The study focuses on the concept of multifunctional traditional Chinese medicine (TCM) formulas and aims to evaluate the efficacy of the classical formula Xiaoyao San (逍遥散). Study employs the integrated evidence chain (Eff-iEC) method to organize, integrate, and evaluate its therapeutic efficacy in treating different diseases with the same therapy, and to investigate the feasibility of using Eff-iEC to evaluate the multifunctionality of TCM formulas. The evaluation covered Xiaoyao San's therapeutic effects on depression, premenstrual syndrome, chronic hepatitis, irritable bowel syndrome, dyspepsia, and menopausal syndrome. Concurrently, the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system was used for evaluation, and authoritative medical documents were incorporated to corroborate the recognition of Xiaoyao San within the medical community. Depression and menopausal syndrome received higher ratings than other conditions in the Eff-iEC, GRADE, and Medical Community Recognition assessments. The Eff-iEC evidence grade for Xiaoyao San was rated as "High" or above for chronic hepatitis, irritable bowel syndrome, dyspepsia, and menopausal syndrome. Premenstrual syndrome received a "Moderate ⁺" rating. The GRADE evidence level was "Low-〇〇⨁⨁" for depression, premenstrual syndrome, and chronic hepatitis; "Moderate-〇⨁⨁⨁" for dyspepsia and menopausal syndrome; and "Very Low-〇〇〇⨁" for irritable bowel syndrome. Depression and menopausal syndrome had the highest inclusion frequency, appearing in all 4 categories. Premenstrual syndrome, chronic hepatitis, and dyspepsia are not recommended in Western medical guidelines, but they are included in TCM guidelines, the China National Basic Medical Insurance Drug List, and the China National Essential Drug List. Irritable bowel syndrome appears only in the China National Basic Medical Insurance Drug List and China National Essential Drug List. The evaluation results obtained using the Eff-iEC method align with Medical Community Recognition, providing an objective and comprehensive assessment of Xiaoyao San's efficacy. The findings suggest that Xiaoyao San has strong evidence for treating depression and menopausal syndrome. However, further experimental and clinical trials are needed to assess its efficacy in treating premenstrual syndrome, chronic hepatitis, irritable bowel syndrome, and dyspepsia. These results support the clinical efficacy and rational use of Xiaoyao San, expand the application scope of the Eff-iEC method, and offer valuable insights and methodological references for the comparative evaluation of multifunctional TCM formulas.

Objective:To investigate the efficacy of tiotropium bromide combined with bilevel positive airway pressure (BiPAP) in the treatment of acute exacerbation of chronic obstructive pulmonary disease (AECOPD) complicated by type 2 respiratory failure and its effects on serum level of inflammatory factors in patients.Methods:A total of 90 patients with AECOPD complicated by type 2 respiratory failure admitted to the Department of Respiratory Medicine, The Affiliated Qingdao Third People's Hospital of Qingdao University from June 2021 to June 2023 were included in this study. This study used a randomized controlled design. The patients included were divided into a control group and an observation group ( n = 45/group) using a random number table method. The control group was given conventional treatment in addition to mechanical ventilation using a BiPAP respirator. Patients in the control group used the spontaneous/timed (S/T) mode, which automatically switched between spontaneous breathing and time-controlled ventilation. The observation group received inhalation treatment with tiotropium bromide in addition to the treatment provided to the control group. The efficacy and serum levels of inflammatory factors (high-sensitivity C-reactive protein, tumor necrosis factor-alpha, and interleukin-6) were compared between the two groups. Results:After treatment, the mMRC (Modified Medical Research Council) Dyspnoea Scale score and chronic obstructive pulmonary disease assessment test score in the observation group were (1.40 ± 0.35) and (12.42 ± 2.57), respectively. These values were significantly lower than those in the control group [(2.62 ± 0.55), (19.05 ± 3.13), t = -4.05, -3.65, both P < 0.05]. After treatment, the acute physiology and chronic health evaluation Ⅱ score in the observation group was (13.85 ± 1.24), which was significantly lower than that in the control group [(18.24 ± 1.58), t = -3.92, P < 0.05]. After treatment, oxygen saturation and partial pressure of oxygen in the observation group were (95.18 ± 5.82) % and (84.37 ± 5.54) mmHg (1 mmHg = 0.133 kPa), respectively. These values were significantly higher than those in the control group [(91.42 ± 5.79) %, (72.41 ± 4.79) mmHg, t = 3.99, 3.96, both P < 0.05]. Partial pressure of carbon dioxide in the observation group was (34.37 ± 1.97) mmHg, which was significantly lower than that in the control group [(41.68 ± 2.19) mmHg, t = -3.72, P < 0.05]. After treatment, high-sensitivity C-reactive protein, tumor necrosis factor-alpha, and interleukin-6 levels in the observation group were (13.18 ± 1.43) mg/L, (8.42 ± 1.26) ng/L, and (9.18 ± 1.05) ng/L, respectively. These values were significantly lower than those in the control group [(19.28 ± 2.36) mg/L, (15.76 ± 1.73) ng/L, (19.38 ± 1.61) ng/L, t = -4.22, -5.23, -6.18, all P < 0.05]. The total response rate in the observation group was significantly higher than that in the control group [91.11% (41/45) vs. 73.33% (33/45), χ2 = 5.86, P < 0.05). Conclusions:Inhalation treatment with tiotropium bromide combined with mechanical ventilation using a BiPAP respirator can effectively reduce the severity of dyspnea and alleviate clinical symptoms in patients with AECOPD complicated by type Ⅱ respiratory failure. This combination therapy reduces hypoxia and carbon dioxide retention, diminishes inflammatory response, and enhances overall clinical efficacy.

