Targeted inhibition of transforming growth factor-ß type I receptor by AZ12601011 improves paraquat poisoning-induced multiple organ fibrosis.

Paraquat (PQ) causes fatal poisoning that leads to systemic multiple organ fibrosis, and transforming growth factor (TGF)-ß1 plays a critical role in this process. In this study, we aimed to investigate the effects of AZ12601011 (a small molecular inhibitor of TGFßRI) on PQ-induced multiple organ fibrosis. We established a mouse model of PQ in vivo and used PQ-treated lung epithelial cell (A549) and renal tubular epithelial cells (TECs) in vitro. Haematoxylin-eosin and Masson staining revealed that AZ12601011 ameliorated pulmonary, hepatic, and renal fibrosis, consistent with the decrease in the levels of fibrotic indicators, alpha-smooth muscle actin (α-SMA) and collagen-1, in the lungs and kidneys of PQ-treated mice. In vitro data showed that AZ12601011 suppressed the induction of α-SMA and collagen-1 in PQ-treated A549 cells and TECs. In addition, AZ12601011 inhibited the release of inflammatory factors, interleukin (IL)-1ß, IL-6, and tumour necrosis factor-α. Mechanistically, TGF-ß and TGFßRI levels were significantly upregulated in the lungs and kidneys of PQ-treated mice. Cellular thermal shift assay and western blotting revealed that AZ12601011 directly bound with TGFßRI and blocked the activation of Smad3 downstream. In conclusion, our findings revealed that AZ12601011 attenuated PQ-induced multiple organ fibrosis by blocking the TGF-ß/Smad3 signalling pathway, suggesting its potential for PQ poisoning treatment.

Advanced Progress of Histone Deacetylases in Rheumatic Diseases.

Rheumatic disease is a disease which is not yet fully clarified to etiology and also involved in a local pathological injury or systemic disease. With the continuous improvement of clinical medical research in recent years, the development process of rheumatic diseases has been gradually elucidated; with the intensely study of epigenetics, it is realized that environmental changes can affect genetics, among which histone acetylation is one of the essential mechanisms in epigenetics. Histone deacetylases (HDACs) play an important role in regulating gene expression in various biological processes, including differentiation, development, stress response, and injury. HDACs are involved in a variety of physiological processes and are promising drug targets in various pathological conditions, such as cancer, cardiac and neurodegenerative diseases, inflammation, metabolic and immune disorders, and viral and parasitic infections. In this paper, we reviewed the roles of HDACs in rheumatic diseases in terms of their classification and function.

Activation of the PERK-CHOP signaling pathway during endoplasmic reticulum stress contributes to olanzapine-induced dyslipidemia.

Olanzapine (OLZ) is a widely prescribed antipsychotic drug with a relatively ideal effect in the treatment of schizophrenia (SCZ). However, its severe metabolic side effects often deteriorate clinical therapeutic compliance and mental rehabilitation. The peripheral mechanism of OLZ-induced metabolic disorders remains abstruse for its muti-target activities. Endoplasmic reticulum (ER) stress is implicated in cellular energy metabolism and the progression of psychiatric disorders. In this study, we investigated the role of ER stress in the development of OLZ-induced dyslipidemia. A cohort of 146 SCZ patients receiving OLZ monotherapy was recruited, and blood samples and clinical data were collected at baseline, and in the 4th week, 12th week, and 24th week of the treatment. This case-control study revealed that OLZ treatment significantly elevated serum levels of endoplasmic reticulum (ER) stress markers GRP78, ATF4, and CHOP in SCZ patients with dyslipidemia. In HepG2 cells, treatment with OLZ (25, 50 µM) dose-dependently enhanced hepatic de novo lipogenesis accompanied by SREBPs activation, and simultaneously triggered ER stress. Inhibition of ER stress by tauroursodeoxycholate (TUDCA) and 4-phenyl butyric acid (4-PBA) attenuated OLZ-induced lipid dysregulation in vitro and in vivo. Moreover, we demonstrated that activation of PERK-CHOP signaling during ER stress was a major contributor to OLZ-triggered abnormal lipid metabolism in the liver, suggesting that PERK could be a potential target for ameliorating the development of OLZ-mediated lipid dysfunction. Taken together, ER stress inhibitors could be a potentially effective intervention against OLZ-induced dyslipidemia in SCZ.

