ObjectiveIt was reported that the transthyretin (TTR) has a neuroprotective effect on Alzheimer’s disease (AD), which is manifested by the ability of TTR to inhibit the pathological aggregation of amyloid beta protein (Aβ). In this work, we investigated the mechanism of the interactions between TTR and Aβ at the molecular level to reveal the neuroprotective effect of TTR on AD. MethodsProtein-protein docking was used to explore the models of interaction between different structural forms of TTR and Aβ, and molecular dynamics simulation was further applied to investigate the dynamic process of the interaction between the two. ResultsBoth TTR tetramer and monomer can interact with Aβ monomer, and the thyroxine-binding channel of TTR tetramer is the main binding site of Aβ monomer. In addition, the EF helix and EF loop of TTR tetramer were also able to bind Aβ monomer. When the TTR tetramer dissociates, the hydrophobic site of the internal TTR monomer is exposed, which has a strong affinity for Aβ monomer. For the interaction between Aβ aggregates and TTR, a higher degree of aggregation can be formed between TTR monomer and Aβ aggregates due to the β-sheet-rich property of TTR monomer and Aβ aggregates, which may therefore reduce the cytotoxicity of Aβ aggregates. ConclusionBoth TTR tetramer and monomer can inhibit Aβ aggregation by “sequestering” Aβ monomer, while TTR monomer can reduce the cytotoxicity of Aβ aggregates by forming large co-aggregation with Aβ aggregates. This work can provide an important theoretical basis for the design and discovery of anti-AD drugs based on the neuroprotective effects of TTR.

OBJECTIVE To investigate the effects of Taohong siwu decoction modified granules on podocyte epithelial- mesenchymal-transition （EMT） and renal fibrosis in diabetic kidney disease （DKD） model rats. METHODS Eight rats were selected as normal group （ordinary feed）； the remaining rats were given a high-glucose and high-fat diet combined with intraperitoneal injection of streptozotocin （35 mg/kg） to induce the DKD model. Model rats were randomly divided into model group， irbesartan group [positive control， 13.5 mg/（kg·d）] and modified Taohong siwu decoction group [6.48 g/（kg·d）]， with 8 rats in each group. All groups were given relevant medicine intragastrically， once a day， for 16 consecutive weeks. Twenty-four- hour urinary total protein （24 h UTP） was detected at the end of the 4th， 8th， 12th and 16th week of administration. After the last medication， the body mass， water intake， food intake， urine output， the levels of fasting blood glucose， serum creatinine （Scr） and blood urea nitrogen （BUN） as well as mRNA and protein expressions of P-cadherin， nephrin， α -smooth muscle actin （α-SMA）， Wilms’ tumor gene 1 （WT1）， transforming growth factor-β1（ TGF-β1） and type Ⅳ collagen （Col-Ⅳ） in renal tissue were determined. The pathological and morphological changes in renal tissue were observed and the thickness of the glomerular basement membrane was determined. RESULTS Compared with the model group， 24 h UTP of rats was significantly decreased in modified Taohong siwu decoction group since the 8th weekend （P＜0.05）； the body weight of rats increased significantly， but the amount of water intake and urine decreased significantly； Scr and BUN level， mRNA expression of α-SMA， mRNA and protein expressions of TGF-β1 and Col-Ⅳ were significantly reduced， while the mRNA expressions of P-cadherin， nephrin and WT1 were increased significantly （P＜0.05）； the protein deposition of α-SMA was reduced， protein depositions of P-cadherin， nephrin and WT1 were increased； the pathological damage and fibrosis of renal tissue were relieved； the thickness of glomerular basement membrane was decreased significantly （P＜0.05）. CONCLUSIONS Taohong siwu decoction modified granules can inhibit the EMT of podocyte in DKD model rats， and alleviate renal pathological damage and podocyte damage， thus protecting renal function， and delaying the process of renal fibrosis.

