Experimental Therapy of Ovarian Cancer with Synthetic Makaluvamine Analog: In Vitro and In Vivo Anticancer Activity and Molecular Mechanisms of Action

The present study was designed to determine the biological effects of novel marine alkaloid analog 7-(4-fluorobenzylamino)-1,3,4,8-tetrahydropyrrolo[4,3,2-de]quinolin-8(1H)-one (FBA-TPQ) on human ovarian cancer cells for its anti-tumor potential and the underlying mechanisms as a novel chemotherapeutic agent. Human ovarian cancer cells (A2780 and OVCAR-3), and Immortalized non-tumorigenic human Ovarian Surface Epithelial cells (IOSE-144), were exposed to FBA-TPQ for initial cytotoxicity evaluation (via MTS assay kit, Promega). The detailed in-vitro (cell level) and in-vivo (animal model) studies on the antitumor effects and possible underlying mechanisms of action of the compounds were then performed. FBA-TPQ exerted potent cytotoxicity against human ovarian cancer A2780 and OVCAR-3 cells as an effective inhibitor of cell growth and proliferation, while exerting lesser effects on non-tumorigenic IOSE-144 cells. Further study in the more sensitive OVCAR-3 cell line showed that it could potently induce cell apoptosis (Annexin V-FITC assay), G2/M cell cycle arrest (PI staining analysis) and also dose-dependently inhibit OVCAR-3 xenograft tumors' growth on female athymic nude mice (BALB/c, nu/nu). Mechanistic studies (both in vitro and in vivo) revealed that FBA-TPQ might exert its activity through Reactive Oxygen Species (ROS)-associated activation of the death receptor, p53-MDM2, and PI3K-Akt pathways in OVCAR-3 cells, which is in accordance with in vitro microarray (Human genome microarrays, Agilent) data analysis (GEO accession number: GSE25317). In conclusion, FBA-TPQ exhibits significant anticancer activity against ovarian cancer cells, with minimal toxicity to non-tumorigenic human IOSE-144 cells, indicating that it may be a potential therapeutic agent for ovarian cancer

Nutrients mediate intestinal bacteria-mucosal immune crosstalk

The intestine is the shared site of nutrient digestion, microbiota colonization and immune cell location and this geographic proximity contributes to a large extent to their interaction. The onset and development of a great many diseases, such as inflammatory bowel disease and metabolic syndrome, will be caused due to the imbalance of body immune. As competent assistants, the intestinal bacteria are also critical in disease prevention and control. Moreover, the gut commensal bacteria are essential for development and normal operation of immune system and the pathogens are also closely bound up with physiological disorders and diseases mediated by immune imbalance. Understanding how our diet and nutrient affect bacterial composition and dynamic function, and the innate and adaptive status of our immune system, represents not only a research need but also an opportunity or challenge to improve health. Herein, this review focuses on the recent discoveries about intestinal bacteria-immune crosstalk and nutritional regulation on their interplay, with an aim to provide novel insights that can aid in understanding their interactions.Peer reviewedAnimal Scienc

Dietary Corn Bran Altered the Diversity of Microbial Communities and Cytokine Production in Weaned Pigs

Corn bran (CB) has been used as an ingredient for pigs, but the underlying mechanisms that improve gut health is less clear. This study was conducted to investigate effects of dietary CB on growth performance, nutrient digestibility, plasma indices related to gut hormones and immunity, gut microbiota composition, and fermentation products in weaned pigs. A total of 60 weaned pigs were allocated to two dietary treatments, and piglets in each group received control (CON) diet or 5% CB diet for 28 days. Growth performance, nutrient digestibility, indices of gut hormones and immunity in plasma were evaluated. Microbiota composition in feces was determined using 16S rRNA amplicon sequencing, and fermentation products were measured by high-performance ion chromatography. The results showed that dietary CB did not affect growth performance, nutrient digestibility, gut hormones, or fermentation products in the trial (P > 0.05). There was an increased response to CB inclusion on interleukin-10 production (P < 0.05). On day 28, piglets fed dietary CB had a higher shannon index (P < 0.05). The population of the Firmicutes in CB treatment were decreased (P < 0.05), while the percentage of the Bacteroidetes were increased (P < 0.05). In particular, the populations of Eubacterium corprostanoligenes, Pevotella, and Fibrobacter related to polysaccharide fermentation of cereal bran were increased (P < 0.05). In conclusion, a post-weaning diet containing 5% CB increased intestinal microbial diversity, especially higher richness of fibrolytic bacteria, and promoted anti-inflammatory response to some extent in piglets, these changes should facilitate the adaptation of the digestive system of piglets in the subsequent growing phases

Impacts of Fructose on Intestinal Barrier Function, Inflammation and Microbiota in a Piglet Model

