Elevated glucose metabolism is a prominent characteristic of fibroblast-like synoviocytes (FLS) in rheumatoid arthritis (RA). However, the efficacy of inhibiting a single target of glucose metabolism in FLS using small molecular inhibitors is limited for RA treatment. Herein, the synergistic inhibition of FLS' survival, proliferation, and activation by combining two glucose metabolism inhibitors, diclofenac (DC) and lonidamine (LND) was first verified. Subsequently, DC and LND were individually conjugated to cystamine-modified hyaluronic acid (HA) to prepare two polymer-prodrug conjugates. A HAP-1 peptide-modified dual polymer-prodrug conjugates-assembled nanoparticles system (^HAP-1NP_DC+LND) was further tailored in the optimal synergistic ratio for targeted and synergistic metabolic modulation of FLS to alleviate RA symptoms. Upon targeted uptake by FLS in inflamed joints, ^HAP-1NP_DC+LND released DC and LND within the intracellular reductive microenvironment, where DC hinders glucose uptake and LND suppresses glycolytic enzymes to eliminate FLS synergistically. Additionally, the secretion of lactic acid and pro-inflammatory factors from FLS were reduced, thereby disrupting the crosstalk between FLS and pro-inflammatory macrophages. Finally, ^HAP-1NP_DC+LND demonstrated promising efficacy in a mouse model of collagen-induced arthritis (CIA). Overall, this research provides valuable insights into novel therapeutic strategies for the safe and effective of treatment RA through targeted and synergistic metabolic modulation of FLS.

OBJECTIVES: To explore the mechanism of Qingda Granules (QDG) for alleviating brain damage in spontaneously hypertensive rats (SHRs). METHODS: Twelve 5-week-old SHRs were randomized into SHR control group and SHR+QDG group treated with QDG by gavage at the daily dose of 0.9 g/kg for 12 weeks. The control rats, along with 6 age-matched WKY rats, were treated with saline only. Blood pressure changes of the rats were monitored, and pathologies and neuronal apoptosis in the cerebral cortex were examined with HE staining and TUNEL staining. Cerebral cortical expressions of miR-124 and STAT3 mRNA were detected using RT-qPCR, and the protein expressions of NeuN, STAT3, Bcl-2, Bax, and cleaved caspase-3 were detected with immunohistochemistry and Western blotting. In a HT22 cell model of oxygen and glucose deprivation/reoxygenation (OGD/R), the effects of QDG on cell viability and apoptosis, expressions of miR-124 and STAT3 mRNA, and protein expressions of STAT3, Bcl-2, Bax, and cleaved caspase-3 were evaluated using CCK8 assay, Hoechst 33342 staining, RT-qPCR, and Western blotting. RESULTS: Compared with WKY rats, SHRs had significantly elevated systolic blood pressure, diastolic blood pressure and mean arterial pressure with significantly increased neuronal apoptosis in the cerebral cortex, reduced expressions of NeuN, miR-124 and Bcl-2, and enhanced expressions of STAT3, Bax and cleaved caspase-3 (P<0.05). All these changes in the SHRs were significantly ameliorated by treatment with QDG (P<0.05). In the HT22 cell model, QDG treatment obviously reduced OGD/R-induced cell apoptosis, increased the expressions of miR-124 and Bcl-2, and suppressed the elevation of protein expressions of STAT3, Bax and cleaved caspase-3. CONCLUSIONS QDG inhibits cerebral cortical neuronal apoptosis and thereby attenuates brain damage in SHR rats by modulating the miR-124/STAT3 signaling axis.
Animals ; Rats, Inbred SHR ; MicroRNAs/metabolism* ; STAT3 Transcription Factor/metabolism* ; Signal Transduction/drug effects* ; Drugs, Chinese Herbal/pharmacology* ; Rats ; Apoptosis/drug effects* ; Rats, Inbred WKY ; Male ; Hypertension

