ObjectiveTo identify the active constituents of Kaixuan Jiedu core prescription （KXJD） and investigate its effective components and therapeutic targets in the treatment of common psoriasis. MethodsUltra-performance liquid chromatography-high resolution mass spectrometry （UPLC-Q-TOF MS） was used to identify and analyze the chemical components of KXJD and its blood-entering chemical components. The chemical components of the single decoction were further identified to clarify the source of the chemical components in KXJD. Then， all identified blood-entering compounds were screened for effective active ingredients through the Swiss ADME database. The active ingredient targets of KXJD were searched on the Swiss Target Prediction platform. The targets of common psoriasis were searched in OMIM， GEO， GeneCards， and DISGNET databases to obtain drug-disease intersection targets. The protein-protein interaction network of intersection targets was constructed using STRING， and then the core blood-entering component-intersection target network of KXJD was constructed. The core target proteins in the network were selected for molecular docking with the core components of KXJD. Small molecules and proteins were pretreated， and appropriate docking sites were selected. AutoDock Vina software was used for continuous local search and repeated iterations to find molecular docking conformations. PyMOL software and LigPlot+ software were used for analysis and visualization. Subsequently， the verification was carried out through animal experiments. SPF-grade male C57 mice were randomly divided into a blank group， a model group， a positive drug methotrexate group， and a KXJD group. In the model group， the methotrexate group， and the KXJD group， imiquimod was applied to the backs of the mice for modeling. The blank group and the model group were administered normal saline by gavage， while the methotrexate group and the KXJD group were respectively administered 1 mg·kg^-1 suspension and 30.42 g·kg^-1 decoction of traditional Chinese medicine by gavage. Five days after administration， the mice were sacrificed， and samples were collected. Hematoxylin-eosin （HE） staining was used to observe the skin tissue samples of mice， and the effect of KXJD on the pathological manifestations of psoriasis mice was analyzed. The expression areas of tumor necrosis factor-α （TNF-α）， cyclooxygenase 2 （PTGS2）， interleukin （IL）-1β， and IL-6 in the skin tissue of mice were detected by immunohistochemistry （IHC）. The mRNA expressions of TNF-α， IL-1β， IL-6， and PTGS2 in the skin tissue of mice were detected by real-time fluorescent quantitative polymerase chain reaction （Real-time PCR）. ResultsIn this study， 208 compounds in KXJD were identified by UPLC-Q-TOF MS， and 44 compounds were detected in serum， including 28 prototype components and 16 metabolites. 12 blood-entering active components were screened， and 1 153 active component targets and 1 076 psoriasis-related targets were identified. Eighty-five targets in the intersection set were drug-disease common targets. PPI network analysis showed that TNF-α， IL-1β， IL-6， PTGS2， and ALB were the key target proteins. The results of molecular docking showed that the binding ability of （+）-hexylphenylglycolic acid to key target proteins such as PTGS2 was stable， and PTGS2 showed high stability with a variety of core compounds. Compared with those in the blank group， the stratum corneum and epidermis in the model group mice were significantly thickened， and the pathological Baker score of the mice's skin in the model group was significantly higher than that of the blank group （P<0.01）. The expression areas of PTGS2， TNF-α， IL-1β， and IL-6 proteins in the skin tissue of the model group mice were significantly increased （P<0.01）， and the expression levels of PTGS2， TNF-α， IL-1β， and IL-6 mRNA in the skin tissue of the model group mice were significantly elevated （P<0.01）. Compared with the model group， the pathological Baker scores of the methotrexate group and the KXJD group were both decreased （P<0.01）， and the expression areas in the skin tissue of the methotrexate group and the KXJD group were significantly reduced （P<0.05， P<0.01）. The expression levels of PTGS2， TNF-α， IL-1β， and IL-6 mRNA in the skin tissue of the methotrexate group and the KXJD group were significantly decreased （P<0.01）. ConclusionKXJD can effectively improve the skin lesions of psoriasis model mice and reduce the expression of TNF-α， IL-1β， IL-6， and PTGS2 in the skin tissue of psoriasis model mice. PTGS2 has a stable binding ability with a variety of compounds in the decoction， which may be a key target for the treatment of psoriasis. The compound （+）-hexylphenylglycolic acid may play a key role.