Objective:To investigate the efficacy of tiotropium bromide combined with bilevel positive airway pressure (BiPAP) in the treatment of acute exacerbation of chronic obstructive pulmonary disease (AECOPD) complicated by type 2 respiratory failure and its effects on serum level of inflammatory factors in patients.Methods:A total of 90 patients with AECOPD complicated by type 2 respiratory failure admitted to the Department of Respiratory Medicine, The Affiliated Qingdao Third People's Hospital of Qingdao University from June 2021 to June 2023 were included in this study. This study used a randomized controlled design. The patients included were divided into a control group and an observation group ( n = 45/group) using a random number table method. The control group was given conventional treatment in addition to mechanical ventilation using a BiPAP respirator. Patients in the control group used the spontaneous/timed (S/T) mode, which automatically switched between spontaneous breathing and time-controlled ventilation. The observation group received inhalation treatment with tiotropium bromide in addition to the treatment provided to the control group. The efficacy and serum levels of inflammatory factors (high-sensitivity C-reactive protein, tumor necrosis factor-alpha, and interleukin-6) were compared between the two groups. Results:After treatment, the mMRC (Modified Medical Research Council) Dyspnoea Scale score and chronic obstructive pulmonary disease assessment test score in the observation group were (1.40 ± 0.35) and (12.42 ± 2.57), respectively. These values were significantly lower than those in the control group [(2.62 ± 0.55), (19.05 ± 3.13), t = -4.05, -3.65, both P < 0.05]. After treatment, the acute physiology and chronic health evaluation Ⅱ score in the observation group was (13.85 ± 1.24), which was significantly lower than that in the control group [(18.24 ± 1.58), t = -3.92, P < 0.05]. After treatment, oxygen saturation and partial pressure of oxygen in the observation group were (95.18 ± 5.82) % and (84.37 ± 5.54) mmHg (1 mmHg = 0.133 kPa), respectively. These values were significantly higher than those in the control group [(91.42 ± 5.79) %, (72.41 ± 4.79) mmHg, t = 3.99, 3.96, both P < 0.05]. Partial pressure of carbon dioxide in the observation group was (34.37 ± 1.97) mmHg, which was significantly lower than that in the control group [(41.68 ± 2.19) mmHg, t = -3.72, P < 0.05]. After treatment, high-sensitivity C-reactive protein, tumor necrosis factor-alpha, and interleukin-6 levels in the observation group were (13.18 ± 1.43) mg/L, (8.42 ± 1.26) ng/L, and (9.18 ± 1.05) ng/L, respectively. These values were significantly lower than those in the control group [(19.28 ± 2.36) mg/L, (15.76 ± 1.73) ng/L, (19.38 ± 1.61) ng/L, t = -4.22, -5.23, -6.18, all P < 0.05]. The total response rate in the observation group was significantly higher than that in the control group [91.11% (41/45) vs. 73.33% (33/45), χ2 = 5.86, P < 0.05). Conclusions:Inhalation treatment with tiotropium bromide combined with mechanical ventilation using a BiPAP respirator can effectively reduce the severity of dyspnea and alleviate clinical symptoms in patients with AECOPD complicated by type Ⅱ respiratory failure. This combination therapy reduces hypoxia and carbon dioxide retention, diminishes inflammatory response, and enhances overall clinical efficacy.

