Objective To explore the relationship between plantar fascia stiffness and windlass mechanism and their impact on the arch,and provide a biomechanical mechanism explanation for plantar fascia and arch-related diseases.Methods A foot-plate model with 30° flexion angle at the metatarsophalangeal joint was constructed.The musculoskeletal model combined with the three-dimensional finite element analysis method was used,and the dynamic data of the foot during walking at the speed of 5 km/h was obtained using dual fluoroscopic imaging system(DFIS).The finite element model was verified,and the influence of plantar fascia stiffness on the capstan mechanism and arch-related mechanical parameters was explored.Results The finite element simulation analysis results were highly consistent with the foot data obtained by DFIS,confirming the validity of the model.With the increase of plantar fascia stiffness,the windlass effect and the stiffness of the longitudinal arch of the foot both showed an increasing trend,but the flexion angle of the metatarsophalangeal joint decreased,the distal stress of the plantar fascia gradually decreased,and the proximal stress increased;when the plantar fascia stiffness was 25％-150％,the width of the transverse arch of the foot increased with the increase of plantar fascia stiffness,while the height of the transverse arch decreased with the increase of plantar fascia stiffness;when the plantar fascia stiffness was 150％-200％,the width of the transverse arch of the foot decreased,the height increased,and the stiffness also increased.Conclusions An increase in plantar fascia stiffness can enhance the windlass mechanism to some extent,but it also leads to a reduction in metatarsophalangeal joint flexion.The stiffness of the plantar fascia affects the metatarsophalangeal joint flexion,thereby impacting the windlass mechanism and the distal tensile force of the plantar fascia.Together with the ground reaction force at the distal end of the metatarsals,these factors collectively influence the stiffness of the transverse arch of the foot.

Objective To explore the relationship between plantar fascia stiffness and windlass mechanism and their impact on the arch,and provide a biomechanical mechanism explanation for plantar fascia and arch-related diseases.Methods A foot-plate model with 30° flexion angle at the metatarsophalangeal joint was constructed.The musculoskeletal model combined with the three-dimensional finite element analysis method was used,and the dynamic data of the foot during walking at the speed of 5 km/h was obtained using dual fluoroscopic imaging system(DFIS).The finite element model was verified,and the influence of plantar fascia stiffness on the capstan mechanism and arch-related mechanical parameters was explored.Results The finite element simulation analysis results were highly consistent with the foot data obtained by DFIS,confirming the validity of the model.With the increase of plantar fascia stiffness,the windlass effect and the stiffness of the longitudinal arch of the foot both showed an increasing trend,but the flexion angle of the metatarsophalangeal joint decreased,the distal stress of the plantar fascia gradually decreased,and the proximal stress increased;when the plantar fascia stiffness was 25％-150％,the width of the transverse arch of the foot increased with the increase of plantar fascia stiffness,while the height of the transverse arch decreased with the increase of plantar fascia stiffness;when the plantar fascia stiffness was 150％-200％,the width of the transverse arch of the foot decreased,the height increased,and the stiffness also increased.Conclusions An increase in plantar fascia stiffness can enhance the windlass mechanism to some extent,but it also leads to a reduction in metatarsophalangeal joint flexion.The stiffness of the plantar fascia affects the metatarsophalangeal joint flexion,thereby impacting the windlass mechanism and the distal tensile force of the plantar fascia.Together with the ground reaction force at the distal end of the metatarsals,these factors collectively influence the stiffness of the transverse arch of the foot.

Objective:To investigate the association between serum uric acid trajectories and the risk of renal function decline and diabetic kidney disease(DKD) incidence in elderly patients with type 2 diabetes mellitus.Methods:This retrospective cohort study included 5 037 elderly patients with type 2 diabetes mellitus aged 60 years and above who underwent at least three health examinations between 2019 and 2023, with 2019 as the baseline. Latent growth mixture modeling(LGMM) was employed to identify distinct serum uric acid trajectories. Renal function changes and DKD incidence were followed from 2020 to 2023. Binary logistic regression models were used to assess the association between serum uric acid trajectories and the risks of renal function decline and DKD.Results:Two distinct serum uric acid trajectory groups were identified based on model selection criteria: A stable group( n=4 485, 89.04%) and an inverted U-shaped group( n=552, 10.96%). After adjusting for potential confounders, compared with the stable trajectory group, the inverted U-shaped group showed a significantly increased risk of estimated glomerular filtration rate(eGFR) <60 mL·min -1·(1.73 m 2) -1, ≥25% decline in eGFR, doubling of serum creatinine, and DKD events, with OR(95% CI) of 1.99(1.28-3.09), 2.27(1.65-3.13), 1.52(1.09-3.02), and 1.52(1.27-1.82), respectively(all P<0.05). In addition, multivariate analysis indicated that elevated baseline serum uric acid levels were also associated with an increased risk of adverse renal outcomes and DKD incidence; However, the magnitude of the associations was lower than that observed for serum uric acid trajectory groups. Conclusions:An inverted U-shaped serum uric acid trajectory is significantly associated with an increased risk of renal function progression and DKD in elderly patients with type 2 diabetes mellitus. These findings highlight the importance of long-term dynamic monitoring of serum uric acid levels to facilitate early identification and intervention for high-risk individuals.