OBJECTIVE:At present,there are many reports on the related factors associated with the incidence of cervical spine instability in patients with rheumatoid arthritis,but there are problems such as small sample size and many confounding factors,and the research results of various studies on the same related factors are also different.This article analyzed the factors related to cervical spine instability in patients with rheumatoid arthritis by means of a systematic review. METHODS:Articles related to cervical spine instability in patients with rheumatoid arthritis were collected by searching both Chinese and English databases until March 2023.The outcome of cervical spine instability in patients with rheumatoid arthritis was used as the grouping criterion to abstract basic information,baseline patient characteristics,laboratory-related tests,medication use,and other relevant risk factors.Meta-analysis was done using Stata 14.0 software. RESULTS:(1)Sixteen relevant studies,all of moderate or above quality,were included,including seven studies with case-control studies and nine with cross-sectional studies.The overall incidence of cervical spine instability in patients with rheumatoid arthritis was 43.08%.(2)Meta-analysis showed:Related risk factors included female(OR=0.60,95%CI:0.44-0.82,P=0.002);age at disease onset(SMD=-0.52,95%CI:-0.86 to-0.18,P=0.003);duration of disease(SMD=0.58,95%CI:0.14-1.02,P=0.01);body mass index(OR=0.74,95%CI:0.63-0.88,P=0.001);rheumatoid factors positive univariate analysis subgroup(OR=1.33,95%CI:1.02 to 1.72,P=0.04),C-reactive protein(SMD=0.26,95%CI:0.16-0.35,P=0.00),erythrocyte sedimentation rate(SMD=0.15,95%CI:0.002-0.29,P=0.047),anti-cyclic-citrullinated peptide antibodies(OR=1.73,95%CI:1.19-2.51,P=0.004),28-joint Disease Activity Score(SMD=0.20,95%CI:0.04-0.37,P=0.02),destruction of peripheral joints(OR=2.48,95%CI:1.60-3.85,P=0.00),and corticosteroids(OR=1.91,95%CI:1.54-2.37,P=0.00)were strongly associated with the development of rheumatoid arthritis-cervical spine instability.Female and corticosteroid use were independently associated with the occurrence of rheumatoid arthritis-cervical spine instability. CONCLUSION:Based on clinical evidence from 16 observational studies,the overall incidence of rheumatoid arthritis-cervical spine instability was 43.08%.However,the incidence of cervical spine instability in rheumatoid arthritis patients varied greatly among different studies.Gender(female)and the use of corticosteroids were confirmed as independent correlation factors for the onset of cervical spine instability in patients with rheumatoid arthritis.The results of this study still provide some guidance for early clinical recognition,diagnosis,and prevention of rheumatoid arthritis-cervical spine instability.

Objective:To explore the efficacy and safety of TiRobot combined with three-dimensional imaging in the minimally invasive surgery for pelvic fractures.Methods:A retrospective analysis was conducted of the 40 patients with pelvic fracture who had been treated by fixation with S1 and S2 sacroiliac screws at Department of Orthopaedics and Traumatology, Yangjiang People's Hospital from January 2019 to May 2021. They were divided into 2 groups according to their treatment methods. In the TiRobot group of 20 cases subjected to percutaneous sacroiliac screw fixation assisted by TiRobot combined with three-dimensional imaging, there were 13 males and 7 females with an age of (38.2 ± 8.8) years. In the manual group of 20 cases subjected to fixation with manual placement of sacroiliac screws under conventional C-arm fluoroscopy, there were 11 males and 9 females with an age of (37.3 ± 9.2) years. The 2 groups were compared in terms of fluoroscopy time for screw placement, guide needle adjustment, operation time, intraoperative blood loss, visual analogue scale (VAS) 72 hours after operation, postoperative hospital stay, time to ambulation, excellent to good rate of screw placement, complication rate, fracture union time, Majeed score at 6 months after operation, and excellent to good rate of functional evaluation.Results:There was no significant difference between the 2 groups in their preoperative general data, showing they were comparable ( P > 0.05). In the TiRobot group, fluoroscopy time for screw placement [(8.2 ± 2.9) s], guide needle adjustment [(0.4 ± 0.2) times], operation time [(67.4 ± 5.5) min], and intraoperative blood loss [(36.5 ± 8.0) mL] were significantly less than those in the manual group [(40.4 ± 4.5) s, (8.6 ± 0.7) times, (78.4 ± 7.2) min, and (41.6 ± 7.8) mL], postoperative VAS [3.0 (4.0, 5.0) points] was significantly lower than that in the manual group [4.0 (5.0, 6.0) points], the excellent to good rate of screw placement (100%, 40/40) was significantly higher than that in the manual group (85.0%, 34/40), and the complication rate (5.0%,1/20) was significantly lower than that in the manual group (35.0%, 7/20) (all P < 0.05). There was no significant difference between the 2 groups in postoperative hospital stay, time to ambulation, fracture union time, Majeed score, or excellent to good rate of functional evaluation ( P > 0.05). Conclusion:In the minimally invasive surgery for pelvic fractures, TiRobot combined with three-dimensional imaging leads to positive outcomes, because it can reduce operation time and radiation exposure, improve accuracy of screw placement, and increase safety.