OBJECTIVE To investigate the effects of Taohong siwu decoction modified granules on podocyte epithelial- mesenchymal-transition （EMT） and renal fibrosis in diabetic kidney disease （DKD） model rats. METHODS Eight rats were selected as normal group （ordinary feed）； the remaining rats were given a high-glucose and high-fat diet combined with intraperitoneal injection of streptozotocin （35 mg/kg） to induce the DKD model. Model rats were randomly divided into model group， irbesartan group [positive control， 13.5 mg/（kg·d）] and modified Taohong siwu decoction group [6.48 g/（kg·d）]， with 8 rats in each group. All groups were given relevant medicine intragastrically， once a day， for 16 consecutive weeks. Twenty-four- hour urinary total protein （24 h UTP） was detected at the end of the 4th， 8th， 12th and 16th week of administration. After the last medication， the body mass， water intake， food intake， urine output， the levels of fasting blood glucose， serum creatinine （Scr） and blood urea nitrogen （BUN） as well as mRNA and protein expressions of P-cadherin， nephrin， α -smooth muscle actin （α-SMA）， Wilms’ tumor gene 1 （WT1）， transforming growth factor-β1（ TGF-β1） and type Ⅳ collagen （Col-Ⅳ） in renal tissue were determined. The pathological and morphological changes in renal tissue were observed and the thickness of the glomerular basement membrane was determined. RESULTS Compared with the model group， 24 h UTP of rats was significantly decreased in modified Taohong siwu decoction group since the 8th weekend （P＜0.05）； the body weight of rats increased significantly， but the amount of water intake and urine decreased significantly； Scr and BUN level， mRNA expression of α-SMA， mRNA and protein expressions of TGF-β1 and Col-Ⅳ were significantly reduced， while the mRNA expressions of P-cadherin， nephrin and WT1 were increased significantly （P＜0.05）； the protein deposition of α-SMA was reduced， protein depositions of P-cadherin， nephrin and WT1 were increased； the pathological damage and fibrosis of renal tissue were relieved； the thickness of glomerular basement membrane was decreased significantly （P＜0.05）. CONCLUSIONS Taohong siwu decoction modified granules can inhibit the EMT of podocyte in DKD model rats， and alleviate renal pathological damage and podocyte damage， thus protecting renal function， and delaying the process of renal fibrosis.

Objective To investigate the clinical effect of unilateral percutaneous vertebroplasty(PVP)combined with 3D printing technology for the treatment of thoracolumbar osteoporotic compression fracture.Methods A total of 77 patients with thoracolumbar osteoporotic compression fractures from October 2020 to April 2022 were included in the study,all of which were vertebral body compression fractures caused by trauma.According to different treatment methods,they were di-vided into experimental group and control group.Thirty-two patients used 3D printing technology to improve unilateral transpedicle puncture vertebroplasty in the experimental group,there were 5 males and 27 females,aged from 63 to 91 years old with an average of(77.59±8.75)years old.Forty-five patients were treated with traditional bilateral pedicle puncture vertebroplasty,including 7 males and 38 females,aged from 60 to 88 years old with an average of(74.89±7.37)years old.Operation time,intraoperative C-arm X-ray times,anesthetic dosage,bone cement injection amount,bone cement diffusion good and good rate,complications,vertebral height,kyphotic angle(Cobb angle),visual analogue scale(VAS),Oswestry disability index(ODI)and other indicators were recorded before and after surgery,and statistically analyzed.Results All patients were followed up for 6 to 23 months,with preoperative imaging studies,confirmed for thoracolumbar osteoporosis com-pression fractures,two groups of patients with postoperative complications,no special two groups of patients'age,gender,body mass index(BMI),time were injured,the injured vertebral distribution had no statistical difference(P＞0.05),comparable data.Two groups of patients with bone cement injection,bone cement dispersion rate,preoperative and postoperative vertebral body height,protruding after spine angle(Cobb angle),VAS,ODI had no statistical difference(P＞0.05).The operative time,intra-operative fluoroscopy times and anesthetic dosage were statistically different between the two groups(P＜0.05).Compared with the traditional bilateral puncture group,the modified unilateral puncture group combined with 3D printing technology had shorter operation time,fewer intraoperative fluoroscopy times and less anesthetic dosage.The height of anterior vertebral edge,kyphosis angle(Cobb angle),VAS score and ODI of the affected vertebrae were statistically different between two groups at each time point after surgery(P＜0.05).Conclusion In the treatment of thoracolumbar osteoporotic compression fractures,3D printing technology is used to improve unilateral puncture PVP,which is convenient and simple,less trauma,short operation time,fewer fluoroscopy times,satisfactory distribution of bone cement,vertebral height recovery and kyphotic Angle correction,and good functional improvement.

Iron is indispensable for the viablility of nearly all living organisms, and it is imperative for cells, tissues, and organisms to acquire this essential metal sufficiently and maintain its metabolic stability for survival. Disruption of iron homeostasis can lead to the development of various diseases. There is a robust connection between iron metabolism and infection, immunity, inflammation, and aging, suggesting that disorders in iron metabolism may contribute to the pathogenesis of arthritis. Numerous studies have focused on the significant role of iron metabolism in the development of arthritis and its potential for targeted drug therapy. Targeting iron metabolism offers a promising approach for individualized treatment of arthritis. Therefore, this review aimed to investigate the mechanisms by which the body maintains iron metabolism and the impacts of iron and iron metabolism disorders on arthritis. Furthermore, this review aimed to identify potential therapeutic targets and active substances related to iron metabolism, which could provide promising research directions in this field.

