Triple-negative breast cancer (TNBC) is a subtype of breast cancer that is challenging to treat and lacks targeted therapeutic drugs in the clinic. Natural active ingredients provide promising opportunities for discovering and developing targeted therapies for TNBC. This study investigated the effects of daurisoline on TNBC and elucidated its potential mechanisms. Using network pharmacology, a correlation was identified between daurisoline, derived from Menispermum dauricum, and breast cancer, particularly involving the Notch signaling pathway. The effects of daurisoline on the proliferation, migration, and apoptosis of MDA-MB-231 and MDA-MB-468 cells were evaluated in vitro. Additionally, the impact of daurisoline on the growth of MDA-MB-231 xenograft tumors in nude mice was assessed through in vivo experiments. Expression levels of Notch signaling pathway-related proteins, including Notch-1, NICD, PSEN-1, Bax, and Bcl-2, were examined using molecular docking and Western blotting to explore the underlying mechanisms of daurisoline’s anti-breast cancer effects. It was revealed that daurisoline could effectively inhibit the proliferation and migration of MDA-MB-231 and MDA-MB-468 cells and promote apoptosis. Furthermore, it significantly reduced the growth of subcutaneous tumors in nude mice. Notably, daurisoline could reduce the hydrolytic activity of γ-secretase by binding to the catalytic core PSEN-1, thereby inhibiting activation of the γ-secretase/Notch axis and contributing to its anti-TNBC effects.This study supported the development of naturally targeted drugs for TNBC and provided insights into the research on dibenzylisoquinoline alkaloids, such as daurisoline.

Triple-negative breast cancer (TNBC) is a subtype of breast cancer that is challenging to treat and lacks targeted therapeutic drugs in the clinic. Natural active ingredients provide promising opportunities for discovering and developing targeted therapies for TNBC. This study investigated the effects of daurisoline on TNBC and elucidated its potential mechanisms. Using network pharmacology, a correlation was identified between daurisoline, derived from Menispermum dauricum, and breast cancer, particularly involving the Notch signaling pathway. The effects of daurisoline on the proliferation, migration, and apoptosis of MDA-MB-231 and MDA-MB-468 cells were evaluated in vitro. Additionally, the impact of daurisoline on the growth of MDA-MB-231 xenograft tumors in nude mice was assessed through in vivo experiments. Expression levels of Notch signaling pathway-related proteins, including Notch-1, NICD, PSEN-1, Bax, and Bcl-2, were examined using molecular docking and Western blotting to explore the underlying mechanisms of daurisoline’s anti-breast cancer effects. It was revealed that daurisoline could effectively inhibit the proliferation and migration of MDA-MB-231 and MDA-MB-468 cells and promote apoptosis. Furthermore, it significantly reduced the growth of subcutaneous tumors in nude mice. Notably, daurisoline could reduce the hydrolytic activity of γ-secretase by binding to the catalytic core PSEN-1, thereby inhibiting activation of the γ-secretase/Notch axis and contributing to its anti-TNBC effects.This study supported the development of naturally targeted drugs for TNBC and provided insights into the research on dibenzylisoquinoline alkaloids, such as daurisoline.

Triple-negative breast cancer (TNBC) is a subtype of breast cancer that is challenging to treat and lacks targeted therapeutic drugs in the clinic. Natural active ingredients provide promising opportunities for discovering and developing targeted therapies for TNBC. This study investigated the effects of daurisoline on TNBC and elucidated its potential mechanisms. Using network pharmacology, a correlation was identified between daurisoline, derived from Menispermum dauricum, and breast cancer, particularly involving the Notch signaling pathway. The effects of daurisoline on the proliferation, migration, and apoptosis of MDA-MB-231 and MDA-MB-468 cells were evaluated in vitro. Additionally, the impact of daurisoline on the growth of MDA-MB-231 xenograft tumors in nude mice was assessed through in vivo experiments. Expression levels of Notch signaling pathway-related proteins, including Notch-1, NICD, PSEN-1, Bax, and Bcl-2, were examined using molecular docking and Western blotting to explore the underlying mechanisms of daurisoline’s anti-breast cancer effects. It was revealed that daurisoline could effectively inhibit the proliferation and migration of MDA-MB-231 and MDA-MB-468 cells and promote apoptosis. Furthermore, it significantly reduced the growth of subcutaneous tumors in nude mice. Notably, daurisoline could reduce the hydrolytic activity of γ-secretase by binding to the catalytic core PSEN-1, thereby inhibiting activation of the γ-secretase/Notch axis and contributing to its anti-TNBC effects.This study supported the development of naturally targeted drugs for TNBC and provided insights into the research on dibenzylisoquinoline alkaloids, such as daurisoline.

