Discovery of unusual dimeric piperazyl cyclopeptides encoded by a Lentzea flaviverrucosa DSM 44664 biosynthetic supercluster

Rare actinomycetes represent an underexploited source of new bioactive compounds. Here, we report the use of a targeted metabologenomic approach to identify piperazyl compounds in the rare actinomycete Lentzea flaviverrucosa DSM 44664. These efforts to identify molecules that incorporate piperazate building blocks resulted in the discovery and structural elucidation of two dimeric biaryl-cyclohexapeptides, petrichorins A and B. Petrichorin B is a symmetric homodimer similar to the known compound chloptosin, but petrichorin A is unique among known piperazyl cyclopeptides because it is an asymmetric heterodimer. Due to the structural complexity of petrichorin A, solving its structure required a combination of several standard chemical methods plus in silico modeling, strain mutagenesis, and solving the structure of its biosynthetic intermediate petrichorin C for confident assignment. Furthermore, we found that the piperazyl cyclopeptides comprising each half of the petrichorin A heterodimer are made via two distinct nonribosomal peptide synthetase (NRPS) assembly lines, and the responsible NRPS enzymes are encoded within a contiguous biosynthetic supercluster on the L. flaviverrucosa chromosome. Requiring promiscuous cytochrome p450 crosslinking events for asymmetric and symmetric biaryl production, petrichorins A and B exhibited potent in vitro activity against A2780 human ovarian cancer, HT1080 fibrosarcoma, PC3 human prostate cancer, and Jurkat human T lymphocyte cell lines with IC50 values at low nM levels. Cyclic piperazyl peptides and their crosslinked derivatives are interesting drug leads, and our findings highlight the potential for heterodimeric bicyclic peptides such as petrichorin A for inclusion in future pharmaceutical design and discovery programs.Fil: Li, Chunshun. University Of Hawaii; Estados UnidosFil: Hu, Yifei. University Of Hawaii; Estados Unidos. Washington University in St. Louis; Estados UnidosFil: Wu, Xiaohua. University Of Hawaii; Estados UnidosFil: Stumpf, Spencer D.. Washington University in St. Louis; Estados UnidosFil: Qi, Yunci. Washington University in St. Louis; Estados UnidosFil: D'Alessandro, John M.. Washington University in St. Louis; Estados UnidosFil: Nepal, Keshav K.. Washington University in St. Louis; Estados UnidosFil: Sarotti, Ariel Marcelo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Química Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Química Rosario; ArgentinaFil: Cao, Shugeng. University Of Hawaii; Estados UnidosFil: Blodgett, Joshua A.V.. Washington University in St. Louis; Estados Unido

Influences of beta-alanine and l-histidine supplementation on growth performance, meat quality, carnosine content, and mRNA expression of carnosine-related enzymes in broilers

The current study investigated the effect of dietary L-histidine and beta-alanine sup-plementation on growth performance, meat quality, carnosine content, and gene expression of carnosine-related enzymes in broilers. A two-factor design was adopted in this study. A total of 640 1-day-old male broilers were assigned to eight treatments with factorial arrangement containing four levels of L-histidine (0, 650, 1300, or 1950 mg/kg) and two levels of beta-alanine (0 or 1200 mg/kg) supplementation; 0 mg/kg histidine and/or 0 mg/kg were treated as control groups. Each treatment including eight replicates with 10 birds each and the feeding trial lasted for 42 days. Dietary supple-mentation with L-histidine and beta-alanine did not affect average daily gain (ADG), average daily feed intake (ADFI), and feed conversion ratio (FCR) of broilers during the grower (22–42 days) and the entire phase (1–42 days), compared with the control group (p > 0.05). The only exception was a significantly reduced ADG in the 1950 mg/kg L-histidine group in the starter period (1–21 days, p < 0.05). L-Histidine at 1950 mg/kg significantly decreased redness (a*) and yellowness (b*) values of the meat at 45 min postmortem (p < 0.05), whereas it increased b* value and pH in breast muscle at 24 h postmortem. Moreover, dietary supplementation with beta-alanine alone or combination with L-histidine significantly increased ∆pH in breast muscle (p < 0.01). Dietary L-histidine markedly increased total superoxide dismutase activity and total antioxidant capacity (T-AOC) both in breast muscle (p < 0.01) and in plasma (p < 0.01), and it decreased malondialdehyde (MDA) concentration in breast muscle (p < 0.01). Dietary addition of beta-alanine, alone or combination, significantly increased T-AOC in breast muscle (p < 0.01) and markedly decreased MDA content both in breast muscle and in plasma (p < 0.01). Addition of L-histidine and beta-alanine significantly increased muscle peptide (carnosine and anserine) content (p < 0.05) and upregulated the expression of carno-sine synthase, transporter of carnosine/ L-histidine, and L-histidine decarboxylase genes (p < 0.05), with greater change occurring in the combination group of 1300 mg/kg L-histidine and 1200 mg/kg beta-alanine. Overall, dietary L-histidine and beta-alanine could improve meat quality and antioxi-dant capacity, enhance the carnosine and anserine content, and upregulate the gene expression of carnosine synthesis-related enzymes in broilers