Nucleic acid and protein methylation modification in renal diseases.

Although great efforts have been made to elucidate the pathological mechanisms of renal diseases and potential prevention and treatment targets that would allow us to retard kidney disease progression, we still lack specific and effective management methods. Epigenetic mechanisms are able to alter gene expression without requiring DNA mutations. Accumulating evidence suggests the critical roles of epigenetic events and processes in a variety of renal diseases, involving functionally relevant alterations in DNA methylation, histone methylation, RNA methylation, and expression of various non-coding RNAs. In this review, we highlight recent advances in the impact of methylation events (especially RNA m6A methylation, DNA methylation, and histone methylation) on renal disease progression, and their impact on treatments of renal diseases. We believe that a better understanding of methylation modification changes in kidneys may contribute to the development of novel strategies for the prevention and management of renal diseases.

Pancreatic pseudoaneurysm mimicking pancreatic tumor: A case report and review of literature.

BACKGROUND: Pancreatic pseudoaneurysm is a rare vascular complication of chronic pancreatitis (CP) or necrotizing pancreatitis with an incidence of 4% to 17%, but it is potentially life-threatening. It is well known that most pancreatic pseudoaneurysms are clinically associated with pancreatic pseudocysts and are usually in the peripancreatic body-tail. A minority of intrapancreatic pseudoaneurysms occur in the absence of pseudocyst formation. Noninvasive computed tomography (CT) and magnetic resonance imaging (MRI) are most commonly used examinations for screening pancreatic pseudoaneurysms. Notably, the rare intrapancreatic pseudoaneurysm in the pancreatic head can mimic a hypervascular solid mass and be misdiagnosed as a pancreatic tumor. CASE SUMMARY: We report the case of a 67-year-old man who had been admitted to our hospital due to recurrent abdominal pain for 1 mo that was aggravated for 5 d. CT and MRI revealed a mass in the pancreatic head with significant expansion of the main pancreatic duct and mild atrophy of the pancreatic body-tail. He was admitted to the department of hepatobiliary and pancreatic surgery due to the possibility of a pancreatic tumor. The patient was then referred for endoscopic ultrasonography (EUS) with possible EUS-FNA. However, EUS showed a cystic lesion in the pancreatic head with wall thickness and enhancing nodules, which was doubtful because it was inconsistent with the imaging findings. Subsequently, color doppler flow imaging demonstrated turbulent arterial blood flow in the cystic lesion and connection with the surrounding vessel. Therefore, we highly suspected the possibility of CP complicated with intrapancreatic pseudoaneurysm, combined with the patient's long-term drinking history and the sonographic features of CP. Indeed, angiography revealed an oval area of contrast medium extravasation (size: 1.0 cm × 1.5 cm) at the far-end branch of the superior pancreaticoduodenal artery, and angiographic embolization was given immediately at the same time. CONCLUSION: EUS is an important differential diagnostic tool when pancreatic pseudoaneurysm mimics the imaging appearance of a hypervascular pancreatic tumor.

GRP/GRPR signaling pathway aggravates hyperuricemia-induced renal inflammation and fibrosis via ABCG2-dependent mechanisms.

