Metabolic-associated fatty liver disease (MAFLD) and osteoporosis (OP) are two very common metabolic diseases. A growing body of experimental evidence supports a pathophysiological link between MAFLD and OP. MAFLD is often associated with the development of OP. Rutaecarpine (RUT) is one of the main active components of Chinese medicine Euodiae Fructus. Our previous studies have demonstrated that RUT has lipid-lowering, anti-inflammatory and anti-atherosclerotic effects, and can improve the OP of rats. However, whether RUT can improve both fatty liver and OP symptoms of MAFLD mice at the same time remains to be investigated. In this study, we used C57BL/6 mice fed a high-fat diet (HFD) for 4 months to construct a MAFLD model, and gave the mice a low dose (5 mg·kg^-1) and a high dose (15 mg·kg^-1) of RUT by gavage for 4 weeks. The effects of RUT on liver steatosis and bone metabolism were then evaluated at the end of the experiment [this experiment was approved by the Experimental Animal Ethics Committee of Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences (approval number: IMB-20190124D₃03)]. The results showed that RUT treatment significantly reduced hepatic steatosis and lipid accumulation, and significantly reduced bone loss and promoted bone formation. In summary, this study shows that RUT has an effect of improving fatty liver and OP in MAFLD mice.

Objective:To evaluate the clinical outcomes of mandibular angle osteotomy combined with wing-shaped genioplasty for the correction of low-angle mandibular prominence with microgenia.Methods:A retrospective analysis was conducted on patients who underwent mandibular angle osteotomy and wing-shaped genioplasty at the Second Hospital of Nanjing between January 2020 and December 2022. Preoperative three-dimensional computed tomography and lateral cephalograms were obtained, and relevant parameters were measured, including the Frankfort horizontal plane to mandibular plane angle (∠FH-MP), the lower lip to soft tissue pogonion angle (∠LiaV-Pog) and the facial height index (FHI). Based on the measurements, surgical experience, and patient preference, the osteotomy lines for the mandibular angle and the wing-shaped genioplasty were designed. During the procedure, mandibular angle osteotomy and wing-shaped genioplasty were performed in accordance with the preoperative surgical plan. The distal genial segment was advanced and inferiorly repositioned according to the predetermined measurements and rigidly fixed to the bilateral mental tubercles using titanium plates and screws. The bone segments resected from the mandibular angle were then longitudinally split into either single- or double-layer bone grafts. These grafts were meticulously implanted into the interpositional gap at the genial region to optimize chin projection and refine the lower facial contour. Postoperative monitoring included assessments of wound healing, complications and lower facial contour. At the final follow-up, lateral cephalograms were taken for remeasurement, and patient satisfaction was surveyed. Statistical analysis was performed using SPSS 22.0 software. Pre- and postoperative data for ∠FH-MP, ∠LiaV-Pog, and FHI were presented as Mean ± SD and compared using paired t-tests, with a P-value < 0.05 considered statistically significant. Results:Twelve female patients, aged 22-35 years (mean 28.3), were included. The follow-up period ranged from 6 to 24 months. All surgical sites achieved primary healing without early complications such as hemorrhage, hematoma, or wound infection. However, all patients experienced transient mental numbness, which resolved within 3 to 6 months. All patients achieved a smooth and natural mandibular contour. CT scans confirmed satisfactory survival of the grafted bone. All patients expressed satisfaction with the aesthetic outcomes. Postoperative measurements of ∠FH-MP, ∠LiaV-Pog, and FHI were (25.2±4.6)°, (24.0±1.2)°, and (52.0±1.3)%, respectively, which were significantly improved compared to the preoperative values of (16.8±5.9)°, (36.5±4.8)°, and (66.0±4.3)% (all P < 0.01). Conclusion:The combination of mandibular angle osteotomy and wing-shaped genioplasty is an effective and safe procedure for correcting low-angle mandibular prominence with microgenia. This technique significantly increases the mandibular plane angle, creates a natural and smooth mandibular contour, and yields stable result with high patient satisfaction.

McCune-Albright syndrome(MAS) is a postzygotic somatic mutation disorder caused by activating mutations in the GNAS gene, which encodes the α subunit of the stimulatory G protein. Its clinical features typically include polyostotic fibrous dysplasia, cafe-au-lait skin pigmentation, and endocrine hyperactivity, such as Cushing′s syndrome, hyperthyroidism, and growth hormone excess. Here, we report two rare cases of MAS complicated with adrenocorticotropic hormone(ACTH)-independent Cushing syndrome, and provide a review and analysis of previously reported MAS cases associated with Cushing′s syndrome.

