Objective We aim to analyse semaglutide related adverse events in real-world,overall and by gender and age subgroups and compare the differences of different gender and age patients in adverse events,in order to supply references for security usage in the clinic.Methods OpenVigil 2.1 was used to search FDA Adverse Event Reporting System for semaglutide related adverse events from the establishment of the databases to April 2023.According to age and gender,patients were divided into 18-64 years old group and≥65 years old group,male group and female group.We selected ten adverse events which we interested(nausea,diarrhoea,vomiting,pancreatitis,cholecystitis,cholelithiasis,hypoglycaemia,diabetic retinopathy,acute kidney injury and thyroid cancer/medullary thyroid cancer)and analyzed overall and each group of semaglutide adverse events.Results A total of 5 330 cases and 15 558 adverse events were collected.2 935 patients aged 18-64 old group years with 8 553 adverse events;2 395 patients aged≥65 years old group with 7 005 adverse events.2 231 male group patients with 6 195 adverse events;3 059 female group patients with 9 277 adverse events.The sex of 40 patients was unknown.Nausea(1 089 cases/7.00％),vomiting(775 cases/4.98％)and diarrhoea(545 cases/3.50％)remained the most common adverse events.The constituent ratio of pancreatitis was significantly higher in patients aged 18-64 years old group than in patients aged 65 years old group(P＜0.05);the constituent ratio of diarrhoeaand cholelithiasis was significantly lower in patients aged 18-64 years old group than patients aged≥65 years old group(P＜0.05).The constituent ratio of diarrhoea,vomiting,pancreatitis,cholecystitis,cholelithiasis,diabetic retinopathy,and acute kidney injurywas significantly higher in male group patients than in female group(P＜0.05).Conclusion Nausea,diarrhoea and vomiting remined the most common adverse events of semaglutide.Male should be more concerned about gastrointestinal,pancreatitis,gallbladder events,retinopathy and acute kidney injury.Elderly patients should be more alert diarrhoea and cholelithiasis.

Objective: “Same treatment for different diseases” is a unique treatment strategy under the guidance of traditional Chinese medicine (TCM) theory. Codonopsis Radix (Codonopsis pilosula, Dangshen in Chinese) with spleen-fortifying effect was employed to understand the strategy of “Same treatment for different diseases”, based on its common mechanism in the treatment of gastric diseases including gastric ulcer, gastritis and gastric cancer via network pharmacology research. Methods: Network pharmacology research methods were used to analyze the interaction network and potential mechanisms of Dangshen in treating gastric ulcer, gastritis and gastric cancer. The active components and their target proteins of Dangshen were integrated from TCMSP, BATMAN-TCM databases. The targets of gastric ulcer, gastritis and gastric cancer were collected through GeneCards, PubMed, TDD and DisGeNET Database. Through screening, the key components and the key targets of Dangshen in treating gastric ulcer, gastritis and gastric cancer were obtained. After KEGG pathway analysis and GO analysis, the important pathways and biological processes were analyzed. Results: Through data and literature mining, the common and specific pharmaceutical effects and mechanism of Dangshen were summarized in these three gastric lesions. It was shown that Dangshen mainly acted on gastric ulcer, gastritis and gastric cancer through the overall regulation of the PI3K-AKT signaling pathway. With the development of the disease, it will gradually increase the control of inflammation through TNF, NF-κB and other inflammation-related signaling pathways to reduce inflammatory damage. For tumorigenesis, it pays more attention to inhibiting the ErbB signaling pathways to reduce the proliferation and migration of tumor cells. In addition, Dangshen's regulation of HIF-1 signaling pathway may also be beneficial for the treatment of gastric ulcer, gastritis and gastric cancer. Conclusion: Dangshen achieves spleen-fortifying effect on gastric diseases including gastric ulcer, gastritis and gastric cancer through multiple targets in multiple pathways, especially PI3K-AKT pathway and HIF-1 pathway. It could provide a scientific basis for understanding the strategy of “Same treatment for different diseases” in traditional Chinese medicine.

