BACKGROUND:Various proteins,signaling pathways,and inflammatory mediators are involved in the pathophysiological process of osteoarthritis.The development of small molecule drugs targeting these proteins,signaling pathways,and inflammatory mediators can effectively delay the progression of osteoarthritis and ameliorate its clinical manifestations. OBJECTIVE:To review the research progress of small molecule drugs in the treatment of osteoarthritis based on the pathogenesis of osteoarthritis. METHODS:PubMed,CNKI,and WanFang databases were searched with English search terms"osteoarthritis,arthritis,osteoarthrosis,degenerative,arthritides,deformans,small molecule drugs,small molecule inhibitors,small molecule agents"and Chinese search terms"osteoarthritis,small molecule drugs,small molecule inhibitors."A total of 68 articles were included for review according to the inclusion and exclusion criteria. RESULTS AND CONCLUSION:(1)Currently,studies concerning the pathogenesis of osteoarthritis remain unclear.The occurrence and development of osteoarthritis are strongly associated with proteins,cytokines,and signal transduction pathways,so its therapeutic mechanism is relatively complex.Currently,targeting proteins,cytokines,and signal transduction pathways related to osteoarthritis with small molecule drugs has become a major research focus.(2)Small molecule drugs frequently possess visible intracellular or extracellular targets and efficacy,containing enhancing cartilage repair,resisting joint degradation,attenuating inflammation,and relieving pain.Other anti-osteoarthritis small molecule drugs have shown promise in promoting stem cell chondrogenic differentiation and cartilage matrix reconstruction.(3)At present,small molecule drugs targeting the pathophysiological process of osteoarthritis to delay the progression of osteoarthritis are still in the experimental stage,but most of these small molecule drugs have shown the expected results in the experimental process,and there are no relevant studies to illustrate the efficacy of small molecule drugs in the treatment of osteoarthritis.(4)Small molecule drugs for the treatment of osteoarthritis have reached the expected experimental results in the basic experimental stage.Numerous studies have exhibited that small molecule drugs can target the suppression of specific proteins,cytokines,and signal transduction pathways that cause osteoarthritis,so as to treat osteoarthritis.Nevertheless,its safety and effectiveness still need to be identified by further basic and clinical studies.This process needs to be investigated and studied by more scholars.(5)At present,many scholars in and outside China have made contributions to the treatment of osteoarthritis.Compared with traditional treatment methods,small molecule drugs reveal better efficacy and safety in the basic experimental stage,and it is expected to become an emerging method for the treatment of osteoarthritis in the future to rid patients of pain.

ObjectiveTo compare the differences in color， odor， coumarin content and microbial community composition of Angelicae Dahuricae Radix（ADR） during different drying processes， and to explore the correlation between changes in microbial community composition and changes in quality indexes of ADR. MethodsThe fresh ADR was processed at three drying temperatures（50， 70， 100 ℃） by drying and steaming cutting， semi-fresh cutting and drying， fresh cutting and drying， and sulfur fumigation methods. The color values of samples were extracted by Adobe Photoshop 2022 software and subjected to principal component analysis（PCA）， electronic nose was used to identify the odor information of medicinal powders and subjected to loadings analysis， PCA， and linear discriminant analysis（LDA）， and high performance liquid chromatography（HPLC） was used to determine the contents of five coumarins（bergapten， oxypeucedanin， imperatorin， phellopterin， isoimperatorin）. The samples for microbial detection were taken from fresh dried samples， 50 ℃（dried and steamed cut， sulfur fumigated） samples， and 100 ℃（dried and steamed cut） samples when the water content was 50% and 14%， respectively. And the changes of microbial community composition during processing were determined by high-throughput sequencing method. The relationship between the changes of microbial community composition and the changes of odor， color and active component content of ADR during drying process was analyzed by Pearson correlation analysis. ResultsThe color quantification results showed that an increase in drying temperature led to the decrease of brightness value（L）， and the increases of red-green value（a） and yellow-blue value（b）， and the change of processing method had no obvious effect on the color of medicinal materials. The results of odor quantification showed that W1S， W2S， W5S， W2W and W1W sensor were sensitive to the odor changes of ADR and could be used to distinguish ADR decoction pieces from different processing methods. The results of HPLC showed that the coumarin content of ADR decreased with the increase of drying temperature and the delay of processing time， the optimal processing method was drying and steaming cutting method， and the optimal temperature was 50 ℃. High-throughput sequencing results showed that the dominant bacteria in ADR during processing were Achromobacter， Agrobacterium， Nocardioides， Mycobacterium and Enterobacter， the dominant fungi were Coprinopsis， Meyerozyma and Apiotrichum. The results of correlation analysis showed that the quality indexes of ADR were positively correlated with Agrobacterium， Mycobacterium in bacteria， Candida in fungi， and negatively correlated with Bacillus in bacteria. ConclusionThere are significant differences in the color， odor， coumarin content and microbial community composition of ADR in different drying processes， and the best drying method is drying and steaming cutting at 50 ℃. The relative abundance changes of 9 bacterial genera and 4 fungal genera are closely related to the quality formation of ADR during the drying process.

