Network pharmacology-based investigation and experimental validation of the therapeutic potential and molecular mechanism of Danshen Chuanxiongqin injection in acute pancreatitis.

BACKGROUND: Danshen Chuanxiong Injection (DCI) has demonstrated significant clinical efficacy in the treatment of acute pancreatitis (AP); however, the precise molecular mechanisms underlying its therapeutic effects remain incompletely understood. OBJECTIVE: In this study, we employed network pharmacology analysis to comprehensively investigate the active components, potential targets, and signaling pathways involved in DCI-mediated treatment of AP. METHODS: We utilized the mouse pancreatic acinar cell line 266-6 to establish an cholecystokinin (CCK)-induced AP cell injury model and evaluated cell viability using the Cell counting kit-8 assay. Western blotting and quantitative PCR were employed to determine the expression levels of key target proteins and genes. RESULTS: Network pharmacology analysis identified a total of 144 active components and 430 potential targets within DCI. By integrating data from public databases, we identified 762 AP-related genes. Among these, we identified 93 potential targets that may be involved in the therapeutic effects of DCI for AP. These targets were significantly enriched in biological processes such as oxidative stress, regulation of cytokine production, leukocyte migration, and the TNF signaling pathway. Molecular docking studies revealed a high binding affinity between the active components and the key targets AKT1 and NFKBA, indicative of potential interaction. Additionally, CCK-induced acinar cell injury led to upregulation of AKT1, NFKBA, and P53 proteins, as well as TNF, IL6, and MMP9 genes. Conversely, treatment with DCI dose-dependently attenuated CCK-induced acinar cell injury and restored the expression levels of the aforementioned proteins and genes. CONCLUSION: Overall, this study provides a comprehensive understanding of the molecular mechanisms underlying the therapeutic effects of DCI in the treatment of AP. Our findings confirm the protective effect of DCI against CCK-induced acinar cell injury and its regulation of key targets.

A meta-analysis of the association between vitamin D supplementation and the risk of acute respiratory tract infection in the healthy pediatric group.

No previous meta-analysis had explored the association between vitamin D supplementation in healthy pediatrics and the risk of acute respiratory tract infections (ARTIs). Thus, we meta-analyzed the current evidence in this regard to provide sufficient knowledge about this risk-benefit ratio for vitamin D supplementation in this specific age group. We searched seven databases for randomized controlled trials (RCTs) that investigated the effect of vitamin D supplementation and ARTIs risk on a healthy pediatric population (0-18 years old). Meta-analysis was performed through R software. We included eight RCTs after the screening of 326 records according to our eligibility criteria. There were comparable infection rates between Vitamin D and placebo groups (OR = 0.98, 95% CI = 0.90-1.08, P-value = 0.62), with no significant heterogeneity among the included studies (I2 = 32%; P-value = 0.22). Moreover, there was no significant difference between the two vitamin D regimens (OR = 0.85, 95% CI = 0.64-1.12, P-value = 0.32), with no considerable heterogeneity among the included studies (I2 = 37%; P-value = 0.21). However, there was a significant reduction in Influenza A rates in the high-dose vitamin D group compared to the low dose one (OR = 0.39, 95% CI = 0.26-0.59, P-value < 0.001), with no heterogeneity among the included studies (I2 = 0%; P-value = 0.72). Only two studies of 8,972 patients reported different side effects, with overall acceptable safety profile. Regardless of the dosing regimen used or the type of infection, in the healthy pediatric group, there is no evident benefit of using vitamin D to prevent or reduce the ARTI rates.

Synergistic therapeutic antitumor effect of PD-1 blockade cellular vesicles in combination with Iguratimod and Rhodium nanoparticles.