The gastrin-releasing peptide receptor (GRPR) binds to ligands such as gastrin-releasing peptide (GRP) and plays a variety of biological roles. In this study, we investigated the therapeutic effect of a novel gastrin-releasing peptide receptor antagonist RH-1402 in hyperuricemia-induced kidney fibrosis and its underlying mechanisms. We conducted enzyme linked immunosorbent assay (ELISA) and immunohistochemical analyses and found that proGRP and GRPR expression levels were significantly increased in patients with hyperuricemic nephropathy (HN) and HN mice. GRPR knockdown significantly attenuated inflammatory and fibrotic responses in adenosine-treated human proximal tubule epithelial cells. GRPR knockout or GRPR conditional knockout in renal tubular epithelial cells significantly alleviated the decline in renal function and fibrosis in HN mice in vivo. RNA-seq and String database analysis revealed that GRP/GRPR promoted HN by suppressing the ABCG2/PDZK1 and increasing TGF-ß/Smad3 levels by activating the NF-κB pathway. Overexpression of GRPR increased TGF-ß/Smad3 levels, where as it reduced ABCG2/PDZK1 levels in adenosine-treated HK2 cells, which was reversed by the NF-κB inhibitor. Furthermore, we evaluated the therapeutic effects of the novel GRPR inhibitor RH-1402 on hyperuricaemia-induced renal injury and evaluated the inflammatory and fibrosis responses in vivo and in vitro. Pre-treatment with RH-1402 attenuated hyperuricaemia-induced renal injury, restored renal function, and suppressed renal inflammation and fibrosis. Taken together, GRPR enhances hyperuricaemia-induced tubular injury, inflammation, and renal fibrosis via ABCG2-dependent mechanisms and may serve as a promising therapeutic target for HN treatment.

Emergency entity relationship extraction for water diversion project based on pre-trained model and multi-featured graph convolutional network.

Using information technology to extract emergency decision-making knowledge from emergency plan documents is an essential means to enhance the efficiency and capacity of emergency management. To address the problems of numerous terminologies and complex relationships faced by emergency knowledge extraction of water diversion project, a multi-feature graph convolutional network (PTM-MFGCN) based on pre-trained model is proposed. Initially, through the utilization of random masking of domain-specific terminologies during pre-training, the model's comprehension of the meaning and application of such terminologies within specific fields is enhanced, thereby augmenting the network's proficiency in extracting professional terminologies. Furthermore, by introducing a multi-feature adjacency matrix to capture a broader range of neighboring node information, thereby enhancing the network's ability to handle complex relationships. Lastly, we utilize the PTM-MFGCN to achieve the extraction of emergency entity relationships in water diversion project, thus constructing a knowledge graph for water diversion emergency management. The experimental results demonstrate that PTM-MFGCN exhibits improvements of 2.84% in accuracy, 4.87% in recall, and 5.18% in F1 score, compared to the baseline model. Relevant studies can effectively enhance the efficiency and capability of emergency management, mitigating the impact of unforeseen events on engineering safety.

Tai Chi as a complementary exercise for pulmonary rehabilitation in chronic obstructive pulmonary disease: A randomised controlled trial.

OBJECTIVES: With the characteristics of mindfulness and breathing techniques, Tai Chi has been recommended with therapeutic values in chronic obstructive pulmonary disease (COPD). However, its strengths as a complementary exercise for conventional pulmonary rehabilitation (PR) remain unclear. DESIGN AND SETTING: This single-blinded randomised controlled trial recruited patients with mild to severe stable COPD. Eligible participants were randomly assigned to the group with usual care (control), total body recumbent stepper (TBRS) exercise, Tai Chi (TC), or combined TBRS exercise and Tai Chi (TBRS-TC). Patients received a two-month hospital-based supervised exercise, followed by a ten-month community- or home-based rehabilitation program. RESULTS: A total of 120 participants were recruited, and 102 were included in the per-protocol analysis. The mean changes in St George's Respiratory Questionnaire (SGRQ) total score from baseline to the post-hospital exercise in the control group, TBRS group, TC group, and TBRS-TC group was 2.62 (95 % CI -8.99 to 8.99), -9.28 (95 % CI -13.96 to -4.60), -10.19 (95 % CI -13.72 to -6.67), and -16.75 (95 % CI -20.25 to -13.24), respectively, with a statistically significant difference between groups in favor of the TBRS-TC exercise (P < 0.001). The remarkable effect of TBRS-TC exercise in improving the quality of life maintained until the end of the community- or home-based rehabilitation training (P < 0.001). Besides, a statistically better effect with the TBRS-TC exercise was also observed in the outcomes regarding exercise capacity, pulmonary function, symptom burden, and systemic inflammation after the whole process of 12-month integrative PR exercise programme. CONCLUSIONS: Based on the results, a novel integrated exercise modality combining Tai Chi and conventional pulmonary rehabilitation was developed. It might contribute to more positive effects in patients with stable COPD. REGISTRATION: The study was registered with the Chinese Clinical Trial Registry (ChiCTR-IOR-15006874) prior to commencing recruitment.