The present study analyzed the current Chinese medicinal health products and Chinese patent medicines effective in boosting memory,aiming at providing references for the formulation and development of memory-boosting health products. The information on memory-boosting health products published by the Department of Special Food Safety Supervision and Management,the State Administration for Market Regulation( SAMR) was collected and the Chinese patent medicines on DRUGDATAEXPY were searched. Microsoft Excel and the TCMISS were used to statistically analyze the characteristics of formulations. A total of 212 memory-boosting health products were obtained from SAMR,including 83 ones containing Chinese medicinal materials. Twelve Chinese herbal medicines showed a usage frequency ≥ 8,with 151 times in use. In DRUGDATAEXPY,258 similar Chinese patent medicines were collected.Twelve Chinese herbal medicines showed a usage frequency ≥ 58,with 907 times in use. Through unsupervised hierarchical entropybased clustering of the above-mentioned Chinese medicinal health products and Chinese patent medicines separately,5 and 12 new formulas were obtained. The selection of Chinese herbal medicines for the new formulas was consistent with the principles of traditional Chinese medicine( TCM) theories,i. e.,tonifying kidney and marrow,benefiting Qi,nourishing Yin,resolving phlegm,and eliminating stasis. According to TCM theories,syndrome differentiation of the users was conducted,and the formulas were designed following the correspondence of syndromes with formulas and Chinese herbal medicines. This study is expected to provide new ideas and methods for the development of Chinese medicinal health products and accurately guide practical applications to exert the advantages of TCM in health care based on syndrome differentiation and improve the effect of Chinese medicinal health products.
China ; Drugs, Chinese Herbal ; Humans ; Medicine, Chinese Traditional ; Nonprescription Drugs ; Syndrome

Parkinson's disease (PD) is the second major neurodegenerative disease.The pathogenesis of PI) is still unclear.It is generally believed that neural damage, mitochondrial dysfunction, inflammation, oxidative stress and autophagy dysfunction caused by the transmission and aggregation of a- synuclein play an important role in the occurrence and development of PD.More and more research show- that metabolic disorder is one of the pathogenesis of PD.We examined whether overexpression of a- synuclein could induce metabolic disorder in mice and the possible mechanisms.Mice were divided into two groups: Thyl-aSYN transgenic mice (TG) and the control wild-type (WT) group.The rotarod test was used to analyze motor function in mice.We detected the body weight, plasma insulin content, glucose tolerance and insulin tolerance in the two group mice.The morphology of islets in the two groups were observed by hematoxylin eosin (HE) staining, and the islets were isolated to detect the glucose- stimulated insulin secretion (GSIS).The results showed that compared with the WT group, exercise tolerance of 12-month-old TG group decreased by 23.1% (P < 0.05) , body weight increased by 7% (P < 0.01), glucose tolerance decreased (P < 0.05), insulin tolerance decreased (P < 0.05), and insulin contents in the peripheral blood decreased by 20% (P < 0.05).Compared with the WT group, the levels of ce -syn proteins in the pancreas of the TG group increased by 1.32 times (P < 0.05) , the area of islets in the TG group decreased (P < 0.05 ) , the number of islets decreased (P < 0.01) , and the insulin secretion function decreased (P< 0.01).This study showed that the role of a-synuclein in PD is not limited to the damage of dopaminergic neurons, it also can affect metabolism and the morphology and function of peripheral organs, which provides a new theoretical basis for the pathogenesis of PD.

