BACKGROUND:Developed by the esteemed Chinese medicine master Wei Guikang,Tongan Decoction has proven highly effective in treating knee osteoarthritis.However,the mechanism of action is yet unclear.OBJECTIVE:To elucidate how Tongan Decoction modulates synovial macrophage polarization as a therapeutic strategy for knee osteoarthritis in a rat model.METHODS:(1)We employed high-throughput microRNA sequencing and polymerase chain reaction to analyze the differentially expressed miRNA in synovial macrophages of normal and knee osteoarthritis rats.Predicted target genes of miR-27a were identified using bioinformatics databases,with subsequent validation through luciferase assays.A total of 68 Sprague-Dawley rats were randomly divided into normal control group(n=16),model group(n=16),miR-27a overexpression group(n=12),Tongan Decoction group(n=12),and Tongan Decoction+miR-27a inhibition group(n=12).The miR-27a overexpression group and the Tongan Decoction+miR-27a inhibition group were injected with miR-27a mimic and miR-27a inhibitor in the right knee joint cavity,respectively,once daily for 5 continuous days.On the 15th day after modeling,the Tongan Decoction group and the Tongan Decoction+miR-27a inhibition group were given Tongan Decoction by gastric lavage,and the other three groups were given saline by gastric lavage,once daily for 14 continuous days.After administration,behavioral tests,X-rays,hematoxylin-eosin staining of synovial and cartilage tissues of the knee joint and immunofluorescence staining of synovial tissues of the knee joint,RT-PCR,and Western blot were performed.RESULTS AND CONCLUSION:High-throughput sequencing of miRNA showed low expression of miR-27a in synovial tissues of rats with knee osteoarthritis.The target gene of miR-27a was nuclear factor κB,and luciferase assay showed that the two could bind to each other.Behavioral assays showed that miR-27a overexpression or Tongan Decoction alleviated joint dysfunction in rats with knee osteoarthritis,and miR-27a inhibition antagonized the effect of Tongan Decoction.X-ray films and hematoxylin-eosin staining showed that miR-27a overexpression or Tongan Decoction reduced the degree of knee osteoarthritis and miR-27a inhibition weakened the therapeutic effect of Tongan Decoction.The results of RT-PCR and western blot assay showed that compared with the normal control group,the expression of interleukin 10 was reduced in the model group(P＜0.05),and the expression of matrix metalloproteinase 13,interleukin 1β,and nuclear factor κB was elevated in the model group(P＜0.05).miR-27a overexpression or Tongan Decoction could differently reverse the changes in the above-mentioned indexes,while miR-27a inhibition weakened the effect of Tongan Decoction.Immunofluorescence staining results showed that CD86 protein expression in the model group was higher than that in the normal control group(P＜0.05),and CD206 protein expression was lower than that in the normal control group(P＜0.05);miR-27a overexpression group and Tongan Decoction had lower CD86 protein expression than that in the model group(P＜0.05),and higher CD206 protein expression than that in the model group(P＜0.05);in the Tongan Decoction+miR-27a inhibition group,CD86 protein expression was higher(P＜0.05)and CD206 protein expression was lower than that in the Tongan Decoction group(P＜0.05).Tongan Decoction mitigates knee osteoarthritis by upregulating miR-27a expression and suppressing nuclear factor κB activity,which improves knee joint function and further treats knee osteoarthritis.

