Development of curcumin-loaded galactosylated chitosan-coated nanoparticles for targeted delivery of hepatocellular carcinoma.

Curcumin (CUR) has good antitumor effects, but its poor aqueous solubility severely limits its clinical application and the systemic nonspecific distribution of the free drug in tumor patients is a key therapeutic challenge. In order to overcome the limitations of free drugs and improve the therapeutic efficacy, we developed novel galactosylated chitosan (GC)-modified nanoparticles (GC@NPs) based on poly (ethylene glycol) methyl ether-block-poly (lactide-co-glycolide) (PEG-PLGA), which can target asialoglycoprotein receptor (ASGPR) expressed on hepatocellular carcinoma cells and have excellent biocompatibility. The results showed that the drug loading (DL) of CUR was approximately 4.56 %. A favorable biosafety profile was maintained up to concentrations of 500 µg/mL. Furthermore, in vitro cellular assays showed that GC@NPs could be efficiently internalized by HepG2 cells via ASGPR-mediated endocytosis and successfully released CUR for chemotherapy. More importantly, in vivo anti-tumor experiments revealed that GC@NPs were able to accumulate effectively within tumor sites through EPR effect and ASGPR-mediated endocytosis, leading to superior inhibition of tumor growth compared to free CUR. Overall, GC@NPs are a promising CUR nanocarrier for enhanced tumor therapy with a good biosafety profile.

[Optimization of ethanol reflux extraction process of Ziziphi Spinosae Semen- Schisandrae Sphenantherae Fructus based on network pharmacology combined with response surface methodology].

The present study optimized the ethanol extraction process of Ziziphi Spinosae Semen-Schisandrae Sphenantherae Fructus drug pair by network pharmacology and Box-Behnken method. Network pharmacology and molecular docking were used to screen out and verify the potential active components of Ziziphi Spinosae Semen-Schisandrae Sphenantherae Fructus, and the process evaluation indexes were determined in light of the components of the content determination under Ziziphi Spinosae Semen and Schisandrae Sphenantherae Fructus in the Chinese Pharmacopoeia(2020 edition). The analytic hierarchy process(AHP) was used to determine the weight coefficient of each component, and the comprehensive score was calculated as the process evaluation index. The ethanol extraction process of Ziziphi Spinosae Semen-Schisandrae Sphenantherae Fructus was optimized by the Box-Behnken method. The core components of the Ziziphi Spinosae Semen-Schisandrae Sphenantherae Fructus drug pair were screened out as spinosin, jujuboside A, jujuboside B, schisandrin, schisandrol, schisandrin A, and schisandrin B. The optimal extraction conditions obtained by using the Box-Behnken method were listed below: extraction time of 90 min, ethanol volume fraction of 85%, and two times of extraction. Through network pharmacology and molecular docking, the process evaluation indexes were determined, and the optimized process was stable, which could provide an experimental basis for the production of preparations containing Ziziphi Spinosae Semen-Schisandrae Sphenantherae Fructus.

Review targeted drug delivery systems for norcantharidin in cancer therapy.

Norcantharidin (NCTD) is a demethylated derivative of cantharidin (CTD), the main anticancer active ingredient isolated from traditional Chinese medicine Mylabris. NCTD has been approved by the State Food and Drug Administration for the treatment of various solid tumors, especially liver cancer. Although NCTD greatly reduces the toxicity of CTD, there is still a certain degree of urinary toxicity and organ toxicity, and the poor solubility, short half-life, fast metabolism, as well as high venous irritation and weak tumor targeting ability limit its widespread application in the clinic. To reduce its toxicity and improve its efficacy, design of targeted drug delivery systems based on biomaterials and nanomaterials is one of the most feasible strategies. Therefore, this review focused on the studies of targeted drug delivery systems combined with NCTD in recent years, including passive and active targeted drug delivery systems, and physicochemical targeted drug delivery systems for improving drug bioavailability and enhancing its efficacy, as well as increasing drug targeting ability and reducing its adverse effects.

