A novel RRGW derived peptide is a promising inhibitor of BoNT/A.

Clostridium botulinum neurotoxin type A (BoNT/A) is one of the most potent biotoxins ever known. Its entry into neurons could block vesicle exocytosis to abolish the release of neurotransmitters from nerve terminals, thus leading to muscle paralysis. Although there are so many peptides, antibodies and chemical compounds claimed to have anti-toxin activity, no drug is available in the clinical application except equine antitoxin serum. In the present work, a short peptide inhibitor RRGW of BoNT/A was firstly identified by computer-aided ligand-receptor binding simulation, then an RRGW derived peptide was rational designed based on the fragment of SNAP-25 (141-206 aa). Proteolytic assay showed that the anti-toxin activity of the RRGW derived peptide was much higher than that of RRGW. Digit abduction score assay demonstrated that the derived peptide delayed BoNT/A-induced muscle paralysis at a lower concentration by 20-fold than RRGW. The results supported that RRGW derived peptide can be a potential BoNT/A inhibitor candidate for further treating botulism.

Rhizoma Gastrodiae Water Extract Modulates the Gut Microbiota and Pathological Changes of P-TauThr231 to Protect Against Cognitive Impairment in Mice.

Gastrodiae Rhizoma and its active constituents are known to exhibit neuroprotective effects in Alzheimer's disease (AD). However, the effect of Rhizoma Gastrodiae water extract (WERG) on AD and the detailed mechanism of action remain unclear. In this study, the mechanism of action of WERG was investigated by the microbiome-gut-brain axis using a D-galactose (D-gal)/AlCl3-induced AD mouse model. WERG improved the cognitive impairment of D-gal/AlCl3-induced mice. The expression level of p-Tauthr231 in the WERG-H treatment group was decreased, and p-Tauthr231 was found negative in hippocampal DG, CA1, and CA3 regions. Here, the diversity and composition of the gut microbiota were analyzed by 16sRNA sequencing. WERG-H treatment had a positive correlation with Firmicutes, Bacilli, Lactobacillus johnsonii, Lactobacillus murinus, and Lactobacillus reuteri. Interestingly, the Rikenellaceae-RC9 gut group in the gut increased in D-gal/AlCl3-induced mice, but the increased L. johnsonii, L. murinus, and L. reuteri reversed this process. This may be a potential mechanistic link between gut microbiota dysbiosis and P-TauThr231 levels in AD progression. In conclusion, this study demonstrated that WERG improved the cognitive impairment of the AD mouse model by enriching gut probiotics and reducing P-TauThr231 levels.

Synthesis and anticancer evaluations of novel 1H-imidazole [4,5-f][1,10] phenanthroline derivative for the treatment of colorectal cancer.

1H-imidazole [4,5-f][1,10] phenanthroline is a promising chemical structure for cancer treatment. Herein, we synthesized a novel 1H-imidazole [4,5-f][1,10] phenanthroline derivative named IPM714 and found it exhibited selectively colorectal cancer (CRC) cells inhibitory activities, with half maximal inhibitory concentration (IC50) of 1.74 µM and 2 µM in HCT116 cells and SW480 cells, respectively. The present study is intended to explore the cytotoxicity of IPM714 in cancer cells of various types and its anticancer mechanism in vitro. Cellular functional analyses indicated IPM714 can arrest HCT116 cell cycle in S phase and induce apoptosis in HCT116 and SW480 cells. Western blot and molecular docking showed that IPM714 may suppress PI3K/AKT/mTOR pathway to inhibit cell proliferation and regulate cell cycle as well as apoptosis. This study proved IPM714 to be a promising drug in CRC therapy.

Design, synthesis, and cytotoxic activities of isaindigotone derivatives as potential anti-gastric cancer agents.

A series of novel derivatives of isaindigotone, which comes from the root of isaits indinatca Fort, were synthesised (Compound 1-26). Four human gastrointestinal cancer cells (HCT116, PANC-1, SMMC-7721, and AGS) were employed to evaluate the anti-proliferative activity. Among them, Compound 6 displayed the most effective inhibitory activity on AGS cells with an IC50 (50% inhibitory concentration) value of 2.2 µM. The potential mechanism study suggested that Compound 6 induced apoptosis in AGS cells. The collapse of mitochondrial membrane potential (MMP) in AGS cells was proved. In docking analysis, good affinity interaction between Compound 6 and AKT1 was discovered. Treatment of AGS cells with Compound 6 also resulted in significant suppression of PI3K/AKT/mTOR signal pathway. The collapse of MMP and suppression of PI3K/AKT/mTOR signal pathway may be responsible for induction of apoptosis. This derivative Compound 6 could be useful as an underlying anti-tumour agent for treatment of gastric cancer.