BACKGROUND: Arsenic trioxide (ATO) is indicated as a broad-spectrum medicine for a variety of diseases, including cancer and cardiac disease. While the role of ATO in hepatic ischemia/reperfusion injury (HIRI) has not been reported. Thus, the purpose of this study was to identify the effects of ATO on HIRI. METHODS: In the present study, we established a 70% hepatic warm I/R injury and partial hepatectomy (30% resection) animal models in vivo and hepatocytes anoxia/reoxygenation (A/R) models in vitro with ATO pretreatment and further assessed liver function by histopathologic changes, enzyme-linked immunosorbent assay, cell counting kit-8, and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay. Small interfering RNA (siRNA) for extracellular signal-regulated kinase (ERK) 1/2 was transfected to evaluate the role of ERK1/2 pathway during HIRI, followed by ATO pretreatment. The dynamic process of autophagic flux and numbers of autophagosomes were detected by green fluorescent protein-monomeric red fluorescent protein-LC3 (GFP-mRFP-LC3) staining and transmission electron microscopy. RESULTS: A low dose of ATO (0.75 μmol/L in vitro and 1 mg/kg in vivo ) significantly reduced tissue necrosis, inflammatory infiltration, and hepatocyte apoptosis during the process of hepatic I/R. Meanwhile, ATO obviously promoted the ability of cell proliferation and liver regeneration. Mechanistically, in vitro  studies have shown that nontoxic concentrations of ATO can activate both ERK and phosphoinositide 3-kinase-serine/threonine kinase (PI3K-AKT) pathways and further induce autophagy. The hepatoprotective mechanism of ATO, at least in part, relies on the effects of ATO on the activation of autophagy, which is ERK-dependent. CONCLUSION Low, non-toxic doses of ATO can activate ERK/PI3K-AKT pathways and induce ERK-dependent autophagy in hepatocytes, protecting liver against I/R injury and accelerating hepatocyte regeneration after partial hepatectomy.
Animals ; Arsenic Trioxide ; Autophagy/physiology* ; Reperfusion Injury/prevention & control* ; Mice ; Male ; Proto-Oncogene Proteins c-akt/physiology* ; Arsenicals/therapeutic use* ; Oxides/therapeutic use* ; Liver/metabolism* ; Extracellular Signal-Regulated MAP Kinases/metabolism* ; Mice, Inbred C57BL

Ischemic stroke (IS) is a globally life-threatening disease. Presently, few therapeutic medicines are available for treating IS, and rt-PA is the only drug approved by the US Food and Drug Administration (FDA) in the US. In fact, many agents showing excellent neuroprotection but no blood flow-improving activity in animals have not achieved ideal clinical efficacy, while thrombolytic drugs only improving blood flow without neuroprotection have limited their wider application. To address these challenges and meet the huge unmet clinical need, we have designed and identified a novel compound AAPB with dual effects of neuroprotection and cerebral blood flow improvement. AAPB significantly reduced cerebral infarction and neural function deficit in tMCAO rats, pMCAO rats, and IS rhesus monkeys, as well as displayed exceptional safety profiles and excellent pharmacokinetic properties in rats and dogs. AAPB has now entered phase I of clinical trials fighting IS in China.

Objective To evaluate the clinical value of optic nerve sheath diameter(ONSD)measured on thin-slice CT scan in the diagnosis and prognostic assessment of cerebral venous sinus thrombosis(CVST).Methods The clinical data of patients with CVST,who were admitted to the First Affiliated Hospital of Nanjing Medical University of China to receive treatment from January 1,2016 to December 31,2022,were retrospectively analyzed.The difference in ONSD was compared between CVST patients and normal population,the postoperative changes in ONSD was analyzed.Results A total of 49 patients with CVST(CVST group)and 49 normal persons having no brain disorders(control group)were enrolled in this study.In CVST group,the preoperative ONSD was(5.33±0.50)mm,which was significantly higher than(4.40±0.40)mm in control group(P＜0.001),the postoperative ONSD remarkably decreased to(4.98±0.59)mm(P＜0.01).The difference value between postoperative ONSD and preoperative ONSD in the patients receiving pure anticoagulation treatment was not statistically significant different from that in the patients receiving endovascular treatment[(-0.43±0.22)mm vs.(-0.40±0.42)mm,P=0.84].The preoperative ONSD in the patients having intracranial hemorrhage and in the patients having no intracranial hemorrhage was(5.26±0.51)mm and(5.41±0.49)mm respectively(P=0.31),and the difference value between postoperative ONSD and preoperative ONSD was(-0.39±0.40)mm and(-0.45±0.25)mm respectively(P=0.66).At the three-month follow-up visit,the difference in ONSD between the patients having a good prognosis(mRS score being 0-2 points)and the patients having a poor prognosis was not statistically significant(P＞0.05).Conclusion ONSD that is measured on plain head CT scan can be used as a response indicator of elevated intracranial pressure in CVST patients,which can be used to monitor the changes in intracranial pressure before and after treatment,but its value in assessing the curative efficacy of different therapeutic methods needs to be further explored.

