OBJECTIVE To provide references for the accurate identification and management of immune-related cutaneous adverse events （irCAEs） caused by durvalumab， and ensuring safe clinical drug use. METHODS Clinical pharmacists participated in the diagnosis and treatment process of a patient with gallbladder cancer who developed irCAEs caused by durvalumab. The clinical pharmacists systematically reviewed the patient’s past medical history and medication history， and assisted physicians in assessing the association between adverse drug reactions and administered drugs. Meanwhile， the clinical pharmacists conducted a graded assessment of the adverse reaction， proposed recommendations such as discontinuing durvalumab and adjusting the administration regimen of glucocorticoids， assisted physicians in restarting immunotherapy， and carried out medication education and other pharmaceutical care. RESULTS The occurrence of irCAEs in this patient was “highly likely” related to durvalumab and was classified as severe. The physicians adopted the clinical pharmacist’s opinion， and after symptomatic treatment， the patient’s skin symptoms improved， and discharged with medication. After the completion of glucocorticoid therapy for the patient， the physician restarted immunotherapy with tislelizumab， and no related adverse reactions occurred again in the patient. CONCLUSIONS Durvalumab can cause irCAEs such as severe skin maculopapular rash. In clinical practice， it is crucial to promptly identify and discontinue suspicious drugs， immediately implement effective symptomatic treatment measures， and actively resume immunotherapy to ensure the continuity and safety of the patient’s treatment.

ObjectiveTo investigate the mechanisms by which Mahuang Lianqiao Chixiaodoutang （MLC） improves obesity-type polycystic ovary syndrome （PCOS） through the phosphatidylinositol 3-kinase （PI3K）/protein kinase B （Akt） signaling pathway. MethodsThirty-six female Sprague-Dawley （SD） rats were randomly divided into a blank control group （Con） and an obesity-type PCOS model preparation group. The model was induced by gavage with letrozole （1 mg·kg^-1） combined with a high-fat diet （HFD）. After model establishment， the obesity-type PCOS model preparation group was further divided into the model group （Mod， normal saline）， metformin group （Met， 0.3 g·kg^-1）， low-dose MLC group （MLC-L， 4.3 g·kg^-1）， medium-dose MLC group （MLC-M， 8.6 g·kg^-1）， and high-dose MLC group （MLC-H， 17.2 g·kg^-1）. Active components of MLC and targets of obesity-type PCOS were screened from databases， a protein-protein interaction （PPI） network was constructed， and gene ontology（GO）and Kyoto Encyclopedia of Genes and Genomes （KEGG） pathway enrichment analysis was performed. The gut microbiota structure was analyzed based on 16S rRNA sequencing and correlated with network pharmacology pathways. Body weight and estrous cycle were dynamically monitored. Ovarian morphology was observed by hematoxylin-eosin （HE） staining. Cell apoptosis was detected by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling （TUNEL）. Enzyme-linked immunosorbent assay （ELISA） was used to detect levels of follicle-stimulating hormone （FSH）， luteinizing hormone （LH）， anti-Müllerian hormone （AMH）， testosterone （T）， and estradiol （E₂）. Western blot was used to detect the protein expression levels of phosphorylated PI3K/PI3K （p-PI3K/PI3K）， phosphorylated Akt/Akt （p-Akt/Akt）， B-cell lymphoma-2 （Bcl-2）， and Bcl-2-associated X protein （Bax）. ResultsNetwork pharmacology screening identified 124 active components of MLC and 408 overlapping targets between the herbal formula and the disease. Core targets such as Akt1 and Bcl-2 were revealed. As indicated by 16S rRNA sequencing， the abundances of Lachnospiraceae， Lachnoclostridium， and Dorea were increased in the MLC groups （P<0.05）， while the abundance of Veillonella was decreased （P<0.05）. KEGG correlation analysis integrating network pharmacology and gut microbiota data showed significant enrichment of the PI3K/Akt signaling pathway. Animal experiments showed that， compared with the Mod group， body weight decreased to normal levels in the Met， MLC-M， and MLC-H groups. The estrous cycle became regular. The number of corpora lutea increased and cystic follicles decreased. Serum levels of T， FSH， and LH/FSH were reduced （P<0.05， P<0.01）， while the E₂ level was increased （P<0.01）. Ovarian cell apoptosis was reduced （P<0.01）， and the protein expression levels of p-PI3K/PI3K， p-Akt/Akt， and Bcl-2 in ovarian tissue were significantly increased， whereas Bax protein expression was significantly decreased （P<0.05， P<0.01）. ConclusionMLC can regulate gut microbiota structure， effectively improve ovarian pathology in rats with obesity-type PCOS， and inhibit ovarian granulosa cell apoptosis. The mechanism may be associated with upregulation of the PI3K/Akt signaling pathway.