Immune checkpoint blockade has emerged as a significant therapeutic development in immunotherapy during the past decade. However, only a small percentage of cancer patients respond to checkpoint blockade, suggesting that a fundamental knowledge of the underlying processes of immune checkpoint receptor signaling remains elusive and that novel therapeutic medications are needed. Here, the programmed cell death protein 1(PD-1) expressing nanovesicles were developed to enhance T cell activity. Iguratimod (IGU) and Rhodium (Rh) nanoparticles (NPs) were loaded in PD-1 nanovesicles (NVs) for synergistic therapeutic antitumor effects against lung cancer and metastasis. For the first time, this study revealed that IGU exhibits an antitumor effect by inhibiting the phosphorylation of mammalian target of rapamycin (mTOR) and Rh-NPs provided a photothermal effect by improving reactive oxygen species (ROS)-dependent apoptosis in lung cancer cells. IGU-Rh-PD-1 NVs also reduced the migration ability through the epithelial-mesenchymal transition (EMT) pathway. Furthermore, IGU-Rh-PD-1 NVs reached the targeted site and inhibited tumor growth in vivo. This strategy could boost T cell performance and simultaneously possess chemotherapeutic and photothermal therapy to serve as a new combination therapy for lung cancer and potentially other aggressive cancer.

(1R,3S)-THCCA-Asn: To show the discovery of selective inhibitor of thrombin by successfully combining virtual screening and biological assay.

Thrombin is the most potent platelet aggregator. To discover the selective inhibitor of thrombin that is important to curing platelet aggregation-related diseases, docking experiments were performed to dock (1R,3S)-2,3,4,9-tetrahydro-ß-carboline-3- carboxylic acid, [(1R,3S)-THCCA], and (1S,3S)-2,3,4,9-tetrahydro-ß-carboline-3- carboxylic acid, [(1S,3S)-THCCA], into the p pocket of bovine thrombin. The ideal match supported that (1R,3S)-THCCA could be used as a potential lead compound. In this case 20 natural amino acids were theoretically introduced into the 3-carboxyl of (1R,3S)-THCCA and 20 derivatives, (1R,3S)-THCCA-amino acids, were docked into p pocket of bovine thrombin to perform virtual screening. The screening revealed that comparing to (1R,3S)-THCCA itself the DockScores of 16 derivatives were higher, and (1R,3S)-THCCA-Asn (4j) got the highest DockScore. Thus, 16 derivatives were synthesized for experimental study. The in vitro anti-platelet aggregation assay showed that at 100 µM of concentration the 16 derivatives failed to inhibit the platelet aggregation induced by both adenosine diphosphate and arachidonic acid. On the other hand, however, the IC50 value of the 16 derivatives inhibiting the platelet aggregation induced by platelet activating factor and thrombin ranged from 9.44 µM to 194.64 µM and from 0.07 µM to 9.56 µM, respectively. The in vitro anti-platelet aggregation assay suggested that the 16 derivatives selectively inhibited the platelet aggregation induced by thrombin. In particular, the IC50 of (1R,3S)-THCCA-Asn (4j) had the lowest value. On rat model at 1 nmol/kg of dosage the 16 derivatives effectively prevented thrombus formation. It is worth pointing out that even at 0.01 nmol/kg of dosage, 4j still effectively prevented thrombus formation. 4j hardly has effects on the proliferation of mammalian cells and rat tail bleeding time. In conclusion, the combination of virtual screening and biological assays successfully lead to the discovery of 4j as a promising candidate of selective inhibitor of thrombin.

Expert consensus statement on therapeutic drug monitoring and individualization of linezolid.

Linezolid is an oxazolidinone antibacterial drug, and its therapeutic drug monitoring and individualized treatment have been challenged since its approval. With the in-depth clinical research of linezolid, we have changed our attitude toward its therapeutic drug monitoring and our view of individualized treatment. On the basis of summarizing the existing clinical studies, and based on the practical experience of each expert in their respective professional fields, we have formed this expert consensus. Our team of specialists is a multidisciplinary team that includes pharmacotherapists, clinical pharmacology specialists, critical care medicine specialists, respiratory specialists, infectious disease specialists, emergency medicine specialists and more. We are committed to the safe and effective use of linezolid in patients in need, and the promotion of its therapeutic drug monitoring.

Efficacy of Laparoscopic Surgery Combined With Leuprorelin in the Treatment of Endometriosis Associated With Infertility and Analysis of Influencing Factors for Recurrence.