ObjectiveTo identify the active constituents of Kaixuan Jiedu core prescription （KXJD） and investigate its effective components and therapeutic targets in the treatment of common psoriasis. MethodsUltra-performance liquid chromatography-high resolution mass spectrometry （UPLC-Q-TOF MS） was used to identify and analyze the chemical components of KXJD and its blood-entering chemical components. The chemical components of the single decoction were further identified to clarify the source of the chemical components in KXJD. Then， all identified blood-entering compounds were screened for effective active ingredients through the Swiss ADME database. The active ingredient targets of KXJD were searched on the Swiss Target Prediction platform. The targets of common psoriasis were searched in OMIM， GEO， GeneCards， and DISGNET databases to obtain drug-disease intersection targets. The protein-protein interaction network of intersection targets was constructed using STRING， and then the core blood-entering component-intersection target network of KXJD was constructed. The core target proteins in the network were selected for molecular docking with the core components of KXJD. Small molecules and proteins were pretreated， and appropriate docking sites were selected. AutoDock Vina software was used for continuous local search and repeated iterations to find molecular docking conformations. PyMOL software and LigPlot+ software were used for analysis and visualization. Subsequently， the verification was carried out through animal experiments. SPF-grade male C57 mice were randomly divided into a blank group， a model group， a positive drug methotrexate group， and a KXJD group. In the model group， the methotrexate group， and the KXJD group， imiquimod was applied to the backs of the mice for modeling. The blank group and the model group were administered normal saline by gavage， while the methotrexate group and the KXJD group were respectively administered 1 mg·kg^-1 suspension and 30.42 g·kg^-1 decoction of traditional Chinese medicine by gavage. Five days after administration， the mice were sacrificed， and samples were collected. Hematoxylin-eosin （HE） staining was used to observe the skin tissue samples of mice， and the effect of KXJD on the pathological manifestations of psoriasis mice was analyzed. The expression areas of tumor necrosis factor-α （TNF-α）， cyclooxygenase 2 （PTGS2）， interleukin （IL）-1β， and IL-6 in the skin tissue of mice were detected by immunohistochemistry （IHC）. The mRNA expressions of TNF-α， IL-1β， IL-6， and PTGS2 in the skin tissue of mice were detected by real-time fluorescent quantitative polymerase chain reaction （Real-time PCR）. ResultsIn this study， 208 compounds in KXJD were identified by UPLC-Q-TOF MS， and 44 compounds were detected in serum， including 28 prototype components and 16 metabolites. 12 blood-entering active components were screened， and 1 153 active component targets and 1 076 psoriasis-related targets were identified. Eighty-five targets in the intersection set were drug-disease common targets. PPI network analysis showed that TNF-α， IL-1β， IL-6， PTGS2， and ALB were the key target proteins. The results of molecular docking showed that the binding ability of （+）-hexylphenylglycolic acid to key target proteins such as PTGS2 was stable， and PTGS2 showed high stability with a variety of core compounds. Compared with those in the blank group， the stratum corneum and epidermis in the model group mice were significantly thickened， and the pathological Baker score of the mice's skin in the model group was significantly higher than that of the blank group （P<0.01）. The expression areas of PTGS2， TNF-α， IL-1β， and IL-6 proteins in the skin tissue of the model group mice were significantly increased （P<0.01）， and the expression levels of PTGS2， TNF-α， IL-1β， and IL-6 mRNA in the skin tissue of the model group mice were significantly elevated （P<0.01）. Compared with the model group， the pathological Baker scores of the methotrexate group and the KXJD group were both decreased （P<0.01）， and the expression areas in the skin tissue of the methotrexate group and the KXJD group were significantly reduced （P<0.05， P<0.01）. The expression levels of PTGS2， TNF-α， IL-1β， and IL-6 mRNA in the skin tissue of the methotrexate group and the KXJD group were significantly decreased （P<0.01）. ConclusionKXJD can effectively improve the skin lesions of psoriasis model mice and reduce the expression of TNF-α， IL-1β， IL-6， and PTGS2 in the skin tissue of psoriasis model mice. PTGS2 has a stable binding ability with a variety of compounds in the decoction， which may be a key target for the treatment of psoriasis. The compound （+）-hexylphenylglycolic acid may play a key role.

Objective:To explore the effects of body mass index (BMI) on the incidence of nocturnal hypertension in patients with hypertension.Methods:Totally 341 hospitalized hypertensive patients treated at the Affiliated Hospital of Jining Medical University from February to May 2023 were selected by convenience sampling. Patients' general information, clinical data, and 24-hour ambulatory blood pressure results were collected. A binomial Logistic regression analysis was conducted to investigate the factors affecting the occurrence of nocturnal hypertension in these patients. The relationship between BMI and the incidence of nocturnal hypertension was examined using threshold effect tests and smooth curve fitting.Results:The binomial Logistic regression analysis indicated that blood phosphate level was a factor influencing the occurrence of nocturnal hypertension in hypertensive patients ( P<0.05). Smooth curve fitting and threshold effect test results showed that the relationship between BMI and the incidence of nocturnal hypertension was curve-correlated, with a turning point at 24.61 kg/m 2. To the left of the turning point, there was no correlation ( P=0.130) ; to the right, there was a correlation ( P=0.016) . Conclusions:When the BMI of hypertensive patients exceeds 24.61 kg/m 2, the likelihood of nocturnal hypertension increases with rising BMI, providing a precise intervention target for weight management-based patient care in hypertension.