Diabetic kidney disease(DKD)with increasing global prevalence lacks effective therapeutic targets to halt or reverse its progression.Therapeutic targets supported by causal genetic evidence are more likely to succeed in randomized clinical trials.In this study,we integrated large-scale plasma proteomics,genetic-driven causal inference,and experimental validation to identify prioritized targets for DKD using the UK Biobank(UKB)and FinnGen cohorts.Among 2844 diabetic patients(528 with DKD),we identified 37 targets significantly associated with incident DKD,supported by both observational and causal evi-dence.Of these,22％(8/37)of the potential targets are currently under investigation for DKD or other diseases.Our prospective study confirmed that higher levels of three prioritized targets-insulin-like growth factor binding protein 4(IGFBP4),family with sequence similarity 3 member C(FAM3C),and prostaglandin D2 synthase(PTGDS)—were associated with a 4.35,3.51,and 3.57-fold increased likeli-hood of developing DKD,respectively.In addition,population-level protein-altering variants(PAVs)analysis and in vitro experiments cross-validated FAM3C and IGFBP4 as potential new target candidates for DKD,through the classic NLR family pyrin domain containing 3(NLRP3)-caspase-1-gasdermin D(GSDMD)apoptotic axis.Our results demonstrate that integrating omics data mining with causal inference may be a promising strategy for prioritizing therapeutic targets.

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*

The tumor microenvironment is a crucial factor in tumor occurrence and progression. The hypoxic microenvironment is widely present in tumor tissue and is a key endogenous factor accelerating tumor deterioration. The "blood stasis toxin" theory, as an emerging perspective in tumor research, is regarded as the unique "soil" in tumor progression from the perspective of traditional Chinese medicine(TCM) due to its dynamic evolution mechanism, which closely resembles the formation of the hypoxic microenvironment. Scientifically integrating TCM theories with the biological characteristics of tumors and exploring precise syndrome differentiation and treatment strategies are key to achieving comprehensive tumor prevention and control. This article focused on the hypoxic microenvironment of the tumor, elucidating its formation mechanisms and evolutionary processes and carefully analyzing the internal relationship between the "blood stasis toxin" theory and the hypoxic microenvironment. Additionally, it explored the interaction among blood stasis, toxic pathogens, and hypoxic environment and proposed micro-level prevention and treatment strategies targeting the hypoxic microenvironment based on the "blood stasis toxin" theory, aiming to provide TCM-based theoretical support and therapeutic approaches for precise regulation of the hypoxic microenvironment.
Humans ; Tumor Microenvironment/drug effects* ; Neoplasms/therapy* ; Animals ; Medicine, Chinese Traditional ; Disease Progression ; Drugs, Chinese Herbal

OBJECTIVES: To explore the therapeutic mechanism of puerarin for alleviating synovitis in rats with collagen-induced arthritis (CIA). METHODS: In a SD rat model of CIA, we tested the effects of daily gavage of puerarin at low, moderate and high doses (10, 30, and 100 mg/kg, respectively) for 3 weeks, with tripterygium glycosides (GTW, 10 mg/kg) as the positive control, on swelling in the hind limb joints regions evaluated by arthritis index scoring. Mass fraction of the liver of the rats was calculated, and pathologies in joint synovial membrane were observed with HE staining. The expressions of transforming growth factor β‑activated kinase-1 (TAK1), Toll-like receptor 4 (TLR4), and nuclear factor kappa-Bp65 (NF‑κB p65) at the mRNA and protein levels in the synovial tissues were detected using Real-time PCR and Western blotting. RESULTS: Compared with those in the model group, the rats in GTW group and high-dose puerarin group showed significantly reduced mass fraction of the liver. Treatment with GTW and puerarin at the 3 doses all significantly alleviated plantar swelling, lowered arthritis index scores, and improved synovitis in CIA rats (P<0.05), and the effects of puerarin showed an obvious dose dependence. Both GTW and puerarin treatments significantly lowered TAK1, TLR4, and NF‑κB p65 mRNA and protein expressions in the synovium of CIA rats. CONCLUSIONS Puerarin alleviates synovium damages in CIA rats possibly by suppressing the TLR4/NF‑κB signaling pathway via downregulating TAK1 expression.
Animals ; Toll-Like Receptor 4/metabolism* ; Rats, Sprague-Dawley ; Rats ; MAP Kinase Kinase Kinases/metabolism* ; Signal Transduction/drug effects* ; Arthritis, Rheumatoid/drug therapy* ; NF-kappa B/metabolism* ; Isoflavones/therapeutic use* ; Male ; Arthritis, Experimental/drug therapy* ; Transcription Factor RelA/metabolism* ; Synovial Membrane/metabolism*