ObjectiveTo investigate the mechanisms by which Mahuang Lianqiao Chixiaodoutang （MLC） improves obesity-type polycystic ovary syndrome （PCOS） through the phosphatidylinositol 3-kinase （PI3K）/protein kinase B （Akt） signaling pathway. MethodsThirty-six female Sprague-Dawley （SD） rats were randomly divided into a blank control group （Con） and an obesity-type PCOS model preparation group. The model was induced by gavage with letrozole （1 mg·kg^-1） combined with a high-fat diet （HFD）. After model establishment， the obesity-type PCOS model preparation group was further divided into the model group （Mod， normal saline）， metformin group （Met， 0.3 g·kg^-1）， low-dose MLC group （MLC-L， 4.3 g·kg^-1）， medium-dose MLC group （MLC-M， 8.6 g·kg^-1）， and high-dose MLC group （MLC-H， 17.2 g·kg^-1）. Active components of MLC and targets of obesity-type PCOS were screened from databases， a protein-protein interaction （PPI） network was constructed， and gene ontology（GO）and Kyoto Encyclopedia of Genes and Genomes （KEGG） pathway enrichment analysis was performed. The gut microbiota structure was analyzed based on 16S rRNA sequencing and correlated with network pharmacology pathways. Body weight and estrous cycle were dynamically monitored. Ovarian morphology was observed by hematoxylin-eosin （HE） staining. Cell apoptosis was detected by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling （TUNEL）. Enzyme-linked immunosorbent assay （ELISA） was used to detect levels of follicle-stimulating hormone （FSH）， luteinizing hormone （LH）， anti-Müllerian hormone （AMH）， testosterone （T）， and estradiol （E₂）. Western blot was used to detect the protein expression levels of phosphorylated PI3K/PI3K （p-PI3K/PI3K）， phosphorylated Akt/Akt （p-Akt/Akt）， B-cell lymphoma-2 （Bcl-2）， and Bcl-2-associated X protein （Bax）. ResultsNetwork pharmacology screening identified 124 active components of MLC and 408 overlapping targets between the herbal formula and the disease. Core targets such as Akt1 and Bcl-2 were revealed. As indicated by 16S rRNA sequencing， the abundances of Lachnospiraceae， Lachnoclostridium， and Dorea were increased in the MLC groups （P<0.05）， while the abundance of Veillonella was decreased （P<0.05）. KEGG correlation analysis integrating network pharmacology and gut microbiota data showed significant enrichment of the PI3K/Akt signaling pathway. Animal experiments showed that， compared with the Mod group， body weight decreased to normal levels in the Met， MLC-M， and MLC-H groups. The estrous cycle became regular. The number of corpora lutea increased and cystic follicles decreased. Serum levels of T， FSH， and LH/FSH were reduced （P<0.05， P<0.01）， while the E₂ level was increased （P<0.01）. Ovarian cell apoptosis was reduced （P<0.01）， and the protein expression levels of p-PI3K/PI3K， p-Akt/Akt， and Bcl-2 in ovarian tissue were significantly increased， whereas Bax protein expression was significantly decreased （P<0.05， P<0.01）. ConclusionMLC can regulate gut microbiota structure， effectively improve ovarian pathology in rats with obesity-type PCOS， and inhibit ovarian granulosa cell apoptosis. The mechanism may be associated with upregulation of the PI3K/Akt signaling pathway.