The metabolic disorder caused by excessive fructose intake was reported extensively and often accompanied by intestinal barrier dysfunction. And the rising dietary fructose was consumed at an early age of human. However, related researches were almost conducted in rodent models, while in the anatomy and physiology of gastrointestinal tract, pig is more similar to human beings than rodents. Hence, weaned piglets were chosen as the model animals in our study to investigate the fructose’s impacts on intestinal tight junction, inflammation response and microbiota structure of piglets. Herein, growth performance, inflammatory response, oxidation resistance and ileal and colonic microbiota of piglet were detected after 35-day fructose supplementation. Our results showed decreased tight junction gene expressions in piglets after fructose addition, with no obvious changes in the growth performance, antioxidant resistance and inflammatory response. Moreover, fructose supplementation differently modified the microbiota structures in ileum and colon. In ileum, the proportions of Streptococcus and Faecalibacterium were higher in Fru group (fructose supplementation). In colon, the proportions of Blautia and Clostridium sensu stricto 1 were higher in Fru group. All the results suggested that tight junction dysfunction might be an earlier fructose-induced event than inflammatory response and oxidant stress and that altered microbes in ileum and colon might be the potential candidates to alleviate fructose-induced intestinal permeability alteration

RNA interference revealed the roles of two carboxylesterase genes in insecticide detoxification in Locusta migratoria

Citation: Zhang, J., Li, D., Ge, P., Yang, M., Guo, Y., Zhu, K. Y., Ma, E., & Zhang, J. (2013). RNA interference revealed the roles of two carboxylesterase genes in insecticide detoxification in Locusta migratoria. Chemosphere, 93(6), 1207-1215.Carboxylesterases (CarEs) play key roles in metabolism of specific hormones and detoxification of dietary and environmental xenobiotics in insects. We sequenced and characterized CarE cDNAs putatively derived from two different genes named LmCesA1 and LmCesA2 from the migratory locust, Locusta migratoria, one of the most important agricultural pests in the world. The full-length cDNAs of LmCesA1 (1892 bp) and LmCesA2 (1643 bp) encode 543 and 501 amino acid residues, respectively. The two deduced CarEs share a characteristic α/β-hydrolase structure, including a catalytic triad composed of Ser-Glu (Asp)-His and a consensus sequence GQSAG, which suggests that both CarEs are biologically active. Phylogenetic analysis grouped both LmCesA1 and LmCesA2 into clade A which has been suggested to be involved in dietary detoxification. Both transcripts were highly expressed in all the nymphal and adult stages, but only slightly expressed in eggs. Analyses of tissue-dependent expression and in situ hybridization revealed that both transcripts were primarily expressed in gastric caeca. RNA interference (RNAi) of LmCesA1 and LmCesA2 followed by a topical application of carbaryl or deltamethrin did not lead to a significantly increased mortality with either insecticide. However, RNAi of LmCesA1 and LmCesA2 increased insect mortalities by 20.9% and 14.5%, respectively, when chlorpyrifos was applied. These results suggest that these genes might not play a significant role in detoxification of carbaryl and deltamethrin but are most likely to be involved in detoxification of chlorpyrifos in L. migratoria

The digestive tract histology and geographical distribution of gastrointestinal microbiota in yellow-feather broilers

ABSTRACT: Exhaustive understanding of intestinal physiological characteristics is the critical precondition for the improvement of intestinal health and growth performance of yellow-feather broilers (YFB). As a vital part of gastrointestinal tract, the symbiotic, complex, and variable microbiota have a profound effect on the nutrition, immunity, health, and production of broilers. Hence, the development status of proventriculus, jejunum, and cecum, and spatial heterogeneity of bacterial community in crop, proventriculus, gizzard, jejunum, cecum, and rectum of adult YFB were detected in our study. The results revealed that proventriculus, jejunum, and cecum of broilers are well-developed based on morphological observation. The Chao and Shannon indexes in cecum and rectum are notably higher than other sections and their microbiota structure is also distinct from foregut. Firmicutes and Lactobacillus are the predominant phylum and genus in all gastrointestinal sections, respectively. As feature species of crop, Lactobacillus spp. mainly settle in foregut, whereas some Clostridia species (unclassified Lachnospiraceae, Faecalibacterium, Romboutsia and so on) are characteristic and more abundant in cecum and rectum. Interestingly, there are 2 Ruminococcus torques strains positively and negatively correlated with cecum development, respectively. In a whole, our findings reveal the specialized digestive physiology and regional distribution of intestinal microbiota in YFB, which provides a reference for the future study on the improvement of growth performance and intestinal development through microbiota manipulation in yellow-feather broilers