AIM To evaluate the quality of Beidougen Formula Granules.METHODS Fifteen batches of standard decoctions and three batches of formula granules were prepared,after which paste rate and contents,transfer rates of magnoflorine,daurisoline,dauricine were determined.HPLC specific chromatograms were established,and cluster analysis was adopted in chemical pattern recognition.RESULTS For three batches of formula granules,the paste rates were 15.1%-16.6%,the contents of magnoflorine,daurisoline,dauricine were 18.93-19.39,9.42-9.60,6.79-6.85 mg/g with the transfer rates of 34.42%-35.25%,43.81%-44.65%,27.27%-27.51%from decoction pieces to formula granules,respectively,and there were seven characteristic peaks in the specific chromatograms with the similarities of more than 0.95,which demonstrated good consistence with those of standard decoctions and accorded with related limit requirements.Fifteen batches of standard decoctions were clustered into two types,and the medicinal materials produced from Jilin,Hebei,Shangdong could be used for the preparation of formula granules.CONCLUSION This reasonable and reliable method can provide references for the quality control and clinical application of Beidougen Formula Granules.

BACKGROUND: Patients with atrial fibrillation (AF) and prior stroke history have a high risk of cardiovascular events despite anticoagulation therapy. It is unclear whether catheter ablation (CA) has further benefits in these patients. METHODS: AF patients with a previous history of stroke or systemic embolism (SE) from the prospective Chinese Atrial Fibrillation Registry study between August 2011 and December 2020 were included in the analysis. Patients were matched in a 1:1 ratio to CA or medical treatment (MT) based on propensity score. The primary outcome was a composite of all-cause death or ischemic stroke (IS)/SE. RESULTS: During a total of 4.1 ± 2.3 years of follow-up, the primary outcome occurred in 111 patients in the CA group (3.3 per 100 person-years) and in 229 patients in the MT group (5.7 per 100 person-years). The CA group had a lower risk of the primary outcome compared to the MT group [hazard ratio (HR) = 0.59, 95% CI: 0.47-0.74, P < 0.001]. There was a significant decreasing risk of all-cause mortality (HR = 0.43, 95% CI: 0.31-0.61, P < 0.001), IS/SE (HR = 0.73, 95% CI: 0.54-0.97, P = 0.033), cardiovascular mortality (HR = 0.32, 95% CI: 0.19-0.54, P < 0.001) and AF recurrence (HR = 0.33, 95% CI: 0.30-0.37, P < 0.001) in the CA group compared to that in the MT group. Sensitivity analysis generated consistent results when adjusting for time-dependent usage of anticoagulants. CONCLUSIONS In AF patients with a prior stroke history, CA was associated with a lower combined risk of all-cause death or IS/SE. Further clinical trials are warranted to confirm the benefits of CA in these patients.