Urokinase-type plasminogen activator receptor (uPAR) as a therapeutic target in cancer.

Urokinase-type plasminogen activator receptor (uPAR) is an attractive target for the treatment of cancer, because it is expressed at low levels in healthy tissues but at high levels in malignant tumours. uPAR is closely related to the invasion and metastasis of malignant tumours, plays important roles in the degradation of extracellular matrix (ECM), tumour angiogenesis, cell proliferation and apoptosis, and is associated with the multidrug resistance (MDR) of tumour cells, which has important guiding significance for the judgement of tumor malignancy and prognosis. Several uPAR-targeted antitumour therapeutic agents have been developed to suppress tumour growth, metastatic processes and drug resistance. Here, we review the recent advances in the development of uPAR-targeted antitumor therapeutic strategies, including nanoplatforms carrying therapeutic agents, photodynamic therapy (PDT)/photothermal therapy (PTT) platforms, oncolytic virotherapy, gene therapy technologies, monoclonal antibody therapy and tumour immunotherapy, to promote the translation of these therapeutic agents to clinical applications.

[Quality evaluation of Aralia taibaiensis based on spectrum-activity relationship].

A spectrum-activity relationship is established with high performance liquid chromatography(HPLC) fingerprints and the in vitro antioxidant activity to improve the quality evaluation system of Aralia taibaiensis. The HPLC profiles of 12 batches of samples were collected, and the similarity evaluation, heat map analysis and principal component analysis were conducted for the chemometric study of the fingerprint data. Combined with grey correlation analysis, the contributions of the common peaks in the fingerprints to the antioxidant activity were clarified, and the important peaks reflecting the efficacy were identified. The results showed that 17 common peaks were found in 12 batches of A. taibaiensis samples, and 6 of them were identified as saponins. Similarity evaluation, heat map analysis and principal component analysis roughly classified the A. taibaiensis herbs into two categories, i.e.,(1) S1-S10, S12 and(2) S11. Twelve batches of samples showed different antioxidant activities in a dose-dependent manner. In particular, S9 had the strongest antioxidant activity, while S11 was the weakest in antioxidant capacity, which was basically consistent with the overall score results. The results of grey correlation analysis demonstrated that the 17 common peaks scavenged DPPH radicals in the following order: X_3>X_(17)>X_4>X_8>X_7>X_(13)>X_2>X_6>X_(11)>X_(10)>X_(16)>X_(12)>X_9>X_5>X_(14)>X_1>X_(15), and scavenged ABTS radicals in the order of X_4>X_3>X_7>X_8>X_2>X_(17)>X_(13)>X_6>X_(16)>X_(11)>X_5>X_(12)>X_(10)>X_9>X_(14)>X_1>X_(15). Among them, X_3, X_4, X_7(araloside C), X_8 and X_(17) were the important peaks reflecting the efficacy of A. taibaiensis, which were basically consistent with those contained in the principal component 1. In this study, the correlation between the HPLC fingerprints of 12 batches of A. taibaiensis and its antioxidant activity provides a reference for the Q-marker screening and quality control of A. taibaiensis.

Exploring the Mechanism of Lingzhu San in Treating Febrile Seizures by Using Network Pharmacology.