Background and purpose:Limbs soft tissue sarcoma(STS)is a common malignant tumor,and surgical resection is the main treatment method for it.The concept of barrier made us realize the blocking effect of natural barrier on STS,and we aimed to search for tissues that can act as barrier,and to perform complete resection of surgical margins around the tissue barrier.This study aimed to investigate the feasibility,safety and prognosis of barrier resection in the treatment of limbs STS.Methods:From December 2013 to September 2016,data of 72 patients who underwent barrier resection of STS of extremities in department of oncosurgery,Minhang Branch,Fudan University Shanghai Cancer Center were retrospectively analyzed,and the resection margin was sampled.All 72 patients underwent preoperative magnetic resonance imaging(MRI)or computed tomography(CT)design,and the physiological barrier or at least 3 cm distance was found outward from the anatomical location of the tumor.And en bloc excision was performed outside this barrier or at a distance of 3 cm.The influence of postoperative pathological margin,musculoskeletal tumor society(MSTS)score and postoperative complications on the patients were analyzed.The 1-and 3-year locoregional recurrence-free survival(LRFS)rates and sarcoma-specific survival(SSS)rates were evaluated,and the influencing factors were analyzed.This study was approved by the Ethics Committee of Fudan University Shanghai Cancer Center(number:1212117-12&1212117-12-1301).Results:All patients had negative margins.The 1-and 3-year LRFS rates were 98.2%and 93.3%,respectively.The 1-and 3-year SSS rates were 98.4%and 94.2%,respectively.The mean MSTS scores were 28.3 preoperatively and 25.5 postoperatively.Surgical complications were grade 1 to 2 in 20 cases and grade 3 in 1 case,and there were no grade 4 to 5 complications.Conclusion:Based on the combination of clinical,imaging and pathology data,barrier resection,including tumor resection and functional reconstruction,can be applied to the surgical treatment of STS,with good feasibility and safety,reliable margin and satisfactory local control.

Objective To address the radioactive contamination of wounds caused by transuranic nuclides, wound radiation imaging based on coded aperture imaging technology was investigated. Methods By simulating multiple source terms using Monte Carlo method, the differences in imaging performance between two image reconstruction algorithms under near-field conditions were compared. The effects of detector pixels and detection plane pixels on image resolution were investigated. Results The imaging system was simulated based on the designed dimensions. The simulated imaging field of view was 89.4 mm × 89.4 mm and the simulated angular resolution was 1.98°. Based on the comparison of the average width at half height of the reconstructed point sources under different conditions, it was found that increasing the number of pixels in the detector and detection plane optimized the angular resolution but significantly prolonged the Monte Carlo simulation time. Conclusion According to the simulation results, the parameters of the imaging system can be used to effectively image radioactive contamination. Our results provide methodological support for the measurement of wound contamination caused by transuranic nuclides, and lay the foundation for the development of wound contamination imaging detection systems in the future.

