Background: and Purpose Bilirubin has potent antioxidant, anti-inflammatory, and neuroprotective effects. Herein, we investigated whether total bilirubin (TBIL) modifies the association between hypertension and cerebral small vessel disease (CSVD). Methods: Data were obtained from the PolyvasculaR Evaluation for Cognitive Impairment and vaScular Events study. TBIL and direct bilirubin (DBIL) levels were assayed using fasting venous blood samples. Indirect bilirubin (IBIL) was calculated by subtracting DBIL from TBIL. TBIL was stratified as ≤17 μmol/L and >17 μmol/L based on the biological relevance of Gilbert’s syndrome. Hypertension was defined as blood pressure ≥140/90 mm Hg, self-reported hypertension history, or current use of antihypertensive agents. White matter hyperintensity, lacunes, cerebral microbleeds, and enlarged perivascular spaces were evaluated using magnetic resonance imaging and used to rate CSVD burden according to the criteria proposed by Wardlaw et al. and Rothwell et al. Results: This study included 3,061 participants, with a mean age of 61.2±6.7 years and 46.5% males. After adjusting for confounders, hypertension was associated with increased odds of presence of CSVD (Wardlaw: odds ratio [OR]=1.86, 95% confidence interval [CI] 1.41–2.44, P<0.001; Rothwell: OR=1.84, 95% CI 1.43–2.38, P<0.001) and higher modified total CSVD burden (common OR: 1.85, 95% CI 1.45–2.36, P<0.001) in participants with TBIL ≤17 μmol/L but not in TBIL >17 μmol/L (P for interaction <0.05). Johnson–Neyman analyses showed cut-off concentrations of 22.3–22.4 μmol/L for effect modification by TBIL. IBIL contributed to effect modification, whereas DBIL did not. Conclusions Mildly elevated TBIL may modify the association between hypertension and CSVD.

BACKGROUND:Wolff's law points out that the lack of mechanical stress in the body will lead to the degradation of the microstructure of bone tissue,mass loss,and metabolic disorders,and eventually lead to osteoporosis,which suggests that mechanical stress plays an important role in the growth,reconstruction,and formation of bone tissue.At present,the relevant studies concerning mechanical stress on osteoblasts mainly focus on fluid shear force,but it is difficult to intervene in vivo.Meanwhile,some studies have found that compressive stress can also play a similar role in fluid shear force to a certain extent.Exploring the mode of action and influence of compressive stress on cells in vitro experiments can enrich the interaction relationship between mechanical stress and cells.It helps provide a theoretical basis for studies of metabolic bone diseases,including osteoporosis,and other diseases.OBJECTIVE:To review in vitro experiments,the application of compressive stress to cells,different biological behaviors caused by cells,the possible signaling pathways,and possible future applications.METHODS:We searched PubMed,Web of Science,CNKI,and WanFang databases from January 2000 to March 2024 to include all articles related to compressive stress on cells,including basic research and microscopic mechanism studies,using search terms"compressive stress,mechanical stress,hydrostatic pressure,cell"in Chinese and English.Finally,the 63 included articles were reviewed.RESULTS AND CONCLUSION:(1)There are various ways to apply compressive stress,and different experimental equipment has different ways of pressurizing cells,so it is necessary to further standardize the experimental equipment,standardize the pressurization unit,reduce the confounding factors,and make the reference and comparability between different experimental groups.(2)Compressive stress can cause changes in cell proliferation,differentiation,autophagy,apoptosis,migration,etc.,and the effect of compressive stress is time-or dose-dependent in most cases.(3)At present,most in vitro experimental studies have shown that compressive stress may mainly act on osteoblasts through MAPK signaling pathway and Wnt/β-catenin signaling pathway,causing osteoblasts to produce different responses.(4)The effect of compressive stress on different cells is not the same,and its possible biological effects need to be studied.(5)Further research on compressive stress is helpful to provide a theoretical basis for treatment in orthopedics,stomatology,tumors and other fields,and gentle disinfection using hydrostatic pressure is a promising disinfection method.