The aryl hydrocarbon receptor (AhR) plays a crucial role in regulating many physiological processes. Activating the AhR-CYP1A1 axis has emerged as a novel therapeutic strategy against various inflammatory diseases. Here, a practical in situ cell-based fluorometric assay was constructed to screen AhR-CYP1A1 axis modulators, via functional sensing of CYP1A1 activities in live cells. Firstly, a cell-permeable, isoform-specific enzyme-activable fluorogenic substrate for CYP1A1 was rationally constructed for in-situ visualizing the dynamic changes of CYP1A1 function in living systems, which was subsequently used for discovering the efficacious modulators of the AhR-CYP1A1 axis. Following screening of a compound library, LAC-7 was identified as an efficacious activator of the AhR-CYP1A1 axis, which dose-dependently up-regulated the expression levels of both CYP1A1 and AhR in multiple cell lines. LAC-7 also suppressed macrophage M1 polarization and reduced the levels of inflammatory factors in LPS-induced bone marrow-derived macrophages. Animal tests showed that LAC-7 could significantly mitigate DSS-induced ulcerative colitis and LPS-induced acute lung injury in mice, and markedly reduced the levels of multiple inflammatory factors. Collectively, an optimized fluorometric cell-based assay was devised for in situ functional imaging of CYP1A1 activities in living systems, which strongly facilitated the discovery of efficacious modulators of the AhR-CYP1A1 axis as novel anti-inflammatory agents.

Notum, a negative feedback regulator of the Wnt signaling, has emerged as a promising target for treating glucocorticoid-induced osteoporosis (GIOP). This study showcases an efficient strategy for discovering the anti-Notum constituents from herbal medicines (HMs) as novel anti-GIOP agents. Firstly, a rapid-responding near-infrared fluorogenic substrate for Notum was rationally engineered for high-throughput identifying the anti-Notum HMs. The results showed that Bu-Gu-Zhi (BGZ), a known anti-osteoporosis herb, potently inhibited Notum in a competitive-inhibition manner. To uncover the key anti-Notum constituents in BGZ, an efficient strategy was adapted via integrating biochemical, phytochemical, computational, and pharmacological assays. Among all identified BGZ constituents, three furanocoumarins were validated as strong Notum inhibitors, while 5-methoxypsoralen (5-MP) showed the most potent anti-Notum activity and favorable safety profiles. Mechanistically, 5-MP acted as a competitive inhibitor of Notum via creating strong hydrophobic interactions with Trp128 and Phe268 in the catalytic cavity of Notum. Cellular assays showed that 5-MP remarkably promoted osteoblast differentiation and activated Wnt signaling in dexamethasone (DXMS)-challenged MC3T3-E1 osteoblasts. In dexamethasone-induced osteoporotic mice, 5-MP strongly elevated bone mineral density (BMD) and improved cancellous and cortical bone thickness. Collectively, this study constructs a high-efficient platform for discovering key anti-Notum constituents from HMs, while 5-MP emerges as a promising anti-GIOP agent.

