Pathological vascular remodeling is a hallmark of various vascular diseases. Previous research has established the significance of andrographolide in maintaining gastric vascular homeostasis and its pivotal role in modulating endothelial barrier dysfunction, which leads to pathological vascular remodeling. Potassium dehydroandrographolide succinate (PDA), a derivative of andrographolide, has been clinically utilized in the treatment of inflammatory diseases precipitated by viral infections. This study investigates the potential of PDA in regulating pathological vascular remodeling. The effect of PDA on vascular remodeling was assessed through the complete ligation of the carotid artery in C57BL/6 mice. Experimental approaches, including rat aortic primary smooth muscle cell culture, flow cytometry, bromodeoxyuridine (BrdU) incorporation assay, Boyden chamber cell migration assay, spheroid sprouting assay, and Matrigel-based tube formation assay, were employed to evaluate the influence of PDA on the proliferation and motility of smooth muscle cells (SMCs). Molecular docking simulations and co-immunoprecipitation assays were conducted to examine protein interactions. The results revealed that PDA exacerbates vascular injury-induced pathological remodeling, as evidenced by enhanced neointima formation. PDA treatment significantly increased the proliferation and migration of SMCs. Further mechanistic studies disclosed that PDA upregulated myeloid differentiation factor 88 (MyD88) expression in SMCs and interacted with T-cadherin (CDH13). This interaction augmented proliferation, migration, and extracellular matrix deposition, culminating in pathological vascular remodeling. Our findings underscore the critical role of PDA in the regulation of pathological vascular remodeling, mediated through the MyD88/CDH13 signaling pathway.
Mice ; Rats ; Animals ; Myeloid Differentiation Factor 88/metabolism* ; Vascular Remodeling ; Cell Proliferation ; Vascular System Injuries/pathology* ; Carotid Artery Injuries/pathology* ; Molecular Docking Simulation ; Muscle, Smooth, Vascular ; Cell Movement ; Mice, Inbred C57BL ; Signal Transduction ; Succinates/pharmacology* ; Potassium/pharmacology* ; Cells, Cultured ; Diterpenes ; Cadherins

Objective:To investigate the impact of lifestyle, apolipoprotein E (ApoE) gene, and their interaction on the risk for cognitive frailty in the elderly population in China.Methods:The study participants were from the Chinese Longitudinal Healthy Longevity Survey. The information about their lifestyles were collected by questionnaire survey, and a weighted lifestyle score was constructed based on β coefficients associated with specific lifestyles to assess the combined lifestyle. ApoE genotypes were assessed by rs429358 and rs7412 single nucleotide polymorphisms. Cognitive frailty was assessed based on cognitive function and physical frailty. Cox proportional hazards regression model was used to analyze the association of lifestyle and ApoE gene with the risk for cognitive frailty and evaluate the multiplicative and additive interactions between lifestyle and ApoE gene. Results:A total of 5 676 elderly persons, with median age [ M ( Q1, Q3)] of 76 (68, 85) years, were included, in whom 615 had cognitive frailty. The analysis by Cox proportional hazards regression model indicated that moderate and high levels of dietary diversity could reduce the risk for cognitive frailty by 18% [hazard ratio ( HR)=0.82, 95% CI: 0.68-1.00] and 28% ( HR=0.72, 95% CI: 0.57-0.91), respectively; moderate and high levels of physical activity could reduce the risk by 31% ( HR=0.69, 95% CI: 0.56-0.85) and 23% ( HR=0.77, 95% CI: 0.64-0.93), respectively. Healthy lifestyle was associated with a 40% reduced risk for cognitive frailty ( HR=0.60, 95% CI: 0.46-0.78). ApoE ε4 allele was associated with a 26% increased risk for cognitive frailty ( HR=1.26, 95% CI: 1.02-1.56). No multiplicative or additive interactions were found between lifestyle and ApoE gene. Conclusions:Dietary diversity and regular physical activity have protective effects against cognitive frailty in elderly population. Healthy lifestyle can reduce the risk for cognitive frailty in elderly population regardless of ApoE ε4 allele carriage status.

This paper aims to discuss the ideas and experience about the radiology residency training system of Canada with a presentation of its base accreditation standards for five aspects, competency goals for seven roles, four stages of training arrangement, and two types of final assessment questions. Although the Canada's radiology residency program differs from China's standardized resident and specialist training programs for radiology, there are still several points that are worth referencing, including emphasizing the training priority of competency goals, providing a specific basis for the stratification of training, offering clear guidance for the implementation of training content, and improving assessment methods to focus on competency goals. These points are of great value for improving the standardized radiology resident and specialist training programs in China, so as to provide a reference for the training of excellent radiologists in China.