Diabetic kidney disease (DKD) with increasing global prevalence lacks effective therapeutic targets to halt or reverse its progression. Therapeutic targets supported by causal genetic evidence are more likely to succeed in randomized clinical trials. In this study, we integrated large-scale plasma proteomics, genetic-driven causal inference, and experimental validation to identify prioritized targets for DKD using the UK Biobank (UKB) and FinnGen cohorts. Among 2844 diabetic patients (528 with DKD), we identified 37 targets significantly associated with incident DKD, supported by both observational and causal evidence. Of these, 22% (8/37) of the potential targets are currently under investigation for DKD or other diseases. Our prospective study confirmed that higher levels of three prioritized targets-insulin-like growth factor binding protein 4 (IGFBP4), family with sequence similarity 3 member C (FAM3C), and prostaglandin D2 synthase (PTGDS)-were associated with a 4.35, 3.51, and 3.57-fold increased likelihood of developing DKD, respectively. In addition, population-level protein-altering variants (PAVs) analysis and in vitro experiments cross-validated FAM3C and IGFBP4 as potential new target candidates for DKD, through the classic NLR family pyrin domain containing 3 (NLRP3)-caspase-1-gasdermin D (GSDMD) apoptotic axis. Our results demonstrate that integrating omics data mining with causal inference may be a promising strategy for prioritizing therapeutic targets.

Objective:To evaluate the clinical outcomes of mandibular angle osteotomy combined with wing-shaped genioplasty for the correction of low-angle mandibular prominence with microgenia.Methods:A retrospective analysis was conducted on patients who underwent mandibular angle osteotomy and wing-shaped genioplasty at the Second Hospital of Nanjing between January 2020 and December 2022. Preoperative three-dimensional computed tomography and lateral cephalograms were obtained, and relevant parameters were measured, including the Frankfort horizontal plane to mandibular plane angle (∠FH-MP), the lower lip to soft tissue pogonion angle (∠LiaV-Pog) and the facial height index (FHI). Based on the measurements, surgical experience, and patient preference, the osteotomy lines for the mandibular angle and the wing-shaped genioplasty were designed. During the procedure, mandibular angle osteotomy and wing-shaped genioplasty were performed in accordance with the preoperative surgical plan. The distal genial segment was advanced and inferiorly repositioned according to the predetermined measurements and rigidly fixed to the bilateral mental tubercles using titanium plates and screws. The bone segments resected from the mandibular angle were then longitudinally split into either single- or double-layer bone grafts. These grafts were meticulously implanted into the interpositional gap at the genial region to optimize chin projection and refine the lower facial contour. Postoperative monitoring included assessments of wound healing, complications and lower facial contour. At the final follow-up, lateral cephalograms were taken for remeasurement, and patient satisfaction was surveyed. Statistical analysis was performed using SPSS 22.0 software. Pre- and postoperative data for ∠FH-MP, ∠LiaV-Pog, and FHI were presented as Mean ± SD and compared using paired t-tests, with a P-value < 0.05 considered statistically significant. Results:Twelve female patients, aged 22-35 years (mean 28.3), were included. The follow-up period ranged from 6 to 24 months. All surgical sites achieved primary healing without early complications such as hemorrhage, hematoma, or wound infection. However, all patients experienced transient mental numbness, which resolved within 3 to 6 months. All patients achieved a smooth and natural mandibular contour. CT scans confirmed satisfactory survival of the grafted bone. All patients expressed satisfaction with the aesthetic outcomes. Postoperative measurements of ∠FH-MP, ∠LiaV-Pog, and FHI were (25.2±4.6)°, (24.0±1.2)°, and (52.0±1.3)%, respectively, which were significantly improved compared to the preoperative values of (16.8±5.9)°, (36.5±4.8)°, and (66.0±4.3)% (all P < 0.01). Conclusion:The combination of mandibular angle osteotomy and wing-shaped genioplasty is an effective and safe procedure for correcting low-angle mandibular prominence with microgenia. This technique significantly increases the mandibular plane angle, creates a natural and smooth mandibular contour, and yields stable result with high patient satisfaction.

McCune-Albright syndrome(MAS) is a postzygotic somatic mutation disorder caused by activating mutations in the GNAS gene, which encodes the α subunit of the stimulatory G protein. Its clinical features typically include polyostotic fibrous dysplasia, cafe-au-lait skin pigmentation, and endocrine hyperactivity, such as Cushing′s syndrome, hyperthyroidism, and growth hormone excess. Here, we report two rare cases of MAS complicated with adrenocorticotropic hormone(ACTH)-independent Cushing syndrome, and provide a review and analysis of previously reported MAS cases associated with Cushing′s syndrome.