Resistance monitoring and mechanism in the fall armyworm Spodoptera frugiperda (Lepidoptera: Noctuidae) for chlorantraniliprole from Sichuan Province, China.

The fall armyworm, Spodoptera frugiperda (Noctuidae: Lepidoptera), is a wide-reaching notorious insect pest of important cereal crops, which has developed resistance to multiple classes of insecticides. It invaded the Sichuan Province of China in 2019. In this study, we performed resistance monitoring of insecticides for 11 field-collected populations from Sichuan, and all the populations were susceptible to emamectin benzoate and chlorpyrifos. The variations in resistance level to indoxacarb (resistance ratio (RR), 9.23-45.53-fold), spinetoram (RR, 4.32-18.05-fold), and chlorantraniliprole (RR, 2.02-10.39-fold) were observed among these populations. To investigate the resistance mechanism of chlorantraniliprole, synergism tests were performed and showed that piperonyl butoxide had a slight synergistic effect on chlorantraniliprole for the QJ-20 population (1.43-fold) in moderate resistance (RR, 10.39-fold) compared with the treatment group without synergist. Furthermore, the expression scanning for resistance-related genes showed that five P450 genes (CYP6AE43, CYP321A8, CYP305A1, CYP49A1, and CYP306A1) and the ryanodine receptor gene (Ryr, chlorantraniliprole target) were overexpressed in the QJ-20 population. These results indicated that the fall armyworm in Sichuan has exhibited diverse susceptibilities to several classes of insecticides, and the overexpression of Ryr and several P450 genes may contribute to the development of resistance in S. frugiperda to chlorantraniliprole.

Dose-response relationship between dietary inflammatory index and diabetic kidney disease in US adults.

OBJECTIVE: The impact of the dietary potential inflammatory effect on diabetic kidney disease (DKD) has not been adequately investigated. The present study aimed to explore the association between dietary inflammatory index (DII) and DKD in US adults. DESIGN: This is a cross-sectional study. SETTING: Data from the National Health and Nutrition Examination Survey (2007-2016) were used. DII was calculated from 24-h dietary recall interviews. DKD was defined as diabetes with albuminuria, impaired glomerular filtration rate or both. Logistic regression and restricted cubic spline models were adopted to evaluate the associations. PARTICIPANTS: Data from the National Health and Nutrition Examination Survey (2007-2016) were used, which can provide the information of participants. RESULTS: Four thousand two-hundred and sixty-four participants were included in this study. The adjusted OR of DKD was 1·04 (95 % CI 0·81, 1·36) for quartile 2, 1·24 (95 % CI 0·97, 1·59) for quartile 3 and 1·64 (95 % CI 1·24, 2·17) for quartile 4, respectively, compared with the quartile 1 of DII. A linear dose-response pattern was observed between DII and DKD (Pnonlinearity = 0·73). In the stratified analyses, the OR for quartile 4 of DII were significant among adults with higher educational level (OR 1·83, 95 % CI 1·26, 2·66) and overweight or obese participants (OR 1·67, 95 % CI 1·23, 2·28), but not among the corresponding another subgroup. The interaction effects between DII and stratified factors on DKD were not statistically significant (all P values for interactions were >0·05). CONCLUSIONS: Our findings suggest that a pro-inflammatory diet, shown by a higher DII score, is associated with increased odd of DKD.

Differences in susceptibility to chlorantraniliprole between Chilo suppressalis (Lepidoptera: Crambidae) and two dominant parasitic wasps collected from Sichuan Province, China.