Objective: To perform intrauterine adhesion modeling, and to investigate the repair effect of hypoxic treated bone marrow mesenchymal stem cells (BMSC) and their derived exosomes (BMSC-exo) on endometrial injury. Methods: BMSC and their exosomes BMSC-exo extracted from rats' femur were cultured under conventional oxygen condition (21%O₂) or hypoxia condition (1%O₂). Intrauterine adhesion modeling was performed on 40 healthy female SD rats by intrauterine injection of bacterial lipopolysaccharide after curettage. On the 28th day of modeling, 40 rat models were randomly divided into five groups, and interventions were performed: (1) NC group: 0.2 ml phosphate buffered solution was injected into each uterine cavity; (2) BMSC group: 0.2 ml BMSC (1×10⁶/ml) with conventional oxygen culture was injected intrauterine; (3) L-BMSC group: 0.2 ml of hypoxic cultured BMSC (1×10⁶/ml) was injected intrauterine; (4) BMSC-exo group: 0.2 ml of BMSC-exo cultured with conventional oxygen at a concentration of 500 μg/ml was injected into the uterine cavity; (5) L-BMSC-exo group: 0.2 ml hypoxic cultured BMSC-exo (500 μg/ml) was injected intrauterine. On the 14th and 28th day of treatment, four rats in each group were sacrificed by cervical dislocation after anesthesia, and endometrial tissues were collected. Then HE and Masson staining were used to observe and calculate the number of glands and fibrosis area in the endometrium. The expressions of angiogenesis related cytokines [vascular endothelial growth factor A (VEGFA) and CD₃₁], and fibrosis-related proteins [collagen-Ⅰ, collagen-Ⅲ, smooth muscle actin α (α-SMA), and transforming growth factor β1 (TGF-β1)] in endometrial tissues were detected by western blot. Results: (1) HE and Masson staining showed that the number of endometrial glands in L-BMSC group, BMSC-exo group and L-BMSC-exo group increased and the fibrosis area decreased compared with NC group on the 14th and 28th day of treatment (all P<0.05). Noteworthily, the changes of L-BMSC-exo group were more significant than those of BMSC-exo group (all P<0.05), and the changes of BMSC-exo group were greater than those of BMSC group (all P<0.05). (2) Western blot analysis showed that, compared with NC group, the expressions of collagen-Ⅲ and TGF-β1 in BMSC group, L-BMSC group, BMSC-exo group and L-BMSC-exo group decreased on the 14th and 28th day of treatment (all P<0.05). As the treatment time went on, the expressions of fibrosis-related proteins were different. Compared with BMSC group, the expressions of collagen-Ⅲ, α-SMA and TGF-β1 in the BMSC-exo group and L-BMSC group decreased on the 28th day (all P<0.05). Moreover, the expressions of collagen-Ⅲ and TGF-β1 in L-BMSC-exo group were lower than those in BMSC-exo group on the 28th day (all P<0.05). And the expressions of collagen-Ⅰ, α-SMA and TGF-β1 in L-BMSC-exo group were lower than those in L-BMSC group on the 28th day (all P<0.05). (3) The results of western blot analysis of VEGFA and CD₃₁ showed that, the expressions of VEGFA and CD₃₁ in BMSC group, L-BMSC group, BMSC-exo group and L-BMSC-exo group increased on the 14th and 28th day of treatment compared with NC group (all P<0.05). Treatment for 28 days, the expressions of VEGFA and CD₃₁ in BMSC-exo group and CD₃₁ in L-BMSC group were higher than those in BMSC group (all P<0.05). Moreover, the expressions of VEGFA and CD₃₁ in L-BMSC-exo group were higher than those in BMSC-exo group and L-BMSC group on the 28th day (all P<0.05). Conclusions: Treatment of BMSC and their exosomes BMSC-exo with hypoxia could promote endometrial gland hyperplasia, inhibit tissue fibrosis, and further repair the damaged endometrium in rats with intrauterine adhesion. Importantly, hypoxic treatment of BMSC-exo is the most effective in intrauterine adhesion rats.
Rats ; Female ; Humans ; Animals ; Rats, Sprague-Dawley ; Transforming Growth Factor beta1/metabolism* ; Vascular Endothelial Growth Factor A ; Exosomes/metabolism* ; Uterine Diseases/therapy* ; Collagen ; Hypoxia/therapy* ; Fibrosis ; Mesenchymal Stem Cells/metabolism* ; Oxygen

Valencene, a kind of sesquiterpenoid with a citrus flavor, is mainly found in Valencia orange and is commonly used in cosmetics and food additives, as well as industrial synthetic nootkatone. In this study, synthetic biology was used to create a Saccharomyces cerevisiae cell factory to produce valencene. Fistly, valencene synthase gene (CnVS) from Callitropsis nootkatensis was inserted into the chromosome of the chassis strain YTT-T5. The resulting strain VAL-01 could produce 1.1 mg·L^-1 valencene. Protein fusion technique was used, different valencene synthases were compared and the copy number of key genes was adjusted, yielding valencene to 436.4 mg·L^-1. Then, knocking-out the transcription factor ROX1 resulted in valencene improvement by 17.4%. Moreover, the induction system of galactose was regulated, transcription factor PDR3 and INO2 were overexpressed. The engineered strain VAL-10 could produce 2 798.6 mg·L^-1 valencene by high cell density fermentation method (nearly 2 500 times higher than VAL-01). This study provides a basis for green production of valencene.