OBJECTIVE: To preliminarily investigate the effect of buccal acupuncture therapy on ameliorating postoperative pain and enhancing recovery quality among patients undergoing radical resection of gastrointestinal cancers. METHODS: Fifty-two participants were randomized at a 1:1 ratio to either the buccal acupuncture or the control group. The acupuncture protocol entailed targeting 5 predetermined acupoints [CA-2 (Upper jiao), CA-3 (Middle jiao), CA-4 (Lower jiao), CA-6 (back), and CA-7 (waist) and two adjustable acupoints [CA-1 (head) and CA-8 (sacrum)] on each side of the face. The outcomes included the Numeric Rating Scale (NRS) scores for each day within 7 days postoperatively, 15-Item Quality of Recovery Scale (QoR-15) scores, analgesics consumption during and after surgery, incidences of postoperative nausea and vomiting, and perioperative levels of interleukin-6 and glucose. Adverse events related to acupuncture were recorded. RESULTS: Of the initial 52 participants, 46 completed the study and were included in the analysis. Findings indicated that the buccal acupuncture group experienced significantly reduced resting NRS scores in post-anesthesia care unit and throughout the postoperative phase (P=0.001 and P=0.003, respectively), along with enhanced QoR-15 scores on the 3rd postoperative day (P=0.008), compared to the control group. No notable differences were identified in the remaining indicators (P>0.05). CONCLUSION Buccal acupuncture therapy demonstrated significant effectiveness in reducing postoperative pain and improving recovery quality for patients undergoing radical resection of gastrointestinal cancers, presenting a viable intervention without associated adverse outcomes. (Trial registration No. ChiCTR2200060441).
Humans ; Male ; Pilot Projects ; Female ; Acupuncture Therapy/methods* ; Pain, Postoperative/therapy* ; Middle Aged ; Gastrointestinal Neoplasms/surgery* ; Aged ; Acupuncture Points ; Adult

OBJECTIVE: This study aimed to evaluate the association between susceptibility genes and non-alcoholic fatty liver disease (NAFLD) in children with obesity. METHODS: We conducted a two-step case-control study. Ninety-three participants were subjected to whole-exome sequencing (exploratory set). Differential genes identified in the small sample were validated in 1,022 participants using multiplex polymerase chain reaction and high-throughput sequencing (validation set). RESULTS: In the exploratory set, 14 genes from the NAFLD-associated pathways were identified. In the validation set, after adjusting for sex, age, and body mass index, ECI2 rs2326408 (dominant model: OR = 1.33, 95% CI: 1.02-1.72; additive model: OR = 1.22, 95% CI: 1.01-1.47), C6orf201 rs659305 (dominant model: OR = 1.30, 95% CI: 1.01-1.69; additive model: OR = 1.21, 95% CI: 1.00-1.45), CALML5 rs10904516 (pre-ad dominant model: OR = 1.36, 95% CI: 1.01-1.83; adjusted dominant model: OR = 1.40, 95% CI: 1.03-1.91; and pre-ad additive model: OR = 1.26, 95% CI: 1.04-1.66) polymorphisms were significantly associated with NAFLD in children with obesity ( P < 0.05). Interaction analysis revealed that the gene-gene interaction model of CALML5 rs10904516, COX11 rs17209882, and SCD5 rs3733228 was optional ( P < 0.05), demonstrating a negative interaction between the three genes. CONCLUSION In the Chinese population, the CALML5 rs10904516, C6orf201 rs659305, and ECI2 rs2326408 variants could be genetic markers for NAFLD susceptibility.
