Action Mechanism Underlying Improvement Effect of Fuzi Lizhong Decoction on Nonalcoholic Fatty Liver Disease: A Study Based on Network Pharmacology and Molecular Docking.

OBJECTIVE: This study aimed to decipher the bioactive compounds and potential mechanism of traditional Chinese medicine (TCM) formula Fuzi Lizhong Decoction (FLD) for nonalcoholic fatty liver disease (NAFLD) treatment via an integrative network pharmacology approach. METHODS: The candidate compounds of FLD and its relative targets were obtained from the TCMSP and PharmMapper web server, and the intersection genes for NAFLD were discerned using OMIM, GeneCards, and DisGeNET. Then, the PPI and component-target-pathway networks were constructed. Moreover, GO enrichment and KEGG pathway analysis were performed to investigate the potential signaling pathways associated with FLD's effect on NAFLD. Eventually, molecular docking simulation was carried out to validate the binding affinity between potential core components and key targets. RESULTS: A total of 143 candidate active compounds and 129 relative drug targets were obtained, in which 61 targets were overlapped with NAFLD. The PPI network analysis identified ALB, MAPK1, CASP3, MARK8, and AR as key targets, mainly focusing on cellular response to organic cyclic compound, steroid metabolic process, and response to steroid hormone in the biological processes. The KEGG pathway analysis demonstrated that 16 signaling pathways were closely correlated with FLD's effect on NALFD with cancer pathways, Th17 cell differentiation, and IL-17 signaling pathways as the most significant ones. In addition, the molecular docking analysis revealed that the core active compounds of FLD, such as 3'-methoxyglabridin, chrysanthemaxanthin, and Gancaonin H, had a high binding activity with such key targets as ALB, MAPK1, and CASP3. CONCLUSIONS: This study suggested that FLD exerted its effect on NAFLD via modulating multitargets with multicompounds through multipathways. It also demonstrated that the network pharmacology-based approach might provide insights for understanding the interrelationship between complex diseases and interventions of the TCM formula.

[Application of ICP-MS to detection of mineral elements and heavy metals in Cassava's byproducts].

Cassava is a main cultivated tropical crop in China, its rich starch roots are often used to produce fuel ethanol in recent years, so it's a kind of hot biomass energy crops. But cassava's byproducts such as leaves, stems and peels are regarded as waste, and are not fully utilized. Cassava's byproducts contain many nutrients, and can be used to process high value food products. The contents of mineral elements and heavy metals in cassava's byproducts were studied by ICP-MS. The results showed that cassava's byproducts contained many elements necessary to human health, the sequence of macroelements was K>Ca>P> Mg>S>Mn>Zn>Na>Fe>B>Cu, particularly, the contents of Fe, Mn, Zn and B ranged from 10 to 800 microg x g(-1) (DW), while the contents of microelements including Mo, Co, Se and Ge ranged from 0.01 to 0.2 microg x g(-1) (DW), which are important to human health. Besides macroelements and microelements, the contents of heavy metals (As, Cr, Pb and Hg) were also important to identify the quality of farm products, and the results showed that cassava's byproducts contained little heavy metals except Pb (2.19 microg x g(-1) (DW) in stalk peels). All the data showed that cassava's byproducts accorded with the national hygiene standards.

A modified comprehensive learning particle swarm optimizer and its application in cylindricity error evaluation problem.

Particle swarm optimizer was proposed in 1995, and since then, it has become an extremely popular swarm intelligent algorithm with widespread applications. Many modified versions of it have been developed, in which, comprehensive learning particle swarm optimizer is a very powerful one. In order to enhance its performance further, a local search based on Latin hypercube sampling is combined with it in this work. Due to that a hypercube should become smaller and smaller for better local search ability during the search process, a control method is designed to set the size of the hypercube. Via numerical experiments, it can be observed that the comprehensive learning particle swarm optimizer with the local search based on Latin hypercube sampling has a strong ability on both global and local search. The hybrid algorithm is applied in cylindricity error evaluation problem and it outperforms several other algorithms.

Isoform-selective effects of the depletion of ADP-ribosylation factors 1-5 on membrane traffic.