Objective To explore the effect of intermittent fasting combined with diversified management mode on weight loss of overweight and obese people. Methods A total of 120 overweight and obese patients were selected as research objects, and randomly divided into control group (n=60) and experimental group (n=60). The control group was given intermittent fasting, and the experimental group was given diversified management mode on the basis of the control group. Waist circumference, body mass, body mass index (BMI), waist-to-hip ratio and blood lipid level were compared between the two groups; the scores of hunger, satiety, satisfaction and the incidence of adverse reactions were compared between the two groups. Results After intervention, waist circumference, body mass, BMI, waist-to-hip ratio, total cholesterol (TC), triglyceride (TG) and low-density lipoprotein cholesterol (LDL-C) in the experimental group were significantly lower, and high-density lipoprotein cholesterol (HDL-C) was significantly higher than that in the control group (P < 0.05). After intervention, the hunger score of the experimental group was significantly lower, and the satiety score and satisfaction score were significantly higher than those of the control group (P < 0.05). The total incidence of adverse reactions in the experimental group was 6.67%, which was significantly lower than 20.00% in the control group (P < 0.05). Conclusion The application of intermittent fasting combined with diversified management mode in overweight and obese people is better, which can improve the relevant clinical indicators and blood lipid levels, and has high safety.

The system of compassionate drug use in China is in the preliminary exploration stage， and the formal management methods and specific implementation rules have not been promulgated， which needs to be further optimized and perfected. Japan realizes the advanced use of unapproved drugs by expanded access clinical trial system， and makes clear provisions on information acquisition， target patient， informed consent， subject of application， implementation plan， handling of refusal to administer medication， drug expenses， implementation deadline， compensation for accidental damages， post-approval data review after expanded access clinical trials. When the enterprise refuses to give drugs because of the “legitimacy reasons of the system”， the attending physician can also apply to the Ministry of Health， Labor and Welfare， and the Ministry of Health， Labor and Welfare will conduct the licensing evaluation to maximize the drug for patients. This “refusal to administer” reprocessing is a unique regulation in Japan， which ensures the accessibility of drugs to the greatest extent possible. Based on the analysis of the expanded access clinical trial system in Japan， it is found that our country could further build the information platform for compassionate drug use， play the leading role of physicians， protect the interests of enterprises， pay attention to the ethical review， and make drug cost payment problems further clear in order to improve and optimize the system of compassionate drug use.

Humans ; Cross-Sectional Studies ; East Asian People ; Psoriasis/epidemiology* ; Arthritis, Psoriatic/epidemiology* ; Registries ; Surveys and Questionnaires