Effect of Hydrolyzed Gallotannin on Growth Performance, Immune Function, and Antioxidant Capacity of Yellow-Feather Broilers

Tannins were traditionally considered as anti-nutritional factors in poultry production. Recent studies found that the addition of hydrolyzed gallotannin (HGT) could improve animal health; however, the proper dosage of HGT in chickens’ diet is still unknown. Hence, our study aims to recommend its optimal dose by exploring the effects of HGT from Chinese gallnuts on the growth performance, immune function, and antioxidant capacity of yellow-feather broilers. A total of 288 male yellow-feather broilers (34.10 ± 0.08 g) were randomly allocated to four diet treatments, the basal diet with 0 (CON), 150, 300, and 450 mg/kg HGT for 63 days, respectively, with six replications per treatment and 12 birds per replication. The growth performance, slaughter performance, immune organ index, liver antioxidant-related indicators, and serum immune-related factors were evaluated. Results show that HGT supplementation did not influence the growth performance of broilers, but the diets supplemented with 300 and 450 mg/kg HGT increased the semi-eviscerated rate. Furthermore, HGT increased the content of liver T-AOC and the ratio of GSH/GSSG, which can protect against oxidative damage of birds. Additionally, supplementing HGT raised the contents of serum IL-10, IL-4, IL-6, IgA, and IgM. In conclusion, diet supplemented with 450 mg/kg HGT may be the optimal to the health of yellow-feather broilers on the whole

The Effects of Temperature and Humidity Index on Growth Performance, Colon Microbiota, and Serum Metabolome of Ira Rabbits

This study investigates the effects of different THI values on growth performance, intestinal microbes, and serum metabolism in meat rabbits. The results showed that there were significant differences in THI in different location regions of the rabbit house. The high-THI group (HG) could significantly reduce average daily gain and average daily feed intake in Ira rabbits (p Blautia (p Lachnospiraceae NK4A136 group and reduced bacterial community interaction (p p p p < 0.05). In addition, five metabolites were found to be able to predict THI levels in the environment with an accuracy of 91.7%. In summary, a THI of 26.14 is more suitable for the growth of meat rabbits than a THI of 27.25, providing a reference for the efficient feeding of meat rabbits

Small GTPase FoSec4-Mediated Protein Secretion Is Important for Polarized Growth, Reproduction and Pathogenicity in the Banana Fusarium Wilt Fungus Fusarium odoratissimum

Apical secretion at hyphal tips is important for the growth and development of filamentous fungi. In this study, we analyzed the role of the Rab GTPases FoSec4 involved in the secretion of the banana wilt fungal pathogen Fusarium odoratissimum. We found that the deletion of FoSEC4 affects the activity of extracellular hydrolases and protein secretion, indicating that FoSec4 plays an important role in the regulation of protein secretion in F. odoratissimum. As a typical Rab GTPase, Sec4 participates in the Rab cycle through the conversion between the active GTP-bound state and the inactive GDP-bound state, which is regulated by guanine nucleate exchange factors (GEFs) and GTPase-activating proteins (GAPs). We further found that FoSec2 can interact with dominant-negative FoSec4 (GDP-bound and nucleotide-free form, FoSec4DN), and that FoGyp5 can interact with dominant active FoSec4 (GTP-bound and constitutively active form, FoSec4CA). We evaluated the biofunctions of FoSec4, FoSec2 and FoGyp5, and found that FoSec4 is involved in the regulation of vegetative growth, reproduction, pathogenicity and the environmental stress response of F. odoratissimum, and that FocSec2 and FoGyp5 perform biofunctions consistent with FoSec4, indicating that FoSec2 and FoGyp5 may work as the GEF and the GAP, respectively, of FoSec4 in F. odoratissimum. We further found that the amino-terminal region and Sec2 domain are essential for the biological functions of FoSec2, while the carboxyl-terminal region and Tre-2/Bub2/Cdc16 (TBC) domain are essential for the biological functions of FoGyp5. In addition, FoSec4 mainly accumulated at the hyphal tips and partially colocalized with Spitzenk&ouml;rper; however, FoGyp5 accumulated at the periphery of Spitzenk&ouml;rper, suggesting that FoGyp5 may recognize and inactivate FoSec4 at a specific location in hyphal tips

Key amino acid residues (RF, DQ motifs, residues for nucleophilic elbow, catalytic triads, N-terminal conserved Cys for disulfide bond and oxyanion hole) of 39 carboxylesterases deduced from <i>Locusta migratoria</i> cDNAs.

<p>Key amino acid residues (RF, DQ motifs, residues for nucleophilic elbow, catalytic triads, N-terminal conserved Cys for disulfide bond and oxyanion hole) of 39 carboxylesterases deduced from <i>Locusta migratoria</i> cDNAs.</p