Vanillin Derivatives Reverse Fusobacterium nucleatum-Induced Proliferation and Migration of Colorectal Cancer Through E-Cadherin/ß-Catenin Pathway.

Colorectal cancer (CRC) is a common clinical malignant tumor and closely related to intestinal microbiome disorders. Especially, Fusobacterium nucleatum (F. nucleatum) is one of the most prevalent pathogens in CRC. However, its change in CRC patients of Northwest China, an area with a high incidence of gastrointestinal tumors, is unclear, and therapeutic strategies targeting F. nucleatum remain unresolved. Here, fecal samples of healthy people and CRC patients were studied using 16S rRNA sequencing to explore microbial community alterations. Additionally, vanillin derivate (IPM711 and IPM712) intervention by coculture with CRC cells and potential mechanism were investigated. Results showed that intestinal microbial homeostasis was gradually dysregulated, and the abundance of Fusobacterium was higher in CRC patients. Moreover, IPM711 and IPM712 showed better anti-F. nucleatum activity than vanillin by increasing cell membrane permeability and destroying bacterial integrity. In addition, IPM711 and IPM712 could downregulate the expression of E-cadherin and ß-catenin, thus, suppressing the migration of HCT116. Collectively, IPM711 and IPM712 have both anticolorectal cancer and anti-F. nucleatum activities, providing potential natural product drug candidates for microbe-targeted strategies for the treatment of CRC.

Synthesis of 8-Fluoroneocryptolepine and Evaluation for Cytotoxic Activity against AGS Cancer Cells.

Neocryptolepine derivatives have attracted great interest because of their unique cytotoxic activity. 8-Fluoroneocryptolepine (8FNC) was synthesized, and its cytotoxicity was evaluated by MTT assay in AGS gastric cancer cells and gastric mucosa GES-1 cells. 8-Fluoroneocryptolepine showed greater selectivity and cytotoxicity to AGS cells than the cisplatin (CIS) and fluorouracil (5-Fu) commonly used in clinical treatment of gastric cancer. Most importantly, we significantly improved the cytotoxic effect of 8FNC against AGS cells by structural modification and reduced the cytotoxicity against GES-1 cells compared with neocryptolepine. We further evaluated the activity of 8FNC against AGS cells in vitro. Our results indicate that 8FNC arrests the AGS cell cycle in the G2/M phase, reduces the mitochondrial membrane potential of AGS cells, and drives the initiation of apoptotic body formation in 8FNC-induced apoptosis. Moreover, 8FNC exhibits strong inhibitory effects on AGS cell migration. Studies on the molecular mechanisms of the cytotoxic activities of 8FNC revealed that it may play a significant role in the inhibitory effect on AGS human gastric cancer cells through the PI3K/AKT signaling pathway. In conclusion, 8FNC may become a promising lead compound in the development of potential clinical drug candidates for the treatment of gastric cancer.

Synthesis and biological activity of 1H-imidazo[4,5-f][1,10]phenanthroline as a potential antitumor agent with PI3K/AKT/mTOR signaling.

1H-imidazo[4,5-f][1,10]phenanthroline (IPM713) is a type of tricyclic conjugated rigid planar structure with potential medical applications, but its anticancer activity has not yet been fully studied. In the present research, cells from seven different cancer types were used to study the anticancer effect, and IPM713 was found to inhibit the colorectal cancer cell line HCT116 most significantly, with a half maximal inhibitory concentration (IC50) of 1.7 µM. The mechanisms by which IPM713 exerts anti-colorectal cancer activity were studied. IPM713 blocked the cell cycle in G0/G1 phase and induced apoptosis by suppressing the PI3K/AKT/mTOR axis. In addition, an acute toxicity test showed that the median lethal dose (LD50) was above 5000 mg/kg. The findings of this research suggest that IPM713 can interfere with the PI3K/AKT/mTOR signaling pathway and might be a potential therapeutic candidate for the treatment of colorectal cancer.