The ADP-ribosylation factors (Arfs) are six proteins within the larger Arf family and Ras superfamily that regulate membrane traffic. Arfs all share numerous biochemical activities and have very similar specific activities. The use of dominant mutants and brefeldin A has been important to the discovery of the cellular functions of Arfs but lack specificity between Arf isoforms. We developed small interference RNA constructs capable of specific depletion of each of the cytoplasmic human Arfs to examine the specificity of Arfs in live cells. No single Arf was required for any step of membrane traffic examined in HeLa cells. However, every combination of the double knockdowns of Arf1, Arf3, Arf4, and Arf5 yielded a distinct pattern of defects in secretory and endocytic traffic, demonstrating clear specificity for Arfs at multiple steps. These results suggest that the cooperation of two Arfs at the same site may be a general feature of Arf signaling and provide candidates at several cellular locations that when paired with data on the localization of the many different Arf guanine nucleotide exchange factors, Arf GTPase activating proteins, and effectors will aid in the description of the mechanisms of specificity in this highly conserved and primordial family of regulatory GTPases.

Effects of 1,25(OH)2D3 on proliferation and apoptosis of human glomerular mesangial cells.

OBJECTIVE: To investigate the effect of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] on cell proliferation and apoptosis of human glomerular mesangial cells. METHODS: Human glomerular mesangial cells were cultured for 48 h and randomly divided into four groups, normal control group (N group), proliferation group (EGF group ), vitamin D3 intervention group (VD3 group), proliferation intervention group (EGF+VD3 group ). Flow cytometry was used to detect the cell cycle and apoptosis rate, and Western blot was used to detect the PCNA and Caspases-3 expression. The effect of 1,25(OH)2D3 on human mesangial cell proliferation was detected by CCK-8. RESULTS: Compared with the control group, G1 phase cells in EGF group were significantly reduced, S, G2/M phase cells were increased, and the higher PI and PCNA expression levels were increased; G1 phase cells in VD3 group were increased, S, G2/M phase cells were decreased, and the lower PI and PCNA expression levels were reduced. Compared with EGF group, G1 phase cells in EGF+VD3 group were increased, S, G2/M phase cells were decreased, and the lower PI and PCNA expression levels were significantly reduced. Compared with normal control group, the apoptosis rate in EGF group was significantly lower, and the Caspase-3 expression level was reduced; the apoptosis rate in VD3 group was significantly higher, and Caspase-3 expression was significantly increased. Compared with EGF group, the apoptotic rate of mesangial cells in EGF+VD3 group was significantly increased, and the Caspase-3 expression level was increased, with significant difference. CONCLUSION: 1,25(OH)2D3 inhibited the proliferation of mesangial cells and induced their apoptosis by blocking the cell cycle, inhibiting expression of PCNA, and upregulating Caspase-3 expression.

[Comparision of high dose impulsion and low dose density chemotherapeutic regimens with paclitaxel plus cisplatin in advanced NSCLC].

OBJECTIVE: To explore high effective and low toxic chemotherapeutic regimens in the treatment of non-small-cell lung cancer (NSCLC). METHODS: A total of 126 patients with advanced NSCLC (Stage III, IV) were randomly divided into two groups: high dose impulsion chemotherapy group (HDIC group) and low dose density chemotherapy group (LDDC group) with 54 patients in HDIC group who received paclitaxel 135-175 mg/m2 on day 1, DDP 80-100 mg/m2 on day 1 and BCNU 125 mg given for brain metastasis on days 1-3 in a 4-6 weeks cycle. Seventy-two patients in LDDC group were given paclitaxel 60-80 mg/m2 on day 1, DDP 40-80 mg/m2 on day 1 repeated weekly and BCNU 125 mg given for brain metastasis with an interval of 2 weeks, in a 4-6 weeks cycle. Antiemetic agent and fluid were administered routinely in HDIC group whereas LDDC group was given antiemetic agent only. RESULTS: Of 157 courses in HDIC group, an average of 2.9 courses per patient, CR 3, PR 23, SD 17 and PD 11 were observed. The effective remission rate was 48.1%, the median effective remission period was 4.5 months and the 1-year survival rate was 46.3%. Of 184 courses in LDDC group, an average of 2.6 courses per patient, CR 9, PR 30, SD 24 and PD 9 were observed. The effective remission rate was 54.2%, the median effective remission period was 6 months and the 1-year survival rate was 56.9%. The effective remission rate and the 1-year survival rate were higher in HDIC group than those in LDDC group, but there was no statistical difference between the two groups (P > 0.05). Severe toxicity was higher in HDIC group than in LDDC group. Two patients in HDIC group died of treatment-related complications (3.7%). Quality of life was better in LDDC group (70.8%) than in HDIC group (51.9%). CONCLUSION: When comparing with high dose impulsion, low dose density regimen of paclitaxel plus cisplatin is more effective and better tolerated with improvement of quality of patients' life in the treatment of NSCLC due to its low dose and short interval duration.