OBJECTIVES: Wild-caught Microtus fortis (M. fortis) at the age of 9-15 months can develop epithelial ovarian cancers similar to human epithelial ovarian cancers under natural conditions during experimental animal breeding, but its pathological types and biological characteristics remain unclear. This study aims to analyze the biological characteristics of spontaneous ovarian cancer in M. fortis, intending to develop M. fortis as an animal model for human epithelial ovarian cancer. METHODS: The female M. fortis (9-15 months old) with spontaneous ovarian cancer were selected as the experimental group, and healthy M. fortis from the same litter were selected as the control group. The ovarian pathological changes of the two groups were observed by dissection. Blood routine and biochemical indicators were measured by biochemical analysis. Hematoxylin and eosin (HE) staining was performed to observe the pathological changes in the ovarian cancer tissue of M. fortis. Immunohistochemical staining was used to detect the protein expression of common ovarian cancer markers, and real-time RT-PCR was used to analyze the transcription levels of ovarian cancer-related genes. RESULTS: Spontaneous ovarian cancer in M. fortis mainly affects both ovaries, with tumors appearing solid or cystic. HE staining and histopathological analysis confirmed that the ovarian tumors originated from ovarian surface epithelium. Compared to the control group, the experimental group showed significantly decreased hemoglobin (P<0.01), hematocrit (P<0.05), albumin (P<0.05), and blood glucose levels (P<0.01), while lymphocyte percentage (P<0.05), monocyte percentage (P<0.05), cholesterol (P<0.01), and progesterone (P<0.01) levels were significantly increased. Expression of ovarian cancer-related genes, including ID3, CDC42, RHOA, RB1CC1, NF1, PIN1, MIB1, PDS5A, MCM7, and MLH1, was significantly downregulated (all P<0.05), while PAX8 gene expression was significantly upregulated (P<0.05). Immunohistochemical results showed that Wilms' tumor gene 1 (WT1) protein was mainly distributed throughout the cell, with significantly higher expression in ovarian cancer M. fortis. Tumor protein 53 (TP53) was expressed in both healthy and ovarian cancer M. fortis and was distributed throughout the cell. Hepatocyte nuclear factor 1 beta (HNF1B) and progesterone receptor (PR) protein were highly expressed in the ovarian tissue of healthy M. fortis but were significantly reduced in the ovarian cancer M. fortis, though both were located in the cytoplasm. CONCLUSIONS Spontaneous ovarian cancer in M. fortis is serous ovarian cancer. Compared to healthy M. fortis, significant differences were observed in ovarian tissue morphology, biochemical indicators, ovarian cancer-related gene expression, and protein expression, which show similarity to the biological characteristics of human serous ovarian cancer. This suggests that M. fortis could be an ideal animal model for studying human serous ovarian cancer.
Female ; Ovarian Neoplasms/metabolism* ; Animals ; Carcinoma, Ovarian Epithelial ; Disease Models, Animal ; Humans ; Neoplasms, Glandular and Epithelial/metabolism* ; Ovary/pathology*

OBJECTIVES: To investigate the effects of dihydroartemisinin (DHA) combined with doxorubicin (DOX) on proliferation and apoptosis of triple-negative breast cancer cells and explore the underlying molecular mechanism. METHODS: MDA-MB-231 cells were treated with 50, 100 or 150 μmol/L DHA, 0.5 μmol/L DOX, or with 50 μmol/L DHA combined with 0.5 μmol/L DOX. The changes in proliferation and survival of the treated cells were examined with MTT assay and colony-forming assay, and cell apoptosis was analyzed with flow cytometry. Western blotting was performed to detect the changes in protein expression levels of PCNA, cleaved PARP, Bcl-2, Bax, STAT3, p-STAT3, HIF-1α and survivin. RESULTS: The IC₅₀ of DHA was 131.37±29.87 μmol/L in MDA-MB-231 cells. The cells with the combined treatment with DHA and DOX showed significant suppression of cell proliferation. Treatment with DHA alone induced apoptosis of MDA-MB-231 cells in a dose-dependent manner, but the combined treatment produced a much stronger apoptosis-inducing effect than both DHA and DOX alone. DHA at 150 μmol/L significantly inhibited clone formation of MDA-MB-231 cells, markedly reduced cellular expression levels of PCNA, p-STAT3, HIF-1α and survivin proteins, and obviously increased the expression level of cleaved PARP protein and the Bax/Bcl-2 ratio, and the combined treatment further reduced the expression level of p-STAT3 protein and increased the Bax/Bcl-2 ratio. CONCLUSIONS DHA combined with DOX produces significantly enhanced effects for inhibiting cell proliferation and inducing apoptosis in MDA-MB-231 cells possibly as result of DHA-mediated negative regulation of the STAT3/HIF-1α pathway.