Humans ; Non-alcoholic Fatty Liver Disease/genetics* ; Child ; Male ; Female ; Genetic Predisposition to Disease ; Case-Control Studies ; Exome Sequencing ; Adolescent ; Polymorphism, Single Nucleotide ; Obesity/complications* ; Pediatric Obesity/complications* ; China

Objective:To investigate the short-term clinical efficacy of implantation with a 3D-printed microporous titanium prosthesis in the treatment of large segmental infectious tibial defects.Methods:A retrospective analysis was conducted of the electronic medical records of the 47 patients with large segmental tibial defects who had been treated with 3D-printed microporous titanium prostheses at Department of Orthopaedics, 920th Hospital of Joint Logistics Support Force from January 2019 to February 2024. The cohort included 36 males and 11 females, with an age of (46.2±11.8) years and a mean bone defect length of 12.3 (8.0, 16.8) cm. In the 19 patients complicated with soft tissue defects, the area of soft tissue defects ranged from 10.0 cm × 6.0 cm to 33.0 cm × 10.0 cm. For the 28 patients without soft tissue defects at the lower leg, the bone defects were filled with vancomycin-loaded calcium sulfate bone cement at the first stage; for the 19 patients complicated with soft tissue defects, the soft tissue defects at the lower limb were repaired using an anterolateral thigh flap with vascular anastomosis at the same time when bone defects were filled with vancomycin-loaded calcium sulfate bone cement at the first stage. After infection control at 2 to 8 months after surgery, individualized 3D-printed microporous titanium prostheses were implanted at the second stage to reconstruct the bone defects. Postoperative observations included the patients' first standing time, crutch walking time, full weight-bearing time, osseointegration of the tibial fracture and the prosthesis, and complications during follow-up.Results:The follow-up period for the 47 patients was (34.7±14.3) months. The first standing time was (2.2±0.6) months, crutch walking time (3.8±1.1) months, and full weight-bearing time (5.3±1.2) for this cohort. The evaluation by the Paley's bone healing score resulted in 25 excellent cases, 18 good cases, 1 medium case, and 3 poor cases, giving an excellent and good rate of 91.5% (43/47). One year after operation, the X-ray films showed that the tibial fractures and prostheses were well integrated in the 43 patients. Two patients developed recurrent tibial infection which was responded to replacement of the vancomycin-loaded calcium sulfate spacer. The fixation screws for tibial prosthesis were broken in one patient, but no recurrence of infection was observed after revision. The overall incidence of complications was 6.4% (3/47).Conclusion:In the treatment of large segmental infectious tibial defects, by facilitating rapid functional recovery and ensuring a low incidence of complications, implantation with a 3D-printed microporous titanium prosthesis demonstrates fine short-term clinical efficacy.

Objective To evaluate the efficacy and safety of a novel gastrointestinal mucosal elevation gel in vivo porcine model. Methods Eight healthy white pigs were selected, which were uesd to bump height evaluation (n=2) and safety evaluation (n=6). The sample (alimentary canal mucosa bump gel sample) and the control sample (disposable endoscopic submucosal filler of alimentary canal) were respectively injected into the submucosa of pig gastric antrum and gastric body. In the evaluation of elevation height, the morphology, persistence, and clinical safety of mucosal elevation were observed and recorded immediately and 30 minutes after injection. In safety evaluation, endoscopic mucosal resection was performed after injection, and the mucosal protrusion shape, product efficacy, and clinical safety were observed and recorded at immediate and 7-day time points. After observation, all animals were euthanized and tissue samples were collected and excised for histopathological evaluation. Results In elevation height evaluation, sample group showed a steep elevation immediately after surgery, exhibiting a more pronounced elevation morphology compared to control group (P=0.019). Only two (25%) sites of the elevation showed slight collapse in 30 minutes after surgery, and the durability notably increased compared to control group (8 all collapsed, P＜0.001). In safety evaluation, the average trauma area of sample group was 1.77 mm², which was significantly lower than control group (2.65 mm², P＜0.001). There was no statistical difference among average injection dose per unit area, surgical time per unit area, and en bloc resection rate. Sample group showed mild ulcers and only 1 (12.5%) site of mild bleeding at immediate time point after surgery. No bleeding, perforation, ulcer or edema was observed in sample group 7 days after surgery, and no statistical difference was identified compared to control group. Histopathological evaluation found that the gastric antrum and body tissues exhibited moderate injury and mild edema at immediate time point, accompanied by mild inflammatory cellular infiltration. At 7-day time point, gastric antrum tissues demonstrated moderate injury, mild edema and mild inflammatory cellular infiltration, with 1 (12.5%) site of tissues infected, while in gastric body tissues, no bleeding was observed, whereas moderate injury and mild edema were evident, accompanied by mild inflammatory cellular infiltration and 3 (37.5%) sites of tissues infected, all of which were not statistically different from control group. Conclusion The novel gastrointestinal mucosal elevation gel exhibited steep elevation morphology, long-lasting elevation height, and favorable efficacy and safety in preclinical animal trials, showing enormous clinical application potential.