OBJECTIVE: Lingzhu San (LZS) is a traditional Chinese medicine (TCM) prescription that can be effective in treating febrile seizures (FS) and there are few research works conducted on its mechanisms. In order to better guide the clinical use of LZS, we used the research ideas and methods of network pharmacology to find the potential core compounds, targets and pathways of LZS in the complex TCM system for the treatment of FS, and predict the mechanism. MATERIALS AND METHODS: Databases such as BATMAN, TCMSP, TCMID, and SWISS TARGET are used to mine the active compounds and targets of LZS, and the target information of FS is obtained through GENECARDS and OMIM. Using Venny2.1.0 and Cytoscape software, the potential core compounds and targets of FS were obtained. The R language and ClusterProfiler software package are adopted to enrich and analyze the KEGG and GO pathways of the core targets and the biological processes and potential mechanisms of the core targets are also revealed. RESULTS: 187 active compounds and 2113 target proteins of LZS were collected. And 38 potential core compounds, 35 core targets and 775 metabolic and functional pathways were screened, which were involved in mediating FS. Finally, the role of the core compounds, targets and pivotal pathways of LZS in regulating FS in the pathogenesis and the therapeutic mechanism of FS were discussed and clarified. CONCLUSION: In this paper, the multi-compounds, multi-targets and multi-pathways mechanism of LZS in the treatment of FS were preliminarily screened through the analysis of network pharmacology data, which are consistent with the principle of multi-compounds' compatibility with TCM prescriptions and a unified treatment of diseases from multiple aspects, and it provides a new way for TCM to treat complex diseases caused by multiple factors.

Studies on pharmacokinetic properties and absorption mechanism of phloretin: In vivo and in vitro.

Phloretin is a natural dihydrochalcone flavonoid that is mainly distributed in apple, pear and other juicy fruit peels or root peels. Phloretin exhibits several pharmacological properties, such as antidiabetic, antioxidant, anti-inflammatory, and antitumor activities. However, the poor water solubility of phloretin limits its application in the treatment of numerous diseases. To date, the underlying mechanisms of phloretin absorption have not been investigated. In this study, the pharmacokinetics of phloretin orally administered to Sprague-Dawley (SD) rats were examined, and the absorption mechanisms of phloretin were investigated in a Caco-2 cell monolayer and single-pass intestinal perfusion in SD rat. The effects measured by basic parameters, such as compound concentration, time, temperature, paracellular pathway, in different intestinal segments were analyzed, and various inhibitors, such as the P-glycoprotein (P-gp) inhibitor verapamil, the multidrug resistance protein 2 (MRP2) inhibitor indomethacin, the breast cancer resistance protein (BCRP) inhibitor reserpine, and the closely related regulator EDTA, were evaluated to determine their effects on the absorption of phloretin. The pharmacokinetics of phloretin was studied by oral and intravenous injection in rats. The bioavailability was 8.676 %.The SPIP experiments showed that P-gp, MRP2, BCRP protein inhibitor and closely related regulator, could significantly increase the apparent permeability coefficient (Papp) of phloretin. Monolayer transport experiments in Caco-2 cells showed that P-gp, MRP2 protein inhibitor and closely related regulator EDTA, significantly increased the Papp value of phloretin. In conclusion, phloretin is a substrate of P-gp and MRP2, and its modes of transport include active transport, efflux protein transport and cell bypass.

Evaluation of the Therapeutic Effect of Traditional Chinese Medicine on Osteoarthritis: A Systematic Review and Meta-Analysis.

Background: Osteoarthritis (OA) is a common degenerative disease of bone and joint characterized by the damage of articular cartilage and hypertonia, which often occurs in the middle-aged and elderly. Traditional Chinese medicine (TCM) therapy, including acupuncture (ACU), oral administration, and external use of traditional Chinese medicines (TCMs), can significantly improve the therapeutic effect on OA and reduce the occurrence of side effects. We provide a latest meta-analysis on the treatment of OA with TCM. Materials and Methods: In the electronic database, appropriate articles without language restrictions on keywords were selected until August 1, 2019. All trajectories are screened according to certain criteria. The quality of qualified research was also assessed. We have made a detailed record of the results of the measurement. Meta-analysis was carried out with Revman 5.3 software. Results: Forty-four articles involving 4014 patients (2012 cases in the experimental group and 2002 cases in the control group) with OA were selected. This article focuses on the study of the treatment of OA by using the general mode of TCM. The quality evaluation included in the study was evaluated independently according to the Cochrane intervention system evaluation manual. In this meta-analysis, 68.18% of the literature correctly described the conditions for the generation of random assignment sequences, only 6.82% of the literature correctly mentioned the hidden details of allocation, and all studies mentioned randomly assigned participants. Compared with Western medicine, the total effective rate (TER) of OA treatment in TCM was significantly increased and the recurrence rate (RR) was significantly decreased (P < 0.00001). In addition, the experimental group was also superior to the control group in terms of the indicators of joint activity function, inflammatory factor content, and various indicators affecting bone metabolism. It can be showed by the network analysis diagram that Aconiti Radix, Achyranthis Bidentatae Radix, and other TCMs can inhibit inflammatory stimulation and relieve the pain symptoms of patients with OA. ACU at Yinlingquan, Xiyan, and other acupoints can effectively improve the clinical symptoms of patients with OA. Conclusion: TCM therapy in treatment of patients with OA could effectively restore joint function, enhance the TER, and reduce RR. However, the results of this study should be handled with care due to the limitations existing. Some rigorous randomized controlled trials (RCTs) are needed to confirm these findings.