Active Pin1 is a key target of all-trans retinoic acid in acute promyelocytic leukemia and breast cancer

A common key regulator of oncogenic signaling pathways in multiple tumor types is the unique isomerase Pin1. However, available Pin1 inhibitors lack the required specificity and potency. Using mechanism-based screening, here we find that all-trans retinoic acid (ATRA)--a therapy for acute promyelocytic leukemia (APL) that is considered the first example of targeted therapy in cancer, but its drug target remains elusive--inhibits and degrades active Pin1 selectively in cancer cells by directly binding to the substrate phosphate- and proline-binding pockets in the Pin1 active site. ATRA-induced Pin1 ablation degrades the fusion oncogene PML-RARα and treats APL in cell and animal models and human patients. ATRA-induced Pin1 ablation also inhibits triple negative breast cancer cell growth in human cells and in animal models by acting on many Pin1 substrate oncogenes and tumor suppressors. Thus, ATRA simultaneously blocks multiple Pin1-regulated cancer-driving pathways, an attractive property for treating aggressive and drug-resistant tumors

New Alkaloids From a Hawaiian Fungal Strain Aspergillus felis FM324

Two new alkaloids tryptoquivaline Y (1) and pseurotin I (2), together with eight known compounds (3–10), were purified from a fungal strain Aspergillus felis FM324, which was isolated from a Hawaiian beach soil sample. The absolute configuration and physicochemical data of tryptoquivaline Z (3) were reported for the first time here in this paper. Compound 1 is an uncommon tryptoquivaline analog containing a 3-Oisobutanoyl group. The structures of the new compounds 1–2 and known compound 3 were elucidated through HRESIMS, NMR spectroscopy and ECD analysis. All the compounds were evaluated for their antiproliferative, antibacterial and NF-κB inhibitory activities. Compound 4 showed weak antibacterial activity against Staphylococcus aureus, methicillin resistant Staphylococcus aureus and Bacillus subtilis with the same MIC value of 59.2 µM. Compounds 3 and 2 inhibited NF-κB with IC50 values of 26.7 and 30.9 μM, respectively.Fil: Wang, Cong. University of Hawaiʻi at Hilo. Daniel K. Inouye College of Pharmacy. Department of Pharmaceutical Sciences; United States.Fil: Wang, Cong. Guangxi University for Nationalities. School of Chemistry and Chemical Engineering. Guangxi Collaborative Innovation Center for Chemistry and Engineering of Forest Products. Guangxi Key Laboratory of Chemistry and Engineering of Forest Products. State Ethnic Affairs Commission. Key Laboratory of Chemistry and Engineering of Forest Products; China.Fil: Sarotti, Ariel Marcelo. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Química Rosario (IQUIR-CONICET); ArgentinaFil: Uz Zaman, Ahammad. University of Hawaiʻi at Hilo. Daniel K. Inouye College of Pharmacy. Department of Pharmaceutical Sciences; United States.Fil: Wu, Xiaohua. University of Hawaiʻi at Hilo. Daniel K. Inouye College of Pharmacy. Department of Pharmaceutical Sciences; United States.Fil: Cao, Shugeng. University of Hawaiʻi at Hilo. Daniel K. Inouye College of Pharmacy. Department of Pharmaceutical Sciences; United States

Nutritional modulation of health, egg quality and environmental pollution of the layers