Chuanxiong Rhizoma (CX, the dried rhizome of Ligusticum wallichii Franch.), a well-known traditional Chinese medicine, is clinically used for treating cardiovascular, cerebrovascular and hepatobiliary diseases. Cholestatic liver damage is one of the chronic liver diseases with limited effective therapeutic strategies. Currently, little is known about the mechanism links between CX-induced anti-cholestatic action and intercellular communication between cholangiocytes and hepatic stellate cells (HSCs). The study aimed to evaluate the hepatoprotective activity of different CX extracts including the aqueous, alkaloid, phenolic acid and phthalide extracts of CX (CX_AE, CX_AL, CX_PA and CX_PHL) and investigate the intercellular communication-related mechanisms by which the most effective extracts work on cholestatic liver injury. The active compounds of different CX extracts were identified by UPLC-MS/MS. A cholestatic liver injury mouse model induced by bile duct ligation (BDL), and transforming growth factor-β (TGF-β)-treated human intrahepatic biliary epithelial cholangiocytes (HIBECs) and HSC cell line (LX-2 cells) were used for in vivo and in vitro studies. Histological and other biological techniques were also applied. The results indicated that CX_AE, CX_AL and CX_PHL significantly reduced ductular reaction (DR) and improved liver fibrosis in the BDL mice. Meanwhile, both CX_AE and CX_PHL suppressed DR in injured HIBECs and reduced collagen contraction force and the expression of fibrosis biomarkers in LX-2 cells treated with TGF-β. CX_PHL suppressed the transcription and transfer of plasminogen activator inhibitor-1 (PAI-1) and fibronectin (FN) from the 'DR-like' cholangiocytes to activated HSCs. Mechanistically, the inhibition of PAI-1 and FN by CX_PHL was attributed to the untight combination of the acetyltransferase KAT2A and SMAD3, followdd by the suppression of histone 3 lysine 9 acetylation (H3K9ac)-mediated transcription in cholangiocytes. In conclusion, CX_PHL exerts stronger anti-cholestatic activity in vivo and in vitro than other CX extracts, and its protective effect on the intracellular communication between cholangiocytes and HSCs is achieved by reducing KAT2A/H3K9ac-mediated transcription and release of PAI-1 and FN.

【Objective】 To construct a prediction model of severe obstructive sleep apnea (OSA) risk in the general population by using nomogram in order to explore the independent risk factors of severe OSA and guide the early diagnosis and treatment. 【Methods】 We retrospectively enrolled patients who had been diagnosed by polysomnography and divided them into training and validation sets at the ratio of 7∶3. Patients were divided into severe OSA group and non-severe OSA group according to apnea hypopnea index (AHI)>30. Variables entering the model were identified by least absolute shrinkage and selection operator regression model (Lasso), and logistic regression (LR) method. Then, multivariable logistic regression analysis was used to establish the nomogram, and the area under the receiver operating characteristic curve (AUC) was used to evaluate the discriminative properties of the nomogram model. Finally, we conducted decision curve analysis (DCA) of nomogram model, STOP-Bang questionnaire and Berlin questionnaire to assess clinical utility. 【Results】 Through single factor and multiple factor logistic regression analyses, the independent risk factors for severe OSA were screened out, including moderate and severe sleepiness, family history of hypertension, history of smoking, drinking, snoring, history of suffocation, sedentary lifestyle, male, age, body mass index (BMI), waist and neck circumference. Lasso logistic regression identified smoke, suffocation time, snoring time, waistline, Epworth sleepiness scale (ESS) and BMI as predictive factors for inclusion in the nomogram. The AUC of the model was 0.795 [95% confidence interval (CI): 0.769-0.820] . Hosmer-Lemeshow test indicated that the model was well calibrated (χ²=3.942, P=0.862). The DCA results on the visual basis confirmed that the nomogram had superior overall net benefits within a wide, practical threshold probability range which displayed the nomogram was higher than that of STOP-Bang questionnaire and Berlin questionnaire, which is clinically useful. The Clinical Impact Curve (CIC) analysis showed the clinical effectiveness of the prediction model when the threshold probability was greater than 82% of the predicted score probability value. The prediction model determined that the high-risk population with severe OSA was highly matched with the actual population with severe OSA, which confirmed the high clinical effectiveness of the prediction model. 【Conclusion】 The model performed better than STOP-Bang questionnaire and Berlin questionnaire in predicting severe OSA and can be applied to screening. And it can be helpful to the early diagnosis and treatment of OSA in order to reduce social burden.