Objective This study compared the effects of intraoperative intercostal nerve block(ICNB)and preoperative ultrasound-guided paravertebral block(US-PVB)on postoperative complications in patients undergoing thoracoscopic lung surgery.Methods Data from 240 patients who underwent video-assisted thoracoscopic lung surgery under general anesthesia between January 2019 and December 2020 was retrospectively collected.These patients either received intraoperative intercostal nerve block(ICNB)(202 cases)or pre-operative ultrasound-guided paravertebral block(US-PVB)(38 cases).The incidence rates of overall postoperative complications,postoperative pulmonary complications,postoperative cardiac complications,postoperative cerebral complications,other postoperative complications,remedial analgesia requirement in the PACU,intraoperative fentanyl consumption,postoperative oral morphine equivalent(OME),perioperative OME,duration of postoperative drainage tube,postoperative ICU stay,and postoperative hospital stay were compared between the ICNB group and the US-PVB group.Univariate and multivariate regression were used to analyze the effects of different analgesia methods on postoperative complicationsResults There was no statistically significant difference in postoperative overall complications between the ICNB group and the US-PVB group(P＞0.05).In the univariate analysis,no significant difference was found in the overall postoperative complications between the ICNB group(16.3％)and the US-PVB group(13.2％)(OR=0.642,95％CI 0.239-1.786;P=0.404.Multivariate analysis also did not reveal any differences between the two groups(OR=0.843,95％CI 0.299-2.377;P=0746).For the analysis of secondary outcomes,according to multivariate analysis,there was no significant difference between the two groups in postoperative pulmonary complications,postoperative cardiac complications,other postoperative complications,remedial analgesia requirement in the PACU,intraoperative fentanyl consumption,postoperative OME,perioperative OME,duration of postoperative drainage tube,postoperative ICU stay or postoperative hospital stay(P＞0.05).Conclusion In this study,we found no difference in postoperative complications between intraoperative ICNB and preoperative US-PVB.

Objectives: . Branchio-oto syndrome (BOS) primarily manifests as hearing loss, preauricular pits, and branchial defects. EYA1 is the most common pathogenic gene, and splicing mutations account for a substantial proportion of cases. However, few studies have addressed the structural changes in the protein caused by splicing mutations and potential pathogenic factors, and several studies have shown that middle-ear surgery has limited effectiveness in improving hearing in these patients. BOS has also been relatively infrequently reported in the Chinese population. This study explored the genetic etiology in the family of a proband with BOS and provided clinical treatment to improve the patient’s hearing. Methods: . We collected detailed clinical features and peripheral blood samples from the patients and unaffected individuals within the family. Pathogenic mutations were identified by whole-exome sequencing and cosegregation analysis and classified according to the American College of Medical Genetics and Genomics guidelines. Alternative splicing was verified through a minigene assay. The predicted three-dimensional protein structure and biochemical experiments were used to investigate the pathogenicity of the mutation. The proband underwent middle-ear surgery and was followed up at 1 month and 6 months postoperatively to monitor auditory improvement. Results: . A novel heterozygous EYA1 splicing variant (c.1050+4 A>C) was identified and classified as pathogenic (PVS1(RNA), PM2, PP1). Skipping of exon 11 of the EYA1 pre-mRNA was confirmed using a minigene assay. This mutation may impair EYA1-SIX1 interactions, as shown by an immunoprecipitation assay. The EYA1-Mut protein exhibited cellular mislocalization and decreased protein expression in cytological experiments. Middle-ear surgery significantly improved hearing loss caused by bone-conduction abnormalities in the proband. Conclusion . We reported a novel splicing variant of EYA1 in a Chinese family with BOS and revealed the potential molecular pathogenic mechanism. The significant hearing improvement observed in the proband after middle-ear surgery provides a reference for auditory rehabilitation in similar patients.