Objective To analyze the differences of free and esterified oxo-eicosatetraenoic acids (oxo-ETEs) in blood cells and plasma from arterial and venous blood in hemodialysis (HD) patients. Methods Arterial and venous blood samples from 12 patients with end-stage renal disease (ESRD) before and after HD treatment at Charité – Universitätsmedizin Berlin, Germany, from June to December 2020 were collected. The esterified and free oxo-ETEs derived from arachidonic acid in blood cells and plasma were measured by high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). Results Neither esterified nor free oxo-ETEs in blood cells displayed significant arteriovenous differences before and after HD. HD predominantly affected the metabolic levels of esterified and free oxo-ETEs in plasma. HD reduced the arteriovenous differences of esterified 12-oxo-ETE, free 15-oxo-ETE, and free 5-oxo-ETE in plasma, while raised the arteriovenous differences of esterified 15-oxo-ETE. Conclusions The oxo-ETEs in blood cells are relatively well-stabilized responding to HD treatment, whereas arteriovenous differences of free and esterified oxo-ETEs in plasma are present and active in response to HD treatment, potentially contributing to the cardiovascular disease.

Objective To establish a method for rapid detection of tramadol in urine by liquid-liquid extraction（LLE）-surface-enhanced Raman spectroscopy （SERS）. Methods Tramadol was extracted from urine with chloroform∶isopropyl alcohol （9∶1） extractant and detected in urine samples by enhanced Raman spectroscopy （wavelength 785 nm）. Results The quantitative curve of tramadol was Y=204.35 X−465.62, r=0.9952, and the linear range was 1-100 μg/ml. The detection limit of tramadol by this method （S/N=3） was 0.53 μg/ml. The sensitivity of SERS was higher than that of conventional methods, and it had reasonable reproducibility. Conclusion This method is simple, efficient and economical, and can be used for qualitative and quantitative analysis of tramadol personalized medicine.

BACKGROUND: The available evidence regarding the benefits of percutaneous coronary intervention (PCI) on patients receiving dialysis with coronary artery disease (CAD) is limited and inconsistent. This study aimed to evaluate the association between PCI and clinical outcomes as compared with medical therapy alone in patients undergoing dialysis with CAD in China. METHODS: This multicenter, retrospective study was conducted in 30 tertiary medical centers across 12 provinces in China from January 2015 to June 2021 to include patients on dialysis with CAD. The primary outcome was major adverse cardiovascular events (MACE), defined as a composite of cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke. Secondary outcomes included all-cause death, the individual components of MACE, and Bleeding Academic Research Consortium criteria types 2, 3, or 5 bleeding. Multivariable Cox proportional hazard models were used to assess the association between PCI and outcomes. Inverse probability of treatment weighting (IPTW) and propensity score matching (PSM) were performed to account for potential between-group differences. RESULTS: Of the 1146 patients on dialysis with significant CAD, 821 (71.6%) underwent PCI. After a median follow-up of 23.0 months, PCI was associated with a 43.0% significantly lower risk for MACE (33.9% [ n  = 278] vs . 43.7% [ n  = 142]; adjusted hazards ratio 0.57, 95% confidence interval 0.45-0.71), along with a slightly increased risk for bleeding outcomes that did not reach statistical significance (11.1% vs . 8.3%; adjusted hazards ratio 1.31, 95% confidence interval, 0.82-2.11). Furthermore, PCI was associated with a significant reduction in all-cause and cardiovascular mortalities. Subgroup analysis did not modify the association of PCI with patient outcomes. These primary findings were consistent across IPTW, PSM, and competing risk analyses. CONCLUSION This study indicated that PCI in patients on dialysis with CAD was significantly associated with lower MACE and mortality when comparing with those with medical therapy alone, albeit with a slightly increased risk for bleeding events that did not reach statistical significance.
Humans ; Percutaneous Coronary Intervention/methods* ; Male ; Female ; Coronary Artery Disease/drug therapy* ; Retrospective Studies ; Renal Dialysis/methods* ; Middle Aged ; Aged ; China ; Proportional Hazards Models ; Treatment Outcome