Chilo suppressalis Walker (Lepidoptera: Crambidae) is one of the most destructive pests occurring in the rice-growing regions of Asia. Parasitoids, mainly egg parasitoids, have been of interest for several years even with practical used cases. Therefore, the potential impact of insecticides on natural enemies needs great attention. In this study, chlorantraniliprole was evaluated for its impact on C. suppressalis and two dominant parasitic wasps. Bioassays showed that chlorantraniliprole had negligible toxicity to Eriborus terebrans but was significantly toxic to Chelonus munakatae; the mortality exceeded 50% when the concentration reached 46.83 ng/cm2. Enzyme assays suggested that the significantly different carboxylesterase activity may be involved in the high-level detoxification metabolism of E. terebrans. According to the results of enzyme gene correlation analysis, P450s may be the dominant factor in the detoxification metabolism of C. munakatae. In addition, the ryanodine receptor C-terminus of C. suppressalis (CsRyR), C. munakatae (CmRyR) and E. terebrans (EtRyR) were successfully cloned. Different amino acids at resistance mutation I4758 M between susceptible C. suppressalis (I) and parasitic wasps (M) may be related to susceptibility differences. Simulated docking showed that CsRyR and CmRyR can interact with chlorantraniliprole but not EtRyR. More interaction forces were formed between CsRyR and chlorantraniliprole than CmRyR. Furthermore, a Pi-Pi T-shape formed between 73PHE in CsRyR and the benzene ring in chlorantraniliprole. These results indicated that both detoxification metabolism and the target site could mediate the susceptibility difference between C. suppressalis and its parasitic wasps.

[Secondary metabolites of endophyte fungi Xylaria sp. from Coptis chinensis].

Two new polyketides, lasobutone A(1) and lasobutone B(2), along with three known compounds, guignardianone C(3), guignardic acid(4), and 4-hydroxy-17R-methylincisterol(5), were isolated from the endophytic fungi Xylaria sp. by silica gel, MCI, and preparative HPLC, which was separated from the Chinese medicinal material Coptis chinensis and cultivated through solid fermentation with rice. Their structures were elucidated on the basis of spectroscopic methods, such as MS, NMR, IR, UV, and ECD. Compounds 2 and 4 showed inhibitory activities against the nitric oxide(NO) production in the LPS-induced macrophage RAW264.7 with IC_(50) values of 58.7 and 42.5 µmol·L~(-1) respectively, while compound 5 exhibited cytotoxic activities against HT-29 with IC_(50) value of 14.3 µmol·L~(-1).

Drought prediction based on an improved VMD-OS-QR-ELM model.

To overcome the low accuracy, poor reliability, and delay in the current drought prediction models, we propose a new extreme learning machine (ELM) based on an improved variational mode decomposition (VMD). The model first redefines the output of the hidden layer of the ELM model with orthogonal triangular matrix decomposition (QR) to construct an orthogonal triangular ELM (QR-ELM), and then introduces an online sequence learning mechanism (OS) into the QR-ELM to construct an online sequence OR-ELM (OS-QR-ELM), which effectively improves the efficiency of the ELM model. The mutual information extension method was then used to extend both ends of the original signal to improve the VMD end effect. Finally, VMD and OS-QR-ELM were combined to construct a drought prediction method based on the VMD-OS-QR-ELM. The reliability and accuracy of the VMD-OS-QR-ELM model were improved by 86.19% and 93.20%, respectively, compared with those of the support vector regression model combined with empirical mode decomposition. Furthermore, the calculation efficiency of the OS-QR-ELM model was increased by 88.65% and 85.32% compared with that of the ELM and QR-ELM models, respectively.

Screening S protein - ACE2 blockers from natural products: Strategies and advances in the discovery of potential inhibitors of COVID-19.