This study investigated the effect of Wuling San on transforming growth factor-β1(TGF-β1)-induced fibrosis, inflammation, and oxidative stress in human renal tubular epithelial cells(HK-2) and its mechanism of antioxidant stress injury. HK-2 cells were cultured in vitro and divided into a control group, a TGF-β1 model group, and three treatment groups receiving Wuling San-containing serum at low(2.5%), medium(5.0%), and high(10.0%) doses. TGF-β1 was used to establish the model in all groups except the control group. CCK-8 was used to analyze the effect of different concentrations of Wuling San on the activity of HK-2 cells with or without TGF-β1 stimulation. The expression of key fibrosis molecules, including actin alpha 2(Acta2), collagen type Ⅰ alpha 1 chain(Col1α1), collagen type Ⅲ alpha 1 chain(Col3α1), TIMP metallopeptidase inhibitor 1(Timp1), and fibronectin 1(Fn1), was detected using qPCR. The expression levels of inflammatory cytokines, including tumor necrosis factor-α(TNF-α), interleukin-1β(IL-1β), interleukin-6(IL-6), interleukin-8(IL-8), and interleukin-4(IL-4), were measured using ELISA kits. Glutathione peroxidase(GSH-Px), malondialdehyde(MDA), catalase(CAT), and superoxide dismutase(SOD) biochemical kits were used to analyze the effect of Wuling San on TGF-β1-induced oxidative stress injury in HK-2 cells, and the expression of nuclear factor E2-related factor 2(Nrf2), heme oxygenase 1(HO-1), and NAD(P)H quinone oxidoreductase 1(NQO1) was analyzed by qPCR and immunofluorescence. The CCK-8 results indicated that the optimal administration concentrations of Wuling San were 2.5%, 5.0%, and 10.0%. Compared with the control group, the TGF-β1 model group showed significantly increased levels of key fibrosis molecules(Acta2, Col1α1, Col3α1, Timp1, and Fn1) and inflammatory cytokines(TNF-α, IL-1β, IL-6, IL-8, and IL-4). In contrast, the Wuling San administration groups were able to dose-dependently inhibit the expression levels of key fibrosis molecules and inflammatory cytokines compared with the TGF-β1 model group. Wuling San significantly increased the activities of GSH-Px, CAT, and SOD enzymes in TGF-β1-stimulated HK-2 cells and significantly inhibited the level of MDA. Furthermore, compared with the control group, the TGF-β1 model group exhibited a significant reduction in the expression of Nrf2, HO-1, and NQO1 genes and proteins. After Wuling San intervention, the expression of Nrf2, HO-1, and NQO1 genes and proteins was significantly increased. Correlation analysis showed that antioxidant stress enzymes(GSH-Px, CAT, and SOD) and Nrf2 signaling were significantly negatively correlated with key fibrosis molecules and inflammatory cytokines in the TGF-β1-stimulated HK-2 cell model. In conclusion, Wuling San can inhibit TGF-β1-induced fibrosis in HK-2 cells by activating the Nrf2 signaling pathway, improving oxidative stress injury, and reducing inflammation.