Humans ; STAT3 Transcription Factor/metabolism* ; Apoptosis/drug effects* ; Hypoxia-Inducible Factor 1, alpha Subunit/metabolism* ; Doxorubicin/pharmacology* ; Triple Negative Breast Neoplasms/metabolism* ; Cell Line, Tumor ; Artemisinins/pharmacology* ; Female ; Cell Proliferation/drug effects* ; Signal Transduction/drug effects* ; Survivin

Periodontitis is a common oral disease characterized by progressive alveolar bone resorption and inflammation of the periodontal tissues. Dimethyl fumarate (DMF) has been used in the treatment of various immune-inflammatory diseases due to its excellent anti-inflammatory and antioxidant functions. Here, we investigated for the first time the therapeutic effect of DMF on periodontitis. In vivo studies showed that DMF significantly inhibited periodontal destruction, enhanced mitophagy, and decreased the M1/M2 macrophage ratio. In vitro studies showed that DMF inhibited macrophage polarization toward M1 macrophages and promoted polarization toward M2 macrophages, with improved mitochondrial function, inhibited oxidative stress, and increased mitophagy in RAW 264.7 cells. Furthermore, DMF increased intracellular mitochondrial Tu translation elongation factor (TUFM) levels to maintain mitochondrial homeostasis, promoted mitophagy, and modulated macrophage polarization, whereas TUFM knockdown decreased the protective effect of DMF. Finally, mechanistic studies showed that DMF increased intracellular TUFM levels by protecting TUFM from degradation via the ubiquitin-proteasomal degradation pathway. Our results demonstrate for the first time that DMF protects mitochondrial function and inhibits oxidative stress through TUFM-mediated mitophagy in macrophages, resulting in a shift in the balance of macrophage polarization, thereby attenuating periodontitis. Importantly, this study provides new insights into the prevention of periodontitis.
Dimethyl Fumarate/pharmacology* ; Mitophagy/drug effects* ; Animals ; Mice ; Macrophages/metabolism* ; Periodontitis/prevention & control* ; RAW 264.7 Cells ; Oxidative Stress/drug effects* ; Peptide Elongation Factor Tu/metabolism* ; Mice, Inbred C57BL ; Male ; Mitochondria/drug effects*

Perimenopausal depression seriously affects women's physical and mental health.It is caused primarily by gonadal function decline,which is typically characterized by low mood,anxiety,slow thinking,and loss of interest,and is accompanied by autonomic dysfunction and endocrine dysfunction.The pathogenesis of perimenopausal depression remains unclear and controversial.Many scholars have conducted scientific research that is based on animal models of perimenopausal depression.Indeed,a good animal model of perimenopausal depression is the basic premise for studying its pathophysiological mechanisms and for facilitating reliability of the scientific result.Therefore,this paper combines the modern research mechanisms of perimenopausal depression and the current status of animal models in China,and provides an overview,evaluation,and generalization of the modeling method,principles and result,to provide a scientific basis and reference for the selection of suitable animal models for scientific research experiments.

BACKGROUND: The combination of immune checkpoint inhibitors and chemotherapy (ICI + Chemo) shows promise in treatment of recurrent or metastatic nasopharyngeal carcinoma (RM-NPC), but some patients received limited benefit and the prognostic factors of the treatments remain unclear. Furthermore, ICIs efficacy in subsequent treatments needs further evaluation. METHODS: A systematic search on PubMed, Embase, the Cochrane Library, and major conference proceedings was conducted to identify relevant studies for meta-analysis. The study was designed to compare ICI + Chemo with chemotherapy in first-line treatment and identify efficacy predictors, and to evaluate ICIs alone in subsequent-line treatment for RM-NPC, with a focus on progression-free survival (PFS), objective response rate (ORR), and treatment-related adverse events (AEs). RESULTS: Fifteen trials involving 1928 patients were included. Three trials compared ICI + Chemo with chemotherapy as a first-line treatment, while 12 trials evaluated ICIs alone in subsequent-line treatment of RM-NPC patients. First-line ICI + Chemo showed superior PFS (hazard ratio [HR] = 0.52, 95% confidence interval [CI], 0.43-0.63; P <0.001) and ORR (risk ratio [RR] = 1.14, 95% CI, 1.05-1.24; P <0.001) compared to chemotherapy, without increased AEs (RR = 1.01, 95% CI, 0.99-1.03; P = 0.481). Neither programmed death-ligand 1 (PD-L1) nor other factors predicted the efficacy of ICI + Chemo vs . chemotherapy. Subsequent-line ICIs alone had a median PFS of 4.12 months (95% CI, 2.93-5.31 months), an ORR of 24% (95% CI, 20-28%), with grade 1-5/grade 3-5 AEs at 79%/14%. However, ICIs alone were associated with significantly shorter PFS (HR = 1.31, 95% CI, 1.01-1.68; P = 0.040) than chemotherapy alone. CONCLUSIONS ICI + Chemo confers superior survival benefits compared to chemotherapy in first-line RM-NPC treatment, independent of PD-L1 expression or other factors. However, ICIs alone demonstrate a manageable safety profile but do not surpass chemotherapy in efficacy for subsequent-line treatment.