The Coronavirus disease, 2019 (COVID-19) is caused by severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2), which poses a major threat to human life and health. Given its continued development, limiting the spread of COVID-19 in the population remains a challenging task. Currently, multiple therapies are being tried around the world to deal with SARS-CoV-2 infection, and a variety of studies have shown that natural products have a significant effect on COVID-19 patients. The combination of SARS-CoV-2 S protein with Angiotensin converting enzyme II(ACE2) of host cell to promote membrane fusion is an initial critical step for SARS-CoV-2 infection. Therefore, screening natural products that inhibit the binding of SARS-CoV-2 S protein and ACE2 also provides a feasible strategy for the treatment of COVID-19. Establishment of high throughput screening model is an important basis and key technology for screening S protein-ACE2 blockers. Based on this, the molecular structures of SARS-CoV-2 and ACE2 and their processes in the life cycle of SARS-CoV-2 and host cell infection were firstly reviewed in this paper, with emphasis on the methods and techniques of screening S protein-ACE2 blockers, including Virtual Screening (VS), Surface Plasmon Resonance (SPR), Biochromatography, Biotin-avidin with Enzyme-linked Immunosorbent assay and Gene Chip Technology. Furthermore, the technical principle, advantages and disadvantages and application scope were further elaborated. Combined with the application of the above screening technologies in S protein-ACE2 blockers, a variety of natural products, such as flavonoids, terpenoids, phenols, alkaloids, were summarized, which could be used as S protein-ACE2 blockers, in order to provide ideas for the efficient discovery of S protein-ACE2 blockers from natural sources and contribute to the development of broad-spectrum anti coronavirus drugs.

Use of diffusion-weighted magnetic resonance imaging (DW-MRI) to predict early response to anti-tumor therapy in advanced non-small cell lung cancer (NSCLC): a comparison of intravoxel incoherent motion-derived parameters and apparent diffusion coefficient.

BACKGROUND: The intravoxel incoherent motion (IVIM) method of magnetic resonance imaging (MRI) analysis can provide information regarding many physiological and pathological processes. This study aimed to investigate whether IVIM-derived parameters and the apparent diffusion coefficient (ADC) can act as imaging biomarkers for predicting non-small cell lung cancer (NSCLC) response to anti-tumor therapy and compare their performances. METHODS: This prospective study included 45 patients with NSCLC treated with chemotherapy (29 men and 16 women, mean age 57.9±9.7 years). Diffusion-weighted imaging was performed with 13 b-values before and 2-4 weeks after treatment. The IVIM parameter pseudo-diffusion coefficient (D*), perfusion fraction (f), diffusion coefficient (D), and ADC from a mono-exponential model were obtained. Responses 2 months after chemotherapy were assessed. The diagnostic performance was evaluated, and optimal cut-off values were determined by receiver operating characteristic (ROC) curve analysis, and the differences of progression-free survival (PFS) in groups of responders and non-responders were tested by Cox regression and Kaplan-Meier survival analyses. RESULTS: Of 45 patients, 30 (66.7%) were categorized as responders, and 15 as non-responders. Differences in the diffusion coefficient D and ADC between responders and non-responders were statistically significant (all P<0.05). Conversely, differences in f and D* between responders and non-responders were both not statistically significance (all P>0.05). The ROC analyses showed the change in D value (ΔD) was the best predictor of early response to anti-tumor therapy [area under the ROC curve (AUC), 0.764]. The Cox-regression model showed that all ADC and D parameters were independent predictors of PFS, with a range of reduction in risk from 56.2% to 82.7%, and ΔD criteria responders had the highest reduction (82.7%). CONCLUSIONS: ADC and D derived from IVIM are potentially useful for the prediction of NSCLC treatment response to anti-tumor therapy. Although ΔD is best at predicting response to treatment, ΔADC measurement may simplify manual efforts and reduce the workload.

Sinomenine Attenuated Capsaicin-Induced Increase in Cough Sensitivity in Guinea Pigs by Inhibiting SOX5/TRPV1 Axis and Inflammatory Response.