Humans ; Oxidative Stress/drug effects* ; Transforming Growth Factor beta1/metabolism* ; Fibrosis/genetics* ; Cell Line ; Drugs, Chinese Herbal/pharmacology* ; Epithelial Cells/immunology* ; Inflammation/metabolism*

Jiuwei Xifeng Granules have become a Chinese patent medicine in the market. Because the formula contains Os Draconis, a top-level protected fossil of ancient organisms, the formula was to be improved by replacing Os Draconis with Ostreae Concha. To evaluate whether the improved formula has the same effectiveness and safety as the original formula, a randomized, double-blind, parallel-controlled, equivalence clinical trial was conducted. This study enrolled 288 tic disorder(TD) of children and assigned them into two groups in 1∶1. The treatment group and control group took the modified formula and original formula, respectively. The treatment lasted for 6 weeks, and follow-up visits were conducted at weeks 2, 4, and 6. The primary efficacy endpoint was the difference in Yale global tic severity scale(YGTSS)-total tic severity(TTS) score from baseline after 6 weeks of treatment. The results showed that after 6 weeks of treatment, the declines in YGTSS-TSS score showed no statistically significant difference between the two groups. The difference in YGTSS-TSS score(treatment group-control group) and the 95%CI of the full analysis set(FAS) were-0.17[-1.42, 1.08] and those of per-protocol set(PPS) were 0.29[-0.97, 1.56], which were within the equivalence boundary [-3, 3]. The equivalence test was therefore concluded. The two groups showed no significant differences in the secondary efficacy endpoints of effective rate for TD, total score and factor scores of YGTSS, clinical global impressions-severity(CGI-S) score, traditional Chinese medicine(TCM) response rate, or symptom disappearance rate, and thus a complete evidence chain with the primary outcome was formed. A total of 6 adverse reactions were reported, including 4(2.82%) cases in the treatment group and 2(1.41%) cases in the control group, which showed no statistically significant difference between the two groups. No serious suspected unexpected adverse reactions were reported, and no laboratory test results indicated serious clinically significant abnormalities. The results support the replacement of Os Draconis by Ostreae Concha in the original formula, and the efficacy and safety of the modified formula are consistent with those of the original formula.
Adolescent ; Child ; Child, Preschool ; Female ; Humans ; Male ; Double-Blind Method ; Drugs, Chinese Herbal/therapeutic use* ; Tic Disorders/drug therapy* ; Treatment Outcome

This study explored the potential therapeutic targets and mechanisms of Danggui Shaoyao San(DSS) in the prevention and treatment of Alzheimer's disease(AD) through transcriptomics and metabolomics, combined with animal experiments. Fifty male C57BL/6J mice, aged seven weeks, were randomly divided into the following five groups: control, model, positive drug, low-dose DSS, and high-dose DSS groups. After the intervention, the Morris water maze was used to assess learning and memory abilities of mice, and Nissl staining and hematoxylin-eosin(HE) staining were performed to observe pathological changes in the hippocampal tissue. Transcriptomics and metabolomics were employed to sequence brain tissue and identify differential metabolites, analyzing key genes and metabolites related to disease progression. Reverse transcription-quantitative polymerase chain reaction(RT-qPCR) was employed to validate the expression of key genes. The Morris water maze results indicated that DSS significantly improved learning and cognitive function in scopolamine(SCOP)-induced model mice, with the high-dose DSS group showing the best results. Pathological staining showed that DSS effectively reduced hippocampal neuronal damage, increased Nissl body numbers, and reduced nuclear pyknosis and neuronal loss. Transcriptomics identified seven key genes, including neurexin 1(Nrxn1) and sodium voltage-gated channel α subunit 1(Scn1a), and metabolomics revealed 113 differential metabolites, all of which were closely associated with synaptic function, oxidative stress, and metabolic regulation. RT-qPCR experiments confirmed that the expression of these seven key genes was consistent with the transcriptomics results. This study suggests that DSS significantly improves learning and memory in SCOP model mice and alleviates hippocampal neuronal pathological damage. The mechanisms likely involve the modulation of synaptic function, reduction of oxidative stress, and metabolic balance, with these seven key genes serving as important targets for DSS in the treatment of AD.
Animals ; Alzheimer Disease/genetics* ; Male ; Drugs, Chinese Herbal/administration & dosage* ; Mice ; Mice, Inbred C57BL ; Metabolomics ; Transcriptome/drug effects* ; Maze Learning/drug effects* ; Hippocampus/metabolism* ; Humans ; Disease Models, Animal ; Memory/drug effects*