Evidence and value：impact on DEcisionMaking （EVIDEM） framework was developed by EVIDEM collaboration. Its core is the combination of multiple criteria decision analysis （MCDA） model and standardized health technology assessment （HTA） report， which aims to evaluate the overall value of medical interventions. It has been tested and implemented in the real-world evaluation environments. After more than 10 years of development， EVIDEM framework has been updated to version 10， and the relevant operation manuals have been published. More than 40 countries have joined the collaboration and more than 20 countries have carried out relevant studies. The framework is constructed with patients， population and sustainability as the overall goals， combing the evidence and value， forming a relatively complete decision-making framework system composed of 2 levels， 7 dimensions and 20 criteria. The two levels include normative universal criteria and contextual criteria. The normative universal criteria， namely EVIDEM core model， is the quantitative evaluation， consisting of 5 dimensions and 13 criteria. Contextual criteria， namely contextual tools， are qualitative evaluation， consisting of 2 dimensions and 7 criteria. The specific operation steps of EVIDEM framework include selecting and constructing criteria， assigning weights， integrating and evaluating evidence， quantitative and qualitative evaluation of value， comprehensive value estimation and ranking based on value estimation. EVIDEM framework is applicable to disease diagnosis， treatment， management and other fields. Its application scope includes medical insurance reimbursement， clinical practice decision-making， drug selection and so on， which can provide a method for more systematic， transparent and scientific healthcare decision-making. At present， the framework has been introduced into the field of traditional Chinese medicine and can provide a scientific and feasible evaluation tool and methodology system for the clinical comprehensive evaluation of Chinese patent medicine.

Objective: To investigate hypertriglyceridemia and hepatomegaly caused by Schisandrae Sphenantherae Fructus (FSS) and Schisandra chinensis Fructus (FSC) oils in mice. Methods: Mice were orally administered a single dose of Schisandrae Fructus oils. Serum and hepatic triglyceride (TG), triglyceride transfer protein (TTP), apolipoprotein B48 (Apo B48), very-low-density lipoprotein (VLDL), hepatocyte growth factor (HGF), alanine aminotransfease (ALT) and liver index were measured at 6-120 h post-dosing. Results: FSS and FSC oil caused time and dose-dependent increases in serum and hepatic TG levels, with maximum increases in the liver (by 297% and 340%) at 12 h post-dosing and serum (244% and 439%) at 24-h post-dosing, respectively. Schisandrae Fructus oil treatments also elevated the levels of serum TTP by 51% and 63%, Apo B48 by 152% and 425%, and VLDL by 67% and 38% in mice, respectively. FSS and FSC oil treatments also increased liver mass by 53% and 55% and HGF by 106% and 174%, but lowered serum ALT activity by 38% and 22%, respectively. Fenofibrate pre/ co-treatment attenuated the FSS and FSC oil-induced elevation in serum TG levels by 41% and 49% at 48 h post-dosing, respectively, but increased hepatic TG contents (by 38% and 33%, respectively) at 12 h post-dosing. Conclusions: Our findings provide evidence to support the establishment of a novel mouse model of hypertriglyceridemia by oral administration of FSS oil (mainly increasing endogenous TG) and FSC oil (mainly elevating exogenous TG).

Ginsenoside Rh_2 is a rare active ingredient in precious Chinese medicinal materials such as Ginseng Radix et Rhizoma, Notoginseng Radix et Rhizoma, and Panacis Quinquefolii Radix. It has important pharmacological activities such as anti-cancer and improving human immunity. However, due to the extremely low content of ginsenoside Rh_2 in the source plants, the traditional way of obtaining it has limitations. This study intended to apply synthetic biological technology to develop a cell factory of Saccharomyces cerevisiae to produce Rh_2 by low-cost fermentation. First, we used the high protopanaxadiol(PPD)-yielding strain LPTA as the chassis strain, and inserted the Panax notoginseng enzyme gene Pn1-31, together with yeast UDP-glucose supply module genes[phosphoglucose mutase 1(PGM1), α-phosphoglucose mutase(PGM2), and uridine diphosphate glucose pyrophosphorylase(UGP1)], into the EGH1 locus of yeast chromosome. The engineered strain LPTA-RH2 produced 17.10 mg·g~(-1) ginsenoside Rh_2. This strain had low yield of Rh_2 while accumulated much precursor PPD, which severely restricted the application of this strain. In order to further improve the production of ginsenoside Rh_2, we strengthened the UDP glucose supply module and ginsenoside Rh_2 synthesis module by engineered strain LPTA-RH2-T. The shaking flask yield of ginsenoside Rh_2 was increased to 36.26 mg·g~(-1), which accounted for 3.63% of the dry weight of yeast cells. Compared with those of the original strain LPTA-RH2, the final production and the conversion efficiency of Rh_2 increased by 112.11% and 65.14%, respectively. This study provides an important basis for further obtaining the industrial-grade cell factory for the production of ginsenoside Rh_2.
Fermentation ; Ginsenosides ; Humans ; Panax/genetics* ; Panax notoginseng ; Saccharomyces cerevisiae/genetics* ; Uridine Diphosphate Glucose