[Experimental study on protective effect and mechanism of Shengdihuang Decoction on ovary of rats with premature ovarian failure].

The aim of this paper was to investigate the protective effect of Shengdihuang Decoction(SDHD) on premature ovarian failure in rats and to explore its protective mechanism. Totally 48 adult female SD rats were randomly divided into six groups with 8 rats in each group: control group,model group,Bujiale group,SDHD high,medium and low dose group(12,6,3 g·kg-1). Rats were administered with Tripterygium Glycosides Tablets for 14 d to make model of premature ovarian failure except for control group. Rats were treated with corresponding medicines for 21 d after that. The oestrous cycle was observed,ovarian index and uterine index were detected,respectively. The variation in contents of E2,P,FSH,LH was detected with radioimmunoassay,the morphological changes of ovary and uterus were observed by HE staining,SOD activity and MDA content were detected in serum. The expression of ERα in ovarian and uterine tissues was detected by SABC,and the expression of ERα in uterus tissue was detected by Western blot. Compared with the model group,the index of the uterus and ovary in the high and middle dose group of Shengdihuang Decoction increased(P<0. 05),the level of serum E2 and P increased(P<0. 01,P<0. 05) and the level of LH decreased(P<0. 01). The number of ovarian follicles increased,the endometrium thickened,and the glands were developed,the activity of SOD was enhanced and the content of MDA decreased in serum,the expression of ERα in the follicle granulosa cells and the epithelial cells of the uterus increased,and the expression of ERα in the uterus increased. Shengdihuang Decoction could improve the morphology and function of the uterus and ovary,and relieve the premature failure of the ovary. The effect may be achieved by enhancing the antioxidant capacity of ovarian granulosa cells,restoring ovarian function,promoting serum estradiol and progesterone secretion,and increasing the expression of ER in uterine mucosal epithelial cells and ovarian granulosa cells.

Therapeutic Efficacy of Kangfuxin Liquid Combined with PPIs in Gastric Ulcer.

OBJECTIVE: To evaluate the clinical efficacy and safety of Kangfuxin liquid (KFX) combined with proton pump inhibitors (PPIs) in the treatment of gastric ulcer (GU). MATERIALS AND METHODS: Electronic databases including PubMed, Wanfang, CNKI, VIP, Embase, Cochrane Library, and CBM were examined for appropriate articles without language limitations on key words before March 10, 2019. RevMan 5.3 software was applied to execute outcome assessment and finish the meta-analysis. RESULTS: 22 articles involving 2,024 patients with a gastric ulcer were selected. Total efficacy rate and efficacy rate of gastroscopy were significantly enhanced for the combination of KFX with PPIs compared to those of PPI treatment alone (OR = 6.95, 95% CI: 4.87, 9.91, P < 0.00001; OR = 2.96, 95% CI: 1.98, 4.42, P < 0.00001, respectively). Same results were found for different PPIs in combination on total efficacy rate, respectively. The combination also significantly reduced the adverse events (OR = 0.39, 95% CI: 0.22, 0.70, P=0.002). In addition, KFX combined with PPI could suppress the inflammation (MD = -6.11, 95% CI: -7.45, -4.77, P < 0.00001), reduce the recurrence rate (OR = 0.31, 95% CI: 0.14, 0.70, P=0.005), and enhance the clearance rate of Helicobacter pylori (HP, OR = 3.76, 95% CI: 1.80, 7.87, P=0.0004). It seemed like the combination would influence immune function by increasing levels of T-lymphocyte subsets CD4 and CD8 but not CD3 (MD = 2.40, 95% CI: 1.25, 3.55, P < 0.0001); MD = 25.72, 95% CI: 14.55, 36.90, P < 0.00001; MD = 0.72, 95% CI: -0.66, 2.09, P=0.31, respectively). CONCLUSION: KFX combined with PPIs in treatment of patients with GU could improve the total efficacy rate and efficacy rate of gastroscopy and reduce adverse events and the recurrence rate. However, the results of this study should be handled with care due to the limitations. Several rigorous RCTs are in need to confirm these findings.