Objective To investigate the expression of long non-coding RNA(lncRNA)X-inac-tive specific transcript(XIST)and microRNA-410-3p(miR-410-3p)in serum of patients with rheu-matoid arthritis(RA),and their correlation with bone mineral density(BMD)and bone metabolism indicators.Methods A total of 109 RA patients were selected as research subjects.After measuring BMD using dual-energy X-ray absorptiometry(DXA),they were divided into osteoporosis group(53 cases)and non-osteoporosis group(56 cases).BMD at different sites and serum levels of lncRNA XIST,miR-410-3p,and bone metabolism indicators[β-C-terminal telopeptide of type Ⅰ collagen(β-CTX),parathyroid hormone(PTH),osteocalcin(OC),osteoprotegerin(OPG),and N-terminal propeptide of type Ⅰ procollagen(PⅠNP)]were compared between the two groups.Pearson correlation analysis was used to analyze the correlation between lncRNA XIST and miR-410-3p,as well as their correlation with BMD and bone metabolism indicators.Logistic regression analysis was used to screen the influencing factors for osteoporosis in RA patients.Results Compared with the non-oste-oporosis group,the osteoporosis group had lower BMD at the lumbar spine,femoral neck,greater trochanter,and Ward's triangle area,higher levels of OPG,β-CTX,and lncRNA XIST,and lower levels of mi R-410-3p,with statistically significant differences(P＜0.05).There were no statistical-ly significant differences in PTH,OC,and PⅠNP levels between the two groups(P＞0.05).Pear-son correlation analysis showed that serum lncRNA XIST levels were negatively correlated with miR-410-3p levels(r=-0.435,P＜0.001).Serum lncRNA XIST levels were negatively correlated with BMD at the lumbar spine,femoral neck,greater trochanter,and Ward's triangle area(P＜0.05),and positively correlated with OC levels(P＜0.05).Serum mniR-410-3p levels were positively correlated with BMD at the lumbar spine,femoral neck,greater trochanter,and Ward's triangle area(P＜0.05),and negatively correlated with OC levels(P＜0.05).Multivariate logistic regression analysis showed that BMD,lncRNA XIST,and miR-410-3p were all independent influencing factors for osteoporosis in RA patients(P＜0.05).Conclusion LncRNA XIST expression is upregulated in serum of RA patients with osteoporosis,while mi R-410-3p expression is downregulated.They are closely related to BMD at the lumbar spine,femoral neck,greater trochanter,and Ward's triangle area,as well as OC levels of bone metabolism indicators.

Objective:This study aimed to explore the impact of a single Scutellaria baicalensis decoction on the intestinal flora and barrier function in sepsis rats subjected to an endotoxin "second strike."Methods:Twenty-eight healthy adult male SPF-grade SD rats were utilized to develop an acute lung injury model of sepsis induced by an endotoxin "second strike." The rats were randomLy allocated into four groups: sham operation, model, normal dose Scutellaria baicalensis, and high dose Scutellaria baicalensis, with seven rats in each group. Six hours prior to model induction, the normal dose group received 2 mL of Scutellaria baicalensis decoction at 1 g/kg, while the high dose group received 4 g/kg. Both the sham operation and model groups were administered an equivalent volume of normal saline once daily for three consecutive days. Post-experiment, intestinal tissue, blood, and stool samples were collected. HE staining was used to observe intestinal histopathological changes, ELISA to detect serum D-lactic acid and Fn levels, Western blot to measure intestinal tissue NF-κB, and 16S rRNA gene sequencing to analyze intestinal flora. Correlations between intestinal flora and D-lactic acid, Fn, and NF-κB were examined.Results:Compared to the sham operation group, the model group exhibited inflammatory cell infiltration and tissue structure damage in the intestinal tissue, significantly increased NF-κB expression, markedly decreased serum Fn, and elevated D-lactic acid levels. The abundance of Firmicutes and Lactobacillus in the intestine significantly decreased, while Bacteroidota increased ( P<0.05). In contrast, the normal and high dose groups showed significantly reduced serum Fn and D-lactic acid levels, decreased intestinal NF-κB expression, and increased Firmicutes and Lactobacillus abundance ( P<0.05). Bacteroidota levels decreased, and intestinal tissue inflammatory pathology was notably alleviated. No significant differences were observed in Fn, D-lactic acid, and NF-κB expressions between the normal and high dose groups, nor in the abundance of Firmicutes, Bacteroidota, and Lactobacillus. Firmicutes abundance and the Firmicutes/Bacteroidota ratio positively correlated with Fn ( P<0.01) but negatively with D-lactic acid and NF-κB ( P<0.01). Bacteroidota abundance negatively correlated with Fn ( P<0.01) and positively with D-lactic acid and NF-κB ( P<0.01). Conclusions:Alterations in intestinal flora and mucosal barrier damage are implicated in the lung injury of sepsis rats induced by an endotoxin "second strike." Scutellaria baicalensis decoction exerts a protective effect on intestinal function in these rats, potentially by optimizing the abundance of beneficial intestinal flora, preserving the intestinal mucosal barrier, mitigating inflammatory responses, and safeguarding endothelial cell function.