Potential application of a knowledgebase of iron metabolism of Acidithiobacillus ferrooxidans as an alternative platform

BACKGROUND: Acidithiobacillus ferrooxidans is a facultative anaerobe that depends on ferrous ion oxidation as well as reduced sulfur oxidation to obtain energy and is widely applied in metallurgy, environmental protection, and soil remediation. With the accumulation of experimental data, metabolic mechanisms, kinetic models, and several databases have been established. However, scattered data are not conducive to understanding A. ferrooxidans that necessitates updated information informed by systems biology. RESULTS: Here, we constructed a knowledgebase of iron metabolism of A. ferrooxidans (KIMAf) system by integrating public databases and reviewing the literature, including the database of bioleaching substrates (DBS), the database of bioleaching metallic ion-related proteins (MIRP), the A. ferrooxidans bioinformation database (Af-info), and the database for dynamics model of bioleaching (DDMB). The DBS and MIRP incorporate common bioleaching substrates and metal ion-related proteins. Af-info and DDMB integrate nucleotide, gene, protein, and kinetic model information. Statistical analysis was performed to elucidate the distribution of isolated A. ferrooxidans strains, evolutionary and metabolic advances, and the development of bioleaching models. CONCLUSIONS: This comprehensive system provides researchers with a platform of available iron metabolism-related resources of A. ferrooxidans and facilitates its application.

Human Gut Microbiome-Based Knowledgebase as a Biomarker Screening Tool to Improve the Predicted Probability for Colorectal Cancer.

Colorectal cancer (CRC) is a common clinical malignancy globally ranked as the fourth leading cause of cancer mortality. Some microbes are known to contribute to adenoma-carcinoma transition and possess diagnostic potential. Advances in high-throughput sequencing technology and functional studies have provided significant insights into the landscape of the gut microbiome and the fundamental roles of its components in carcinogenesis. Integration of scattered knowledge is highly beneficial for future progress. In this study, literature review and information extraction were performed, with the aim of integrating the available data resources and facilitating comparative research. A knowledgebase of the human CRC microbiome was compiled to facilitate understanding of diagnosis, and the global signatures of CRC microbes, sample types, algorithms, differential microorganisms and various panels of markers plus their diagnostic performance were evaluated based on statistical and phylogenetic analyses. Additionally, prospects about current changelings and solution strategies were outlined for identifying future research directions. This type of data integration strategy presents an effective platform for inquiry and comparison of relevant information, providing a tool for further study about CRC-related microbes and exploration of factors promoting clinical transformation (available at: http://gsbios.com/index/experimental/dts_ mben?id=1).

IPM712, a vanillin derivative as potential antitumor agents, displays better antitumor activity in colorectal cancers cell lines.

Colorectal cancer (CRC), a major health threat in the world, ranks third in incidence and second in mortality among cancers. Chemotherapy, an important treatment for colorectal cancer, have be limited in the clinic due to the resistance and side effect. Studies have shown that PI3K-related regulatory pathways play a colossal role in colorectal cancer. Therefore, it is a good strategy to find a new drug which works by affecting the PI3K signaling pathway. In this paper, we obtained a new vanillin derivative (IPM712) by modifying the structure of IPM711 and tested its anticancer activity in vitro and toxicity in vivo. Results showed that IPM712 has a better anticancer activity than 5-Fu in HCT116 and SW480 cell lines. Furthermore, IPM712 can inhibit cell proliferation, migration and induce the apoptosis by affecting PI3K-related protein expression. Acute toxicity experiments show that IPM712 has no significant toxicity at therapeutic concentrations. Based on these results, IPM712 is a promising anticancer drug candidate for human colorectal cancer therapy.

Bioleaching of realgar nanoparticles using the extremophilic bacterium Acidithiobacillus ferrooxidans DLC-5

BACKGROUND: This paper presents micro- and nano-fabrication techniques for leachable realgar using the extremophilic bacterium Acidithiobacillus ferrooxidans (A. ferrooxidans) DLC-5. RESULTS: Realgar nanoparticles of size ranging from 120 nm to 200 nm were successfully prepared using the highenergy ball mill instrument. A. ferrooxidans DLC-5 was then used to bioleach the particles. The arsenic concentration in the bioleaching system was found to be increased significantly when compared with that in the sterile control. Furthermore, in the comparison with the bioleaching of raw realgar, nanoparticles could achieve the same effect with only one fifth of the consumption. CONCLUSION: Emphasis was placed on improving the dissolvability of arsenic because of the great potential of leachable realgar drug delivery in both laboratory and industrial settings

A vanillin derivative suppresses the growth of HT29 cells through the Wnt/ß-catenin signaling pathway.