Objective:To evaluate the safety of venetoclax alone or combined with CD20 monoclonal antibody (mAb) in treatment of patients with relapsed/refractory chronic lymphoblastic leukemia (R/R CLL).Methods:Databases of PubMed, Embase, CNKI, Wanfang Med Online, VIP, and SinoMed and websites such as ClinicalTrials.gov, the U.S. Food and Drug Administration (FDA), and the European Drug Administration (EMA) were searched. The clinical studies with safety indicators of venetoclax alone or in combination with CD20 mAb in treatment of patients with R/R CLL were collected. Safety-relevant data were extracted and the meta-analysis was performed using R software. The effect values were the ratio of relative risk ( RRR) and 95% confidence interval ( CI). Results:A total of 9 studies were enrolled in the analysis, all of which were single arm studies (8 prospective studies and 1 retrospective study). Eight hundred and nineteen patients were involved in the 9 studies, 719 of which were in the monotherapy group and 100 in the 2-drug combination group. The most common adverse events in venetoclax monotherapy or combined with CD20 mAb were hematologic adverse events. The risk of developing grade 3-4 neutrophilia, thrombocytopenia, and anemia was 46.96% (95 %CI: 40.27%-53.76%), 20.46% (95 %CI: 14.79%-27.59%), and 15.31% (95 %CI: 10.30%-22.15%), respectively. Other grade 3-4 adverse events mainly included infection [17.79% (95 %CI: 15.15%-20.77%)], tumor lysis syndrome [3.00% (95 %CI: 1.75%-5.09%)], increased blood glucose [5.98% (95 %CI: 3.80%-9.29%)], and hypokalemia [4.27% (95 %CI: 2.54%-7.08%)]. Due to the adverse events, 28.82% (95 %CI: 16.56%-45.24%) of patients interrupted venetoclax treatment for at least one dose, 17.19% (95 %CI: 10.96%-25.94%) of patients reduced the venetoclax dose, 9.56% (95 %CI: 7.64%-11.89%) of patients permanently discontinued venetoclax, and 1.90% (95 %CI: 0.86%-4.17%) of patients died. Risks of grade 3-4 neutropenia and dose reduction of venetoclax were significantly higher in patients treated with venetoclax combined with CD20 mAb than in those treated with venetoclax alone (57.00% vs. 41.69%, RRR=1.36,95 %CI: 1.12-1.66; 38.18% vs. 14.97%, RRR=2.55, 95 %CI: 1.48-4.39). Conclusions:The adverse events in venetoclax treated R/R CLL were mainly hematological adverse events and the risk of grade 3-4 neutropenia was more than 40%. After the combination with CD20 mAb, the risks of the other adverse events did not increase except for those of grade 3-4 neutropenia and dose reduction of venetoclax due to adverse events.

Objective:To evaluate the safety of venetoclax alone or combined with CD20 monoclonal antibody (mAb) in treatment of patients with relapsed/refractory chronic lymphoblastic leukemia (R/R CLL).Methods:Databases of PubMed, Embase, CNKI, Wanfang Med Online, VIP, and SinoMed and websites such as ClinicalTrials.gov, the U.S. Food and Drug Administration (FDA), and the European Drug Administration (EMA) were searched. The clinical studies with safety indicators of venetoclax alone or in combination with CD20 mAb in treatment of patients with R/R CLL were collected. Safety-relevant data were extracted and the meta-analysis was performed using R software. The effect values were the ratio of relative risk ( RRR) and 95% confidence interval ( CI). Results:A total of 9 studies were enrolled in the analysis, all of which were single arm studies (8 prospective studies and 1 retrospective study). Eight hundred and nineteen patients were involved in the 9 studies, 719 of which were in the monotherapy group and 100 in the 2-drug combination group. The most common adverse events in venetoclax monotherapy or combined with CD20 mAb were hematologic adverse events. The risk of developing grade 3-4 neutrophilia, thrombocytopenia, and anemia was 46.96% (95 %CI: 40.27%-53.76%), 20.46% (95 %CI: 14.79%-27.59%), and 15.31% (95 %CI: 10.30%-22.15%), respectively. Other grade 3-4 adverse events mainly included infection [17.79% (95 %CI: 15.15%-20.77%)], tumor lysis syndrome [3.00% (95 %CI: 1.75%-5.09%)], increased blood glucose [5.98% (95 %CI: 3.80%-9.29%)], and hypokalemia [4.27% (95 %CI: 2.54%-7.08%)]. Due to the adverse events, 28.82% (95 %CI: 16.56%-45.24%) of patients interrupted venetoclax treatment for at least one dose, 17.19% (95 %CI: 10.96%-25.94%) of patients reduced the venetoclax dose, 9.56% (95 %CI: 7.64%-11.89%) of patients permanently discontinued venetoclax, and 1.90% (95 %CI: 0.86%-4.17%) of patients died. Risks of grade 3-4 neutropenia and dose reduction of venetoclax were significantly higher in patients treated with venetoclax combined with CD20 mAb than in those treated with venetoclax alone (57.00% vs. 41.69%, RRR=1.36,95 %CI: 1.12-1.66; 38.18% vs. 14.97%, RRR=2.55, 95 %CI: 1.48-4.39). Conclusions:The adverse events in venetoclax treated R/R CLL were mainly hematological adverse events and the risk of grade 3-4 neutropenia was more than 40%. After the combination with CD20 mAb, the risks of the other adverse events did not increase except for those of grade 3-4 neutropenia and dose reduction of venetoclax due to adverse events.