World egg production and consumption have been increasing for the past decades. Traditional strategies in poultry nutrition have made vital contributions to this great growth in quantity. However, current global issues should be considered in modern egg production such as growing populations and food security, food safety and quality, limited resources and environmental problems. The development of knowledge of poultry nutrition and modern biotechnology provides novel nutritional approaches to closely fit the requirement of pullets and laying hens, which will consequently decrease the nutrition emissions and maintain the lower cost of feed. Nutrition has also been widely accepted as a strategy to influence health and diseases of laying hens. The maintenance of good health is an important prerequisite for improving productivity and egg quality. In addition, there are many measures and strategies for minimizing the incidence of egg defects and providing a choice of lifestyle to enhance human health. This paper reviews current research progress on developing innovative technologies and strategies to maximize animal health and performance, improve the quality of egg products and minimize pollution caused by poultry production

Effects of Dietary Calcium Lactate Supplementation on Laying Performance, Blood Index, Shinbone Quality, Jejunal Immunity, and Egg Quality of Aged Laying Hens

This study aimed to verify the potential of calcium lactate for the performance, blood index, shinbone quality, jejunal immunity, and egg quality of aged laying hens. A total of 360 62-week-old Hy-Line Brown laying hens were randomly divided into four treatments, with six replicates and 15 chickens per replicate. Experimental groups were fed with 0.25%, 0.5%, and 1.0% calcium lactate to substitute limestone in the control group (maintaining the same amount of calcium). The feeding trial lasted for 12 weeks. The laying rate and daily egg mass of laying hens fed the diets supplemented with calcium lactate was increased relative to those of the control group. The dietary addition of calcium lactate for laying hens enhanced the eggshell ratio, eggshell thickness, eggshell strength, and albumen height of eggs, and the addition level of 0.5% had the best effect. Dietary calcium lactate increased the number of red blood cells, corpuscular hemoglobin, mononuclear leucocytes and basophilic granulocytes, and decreased heterophils in the blood of laying hens. The activities of serum alanine transaminase and creatine kinase in laying hens was reduced by the dietary addition of calcium lactate. Calcium lactate supplementation in diets increased the serum calcium and phosphorus contents of laying hens. The dietary inclusion of calcium lactate increased the contents of IgA, IgG, lysozyme, and sIgA in the jejunal mucosa, and the 0.5% addition level worked best, but the IL-2 content decreased. The addition of 0.5% calcium lactate to the diet reduced the maximal force of the shinbone and increased the work required for shinbone rupture in laying hens. In conclusion, the dietary addition of calcium lactate improved the performance and egg quality of laying hens, probably by its positive effects on body health, intestinal digestible ability, calcium bioavailability, and jejunal mucosal immunity. The optimum amount of calcium lactate in the diet of laying hens is recommended to be 0.5%

New and bioactive polyketides from Hawaiian marine-derived fungus Trichoderma sp. FM652

Two new sorbicillinoid derivatives (1 and 2), together with ten other related compounds (3–12) were isolated from a Hawaiian marine fungal strain Trichoderma sp. FM652. The structures of compounds 1 and 2, including the absolute configuration, were elucidated by extensive analysis of NMR spectroscopy, HRESIMS and electronic circular dichroism (ECD) data. Compounds 6–12 exhibited significant anti-proliferative activity against ovarian cancer cell line A2780, with the IC50 values ranging from 0.5 to 8.07 μM. Moreover, compounds 1, 7 and 8 showed significant inhibition against NF-κB with IC50 values of 13.83, 24.40 and 14.63 µM, respectively. Compounds 6, 9 and 12 also demonstrated moderate inhibitory activity against S. aureus and methicillin resistant S. aureus with the MIC values in the range of 10–40 μg/mL.Fil: Zaman, KH Ahammad Uz. University Of Hawaii; Estados UnidosFil: Wu, Xiaohua. University Of Hawaii; Estados UnidosFil: Sarotti, Ariel Marcelo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Química Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Química Rosario; ArgentinaFil: Cao, Shugeng. University Of Hawaii; Estados Unido

Dietary Supplementation of a New Probiotic Compound Improves the Growth Performance and Health of Broilers by Altering the Composition of Cecal Microflora