Obesity is a worldwide health problem. An imbalance in energy metabolism is an important cause of obesity and related metabolic diseases. Our previous studies showed that inhibition of miR-429 increased the protein level of uncoupling protein 1 (UCP1) in beige adipocytes; however, whether local inhibition of miR-429 in subcutaneous adipose tissue affects diet-induced obesity and related metabolic disorders remains unclear. The aim of this study was to investigate the effect of local overexpression of miR-429 sponge in subcutaneous adipose tissue on obesity and related metabolic disorders. The control adeno-associated virus (AAV) or AAV expressing the miR-429 sponge was injected into mouse inguinal white adipose tissue. Seven days later, the mice were fed a high-fat diet for 10 weeks to induce obesity. The effects of the miR-429 sponge on body weight, adipose tissue weight, plasma glucose and lipid levels, and hepatic lipid content were explored. The results showed that the overexpression of miR-429 sponge in subcutaneous white adipose tissue reduced body weight and fat mass, decreased fasting blood glucose and plasma cholesterol levels, improved glucose tolerance, and alleviated hepatic lipid deposition in mice. Mechanistic investigation showed that the inhibition of miR-429 significantly upregulated the expression of UCP1 in adipocytes and adipose tissue. These results suggest that local inhibition of miR-429 in subcutaneous white adipose tissue ameliorates obesity and related metabolic disorders potentially by upregulating UCP1, and miR-429 is a potential therapeutic target for the treatment of obesity and related metabolic disorders.
Animals ; MicroRNAs/physiology* ; Obesity/metabolism* ; Mice ; Adipose Tissue, White/metabolism* ; Metabolic Diseases ; Subcutaneous Fat/metabolism* ; Male ; Uncoupling Protein 1/metabolism* ; Diet, High-Fat ; Mice, Inbred C57BL

Aconitum kusnezoffii is a perennial herbaceous medicinal plant of the family Ranunculaceae, with unique medicinal value. Damping off is one of the most important seedling diseases affecting A. kusnezoffii, occurring widely and often causing large-scale seedling death in the field. To clarify the species of the pathogen causing damping off in A. kusnezoffii and to formulate an effective control strategy, this study conducted pathogen identification, research on biological characteristics, and evaluation of fungicide inhibitory activity. Through morphological characteristics, cultural traits, and phylogenetic tree analysis, the pathogen causing damping off in A. kusnezoffii was identified as Rhizoctonia solani, belonging to the AG5 anastomosis group. The optimal temperature for mycelial growth of the pathogen was 25-30 ℃, with OA medium as the most suitable medium, pH 8 as the optimal pH, and sucrose and yeast as the best carbon and nitrogen sources, respectively. The effect of light on mycelial growth was not significant. In evaluating the inhibitory activity of 45 chemical fungicides, including 30% hymexazol, and 4 biogenic fungicides, including 0.3% eugenol, it was found that 30% thifluzamide and 50% fludioxonil had significantly better inhibitory effects on R. solani than other tested agents, with EC_(50) values of 0.129 6,0.220 6 μg·mL~(-1), respectively. Among the biogenic fungicides, 0.3% eugenol also showed an ideal inhibitory effect on the pathogen, with an EC_(50) of 1.668 9 μg·mL~(-1). To prevent the development of resistance in the pathogen and to reduce the use of chemical fungicides, it is recommended that the three fungicides above be used in rotation during production. These findings provide a theoretical basis for the accurate diagnosis and effective control strategy for R. solani causing damping off in A. kusnezoffii.
Fungicides, Industrial/pharmacology* ; Plant Diseases/microbiology* ; Rhizoctonia/growth & development* ; Aconitum/microbiology* ; Phylogeny ; Mycelium/growth & development*