Aim To investigate the effect of nitidine chloride (NC) on the apoptosis of cervical cancer cells and its mechanism. Methods Cervical cancer cell lines HeLa and SiHa were selected as subjects. The cytotoxicity of NC and its inhibitory effect on cell growth were detected by CCK-8 assay and clone formation assay. The effect of NC on the apoptosis of cervical cancer cells was detected by TUNEL assay, and the expression of apoptosis-related proteins was detected by Western blot. The effects of NC on the interaction between p53 and E6AP protein, the level of p53 ubiquitination modification and the stability of p53 protein in cervical cancer cells were analyzed by immunoprecipi-tation assay, ubiquitination assay and Western blot assay. Results NC could significantly inhibit the proliferation and induce apoptosis of cervical cancer cells. NC could inhibit the interaction between tumor suppressor protein p53 and E6AP in cervical cancer cells, reduce the level of p53 ubiquitination modification, delay the degradation of p53 and increase the expression level of p53 protein. Conclusions NC can inhibit the ubiquitination and degradation of p53, improve the expression level of p53 protein, restore its tumor suppressor function, and thus play an anti -cervical cancer role.

OBJECTIVE: To investigate the clinicopathological characteristics of anorectal mucosal melanoma (ARMM), and to evaluate the prognostic factors. METHODS: A total of 68 primary ARMM surgical specimens from 2010 to 2018 were retrospectively studied. Slides were reviewed to evaluate pathological features. Slingluff staging method was used for staging. RESULTS: (1) Clinical features: The median age at diagnosis in this group was 61.5 years, with a male-to-female ratio 1 ∶1.62. The most common complaint was blooding (49 cases). For anatomic site, anorectum was the prevalent (66.2%), followed by rectum (20.6%). At the time of diagnosis, 28 cases were stage Ⅰ (localized stage, 41.2%), 25 cases were stage Ⅱ (regional lymph node metastasis, 36.8%), and 15 cases were stage Ⅲ (distant metastasis, 22.1%). Five patients underwent wide local excision, the rest abdominoperineal resection, and 48 patients received adjuvant therapy after surgery. (2) Pathological features: Grossly 88.2% of the tumors were exophytic polypoid masses, with the median tumor size 3.5 cm and the median tumor thickness 1.25 cm. Depth of invasion below lamina muscularis mucosae ranged from 0-5.00 cm (median 1.00 cm). The deepest site of tumor invasion reached muscular layer in 27 cases, and perirectal tissue in 16 cases. Melanin pigmentation was absent or not obvious in 67.6% of the cases. The predominant cytology was epithelioid (45 cases, 66.2%). The rate for ulceration, necrosis, lymphovascular invasion, and perineural invasion was 89.7%, 35.3%, 55.9%, and 30.9%, respectively. The median mitotic count was 18/mm². The positive rate of S100, HMB-45 and Melan-A were 92.0%, 92.6% and 98.0%, respectively. The median of Ki-67 was 50%. The incidences of mutations within CKIT, BRAF and NRAS genes were 17.0% (9 cases), 3.8% (2 cases) and 9.4% (5 cases), respectively. (3) Prognosis: Survival data were available in 66 patients, with a median follow-up of 17 months and a median survival time of 17.4 months. The 1-year, 2-year and 5-year overall survival rate was 76.8%, 36.8% and 17.2%, respectively. The rate of lymphatic metastasis at diagnosis was 56.3%. Forty-nine patients (84.5%) suffered from distant metastasis, and the most frequent metastatic site was liver. Univariate analysis revealed that tumor size (>3.5 cm), depth of invasion below lamina muscularis mucosae (>1.0 cm), necrosis, lymphovascular invasion, BRAF gene mutation, lack of adjuvant therapy after surgery, deep site of tumor invasion, and high stage at diagnosis were all poor prognostic factors for overall survival. Multivariate model showed that lymphovascular invasion and BRAF gene mutation were independent risk factors for lower overall survival, and high stage at diagnosis showed borderline negative correlation with overall survival. CONCLUSION The overall prognosis of ARMM is poor, and lymphovascular invasion and BRAF gene mutation are independent factors of poor prognosis. Slingluff staging suggests prognosis effectively, and detailed assessment of pathological features, clear staging and genetic testing should be carried out when possible. Depth of invasion below lamina muscularis mucosae of the tumor might be a better prognostic indicator than tumor thickness.
Humans ; Male ; Female ; Middle Aged ; Neoplasm Staging ; Retrospective Studies ; Proto-Oncogene Proteins B-raf ; Prognosis ; Melanoma/surgery*