Humans ; Immune Checkpoint Inhibitors/adverse effects* ; Nasopharyngeal Carcinoma/drug therapy* ; Nasopharyngeal Neoplasms/drug therapy* ; Neoplasm Recurrence, Local/drug therapy*

OBJECTIVE: To investigate the safety and effectiveness of using the Taylor spatial frame (TSF) based on the Ilizarov tension-stress principle for treatment of post-burn foot and ankle deformities in adults. METHODS: A clinical data of 6 patients with post-burn foot and ankle deformities treated between April 2019 and November 2023 was retrospectively analyzed. There was 1 male and 5 females with an average age of 28.7 years (range, 20-49 years). There were 3 cases of simple ankle equinus, 2 cases of ankle equinus, midfoot rocker-bottom foot, and forefoot pronation, and 1 case of calcaneus foot and forefoot pronation. Preoperative American Orthopedic Foot and Ankle Society (AOFAS) score was 45.3±18.2, 12-Item Short-Form Health Survey (SF-12)-Physical Component Summary (PCS) score was 34.3±7.3 and Mental Component Summary (MCS) score was 50.4±8.8. Imaging examination showed tibial-calcaneal angle of (79.8±31.5)°, calcaneus-first metatarsal angle of (154.5±45.3)°, talus-first metatarsal angle of (-19.3±35.0)°. Except for 1 case with severe deformity that could not be measured, the remaining 5 cases had talus-second metatarsal angle of (40.6±16.4)°. The deformities were fixed with TSF after soft tissue release and osteotomy. Then, the residual deformities were gradually corrected according to software-calculated prescriptions. TSF was removed after maximum deformity correction and osteotomy healing. External fixation time, brace wearing time after removing the TSF, and pin tract infection occurrence were recorded. Infection severity was evaluated based on Checketts-Otterburns grading. Joint function was evaluated using AOFAS score and SF-12 PCS and MCS scores. Patient satisfaction was assessed using Likert score. Imaging follow-up measured relevant indicators to evaluate the degree of deformity correction. Deformity recurrence was observed during follow-up. RESULTS: The external fixation time was 103-268 days (mean, 193.5 days). The mild pin tract infections occurred during external fixation in all patients, which healed after pin tract care and oral antibiotics. No serious complication such as osteomyelitis, fractures, neurovascular injury, or skin necrosis occurred. After external fixation removal, 3 cases did not wear braces, while the remaining 3 cases wore braces continuously for 6 weeks, 8 weeks, and 3 years, respectively. All patients were followed up 13.9-70.0 months, with an average of 41.7 months. During follow-up, none of the 6 patients had recurrence of foot deformity. At 1 year after operation, the AOFAS score was 70.0±18.1, SF-12-PCS and MCS scores were 48.9±4.5 and 58.8±6.4, respectively, all showing significant improvement compared to preoperative values ( P<0.05). Imaging follow-up showed that all osteotomies healed, and all distraction cases achieved bony union at 6 months after stopping stretching. At 1 year after operation, tibial-calcaneal angle was (117.5±12.8)° and talus-first metatarsal angle was (-3.3±19.3)°, both showing significant improvement compared to preoperative values ( P<0.05). Calcaneus-first metatarsal angle was (132.0±14.4)°, which also improved compared to preoperative values but without significant difference ( P>0.05). Except for 1 case with severe deformity that could not be measured, the remaining 5 cases had talus-second metatarsal angle of (18.0±6.4)°. And there was no significant difference ( P>0.05) between pre-and post-operative data of 4 patients with complete data. At 1 year after operation, 1 patient was satisfied with effectiveness and 5 patients were very satisfied. CONCLUSION The TSF, by applying the Ilizarov tension-stress principle for gradual distraction and multi-planar adjustment, combined with soft tissue release and osteotomy, can effectively correct foot and ankle deformities after burns, especially equinus deformity with contracture of the posterior soft tissues of the lower leg. There are still limitations in treating cases with tight, adherent scars on the dorsum of the foot that require long-distance distraction. If necessary, a multidisciplinary approach combined with microsurgical techniques can be utilized.