Objective To investigate the protective effect of recombinant adult serine protease inhibitor from Trichinella spiralis (TsadSPI) on sepsis-associated acute kidney injury in mice. Methods A total of 18 male BALB/c mice were randomly divided into the sham-operation group, the model group, and the TsadSPI treatment group, of 6 mice in each group. Sepsis-associated acute kidney injury was modeled in the model group and TsadSPI treatment group by cecal ligation puncture (CLP), while mice in the sham-operation group were only given exploratory laparotomy without ligation or perforation of the cecum. After 30 min of CLP, mice in the sham-operation group and the model group were intraperitoneally injected with PBS (100 μL), and mice in the TsadSPI treatment group were intraperitoneally injected with PBS (100 μL) containing TsadSPI (2 μg). At 12 h following modeling, the serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatinine (Cr) and urea nitrogen (BUN) were measured to assess the liver and kidney functions, and the changes of the mouse kidney structure were observed using HE staining. In addition, the serum levels of tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-10 and transforming growth factor (TGF)-β were measured using an enzyme-linked immunosorbent assay (ELISA), and the myeloid differentiation factor 88 (MyD88) and nuclear factor kappa-B (NF-κB) p65 expression was determined in kidney tissues using immunohistochemical staining. Results At 12 h following CLP, there were significant differences in the serum levels of ALT (F = 41.031, P < 0.001), AST (F = 54.757, P < 0.001), Cr (F = 24.142, P < 0.001) and BUN (F = 214.849, P < 0.001) among the three groups, and higher levels of ALT, AST, Cr and BUN were measured in model group than in the sham-operation group (P < 0.001), while lower ALT, AST, Cr and BUN levels were found in the TsadSPI treatment group than in the model group (P < 0.001). HE staining showed severe mouse kidney injuries following CLP, and TsadSPI treatment resulted in remarkable alleviation of the injury. ELISA measured significant differences in the TNF-α (F = 47.502, P < 0.001) and IL-6 levels (F = 222.061, P < 0.001) among the three groups, and showed a remarkable reduction in the TNF-α and IL-6 levels in the TsadSPI treatment group as compared to those in the model group (P < 0.001). In addition, there were significant differences in serum IL-10 (F = 16.227, P < 0.001) and TGF-β levels (F = 52.092, P < 0.001) among the three groups, and higher IL-10 and TGF-β levels were seen in the TsadSPI treatment group than in the model group (P < 0.001). Immunohistochemical staining showed greater MyD88 expression and a higher nuclear positive rate of NF-κB p65 in kidney tissues in the model group than in the TsadSPI treatment group. Conclusions TsadSPI may reduce the MyD88 expression and nuclear positive rate of NF-κB p65 in mouse kidney tissues to up-regulate the expression of immunomodulatory factors and down-regulate the expression of pro-inflammatory cytokines, thereby protecting sepsis-associated acute kidney injury.