OBJECTIVE To explore the intervention effect and related mechanism of Tongxinluo capsule on renal fibrosis in rats with diabetic nephropathy （DN）. METHODS Eight rats were selected as control group （ordinary feed）， the remaining rats were given high-glucose and high-fat diet combined with ip injection of streptozotocin （35 mg/kg） to induce DN model. Model rats were randomly divided into model group （purified water）， irbesartan group （positive control， 14.12 mg/kg） and Tongxinluo capsule group （0.3 g/kg）， including 12 rats in the model group and 11 rats for each of the other two groups. All groups were given relevant medicine or water intragastrically， once a day， for 16 consecutive weeks. After the last medication， fasting blood glucose and 24 h urinary total protein （24 h UTP） were detected. Pathological changes in renal cortex of rats in each group were observed. Serum levels of tissue-type plasminogen activator （PA） and plasminogen activator inhibitor 1 （PAI-1） were measured. mRNA expressions of transforming growth factor-β（1 TGF-β1）， type Ⅳ collagen（COL-Ⅳ）， Wnt4 and β-catenin in renal cortex of rats were detected. The protein depositions or expressions of TGF-β1， COL-Ⅳ， focal adhesion kinase （FAK）， integrin-linked kinase （ILK）， E-cadherin， PA， PAI-1， Wnt4 and β-catenin in renal cortex of rats were observed or determined. RESULTS Compared with model group， 24 h UTP of rats in Tongxinluo capsule group were all significantly reduced （P＜0.05）； pathological damage and fibrosis of renal cortex were relieved； the expression of PA in serum and renal cortex was significantly increased， while PAI-1 level was significantly reduced （P＜0.05）； the depositions of COL-Ⅳ and TGF-β1 in renal cortex were all reduced， and corresponding mRNA expression was decreased significantly （P＜0.05）； the depositions of ILK and FAK were decreased， while the deposition of E-cadherin was increased； protein and mRNA expressions of Wnt4 and β-catenin were significantly reduced （P＜0.05）. CONCLUSIONS Tongxinluo capsule can relieve pathological damage to renal tissue and renal fibrosis of DN model rats， and reduce extracellular matrix deposition. The mechanism may be related to regulation of fibrinolytic system activity， the decrease of ILK and FAK expression， and inhibition of Wnt/β-catenin signaling pathway.

Objective: To analyze and compare therapy responses, outcomes, and incidence of severe hematologic adverse events of flumatinib and imatinib in patients newly diagnosed with chronic phase chronic myeloid leukemia (CML) . Methods: Data of patients with chronic phase CML diagnosed between January 2006 and November 2022 from 76 centers, aged ≥18 years, and received initial flumatinib or imatinib therapy within 6 months after diagnosis in China were retrospectively interrogated. Propensity score matching (PSM) analysis was performed to reduce the bias of the initial TKI selection, and the therapy responses and outcomes of patients receiving initial flumatinib or imatinib therapy were compared. Results: A total of 4 833 adult patients with CML receiving initial imatinib (n=4 380) or flumatinib (n=453) therapy were included in the study. In the imatinib cohort, the median follow-up time was 54 [interquartile range (IQR), 31-85] months, and the 7-year cumulative incidences of CCyR, MMR, MR(4), and MR(4.5) were 95.2%, 88.4%, 78.3%, and 63.0%, respectively. The 7-year FFS, PFS, and OS rates were 71.8%, 93.0%, and 96.9%, respectively. With the median follow-up of 18 (IQR, 13-25) months in the flumatinib cohort, the 2-year cumulative incidences of CCyR, MMR, MR(4), and MR(4.5) were 95.4%, 86.5%, 58.4%, and 46.6%, respectively. The 2-year FFS, PFS, and OS rates were 80.1%, 95.0%, and 99.5%, respectively. The PSM analysis indicated that patients receiving initial flumatinib therapy had significantly higher cumulative incidences of CCyR, MMR, MR(4), and MR(4.5) and higher probabilities of FFS than those receiving the initial imatinib therapy (all P<0.001), whereas the PFS (P=0.230) and OS (P=0.268) were comparable between the two cohorts. The incidence of severe hematologic adverse events (grade≥Ⅲ) was comparable in the two cohorts. Conclusion: Patients receiving initial flumatinib therapy had higher cumulative incidences of therapy responses and higher probability of FFS than those receiving initial imatinib therapy, whereas the incidence of severe hematologic adverse events was comparable between the two cohorts.
Adult ; Humans ; Adolescent ; Imatinib Mesylate/adverse effects* ; Incidence ; Antineoplastic Agents/adverse effects* ; Retrospective Studies ; Pyrimidines/adverse effects* ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy* ; Treatment Outcome ; Benzamides/adverse effects* ; Leukemia, Myeloid, Chronic-Phase/drug therapy* ; Aminopyridines/therapeutic use* ; Protein Kinase Inhibitors/therapeutic use*

Humans ; Lymphohistiocytosis, Hemophagocytic/complications* ; Neoplasms