As for the treatment of microtia, the status quo is as follows. The ear reconstruction with autologous costal cartilage has been generally accepted as the therapeutic strategy for type Ⅲ/Ⅳ patients with only small ear lobe remaining or complete absence of auricle, and the outcomes are improved steadily with the advances in technology; but for type Ⅰ/Ⅱ patients with larger remnant ear, there is insufficient evidence to be able to support any specific treatment methods as the potential unified approach for surgeons to choose from. Non-surgical treatment with appliance wearing may play an auxiliary role in the treatment of microtia, which is worthy of further research. The authors proposed a serialized treatment system based on their clinical practice and literature review. It is expected to be helpful for the treatment of microtia.

As for the treatment of microtia, the status quo is as follows. The ear reconstruction with autologous costal cartilage has been generally accepted as the therapeutic strategy for type Ⅲ/Ⅳ patients with only small ear lobe remaining or complete absence of auricle, and the outcomes are improved steadily with the advances in technology; but for type Ⅰ/Ⅱ patients with larger remnant ear, there is insufficient evidence to be able to support any specific treatment methods as the potential unified approach for surgeons to choose from. Non-surgical treatment with appliance wearing may play an auxiliary role in the treatment of microtia, which is worthy of further research. The authors proposed a serialized treatment system based on their clinical practice and literature review. It is expected to be helpful for the treatment of microtia.

Objective:To investigate the clinicopathological features, immunophenotype, molecular characteristics and differential diagnosis of primary skull base chondrosarcoma.Methods:Nine cases of primary skull base chondrosarcoma were collected at the First Affiliated Hospital of Fujian Medical University, from January 2006 to June 2019, reviewed for the clinical and radiologic data and morphologic features, immunophenotype and molecular characteristics.Results:Among all the 9 cases, six were male, three were frmale, with average age 47 years, and median age 47 years; five cases were WHO gradeⅠ, and four were WHO grade Ⅱ. Microscopically, the tumor showed lobulated growth pattern with low-medium cellularity within a chondroid or mucoid background. The tumor cells showed mild-moderate atypia, with binucleated forms, and mitosis was rare or occasional. Immunohistochemistry (IHC) showed tumor cells were positive for S-100 protein, vimentin, SOX-9 and D2-40, and negative for Brachyury, CK, EMA and CK8/18; the Ki-67 index was low (1% to 5%). Molecular analysis showed IDH1 R132C mutation in four cases.Conclusions:Skull base chondrosarcoma is a rare cartilaginous malignant tumor with a good prognosis. Its characteristic morphologies, combined with IHC and molecular detection are helpful for the differential diagnosis.

Objective:To study the differential expression and significance of auricular cartilage protein phosphorylation profile in different degrees of development on the normal and the abnormal side of patients with congenital non-syndromic microtia.Methods:Collected 4 cases of unilateral congenital non-syndromic patients from March 2017 to March 2019 in Chinese Academy of Medical Sciences Plastic Surgery Hospital, including 4 pairs of matched normal auricle cartilage and residual auricle cartilage (2 males and 2 females, aged 6 years). Signal phosphorylation broad-spectrum screening antibody chip (PEX100) was used to screen the protein phosphorylation profiles of the cartilage on the normal and abnormal cartilages. The residual ear cartilage group was used as the experimental group, and the normal ear cartilage was used as the control group. The ratio of phosphorylation of the cartilage in the residual ear of patients was compared with that of the control group. Residual ear cartilage protein phosphorylation / normal ear cartilage protein phosphorylation ratio ≥2.0 indicates an up-regulated protein, and ≤0.5 indicates a down-regulated protein. The differential proteins obtained from the experiments were analyzed using String database and KEGG(Kyoto Encyclopedia of Genes and Genomes) PATHWAY databases.Results:The experimental/control group (residual ear cartilage/ normal ear cartilage) had a protein phosphorylation ratio of FC ≥ 2 and ≤ 0.5 with 110 proteins. Among them, 102 were up-regulation and 8 were down-regulation. The KEGG database was used to perform signal pathway enrichment analysis of proteins showing differences in phosphorylation levels. The screened differential proteins were enriched in 20 signaling pathways including PI3K-AKT, Focal adhension singaling pathway except the classic signaling pathways and the list of differentially phosphorylated proteins was imported into the STRING database to map the protein interactions network.Conclusions:There is a significant difference in the phosphorylation of proteins between normal auricle cartilage and residual auricle cartilage. Differentially phosphorylated proteins are enriched in signal pathways such as PI3K-AKT and focal adhesion, which suggests that the cause of the difference in development of bilateral ear cartilage may be related to ear cartilage proliferation, adhesion, migration and other activities during the embryonic period.