This study engineered β-carotene ketolase CrtW and β-carotene hydroxylase CrtZ to improve biosynthesis of astaxanthin in Escherichia coli. Firstly, crtW was randomly mutated to increase CrtW activities on conversion from β-carotene to astaxanthin. A crtW* mutant with A6T, T105A and L239M mutations has improved 5.35-fold astaxanthin production compared with the wild-type control. Secondly, the expression levels of crtW* and crtZ on chromosomal were balanced by simultaneous modulation RBS regions of their genes using RBS library. The strain RBS54 selected from RBS library, directed the pathway exclusively towards the desired product astaxanthin as predominant carotenoid (99%). Lastly, the number of chromosomal copies of the balanced crtW-crtZ cassette from RBS54 was increased using a Cre-loxP based technique, and a strain with 30 copies of the crtW*-crtZ cassette was selected. This final strain DL-A008 had a 9.8-fold increase of astaxanthin production compared with the wild-type control. Fed-batch fermentation showed that DL-A008 produced astaxanthin as predominant carotenoid (99%) with a specific titer of 0.88 g·L without addition of inducer. In conclusion, through constructing crtW mutation, balancing the expression levels between crtW* and crtZ, and increasing the copy number of the balanced crtW*-crtZ cassette, the activities of β-carotene ketolase and β-carotene hydroxylase were improved for conversion of β-carotene to astaxanthin with higher efficiency. The series of conventional and novel metabolic engineering strategies were designed and applied to construct the astaxanthin hetero-producer strain of E. coli, possibly offering a general approach for the construction of stable hetero-producer strains for other natural products.

UPLC-Q-TOF-MS technology was used to analyze the chemical constituents from classical prescription Huangqi Guizhi Wuwu Tang standard decoction. Acquity HSS T3 column(2.1 mm × 100 mm, 1.8 μm) was used as the chromatographic column, with 0.1% formic acid solution-0.1% formic acid acetonitrile as the mobile phase for gradient elution. The volume flow rate was 0.4 mL·min~(-1) and the column temperature was 40 ℃. Mass spectrometry data of Huangqi Guizhi Wuwu Tang standard decoction were collected in positive and negative ion modes. The chemical constituents from classical prescription Huangqi Guizhi Wuwu Tang standard decoction were analyzed and identified by Masslynx 4.1 software combined with SciFinder database, comparison with reference mate-rials, mass spectrometry data analysis and reference to relevant literature. A total of 110 compounds were analyzed and identified, including 33 flavonoids, 14 monoterpene glycosides, 8 triterpenoids, 8 gingerols, 17 phenylpropanoids, 12 organic acids, 7 amino acids and 11 other compounds. The results of this study provide an experimental basis for the further research on the substance basis and quality control of Huangqi Guizhi Wuwu Tang standard decoction.
Chromatography, High Pressure Liquid ; Drugs, Chinese Herbal ; Flavonoids/analysis* ; Glycosides ; Prescriptions ; Reference Standards

Boiling processing is commonly used in post-harvest handling of White Paeony Root (WPR), in order to whiten the herbal materials and preserve the bright color, since such WPR is empirically considered to possess a higher quality. The present study was designed to investigate whether and how the boiling processing affects overall quality of WPR. First, an ultra-high performance liquid chromatography quadrupole/time-of-flight mass spectrometry-based metabolomics approach coupled with multivariate statistical analysis was developed to compare the holistic quality of boiled and un-boiled WPR samples. Second, ten major components in WPR samples boiled for different durations were quantitatively determined using high performance liquid chromatography to further explore the effects of boiling time on the holistic quality of WPR, meanwhile the appearance of the processed herbal materials was observed. The results suggested that the boiling processing conspicuously affected the holistic quality of WPR by simultaneously and inconsistently altering the chemical compositions and that short-time boiling processing between 2 and 10 min could both make the WPR bright-colored and improve the contents of major bioactive components, which were not achieved either without boiling or with prolonged boiling. In conclusion, short-term boiling (2-10 min) is recommended for post-harvest handling of WPR.
Chromatography, High Pressure Liquid ; methods ; Drugs, Chinese Herbal ; chemistry ; standards ; Hot Temperature ; Mass Spectrometry ; methods ; Paeonia ; chemistry ; Plant Roots ; chemistry ; Technology, Pharmaceutical ; Water