Humans ; Adult ; Male ; Female ; Middle Aged ; Retrospective Studies ; External Fixators ; Young Adult ; Burns/complications* ; Foot Deformities, Acquired/etiology* ; Treatment Outcome ; Ilizarov Technique/instrumentation*

Objective To review the damage outcomes of patients in medical damage events and to analyze the influencing factors of medical causality determination in medical damage events in Tianjin city,with a view to reducing the occurrence of medical damage events by avoiding risk factors and standardizing the diagnostic and therapeutic activities of medical personnel.Methods 316 cases of medical damage events handled by the Medical Damage Identification Office of Tianjin Medical Association from 2017 to 2023 were selected as the research object,and descriptive analysis was used to summarize the basic situation of medical damage events,and the medical fault factors affecting the magnitude of the cause force of the medical side of medical damage events were explored through single-factor analysis and the construction of multiomal logistic regression models.Results Medical malpractice(OR=3.140)and incomplete preoperative assessment(OR=6.008)are factors that influence the determination of the liability of the medical institution in medical malpractice events(P＜0.05),and all three regression coefficients were greater than 0,all three were positively correlated with the probability that the medical cause power was judged to be greater than or equal to the equivalent cause.Conclusion The number of medical damage incidents in Tianjin shows a fluctuating downward trend.In Tianjin,the number of medical injury incidents showed a fluctuating downward trend,and the number of medical injury incidents in tertiary public general hospitals was the largest.Therefore,medical institutions should establish and improve multidisciplinary diagnosis and treatment mode to improve the level of diagnosis and treatment.Strengthen preoperative evaluation to avoid surgical risk.

Objective:To analyze the clinical data of seven patients with a clinical diagnosis of likely sporadic Creutzfeldt-Jakob disease (sCJD) in order to improve the understanding and diagnosis of sporadic Creutzfeldt-Jakob disease.Methods:The clinical data of 7 sCJD patients admitted to the Department of Neurology of Our Hospital from 2021 to 2023 were retrospectively analyzed.Results:All seven patients had a subacute onset of disease, and the main clinical features included rapidly progressive dementia (RPD), cerebellar symptoms, pyramidal signs, myoclonus and akinetic mutism. Magnetic resonance diffusion-weighted imaging (DWI) reveals widespread asymmetrical lace-like high signal distributed along the cortex and a basal curved ball-and-stick sign. Electroencephalography (EEG) shows diffuse spiking and spiking slow waves, and periodic triphasic waves in advanced stages of the disease. Cerebrospinal fluid 14-3-3 protein testing was performed in 6 of the 7 patients, and 4 were positive. Four patients died within six months of onset of illness.Conclusions:The disease is prevalent in middle-aged and elderly patients, with a non-significant male-to-female ratio, and is dominated by the presence of Rapidly Progressive Dementia (RPD), especially the presence of cortical high signals in the DWI sequences and diffuse sharp and slow wave issuance in the electroencephalograph (EEG), which need to be alerted to the occurrence of Creutzfeldt-Jakob Disease. Dynamic review of MRI, EEG, cerebrospinal fluid 14-3-3 protein, prion protein gene (PRNP) sequence analysis and cerebrospinal fluid prion real-time vibration-induced protein amplification (RT-QuIC) monitoring whenever possible to avoid misdiagnosis, under-diagnosis, and under-recognition.