BACKGROUND: Chronic cough is a common complaint which affects a large number of patients worldwide. Increased cough sensitivity is a very important cause of chronic persistent cough. However, there are limited clinical diagnosis and treatment for increased cough sensitivity. Transient receptor potential vanilloid-1 (TRPVl) is a member of the transient receptor potential (TRP) family of channels which is very closely associated with respiratory diseases. However, the mechanism through which TRPV1 that influences downstream events is still poorly understood. RESULTS: Capsaicin induced increase in cough sensitivity by upregulating the protein level of TRPV1, leading to the secretions of Substance P and neurokinin A which stimulated neurogenic inflammation. However, sinomenine, a component of traditional Chinese medicine, significantly attenuated the capsaicin-induced cough by inhibiting the expression of TRPV1 in guinea pigs. In addition, capsaicin increased the expression of SOX5 which mediated the transcriptional upregulation of TRPV1. However, pretreatment with sinomenine reduced the expression of SOX5. CONCLUSION: These results indicate that capsaicin induced increase in cough sensitivity by activating neurogenic inflammation, while sinomenine attenuated the increase in cough sensitivity by inhibiting the expressions of SOX5 and TRPV1 in guinea pigs. This finding may provide a novel target for the treatment of aggravated cough sensitivity.

Brexpiprazole caused glycolipid metabolic disorder by inhibiting GLP1/GLP1R signaling in rats.

Brexpiprazole (Bre) is a new multi-target antipsychotic drug (APD) approved by the US FDA in 2015, and shows good therapeutic potential. But it lacks assessments on the metabolic side effects, which obstructs the treatment of schizophrenia. Glucagon-like peptide 1 (GLP1), an incretin associated with insulin action and metabolism, is involved in the metabolic syndrome (MS) caused by most APDs. In this study, we examined the adverse effects of Bre on glycolipid metabolism in rats and determined whether GLP1 was involved in Bre-caused MS. In the first part of experiments, rats were orally administered Bre (0.5 mg· kg-1· d-1) for 28 days with aripiprazole (1.0 mg· kg-1· d-1) or olanzapine (1.0 mg· kg-1· d-1) as the controls. Compared to vehicle, Bre administration significantly increased the weight gain, serum lipid (TG, TC, LDL, FFA), and blood glucose levels accompanied by the hormonal (insulin, glucagon, GLP1) imbalance, and the impaired glucose tolerance and insulin sensitivity. Moreover, we demonstrated that Bre administration significantly decreased the protein and mRNA levels of GLP1 in pancreas and small intestine by suppressing CaMKIIα, AMPK, and ß-catenin; Bre administration also caused islet dysfunction with decreased GLP1R, PI3K, IRß expression in pancreas, and the interference of IRS1, PI3K, p-AKT, and GLUT4 expression in the liver and skeletal muscle that represented the insulin resistance. In the second part of experiments, rats were orally administered Bre (0.5 mg· kg-1· d-1) for 42 days. We showed that co-administration with the GLP1 receptor (GLP1R) agonist liraglutide (0.125 mg· kg-1· d-1, ip) could ameliorate Bre-caused metabolic abnormalities. Our results demonstrate that GLP1/GLP1R signaling is involved in Bre-induced glycolipid metabolic disorders and co-treatment with liraglutide is an effective intervention against those abnormal metabolisms.

Pharmacokinetics of five phthalides in volatile oil of Ligusticum sinense Oliv.cv. Chaxiong, and comparison study on physicochemistry and pharmacokinetics after being formulated into solid dispersion and inclusion compound.