Colorectal cancer (CRC) is a common malignancy and the leading cause of cancer death worldwide. According to previous studies, vanillin possesses pharmacological and anticancer activities. In this work, we have modified the structure of vanillin to obtain a vanillin derivative called 4-(1H-imidazo [4,5-f][1,10]-phenanthrolin-2-yl)-2-methoxyphenol (IPM711), which has improved anticancer activity. The present study is intended to explore the anti-colorectal cancer activity of IPM711 in HT29 and HCT116 cells. The results of this study suggest that IPM711 can inhibit the growth, invasion and migration of HT29 and HCT116 cells. Western blot and molecular docking showed that IPM711 could bind to a Wnt/ß-catenin signaling receptor to inhibit cell growth, invasion and migration in HT29 cells. Based on these results, IPM711 is a promising anticancer drug candidate for human colorectal cancer therapy.

Starch biotransformation into isomaltooligosaccharides using thermostable alpha-glucosidase from Geobacillus stearothermophilus.

The present study first identified the biotransformation of starch as a novel preparation method was investigated using the alpha-transglucosidase-producing Geobacillus stearothermophilus U2. Subsequently, 5 L- and 20 L-scale fermentations were performed. After isolation and purification, liquid alpha-glucosidase preparations were obtained. Through covalent cross-linking and adsorption cross-linking using chitosan as the carrier and glutaraldehyde as the crosslinking agent, the conditions for immobilization of alpha-glucosidase on chitosan were determined. Moreover, Isomaltooligosaccharides (IMOs) were then prepared using chitosan membrane-immobilized alpha-glucosidase, beta-amylase, pullulanase, fungal alpha-amylase and starch as substrate. The mixed syrup that contained IMOs was evaluated and analyzed by thin-layer chromatography (TLC) and high-performance liquid chromatography (HPLC). In addition, small-scale preparation of IMOs was performed. These results are a strong indication that the alpha-transglucosidase-producing G. stearothermophilus as a potential application technique can be successfully used to prepare industrial IMOs.

Arsenic trioxide combined with transarterial chemoembolization for unresectable primary hepatic carcinoma: A systematic review and meta-analysis.

BACKGROUND: Primary hepatic carcinoma (PHC) is the third commonest leading to cancer death around the world, and transarterial chemoembolization (TACE) has been proposed as the first-line therapeutic treatment for patients with unresectable PHC. This study aims to determine whether the combination of As2O3 and TACE is superior to alone TACE for achieving more clinical therapeutic efficacy, survival time, life quality and safety in patients with unresectable PHC. METHODS: A comprehensive literature search was conducted on the clinical controlled trials comparing therapeutic effects of As2O3 & TACE versus alone TACE for unresectable PHC through English databases (including PubMed, Embase, and the Cochrane Library) and Chinese databases (including China Knowledge Resource Integrated Database, Wanfang Database, Weipu Database, and Chinese Biomedical Database). The last search was in 30 August 2017. A recursive search was performed with bibliographies of relevant studies. There were no language restrictions. Primary outcomes, defined a priori, were therapeutic responses (clinical effective rate and clinical benefit rate), survival time, life quality, and adverse events of As2O3 & TACE compared with alone TACE expressed as relative risk (RR) with 95% confidence intervals (CI). RESULTS: 25 clinical controlled trials involving 1886 participants were included. We found that there were significant superiority associated with As2O3 & TACE compared with alone TACE in clinical benefit rate (RR: 1.24, 95% CI: 1.12-1.37), clinical effective rate (RR: 1.35, 95% CI: 1.17-1.55), 2-year survival rate (RR: 1.45, 95% CI: 1.20-1.75), and improving of KPS (RR: 1.31, 95% CI: 1.14-1.50). These associations were also observed in subgroups by intervened methods of As2O3 and pulmonary metastasis. Notably, the pooled relative risk of retention of sodium and water was obviously raised in patients with As2O3 & TACE therapy (RR: 16.616, 95% CI: 8.01 - 34.486). CONCLUSION: The superiority of adjuvant As2O3 therapy combined with TACE in PHC individuals will outweigh alone TACE therapy, especially in PHC populations with pulmonary metastasis.