The current study aimed to investigate the effects of a new probiotic compound developed as a potential alternative to synthetic antibiotics for broilers. A total of 360 newly hatched Arbor Acres male chicks were randomly divided into three treatment groups. Each treatment consisted of six replicates with 20 birds in each replicate. The negative control group was fed the basal diet. The positive control group was fed the basal diet supplemented with a commercial antimicrobial, virginiamycin, at 30 mg/kg of basal feed. The compound probiotics group was fed a basal diet containing 4.5 × 106 CFU of Lactobacillus LP184 and 2.4 × 106 CFU of Yeast SC167 per gram of basal feed. The feeding trial lasted for 42 days. The results showed that the compound probiotics were a competent alternative to synthetic antibiotics for improving the growth performance and carcass traits of broilers. The compound probiotics enhanced the immune and antioxidant capacities of the broilers, while antibiotics lacked such merits. The positive effects of compound probiotics could be attributed to an improvement in the intestinal morphology and cecal microbial diversity of broilers, effects which are distinct from those of antibiotics. These findings revealed the differences between probiotics and antibiotics in terms of improving broilers’ performance and enriched the basic knowledge surrounding the intestinal microbial structure of broilers

Effects of Dietary Rare Earth Chitosan Chelate on Performance, Egg Quality, Immune and Antioxidant Capacity, and Intestinal Digestive Enzyme Activity of Laying Hens

Rare earth chitosan chelate salt (RECC) is a potential feed additive and is a product of the chelation effect between rare earth ions and chitosan. This research study aims to explore the effects of dietary RECC on performance, egg quality, intestinal digestive function, and the immune and antioxidant capacity of laying hens in the late phase of production. A total of 360 56-week-old Dawu Jinfeng laying hens were randomly allotted into four treatment groups with six replicates per treatment and 15 birds per replicate. The laying hens were fed the basal diet supplemented with, respectively, 0 (control: CON), 100 (R1), 200 (R2), and 400 (R3) mg/kg for 8 weeks. Dietary RECC significantly improved average daily feed intake (ADFI) and average daily egg yield in both linear and quadratic manner (p p p p p p p < 0.05). The utilization of RECC as a feed additive in the diet of aged laying hens exerted beneficial effects on egg production, albumen quality, humoral immunity, inflammatory response, and activity of digestive enzymes. Thus, the regulation of antioxidant capacity and duodenal function via increased enzyme activity and immune and inflammatory response were critical to the improvement of laying performance and egg quality in aged hens. The optimal supplemental dose is 100–200 mg/kg

Dual Beneficial Effects of Methylnissolin-3-O-&beta;-d-Glucopyranoside on Obesity-Induced Inflammatory Responses in Adipocyte-Macrophage Co-Culture

Methylnissolin-3-O-&beta;-d-glucopyranoside (MNG) is a pterocarpan analog, which protects EA.hy926 cells against oxidative damage through the Nrf2/HO-1 pathway. However, the effects of MNG on obesity-induced inflammatory responses in adipocyte-macrophage co-culture remain unclear. A differentiated murine preadipocyte cell line (3T3-L1) was co-cultured with a murine macrophage cell line (RAW264.7). Intracellular lipid accumulation was determined using Oil Red O staining. Western blotting was performed to investigate the expression of adipogenesis- and inflammation-associated proteins. Cell culture supernatants were assayed using ELISA kits to measure the levels of proinflammatory cytokines such as interleukin 6 (IL-6) and monocyte chemoattractant protein-1 (MCP-1). MNG inhibited lipid accumulation and the production of IL-6 and MCP-1 in the 3T3-L1 and RAW264.7 cell co-culture. Moreover, MNG inhibited the protein expression of CCAAT/enhancer-binding protein alpha (C/EBP&alpha;), C/EBP&beta;, peroxisome proliferator-activated receptor &gamma; (PPAR&gamma;), cyclooxygenase 2 (COX-2), and inducible nitric oxide synthase (iNOS) under the same co-culture conditions. MNG also inhibited IL-6 and MCP-1 production compared with the co-culture control. These findings demonstrate that MNG inhibited lipid accumulation and inflammatory response by downregulating IL-6 and MCP-1 production and protein expression of C/EBP&beta;, C/EBP&alpha;, PPAR&gamma;, COX-2, and iNOS in co-culture conditions with 3T3-L1 and RAW264.7 cells. These results suggest that MNG may be beneficial in preventing obesity-related inflammatory status