

Protrusive facial deformities, characterized by the forward displacement of the teeth and/or jaws beyond the normal range, affect a considerable portion of the population. The manifestations and morphological mechanisms of protrusive facial deformities are complex and diverse, requiring orthodontists to possess a high level of theoretical knowledge and practical experience in the relevant orthodontic field. To further optimize the correction of protrusive facial deformities, this consensus proposes that the morphological mechanisms and diagnosis of protrusive facial deformities should be analyzed and judged from multiple dimensions and factors to accurately formulate treatment plans. It emphasizes the use of orthodontic strategies, including jaw growth modification, tooth extraction or non-extraction for anterior teeth retraction, and maxillofacial vertical control. These strategies aim to reduce anterior teeth and lip protrusion, increase chin prominence, harmonize nasolabial and chin-lip relationships, and improve the facial profile of patients with protrusive facial deformities. For severe skeletal protrusive facial deformities, orthodontic-orthognathic combined treatment may be suggested. This consensus summarizes the theoretical knowledge and clinical experience of numerous renowned oral experts nationwide, offering reference strategies for the correction of protrusive facial deformities.
Humans ; Orthodontics, Corrective/methods* ; Consensus ; Malocclusion/therapy* ; Patient Care Planning ; Cephalometry

Enamel demineralization, the formation of white spot lesions, is a common issue in clinical orthodontic treatment. The appearance of white spot lesions not only affects the texture and health of dental hard tissues but also impacts the health and aesthetics of teeth after orthodontic treatment. The prevention, diagnosis, and treatment of white spot lesions that occur throughout the orthodontic treatment process involve multiple dental specialties. This expert consensus will focus on providing guiding opinions on the management and prevention of white spot lesions during orthodontic treatment, advocating for proactive prevention, early detection, timely treatment, scientific follow-up, and multidisciplinary management of white spot lesions throughout the orthodontic process, thereby maintaining the dental health of patients during orthodontic treatment.
Humans ; Consensus ; Dental Caries/etiology* ; Dental Enamel/pathology* ; Tooth Demineralization/etiology* ; Tooth Remineralization

Clear aligner treatment is a novel technique in current orthodontic practice. Distinct from traditional fixed orthodontic appliances, clear aligners have different material features and biomechanical characteristics and treatment efficiencies, presenting new clinical challenges. Therefore, a comprehensive and systematic description of the key clinical aspects of clear aligner treatment is essential to enhance treatment efficacy and facilitate the advancement and wide adoption of this new technique. This expert consensus discusses case selection and grading of treatment difficulty, principle of clear aligner therapy, clinical procedures and potential complications, which are crucial to the clinical success of clear aligner treatment.
Humans ; Consensus ; Orthodontic Appliance Design ; Orthodontic Appliances, Removable ; Tooth Movement Techniques/methods* ; Malocclusion/therapy* ; Orthodontics, Corrective/instrumentation*