Objective: To explore the curative effect of laparoscopic surgery combined with leuprorelin in the treatment of endometriosis with infertility and the related factors of recurrence after treatment. Methods: A total of 158 patients with endometriosis and infertility were selected in our hospital from January 2019 to June 2020. Patients were randomly divided into the control group and the observation group, with 79 patients in each group. Patients in the control group was treated by laparoscopy surgery combined with dydrogesterone, while those in the observation group was treated with laparoscopic surgery combined with leuprorelin. The hormone levels, recurrence rate, pregnancy rate and adverse reaction of the two groups were compared. Combined with clinical and pathological information, the related factors of postoperative recurrence were analyzed. Results: After treatment, the levels of luteinizing hormone, follicle-stimulating hormone and estradiol in the observation group were lower than those in the control group (P < 0.05). The recurrence rate at 12 months after operation in the observation group was lower than that in the control group, and the pregnancy rate was higher than that in the control group (P < 0.05). However, there was no significant difference in the incidence of adverse reactions between the two groups (P > 0.05). Preoperative dysmenorrhea was an independent risk factor for postoperative recurrence in patients with endometriosis, and postoperative pregnancy was a protective factor for postoperative recurrence in patients with endometriosis (P < 0.05). Conclusion: Laparoscopy combined with leuprorelin in the treatment of endometriosis with infertility can improve hormone levels, increase the pregnancy rate and reduce the recurrence rate. Preoperative dysmenorrhea is an independent risk factor for postoperative recurrence, which should be quantified and included in the recurrence risk prediction model. Postoperative pregnancy can reduce the recurrence rate after operation, and patients with fertility requirements should be encouraged to make activ preparations for postoperative pregnancy.

Preparation and in vitro characterization of pluronic-attached polyamidoamine dendrimers for drug delivery.

CONTEXT: Polyamidoamine (PAMAM) dendrimers have attracted lots of interest as drug carriers. And little study about whether pluronic-attached PAMAM dendrimers could be potential drug delivery systems has been carried on. OBJECTIVE: Pluronic F127 (PF127) attached PAMAM dendrimers were designed as novel drug carriers. METHODS: Two conjugation ratios of PF127-attached PAMAM dendrimers were synthesized. (1)H nuclear magnetic resonance ((1)H-NMR), Fourier transform infrared spectrum (FTIR), element analysis and ninhydrin assay were used to characterize the conjugates. Size, zeta potential and critical micelle concentrations (CMC) were also detected. And DOX was incorporated into the hydrophobic interior of the conjugates. Studies on their drug loading and drug release were carried on. Furthermore, hemolysis and cytotoxicity assay were used to evaluate the toxicity of the conjugates. RESULTS AND DISCUSSION: PF127 was successfully conjugated to the fifth generation PAMAM dendrimer at two molar ratios of 19% and 57% (PF127 to surface amine per PAMAM dendrimer molecular). The conjugates showed an increased size and a reduced zeta potential. And higher CMC values were obtained than pure PF127. Compared with unconjugated PAMAM dendrimer, PF127 conjugation significantly reduced the hemolytic toxicity and cytotoxicity of PAMAM dendrimer in vitro. The encapsulation results showed that the ability to encapsulate DOX by the conjugate of 19% conjugation ratio was better than that of 57% conjugation ratio. And the maximum is ∼12.87 DOX molecules per conjugate molecule. Moreover, the complexes showed a sustained release behavior compared to pure DOX. CONCLUSION: Findings from the in vitro study show that the PF127-attached PAMAM dendrimers may be potential carriers for drug delivery.

[Inhibition of MCF-7/ADR cells by DOX-loaded pluronic-attached PAMAM dendrimer conjugate].

Pluronic modified polyamidoamine (PAMAM) conjugate (PF127-PAMAM) was prepared and the inhibiting effect of MDR against MCF-7/ADR was investigated with doxorubicin (DOX) as model drug. 1H NMR and FTIR spectra showed that the conjugate was synthesized successfully. Element analysis accurately measured that 27.63% amino of per PAMAM was modified by pluronic (PAMAM : PF127, 1 : 35.37 mole ratio). PF127-PAMAM showed an increased size and a reduced zeta potential compared to PAMAM. PF127-PAMAM had lower hemolytic toxicity and cytotoxicity due to the reduced zeta potential and the protection of PF127. Each PF127-PAMAM molecular could load 19.58 DOX molecules, and the complex exhibited sustained and pH-sensitive release behavior. PF127-PAMAM/DOX exhibited weaker cytotoxicity than free DOX in MCF-7 cells; while the complex showed much stronger reverse effect of drug resistance in MCF-7/ADR cells, and resistance reversion index (RRI) was as high as 33.15.