Hypohalous acid-mediated halogenation of resveratrol and its role in antioxidant and antimicrobial activities.

The reactions of resveratrol with proinflammatory oxidants including hypochlorous and hypobromous acids in phosphate-buffered saline/methanol solution were carried out and eight halogenated resveratrol derivatives differing in the number and position of halogen atoms, and the configuration of double bond were obtained. Halogenation of resveratrol took place only at the aromatic A ring, and interestingly, the halogenation increased antioxidant activity of this parent molecule in the 2,2'-azobis(2-amidinopropane) hydrochloride-induced RBC haemolysis model. Additionally, antimicrobial activity of the derivatives against Gram-positive bacteria, Gram-negative bacteria and fungi were tested, and toward Candida albicans, 2-chloro-resveratrol and 2-bromo-resveratrol were more active than the unmodified form and the reference compound fluconazole.

Four ARF GAPs in Saccharomyces cerevisiae have both overlapping and distinct functions.

Previous studies in yeast have revealed the presence of four proteins with a conserved, cysteine-rich, ARF GAP domain that share the ability to suppress the conditional growth defect of the arf1-3 mutant. Three of these proteins have been shown previously to be ADP-ribosylation factor (ARF) GTPase-activating proteins (GAPs). We now demonstrate that the fourth also exhibits in vitro ARF GAP activity and correlates the suppressor and ARF GAP activities for all four. Because the four ARF GAP proteins are quite diverse outside the ARF GAP domain, a genetic analysis was undertaken to define the level of functional cross-talk between them. A large number of synthetic defects were observed that point to a high degree of functional overlap among the four ARF GAPs. However, several differences were also noted in the ability of each gene to suppress the synthetic defects of others and in the impact of single or combined deletions on assays of membrane traffic. We interpret these results as supportive evidence for roles of ARF GAPs in a number of distinct, essential cellular processes that include cell growth, protein secretion, endocytosis and cell cycling. The description of the specificities of the ARF GAPs for the different responses is viewed as a necessary first step in dissecting biologically relevant pathways through a functionally overlapping family of signalling proteins.

Genetic interactions link ARF1, YPT31/32 and TRS130.

A genetic screen for synthetic lethal interactions with arf1(-) identified a recessive mutation in TRS130, one of 10 components in the trafficking protein particle (TRAPP) complex (Sacher et al., 2000). As TRS130 is an essential gene, the synthetic lethal allele (trs130-101) is a novel one that requires ARF1 for viability. This allele was found to exhibit no defects in secretory function, i.e. processing of carboxypeptidase Y or invertase. YPT31 and YPT32 were identified in a subsequent screen as high-copy suppressors of arf1(-)trs130-101. Increasing the gene dosage of YPT31/32 also suppressed lethality resulting from deletion of TRS130 or TRS120 but not three other essential TRAPP subunit-encoding genes. Although unable to suppress defects in several alleles of ARF1, increasing the gene dosage of YPT31/32 suppressed the cold sensitivity of gcs1(-), an Arf GTPase-activating protein (GAP). Thus, these genetic interactions provide initial evidence for linkage of Arf and TRAPP signalling and for Ypt31/32 proteins functioning downstream of both components in the TRAPP complex and of Arf signalling via the Gcs1 Arf GAP.

ARL1 and membrane traffic in Saccharomyces cerevisiae.

To examine the functions of the Arf-like protein, Arl1p, in Saccharomyces cerevisiae, a null allele, arl1delta::HIS3, was constructed in two strains. In one background only, loss of ARL1 resulted in temperature-sensitive (ts) growth (suppressed on high-osmolarity media). Allelic variation at the SSD1 locus accounted for differences between strains. Strains lacking ARL1 exhibited several defects in membrane traffic. First, arl1delta strains secreted less protein as measured by TCA-precipitable radioactivity found in the media of [(35)S]-labelled cells. A portion of newly synthesized carboxypeptidase Y (CPY) was secreted rather than correctly targeted to the vacuole. Uptake of the fluid-phase marker, lucifer yellow, was reduced. All these phenotypes were exacerbated in an ssd1 background. The ts phenotype of the arl1deltassd1 strain was suppressed by YPT1, the yeast Rab1a homologue, suggesting that ARL1 and YPT1 have partially overlapping functions. These findings demonstrate that ARL1 encodes a regulator of membrane traffic.