Objective To investigate the effect and mechanism of zanthoxylum bungeanum seed oil on autophagy and apoptosis of laryngeal cancer cells.Methods Human bronchial epithelial cells BEAS-2B and human laryngeal cancer cells Hep-2 were treated with different volume fractions(v/v)of Zanthoxylum bungeanum seed oil(0,0.02%,0.04%,0.06%,0.08%,0.10%),respectively,cell viability was detected by cell counting kit-8 method(CCK-8).Hep-2 cells in logarithmic growth phase were randomly divided into control group,Zanthoxylum bungeanum seed oil low,medium and high dose groups and Zanthoxylum bungeanum seed oil high dose+insulin-like growth factor 1(IGF-1)(PI3K agonist)group,cell apoptosis and cell cycle progression were detected by flow cytometry(FCM)assay,the formation of autophagic vesicles was detected by monodansyl cadaverine(MDC)staining,the expression of apoptosis,autophagy and phosphatidylinositide 3-kinases(PI3K)/protein kinase B(AKT)/mechanistic target of rapamycin(mTOR)pathway-related proteins were detected by Western blotting(WB).Results Compared with the control group Hep-2(99.03%±0.82%),treatment with zanthoxylum bungeanum seed oil(0.02%,0.04%,0.06%,0.08%,0.10%)(v/v)could reduce cell survival rate(84.63%±0.73%,57.34%±0.84%,19.76%±0.62%,17.22%±0.72%,12.19%±0.81%),and the differences were statistically significant(t=22.718～133.559,all P<0.001),while it has no inhibitory effect on BEAS-2B activity(t=0.283～1.980,all P>0.05).Compared with the control group,the Hep-2 apoptosis rate,G1/G0 phase cell proportion,autophagic vesicle integrated optical density(IOD)value,Cleaved-caspase-3,Bcl-2 associated X protein(Bax),microtubule-associated protein 1A/1B 1ight chain 3I/Ⅱ(LC 3I/Ⅱ)and Beclin-1 expression were all increased in the low,medium,and high-close groups of zantheoxylum bungeanum seed oil(t=4.270～58.425);the proportion of G2/M phase cells,ubiquitin-binding protein P62,Bcl-2 expression and p-PI3K/PI3K,p-AKT/AKT and p-mTOR/mTOR expression were all decreased(t=3.041～58.765),and the differences were statistically significant(all P<0.05).Compared with the high-dose zanthoxylum bungeanum seed oil group,the apoptosis rate of Hep-2,the proportion of G1/G0 phase cells,the expression of Cleaved-caspase-3,Bax,LC3Ⅱ/I and Beclin-1,the IOD value of autophagic vesicles(t=4.931～39.507),the expression of Bcl-2 and ubiquitin-binding protein P62,the proportion of G2/M phase cells,the ratio of p-PI3K/PI3K,p-AKT/AKT and p-mTOR/mTOR in the high-dose zanthoxylum bungeanum seed oil+IGF-1 group were decreased(t=3.402～14.207),and the differences were statistically significant(all P<0.05).Conclusion Zanthoxylum bungeanum seed oil can promote autophagy and apoptosis of Hep-2 cells,and its mechanism may be related to the inhibition of PI3K/AKT/mTOR pathway activation.