Objective: To explore the efficacy and safety of real-world eribulin in the treatment of metastatic breast cancer. Methods: From December 2019 to December 2020, patients with advanced breast cancer were selected from Beijing Chaoyang District Sanhuan Cancer Hospital, Shandong Cancer Hospital, Peking University Cancer Hospital, Baotou Cancer Hospital, Shengjing Hospital Affiliated to China Medical University, and Cancer Hospital of Chinese Academy of Medical Sciences. Kaplan-Meier method and Log rank test were used for survival analysis, and Cox regression model was used for multivariate analysis. Results: The median progression-free survival (PFS) of 77 patients was 5 months, the objective response rate (ORR) was 33.8%, and the disease control rate (DCR) was 71.4%. The ORR of patients with triple-negative breast cancer was 23.1%, and the DCR was 57.7%; the ORR of patients with Luminal breast cancer was 40.0%, and the DCR was 77.8%; the ORR of patients with HER-2 overexpression breast cancer was 33.3%, and the DCR was 83.3%. ORR of 50.0% and DCR of 66.7% for patients treated with eribulin as first to second line treatment, ORR of 29.4% and DCR of 76.5% for patients treated with third to fourth line and ORR of 28.6% and DCR of 71.4% for patients treated with five to eleven line. The ORR of patients in the eribulin monotherapy group was 40.0% and the DCR was 66.0%; the ORR of patients in the combination chemotherapy or targeted therapy group was 22.2% and the DCR was 81.5%. Patients with a history of treatment with paclitaxel, docetaxel, or albumin paclitaxel during the adjuvant phase or after recurrent metastasis had an ORR of 32.9% and a DCR of 69.9% when treated with eribulin. The treatment efficacy is an independent prognostic factor affecting patient survival (P<0.001). The main adverse reactions in the whole group of patients were Grade Ⅲ-Ⅳ neutrophil decline [29.9% (23/77)], and other adverse reactions were Grade Ⅲ-Ⅳ fatigue [5.2% (4/77)], Grade Ⅲ-Ⅳ peripheral nerve abnormality [2.6% (2/77)] and Grade Ⅲ-Ⅳ alopecia [2.6% (2/77)]. Conclusions: Eribulin still has good antitumor activity against various molecular subtypes of breast cancer and advanced breast cancer that has failed multiple lines of chemotherapy, and the adverse effects can be controlled, so it has a good clinical application value.
Breast Neoplasms/pathology* ; Female ; Furans/adverse effects* ; Humans ; Ketones/adverse effects* ; Paclitaxel/adverse effects* ; Treatment Outcome ; Triple Negative Breast Neoplasms/drug therapy*

Aim To study the electrophysiological mechanism of dopamine inhibiting insulin secretion hv voltage-dependent potassium ( Kv) channels.Methods Islets and (3 cells were isolated from male SD rats.D,-like receptor agonist ( SKP38393), D2-like receptor agonist (Quinpirole) and antagonist (Epiclopride) were used according to the experiment.Insulin secretion was detected by insulin radioimmunoassay.Whole-cell j J patch-clamp technique was applied to detect Kv channel currents and action potential duration of p cells.Di- BAC4(3) staining was used to observe membrane potential.Results SKF38393 did not affect insulin secretion and the Kv channel currents.Quinpirole signifi cantly inhibited insulin secretion and increased Kv channel currents.Dopamine significantly inhibited insulin secretion, increased Kv channel currents and shortened action potential duration of p cells, which could be reversed by epiclopride.In addition, dopamine de-creased membrane potential of INS-1 cells.Conclusions Dopamine inhibits insulin secretion by acting on D2-like receptors, resulting in actived Kv channels, shortened action potential duration and decreased cell membrane potential.