Reconstruction of the lncRNA-miRNA-mRNA network based on competitive endogenous RNA reveal functional lncRNAs in Cerebral Infarction.

Functioning as miRNA sponges, long non-coding RNA (lncRNA) exert its pharmacological action via regulating expression of protein-coding genes. However, the lncRNA-mediated ceRNA in cerebral Infarction (CI) remains unclear. In this study, the expression recordsets of mRNA, lncRNA and miRNA of CI samples were obtained from the NCBI GEO datasets separately. The differentially expressed lncRNAs (DELs), miRNAs (DEMis) and mRNAs (DEMs) were identified by limma package in R platform. A total of 267 DELs, 26 DEMis, and 760 DEMs were identified as differentially expressed profiles, with which we constructed the ceRNA network composed of DELs-DEMis-DEMs. Further, clusterProfiler package in R platform is employed for performing Gene Ontology (GO) and KEGG pathway analysis. An aberrant ceRNA network was constructed according to node degrees in CI, including 28 DELs, 19 DEMs and 12 DEMis, from which we extracted the core network, in which 9 nodes were recognized as kernel genes including Tspan3, Eif4a2, rno-miR-208a-3p, rno-miR-194-5p, Pdpn, H3f3b, Stat3, Cd63 and Sdc4. Finally, with the DELs-DEMis-DEMs ceRNA network provided above, we can improve our understanding of the pathogenesis of CI mediated by lncRNA.

[Extraction kinetics of volatile oil from galangal by steam distillation].

To reveal the extraction regularity of volatile oil from galangal by GC-MS analysis. The volatile oil in galangal was extracted by steam distillation. The extract was collected every 30 min, the oil part and the water part were separated. GC-MS was used to analyze the extraction liquid collected at different time periods. A total of 140 volatile components were obtained by GC-MS analysis. Among them, the main components were eucalyptus oil alcohol, alpha-pine oil alcohol and 4-terpene alcohol; 22 special components were dissolved in water, 77 special components were dissolved in oil and 41 components were dissolved in both oil and water. With the increase of specific components in water, the content of Eucalyptus in water increased in a linear manner. The increase of eucalyptus oil further promoted the dissolution or dispersion of alpha PN in water, and the change of specific components in oil was positively correlated with the content of Eucalyptus and alpha-terpilenol in oil. The results of principal component analysis show that the physical and chemical properties of the compounds were important factors affecting the distribution of components. PC1 (molecular weight, melting point, boiling point positive correlation), PC2 (negative correlation of refractive index) and PC3 (positive correlation of water solubility) were the main components that lead to the differences in composition distribution. The process of extracting volatile oil from galangal through steam distillation was affected by the physical and chemical properties of volatile components. Some components were specifically distributed in the fragrance and volatile oil system. The endemic components of aromatic water increased the content of the main components in the water system, which may lead to the "emulsification", reduction of the yield and low quality of the volatile oil.