Objective To investigate the effect and mechanism of zanthoxylum bungeanum seed oil on autophagy and apoptosis of laryngeal cancer cells.Methods Human bronchial epithelial cells BEAS-2B and human laryngeal cancer cells Hep-2 were treated with different volume fractions(v/v)of Zanthoxylum bungeanum seed oil(0,0.02%,0.04%,0.06%,0.08%,0.10%),respectively,cell viability was detected by cell counting kit-8 method(CCK-8).Hep-2 cells in logarithmic growth phase were randomly divided into control group,Zanthoxylum bungeanum seed oil low,medium and high dose groups and Zanthoxylum bungeanum seed oil high dose+insulin-like growth factor 1(IGF-1)(PI3K agonist)group,cell apoptosis and cell cycle progression were detected by flow cytometry(FCM)assay,the formation of autophagic vesicles was detected by monodansyl cadaverine(MDC)staining,the expression of apoptosis,autophagy and phosphatidylinositide 3-kinases(PI3K)/protein kinase B(AKT)/mechanistic target of rapamycin(mTOR)pathway-related proteins were detected by Western blotting(WB).Results Compared with the control group Hep-2(99.03%±0.82%),treatment with zanthoxylum bungeanum seed oil(0.02%,0.04%,0.06%,0.08%,0.10%)(v/v)could reduce cell survival rate(84.63%±0.73%,57.34%±0.84%,19.76%±0.62%,17.22%±0.72%,12.19%±0.81%),and the differences were statistically significant(t=22.718～133.559,all P<0.001),while it has no inhibitory effect on BEAS-2B activity(t=0.283～1.980,all P>0.05).Compared with the control group,the Hep-2 apoptosis rate,G1/G0 phase cell proportion,autophagic vesicle integrated optical density(IOD)value,Cleaved-caspase-3,Bcl-2 associated X protein(Bax),microtubule-associated protein 1A/1B 1ight chain 3I/Ⅱ(LC 3I/Ⅱ)and Beclin-1 expression were all increased in the low,medium,and high-close groups of zantheoxylum bungeanum seed oil(t=4.270～58.425);the proportion of G2/M phase cells,ubiquitin-binding protein P62,Bcl-2 expression and p-PI3K/PI3K,p-AKT/AKT and p-mTOR/mTOR expression were all decreased(t=3.041～58.765),and the differences were statistically significant(all P<0.05).Compared with the high-dose zanthoxylum bungeanum seed oil group,the apoptosis rate of Hep-2,the proportion of G1/G0 phase cells,the expression of Cleaved-caspase-3,Bax,LC3Ⅱ/I and Beclin-1,the IOD value of autophagic vesicles(t=4.931～39.507),the expression of Bcl-2 and ubiquitin-binding protein P62,the proportion of G2/M phase cells,the ratio of p-PI3K/PI3K,p-AKT/AKT and p-mTOR/mTOR in the high-dose zanthoxylum bungeanum seed oil+IGF-1 group were decreased(t=3.402～14.207),and the differences were statistically significant(all P<0.05).Conclusion Zanthoxylum bungeanum seed oil can promote autophagy and apoptosis of Hep-2 cells,and its mechanism may be related to the inhibition of PI3K/AKT/mTOR pathway activation.

ObjectiveThis paper aims to analyze the clinical characteristics and medication rationality of liver injury related to Epimedii Folium preparation （EP） and explore the possible risk factors of liver injury， so as to provide a reference for the safe clinical application of Epimedii Folium （EF）. MethodA retrospective analysis was conducted on liver injury cases related to EP from 2012 to 2016. ResultThe number of reported liver injury cases and the proportion of severe cases related to the use of EP show an increasing trend， indicating the objective existence of liver injury caused by EP. There are more cases of liver injury related to EP in women than in men， with an onset age range of 15-91 years old and a median onset age of 60 years old （median onset ages for men and women are 59 and 60 years old， respectively）. The time span from taking EP alone to the occurrence of liver injury is 1-386 days， with a median of 38 days. The time span from taking both EP and Western medicine to the occurrence of liver injury is 1-794 days， with a median of 34 days. EF-related liver injury preparations are mostly composed of traditional Chinese medicines that promote immunity and tonify the liver and kidney， indicating that immune stress in the body may be the mechanism of liver injury caused by the use of EP alone or in combination. There is no increasing trend of toxicity with time or dose in the liver injury caused by EP. By further exploring its risk factors， it is found that patients have unreasonable medication methods such as excessive dosage， repeated use， and multi-drug combination， which may also be one of the important risk factors for EF-related liver injury. ConclusionEP has a certain risk of liver injury and should be emphasized in clinical diagnosis and treatment. Immune stress may be the mechanism of liver injury caused by EP， and in clinical use， it is necessary to be vigilant about the risk of liver injury caused by unreasonable use and combined use with Western medicine.