Objective:To evaluate and compare efficacy of intravenous immunoglobulin (IVIG) versus recombinant human tumor necrosis factor-α receptor Ⅱ:IgG Fc fusion protein (rhTNFR:Fc) in the treatment of toxic epidermal necrolysis (TEN) .Methods:Clinical data were collected from patients with TEN treated with IVIG or rhTNFR:Fc in Wuhan No.1 Hospital from 2013 to 2019. There were 11 patients in the IVIG group, including 3 males and 8 females, aged 25-72 years, and the median TEN-specific severity-of-illness score (SCORTEN) was 3 points; there were 10 patients in the rhTNFR:Fc group, including 5 males and 5 females, aged 32-84 years, and the median SCORTEN was 2 points. These patients all showed no response to the 5-day treatment with prednisolone acetate at a dose of 0.6-1.0 mg·kg -1·d -1, and then received IVIG at a dose of 400 mg·kg -1·d -1 for 5 consecutive days, or subcutaneous injection of rhTNFR:Fc at a dose of 25 mg every other day for 4-6 sessions. Changes in skin lesions and adverse events were recorded in the 2 groups. Statistical analysis was carried out by using Mann-Whitney U test. Results:Compared with the rhTNFR:Fc group, the IVIG group showed a significant decrease in the time to onset of reduction of skin lesion exudate (1.73 ± 1.19 days vs. 3.00 ± 1.56 days, P < 0.05) , time to onset of pain relief in the lesion area (1.64 ± 1.28 days vs. 3.70 ± 1.63 days, P < 0.05) , time to lightening of color of the lesion base (2.45 ± 1.12 days vs. 3.90 ± 1.59 days, P < 0.05) , time to onset of new epidermis growth (3.09 ± 1.13 days vs. 5.20 ± 1.22 days, P < 0.05) , and in the time to onset of lesion drying at the intertriginous sites (4.82 ± 2.22 days vs. 7.90 ± 3.14 days, P < 0.05) . However, there was no significant difference in the length of hospital stay between the IVIG group (17.70 ± 8.33 days) and rhTNFR:Fc group (16.70 ± 4.71 days, P > 0.05) . No adverse reactions were observed during the treatment, and no recurrence or complications were found in the 21 patients during the follow-up of 6 months. Conclusion:IVIG and rhTNFR:Fc are both effective in the treatment of TEN, but IVIG is superior to rhTNFR:Fc in terms of the time to onset of pain relief, skin lesion exudate reduction and epidermal growth.

A 58-year-old female patient presented with painful and itchy skin lesions on the head, neck, chest and back for 20 days, and was admitted to the hospital in February 2010. The skin lesions manifested as superficial erosions on an erythematous base with positive Nikolsky′s sign. Histopathological examination showed fissures above the granular and spinous cell layers, and scattered dyskeratotic cells. Direct immunofluorescence (DIF) assay revealed IgG and C3 deposits between spinous cells. The patient was initially diagnosed with pemphigus foliaceus. After the treatment with triamcinolone (24 mg/d) , tripterygium glycosides (60 mg/d) , nicotinamide (300 mg/d) and tetracycline (2 g/d) , skin lesions gradually subsided. In June 2017, the patient was readmitted due to itchy skin lesions on the head, neck, chest, back and hands for 15 days, which manifested as tense bullae on an erythematous base with negative Nikolsky′s sign. Histopathological examination showed subepidermal blisters and infiltration of eosinophils and lymphocytes in the blisters and superficial dermis, DIF assay revealed the deposition of IgG and C3 along the basement membrane zone, and enzyme-linked immunosorbent assay showed positive results for anti-BP180 antibody but negative results for anti-Dsg1 and Dsg3 antibodies. Then, a diagnosis of bullous pemphigoid was confirmed. The patient was treated with oral triamcinolone (12 mg/d) , nicotinamide (300 mg/d) and tetracycline (2 g/d) , and the lesions rapidly subsided.