Objective:To investigate the value of 18F-FDG PET/CT combined with conventional imaging modalities in the evaluation of the depth of tumor invasion, regional lymph node metastasis, distant organ and lymph node metastasis (TNM staging), and the adjacent structure invasion of rectal cancer. Methods:Fifty-four patients (28 males, 26 females, age (65.8±11.0) years) with pathologically confirmed rectal cancer admitted to the Affiliated Qingdao Central Hospital of Qingdao University between September 2019 and June 2021 were retrospectively analyzed. 18F-FDG PET/CT examination, conventional imaging modalities including high-resolution MRI (HR-MRI), chest CT plain scan, upper abdominal MRI or CT plain scan+ enhanced examination were performed within 2 weeks before or after the rectal cancer being confirmed. The TNM staging and adjacent structural invasions including circumferential resection margin (CRM), extramural vascular invasion (EMVI), anal sphincter complex involvement were evaluated by 18F-FDG PET/CT and conventional imaging modalities separately or in combination, and those results based on imaging were compared with the pathological results or clinical follow-up results. χ2 test was used to compare the differences of diagnostic sensitivity, specificity and accuracy between the 18F-FDG PET/CT or conventional imaging modalities and combined examination. Results:The accuracy for T staging and the sensitivity and accuracy for N staging of the combined examination were 96.30%(52/54), 98.65%(73/74) and 93.91%(185/197), respectively, which were significantly higher than those of 18F-FDG PET/CT (85.19%(46/54), 66.22%(49/74), 81.73%(161/197); χ2 values: 3.97, 26.88, 13.66, all P<0.05). The specificity (91.06%, 112/123) and accuracy of the combined examination for N staging were higher than those of the conventional imaging modalities (77.24%(95/123), 83.76%(165/197); χ2 values: 8.81, 10.23, both P<0.05). The sensitivity and accuracy of the combined examination for M staging were higher than those of the conventional imaging modalities (97.01%(65/67) vs 73.13%(49/67), 95.95%(71/74) vs 68.92%(51/74); χ2 values: 15.05, 18.66, both P<0.001). The sensitivities of the combined examination in evaluating CRM and EMVI were 100%(22/22) and 95.00%(19/20), and the accuracies were 98.15%(53/54) and 96.30%(52/54), all of which were higher than those of 18F-FDG PET/CT (CRM: 54.55%(12/22), 74.07%(40/54); EVMI: 30.00%(6/20), 74.07%(40/54); χ2 values: 12.94, 13.08, 18.03, 10.56, all P<0.01). The accuracy of the combined examination in evaluating EMVI was higher than that of the conventional imaging modalities (85.19%(46/54); χ2=3.97, P=0.046). Conclusion:18F-FDG PET/CT combined with conventional imaging modalities can improve the diagnostic efficacy for TNM staging and assessment of adjacent structural invasion in rectal cancer.

The aim of this study was to investigate the correlation between porcine epidemic diar-rhea virus(PEDV)S1 IgG antibody levels and neutralizing antibody potency in sow sera.Sera from 5 PEDV-infected farms with a clear immune background,5 non-infected farms and 5 infected farms with an unclear immune background,and sera from return-fed reserve pigs,totaling 716 copies,were collected and measured,and the correlation between PEDV S1 IgG antibodies and neutralizing antibodies was analyzed.The results showed that the PEDV S1 IgG and neutralizing antibodies of sow sera showed highly significant positive correlation,the correlation coefficient was 0.892(P＜0.000 1).Previous studies have shown that the level of PEDV neutralizing antibodies in sow serum correlates with the ability of piglets'maternal antibodies to resist PEDV infection.Therefore,the a-bility of maternal antibodies against PEDV in piglets can be evaluated by detecting PEDV S1 IgG antibodies in the serum of sows.In 10 PEDV-infected farms,the neutralizing antibodies to PEDV in the sera of sows after immunization were generally high,and the S1 IgG antibodies were also high,and their S/P values were higher than 3.5 in 66.9％of the farms(347/519),and the highest anti-body levels were found in the four farms in which PED did not occur,whereas the neutralizing an-tibodies in the immunized sows in the five PEDV-uninfected farms were generally low,and their S1 IgG antibodies were also low,and only 8.1％(13/161)having S/P values higher than 3.5.The re-sults suggest that most sows in PEDV-infected farms can provide good immunoprotection to pig-lets after immunization,while pigs in PEDV-uninfected farms need further immunization if they need to achieve a higher level of immunoprotection.The present study provides a substantial clini-cal basis for the use of PEDV S1 IgG antibody levels to assess the effectiveness of PEDV antibody protection in swine herds.

Molecular knowledge of human gastric corpus epithelium remains incomplete. Here, by integrated analyses using single-cell RNA sequencing (scRNA-seq), spatial transcriptomics, and single-cell assay for transposase accessible chromatin sequencing (scATAC-seq) techniques, we uncovered the spatially resolved expression landscape and gene-regulatory network of human gastric corpus epithelium. Specifically, we identified a stem/progenitor cell population in the isthmus of human gastric corpus, where EGF and WNT signaling pathways were activated. Meanwhile, LGR4, but not LGR5, was responsible for the activation of WNT signaling pathway. Importantly, FABP5 and NME1 were identified and validated as crucial for both normal gastric stem/progenitor cells and gastric cancer cells. Finally, we explored the epigenetic regulation of critical genes for gastric corpus epithelium at chromatin state level, and identified several important cell-type-specific transcription factors. In summary, our work provides novel insights to systematically understand the cellular diversity and homeostasis of human gastric corpus epithelium in vivo.
Humans ; Epigenesis, Genetic ; Gastric Mucosa/metabolism* ; Chromatin/metabolism* ; Stem Cells ; Epithelium/metabolism* ; Fatty Acid-Binding Proteins/metabolism*