ObjectiveTo establish a model of inflammasome activation induced by psoralidin based on bone marrow-derived macrophages （BMDM） in mice， and to explore the immunomodulatory effects of psoralidin combined with echinatin. MethodLipopolysaccharide （LPS） and psoralidin were used to activate inflammasomes， and after 4 h LPS stimulation， echinatin （40 μmol·L^-1） was administered for pre-protection for 1 h， followed by stimulation with psoralidin （10， 20， 40 μmol·L^-1） for 4 h. The protein expression of Caspase-1 p20 in cell supernatant and precursor （pro）-Caspase-1 and pro-interleukin（IL）-1β in cell lysate were simultaneously detected by Western blot. Enzyme-linked immunosorbent assay （ELISA） was adopted to determine the content of IL-β and TNF-α in the supernatant of BMDM. ResultWestern blot revealed that compared with the conditions in the control group， the maturation of psoralidin-induced pro-Caspase-1 and the secretion of IL-1β was inhibited by echinatin （P<0.05，P<0.01）. ELISA showed that the production of IL-1β and TNF-α was enhanced by psoralidin of different concentrations （P<0.05，P<0.01） compared with the condition in the control group. In addition， compared with the psoralidin group， the psoralidin combined with echinatin group reduced the secretion of IL-1β and TNF-α （P<0.01）. ConclusionEchinatin could significantly inhibited the excessive immune-inflammatory response mediated by psoralidin， and thus achieve the effect of toxicity reduction. The present study explored the toxicity-reducing effect of psoralidin combined with echiantin， providing a basis for safe clinical application.

Psoraleae Fructus (PF) is a well-known traditional herbal medicine in China, and it is widely used for osteoporosis, vitiligo, and other diseases in clinical settings. However, liver injury caused by PF and its preparations has been frequently reported in recent years. Our previous studies have demonstrated that PF could cause idiosyncratic drug-induced liver injury (IDILI), but the mechanism underlying its hepatotoxicity remains unclear. This paper reports that bavachin isolated from PF enhances the specific stimuli-induced activation of the NLRP3 inflammasome and leads to hepatotoxicity. Bavachin boosts the secretion of IL-1β and caspase-1 caused by ATP or nigericin but not those induced by poly(I:C), monosodium urate crystal, or intracellular lipopolysaccharide. Bavachin does not affect AIM2 or NLRC4 inflammasome activation. Mechanistically, bavachin specifically increases the production of nigericin-induced mitochondrial reactive oxygen species among the most important upstream events in the activation of the NLRP3 inflammasome. Bavachin increases the levels of aspartate transaminase and alanine aminotransferase in serum and hepatocyte injury accompanied by the secretion of IL-1β via a mouse model of lipopolysaccharide-mediated susceptibility to IDILI. These results suggest that bavachin specifically enhances the ATP- or nigericin-induced activation of the NLRP3 inflammasome. Bavachin also potentially contributes to PF-induced idiosyncratic hepatotoxicity. Moreover, bavachin and PF should be evaded among patients with diseases linked to the ATP- or nigericin-mediated activation of the NLRP3 inflammasome, which may be a dangerous factor for liver injury.
Adenosine Triphosphate ; Animals ; Chemical and Drug Induced Liver Injury/etiology* ; Flavonoids ; Humans ; Inflammasomes ; Mice ; NLR Family, Pyrin Domain-Containing 3 Protein ; Nigericin

[This corrects the article DOI: 10.1016/j.apsb.2019.02.003.].

Aberrant activation of NLRP3 inflammasome has been implicated in the pathogenesis of diverse inflammation-related diseases, and pharmacological molecules targeting NLRP3 inflammasome are of considerable value to identifying potential therapeutic interventions. Cardamonin (CDN), the major active ingredient of the traditional Chinese medicinal herb , has exerted an excellent anti-inflammatory activity, but the mechanism underlying this role is not fully understood. Here, we show that CDN blocks canonical and noncanonical NLRP3 inflammasome activation triggered by multiple stimuli. Moreover, the suppression of CDN on inflammasome activation is specific to NLRP3, not to NLRC4 or AIM2 inflammasome. Besides, the inhibitory effect is not dependent on the expression of NF-B-mediated inflammasome precursor proteins. We also demonstrate that CDN suppresses the NLRP3 inflammasome through blocking ASC oligomerization and speckle formation in a dose-dependent manner. Importantly, CDN improves the survival of mice suffering from lethal septic shock and attenuates IL-1 production induced by LPS , which is shown to be NLRP3 dependent. In conclusion, our results identify CDN as a broad-spectrum and specific inhibitor of NLRP3 inflammasome and a candidate therapeutic drug for treating NLRP3 inflammasome-driven diseases.