BACKGROUNDS: The dried rhizome of Ligusticum sinense Oliv.cv. Chaxiong has been used to treat cardiovascular and cerebrovascular diseases, atherosclerosis, anemia and stroke. A high purity extract from chaxiong (VOC, brownish yellow oil) was extracted and separated. Its main components were senkyunolide A (SA, 33.81%), N-butylphthalide (NBP, 1.38%), Neocnidilide (NOL, 16.53%), Z-ligustilide (ZL, 38.36%), and butenyl phthalide (BP, 2.48%), respectively. Little is known about the pharmacokinetics of these phthalides in Chaxiong, and different preparations to improve the physicochemistry and pharmacokinetics of VOC have not been investigated. METHODS: At different predetermined time points after oral administration or intravenous administration, the concentrations of SA, NBP, NOL, ZL and BP in the rat plasma were determined using LC-MS/MS, and the main PK parameters were investigated. VOC-P188 solid dispersion and VOC-ß-CD inclusion compound were prepared by melting solvent method and grinding method, respectively. Moreover, the physicochemical properties, dissolution and pharmacokinetics of VOC-P188 solid dispersion and VOC-ß-CD inclusion compound in rats were assessed in comparison to VOC. RESULTS: The absorptions of SA, NBP, NOL, ZL and BP in VOC were rapid after oral administration, and the absolute bioavailability was less than 25%. After the two preparations were prepared, dissolution rate was improved at pH 5.8 phosphate buffer solution. Comparing VOC and physical mixture with the solid dispersion and inclusion compound, it was observed differences occurred in the chemical composition, thermal stability, and morphology. Both VOC-P188 solid dispersion and VOC-ß-CD inclusion compound had a significantly higher AUC and longer MRT in comparison with VOC. CONCLUSION: SA, NBP, NOL, ZL and BP in VOC from chaxiong possessed poor absolute oral bioavailability. Both VOC-P188 solid dispersion and VOC-ß-CD inclusion compound could be prospective means for improving oral bioavailability of SA, NBP, NOL, ZL and BP in VOC.

[Pharmacokinetic study on five components in phthalide target areas of Chaxiong and its ß-CD inclusion compounds based on UPLC-MS/MS].

This study aims to establish a method for the determination of the concentration of five main components of phthalide target areas of Chaxiong(CPTA) and its inclusion of ß-CD in the plasma of rats, and determine the pharmacokinetic parameters, absolute bioavailability and relative bioavailability of CPTA/ß-CD inclusion compound in vivo. The plasma concentrations of senkyunolide A, N-butylphthalide, new osthol lactone, Z-ligustilide and butenyl phthalide were determined with UPLC-MS/MS. The content determination was conducted at the chromatographic conditions as follows: Shim-pack GIST C_(18)-AQ HP column(2.1 mm×100 mm, 3 µm), mobile phase of 0.1% formic acid solution(A)-acetonitrile(B), gradient elution, flow rate of 0.3 mL·min~(-1), column temperature of 35 ℃ and injection volume of 2 µL. The mass spectra were obtained with electrospray ion source(ESI), positive ion mode and multi reaction monitoring. CPTA/ß-CD inclusion compound was prepared by grinding method, DAS 2.0 software was used to model the data, and the absolute bioavailability of CPTA and relative bioavailability of inclusion compound were calculated. Finally, the methods for the determination of five components of senkyunolide A, N-butylphthalide, new osthol lactone, Z-ligustilide and butenyl phthalide in CPTA, were successfully established. The linear relationship among the five components was good within their respective ranges, r>0.99. The absolute bioavailability of the five components in rats was 22.30%, 16.32%, 21.90%, 10.16% and 12.43%, respectively. After CPTA/ß-CD inclusion was prepared, the relative bioavailability of the five components was 138.69%, 198.39%, 218.01%, 224.54% and 363.55%, respectively, significantly improved. This method is rapid, accurate and sensitive, so it is suitable for the pharmacokinetic study of extracts in traditional Chinese medicine and their preparations.

[Correlation between internal damage due to seven emotions in traditional Chinese medicine and pathogenesis of breast cancer from perspective of psychological stress].

Breast cancer is a major chronic disease threatening women's health. It has topped the global cancers as the diagnosed cases outnumbered lung cancer patients in 2020. Internal damage due to the seven emotions is an important cause of breast cancer and the disorders of hypothalamic-pituitary-adrenal(HPA) axis and endocrine system and the abnormal immune defense mechanism in response to psychological stress all affect the occurrence and development of breast cancer. It is noteworthy that the theory of seven emotions in traditional Chinese medicine and the psychological stress theory of modern medicine have something in common in some aspects. Therefore, this study explored the correlation between internal damage due to the seven emotions and psychological stress and analyzed the molecular biological mechanisms of psychological stress influencing breast cancer from the perspective of modern medicine, which is helpful to reasonably prevent breast cancer and other related tumors and improve the prognosis of breast cancer patients through emotion regulation.