Objective:To study the differential expression and significance of auricular cartilage protein phosphorylation profile in different degrees of development on the normal and the abnormal side of patients with congenital non-syndromic microtia.Methods:Collected 4 cases of unilateral congenital non-syndromic patients from March 2017 to March 2019 in Chinese Academy of Medical Sciences Plastic Surgery Hospital, including 4 pairs of matched normal auricle cartilage and residual auricle cartilage (2 males and 2 females, aged 6 years). Signal phosphorylation broad-spectrum screening antibody chip (PEX100) was used to screen the protein phosphorylation profiles of the cartilage on the normal and abnormal cartilages. The residual ear cartilage group was used as the experimental group, and the normal ear cartilage was used as the control group. The ratio of phosphorylation of the cartilage in the residual ear of patients was compared with that of the control group. Residual ear cartilage protein phosphorylation / normal ear cartilage protein phosphorylation ratio ≥2.0 indicates an up-regulated protein, and ≤0.5 indicates a down-regulated protein. The differential proteins obtained from the experiments were analyzed using String database and KEGG(Kyoto Encyclopedia of Genes and Genomes) PATHWAY databases.Results:The experimental/control group (residual ear cartilage/ normal ear cartilage) had a protein phosphorylation ratio of FC ≥ 2 and ≤ 0.5 with 110 proteins. Among them, 102 were up-regulation and 8 were down-regulation. The KEGG database was used to perform signal pathway enrichment analysis of proteins showing differences in phosphorylation levels. The screened differential proteins were enriched in 20 signaling pathways including PI3K-AKT, Focal adhension singaling pathway except the classic signaling pathways and the list of differentially phosphorylated proteins was imported into the STRING database to map the protein interactions network.Conclusions:There is a significant difference in the phosphorylation of proteins between normal auricle cartilage and residual auricle cartilage. Differentially phosphorylated proteins are enriched in signal pathways such as PI3K-AKT and focal adhesion, which suggests that the cause of the difference in development of bilateral ear cartilage may be related to ear cartilage proliferation, adhesion, migration and other activities during the embryonic period.

Objective To investigate the relationship between multi‐dimensional myocardial strain and global cardiac function in different stages of cardiac dysfunction in spontaneously hypertensive rats ( SHR ) by two‐dimensional strain echocardiography . MethodsAccording to cardiac function measurements ,SHR of 28 to 102 weeks were divided into 3 groups :Normal group[ Group A , normal left ventricular ejection fraction( LVEF) and left ventricular end‐diastolic pressure( LVEDP) , n ＝13] ,diastolic dysfunction group ( Group B , normal LVEF but increased LVEDP , n ＝24) ,and systolic dysfunction group ( Group C ,decreased LVEF and increased LVEDP , n ＝ 17 ) ,with WKY rats at similar weeks of age as controls ( group a , n ＝ 7 ;group b , n ＝ 12 ; and group c , n ＝ 16 ) . Morphological parameters of left ventricular were measured by echocardiography . Using EchoPac workstation ,systolic peak longitudinal strain ,circumferential and radial strain were calculated at the left ventricular middle levels . Extracellular collagen content was observed histologically . Results Left atrial dimension increased in group B and larger in group C ,and dilated left ventricular and thickened wall were only found in group C .Systolic peak longitudinal strain of group B was significantly lower than group A and group a ( all P ＜ 0 .05 ) ,and deteriorated in group C( P ＜ 0 .05 ) ,while systolic peak circumferential and radial strain and LVEF were only significantly decreased in group C ( all P＜ 0 .05 ) ,w hile there was no significant difference between Group A and Group B( all P ＞0 .05) . Collagen content in endocardial and mid‐layer myocardium increased in group B and C , and increased epicardial collagen occurred in group C . Systolic peak longitudinal strain , circumferential and radial strain were correlated positively with LVEF( r ＝0 .65 ,0 .80 ,0 .80 ,all P ＜0 .01) . Conclusions In SHR ,systolic peak longitudinal strain obtained by echocardiography is decreased in the period of diastolic dysfunction ,w hile the damage of systolic peak circumferential and radial strain leads to the systolic dysfunction .