The Therapeutic Efficacy of Danhong Injection Combined With Percutaneous Coronary Intervention in Acute Coronary Syndrome: A Systematic Review and Meta-Analysis.

Background: Percutaneous coronary intervention (PCI) is widely used in treatment of acute coronary syndrome (ACS) clinically. It is believed that Danhong injection (DHI) extracted from salviae miltiorrhizae and flos carthami combined with PCI could increase the therapeutic efficacy on ACS. We provide an updated meta-analysis with detailed information on combination of DHI and PCI therapy. Materials and Methods: Electronic databases were searched for appropriate articles without language limitations on key words before October 22, 2017. All trails were screened according to certain criteria. Quality of eligible studies was also assessed. We made a detailed record of outcome measurements. RevMan 5.3 software was used to perform the meta-analysis. Results: 14 articles involving 1533 patients with ACS were selected. Compared to PCI treatment alone, total efficacy rate (TER) was enhanced and major adverse cardiovascular events (MACE) were reduced significantly for the combination of DHI and PCI (P < 0.00001). Vascular endothelial function was improved by significantly decreasing the contents of ET-1, vWF and increasing the levels of NO and FMD (P < 0.00001). The serum levels of IL-1, IL-6, IL-18, TNF-α, LpPLA2, MMP-9, and pentraxin-3 were significantly decreased (P < 0.00001), whereas IL-10 in serum was increased (P < 0.00001), indicating a stronger anti-inflammatory effect of the combination. The combination therapy decreased the serum levels of CD62P, PAGT, PADT, FIB-C significantly (P < 0.05), which was beneficial for preventing coagulation of platelets. Blood lipid was also affected by regulating TC, TG, LDL, and HDL, but the results were not statistically significant (P > 0.05). Cardiac function was improved by increasing LEVF (P = 0.006) but not LVED (P = 0.08). The combination treatment was associated with an improvement in antioxidant effect by decreasing MDA and increasing SOD significantly (P < 0.00001). Conclusion: Combination of DHI and PCI in treatment of ACS could improve TER and reduce incidence of MACE after PCI therapy. These effects may be mediated by combined actions of several mechanisms. However, these results of this study should be handled cautiously due to the limitations of this research. Several rigorous RCTs are in need to confirm these findings.

Efficacy of local delivery of ardipusilloside I using biodegradable implants against cerebral tumor growth.

Ardipusilloside I (ADS-I) is a natural compound that can be isolated from the Chinese medicinal herb Ardisiapusilla A.DC, and has been reported to inhibit the growth of glioblastoma cells in cultures. This study was designed to test its efficacy by the delivery using biodegradable implants against glioblastoma in vivo. ADS-I was incorporated into polymer microspheres, which were prepared by a mixture of poly (D, L-lactic acid) and poly (D, L-lactic-co-glycolic acid) polymers and then fabricated into wafers. The anti-glioma activities of ADS-I-loaded wafers were examined by methylthiazol tetrazolium (MTT) assay in cultured rat C6 glioma cells, and by magnetic resonance imaging (MRI) and survival monitoring in C6 glioma-bearing rats. Here, we showed that ADS-I-loaded wafers sustained ADS-I release in vitro for 36 days in Higuchi model of kinetics, and had the same cytotoxic activity as ADS-I in the solution against the growth of C6 glioma cells in cultures. In C6 glioma-bearing rats, ADS-I wafer implants inhibited tumor growth in a dose-dependent matter, and were more effective than the same dosage of ADS-I in the solution. The tumor suppression efficacies of ADS-I wafer implants were positively correlated with an increase in tumor cell apoptosis and prolonged animal survival, and were associated with a decrease in vascular endothelial growth factor, C-reactive protein, tumor necrosis factor-α and interleukin-6, and an increase in interleukin-2 expression. In conclusion, this study demonstrates significant efficacy of local delivery of ADS-I using polymer implants against glioma tumor growth in vivo, suggesting the potential of ADS-I-loaded wafers for glioma treatment.