Objective:To investigate the association between serum uric acid trajectories and the risk of renal function decline and diabetic kidney disease(DKD) incidence in elderly patients with type 2 diabetes mellitus.Methods:This retrospective cohort study included 5 037 elderly patients with type 2 diabetes mellitus aged 60 years and above who underwent at least three health examinations between 2019 and 2023, with 2019 as the baseline. Latent growth mixture modeling(LGMM) was employed to identify distinct serum uric acid trajectories. Renal function changes and DKD incidence were followed from 2020 to 2023. Binary logistic regression models were used to assess the association between serum uric acid trajectories and the risks of renal function decline and DKD.Results:Two distinct serum uric acid trajectory groups were identified based on model selection criteria: A stable group( n=4 485, 89.04%) and an inverted U-shaped group( n=552, 10.96%). After adjusting for potential confounders, compared with the stable trajectory group, the inverted U-shaped group showed a significantly increased risk of estimated glomerular filtration rate(eGFR) <60 mL·min -1·(1.73 m 2) -1, ≥25% decline in eGFR, doubling of serum creatinine, and DKD events, with OR(95% CI) of 1.99(1.28-3.09), 2.27(1.65-3.13), 1.52(1.09-3.02), and 1.52(1.27-1.82), respectively(all P<0.05). In addition, multivariate analysis indicated that elevated baseline serum uric acid levels were also associated with an increased risk of adverse renal outcomes and DKD incidence; However, the magnitude of the associations was lower than that observed for serum uric acid trajectory groups. Conclusions:An inverted U-shaped serum uric acid trajectory is significantly associated with an increased risk of renal function progression and DKD in elderly patients with type 2 diabetes mellitus. These findings highlight the importance of long-term dynamic monitoring of serum uric acid levels to facilitate early identification and intervention for high-risk individuals.

Objective To detect the expression levels of tumor necrosis factor alpha induced protein 3(TN-FAIP3)and LINC00887 in clear cell renal cell carcinoma(ccRCC)tissue,and to study their relationship with clinical pathological parameters and prognosis.Methods A total of 101 ccRCC patients admitted to the hospi-tal from January 2013 to October 2018 were selected.The expression levels of TNFAIP3 and LINC00887 were detected in ccRCC cancer tissue and paired adjacent tissues,respectively.The relationship between TNFAIP3 and LINC00887 expression and clinical pathological parameters and prognosis of ccRCC patients was analyzed,and the influencing factors of poor prognosis in ccRCC patients were also analyzed.Spearman correlation coef-ficient was used to analyze the correlation between TNFAIP3 and LINC00887 expression.Results The posi-tive rate of TNFAIP3 expression in ccRCC(37.62％)was significantly lower than that in adjacent tissues(52.48％),and the difference was statistically significant(X2=4.500,P=0.034).The expression level of LINC00887 in ccRCC(1.38±0.61)was significantly higher than that in adjacent tissues(1.03±0.43),and the difference was statistically significant(t=5.396,P＜0.001).The positive rates of TNFAIP3 protein in pa-tients with maximum tumor diameter ≥4.5 cm and TNM stage Ⅲ-Ⅳ were lower than those in patients with maximum tumor diameter＜4.5 cm and TNM stage Ⅰ-Ⅱ,and the differences were statistically significant(P＜0.05).The positive rates of LINC00887 in patients with maximum tumor diameter ≥ 4.5 cm,pathologi-cal grading Ⅲ-Ⅳ,and TNM stage Ⅲ-Ⅳ were higher than those in patients with maximum tumor diameter＜4.5 cm,pathological grading Ⅰ-Ⅱ,and TNM stage Ⅰ-Ⅱ,and the differences were statistically signifi-cant(P＜0.05).Compared with the TNFAIP3 high expression group,the TNFAIP3 low expression group had a poorer prognosis,and the difference was statistically significant(x2=5.118,P=0.024).Compared with the LINC00887 low expression group of,the LINC00887 high expression group had a poorer prognosis,and the difference was statistically significant(x2=4.638,P=0.031).Low expression of TNFAIP3,high expres-sion of LINC00887,pathological grade Ⅲ-Ⅳ,and TNM stage Ⅲ-Ⅳ were risk factors for poor prognosis in ccRCC patients(P＜0.05).Spearman rank correlation analysis showed that there was a negative correlation between TNFAIP3 and LINC00887 expression in ccRCC tissue(r=-0.638,P=0.012).Conclusion TN-FAIP3 expression is down-regulated and L1NC00887 expression is up-regulated in ccRCC tissue,and there is a negative correlation.They may jointly regulate the occurrence and development of ccRCC,and have the poten-tial to become tumor markers for evaluating the prognosis of ccRCC patients.