This study aims to explore the pharmacodynamic differences of Puerariae Lobatae Radix(PLR), Puerariae Thomsonii Radix(PTR) and their different processed products and the influences of these medical materials on the diversity of intestinal flora. The Sennae Folium-induced diarrhea model, streptozotocin(STZ)-induced diabetes model and L-nitro-arginine methyl ester(L-NAME)-induced hypertension model were used to compare the pharmacodynamic differences in anti-diarrhea, blood glucose reduction and blood pressure lowering among raw, roasted and vinegar-processed PLR and PTR. The effects of raw and processed PLR and PTR on intestinal flora diversity of rats were evaluated by 16 S rDNA high-throughput sequencing. The roasted PLR and PTR performed better in anti-diarrhea, especially the former. PLR and its processed products all presented the efficacy of reducing blood glucose, and the vinegar-processed PLR was the most outstanding. The raw PTR was not that effective in reducing blood glucose, whereas its efficacy was improved after roasting and vinegar processing. Both PLR and PTR were capable of lowering blood pressure to a certain extent, and PLR is superior to PTR in this aspect. Further, the vinegar-processed PLR showed the best effect. The diversity of intestinal flora was different among rats to which different products of PLR and PTR were administered. The roasted PLR led to the highest abundance of Lactobacillus, which was closely related to its best antidiarrheal effect. The highest abilities of vinegar-processed PLR to lower blood glucose and blood pressure were associated with the high abundance of Blautia and Prevotella_9. This study lays a foundation for elucidating the processing mechanisms of PLR and PTR and provides a basis for their further development and application.
Animals ; Drugs, Chinese Herbal ; Gastrointestinal Microbiome ; Plant Roots ; Pueraria ; Rats

OBJECTIVE: To observe the effect of acupuncture-moxibustion on negative emotions and plasma tryptophan (Trip)-kynurenine (Kyn) metabolism in the patients with Crohn's disease (CD) at the mild and moderate active stage. METHODS: A total of 66 CD patients were randomized into an observation group (33 cases, 1 case dropped off) and a control group (33 cases, 2 cases dropped off). In the observation group, acupuncture was applied in combination with moxibustion. In the control group, the sham-acupuncture was used in combination with sham-moxibustion. In both of the observation group and the control group, acupuncture was applied to Zhongwan (CV 12), Shangjuxu (ST 37), Sanyinjiao (SP 6), Gongsun (SP 4), Hegu (LI 4), Quchi (LI 11), Taixi (KI 3) and Taichong (LR 3), and moxibustion was applied to Tianshu (ST 25) and Zusanli (ST 36). The treatment was given once every two days, 3 times a week, totally for 12 weeks. Separately, before and after treatment, the score of the hospital anxiety-depression scale (HADS) and the score of intestinal core symptoms (degree of abdominal pain and frequency of diarrhea) were observed in the patients of the two groups. The concentration of plasma indoleamine 2,3-dioxygenase 1 (IDO1) and the ratios of Kyn/Trp, QuinA/Kyn, KynA/Kyn and KynA/QuinA were compared between the two groups. RESULTS: Compared with before treatment, the scores of HADS-A and HADS-D in the observation group and the score of HADS-A in the control group were all reduced after treatment ( CONCLUSION Acupuncture and moxibustion relieve the negative emotions of anxiety and depression in CD patients at mild and moderate active stage, which is probably related to the regulation of plasma Trp-Kyn metabolic pathway.
Acupuncture Points ; Acupuncture Therapy ; Crohn Disease/therapy* ; Emotions ; Humans ; Moxibustion ; Plasma ; Treatment Outcome ; Tryptophan

OBJECTIVE: To observe the clinical effect of electroacupuncture (EA) on aged insomnia, and explore its possible mechanism. METHODS: A total of 60 patients with aged insomnia were randomly divided into an EA group (30 cases) and a sham EA group (30 cases, 1 case dropped off). The patients in the EA group were treated with acupuncture at Baihui (GV 20), Yintang (GV 29), Shenmen (HT 7), Sanyinjiao (SP 6), Xinshu (BL 15) and Shenshu (BL 23), and EA was used at Baihui (GV 20) and Yintang (GV 29), with intermittent wave, 2 Hz in frequency. In the sham EA group, the acupoints and the EA connection acupoints were the same as those in the EA group, 2-3 mm in depth, but no current was connected. The intervention was given 30 min each time, once every other day, 3 times a week for 4 weeks in the both groups. Before and after treatment, the Pittsburgh sleep quality index (PSQI) and Montreal cognitive assessment (MoCA) scale were used to assess sleep quality and cognitive function, and serum melatonin (MT) and dopamine (DA) levels were detected. RESULTS: After treatment, the total score and sub-item scores of PSQI in the EA group were lower than those before treatment ( CONCLUSION Electroacupuncture can improve sleep quality and cognitive function in aged insomnia patients, and its mechanism may be related to regulating serum MT and DA levels.
Acupuncture Points ; Aged ; Dopamine ; Electroacupuncture ; Humans ; Melatonin ; Sleep Initiation and Maintenance Disorders/therapy*