A concise approach to synthesize paucifloral F was developed via a stereoselective palladium-catalyzed α-arylation reaction. The approach has also been applied in the synthesis of indanone analogues ...of Paucifloral F.
Curcumin (CUR) is a kind of natural orange-yellow phenolic compound mainly extracted from the stems and roots of turmeric plants and other species in the genus Curcuma, furthermore, it is also the ...most important active ingredient exerting pharmacological functions in turmeric. In recent years, CUR has been frequently reported and has attracted widespread attention from scholars all over the world due to its numerous biological functions and good application prospects, such as anti-inflammatory, anticancer, antioxidant and providing lipid-lowering effects, etc. In addition, adding a certain dose of CUR to livestock and poultry feed is important for animal growth and development, which plays a key role in animal metabolism, reproduction, immunity and clinical health care. This review aims to summarize, based on the published papers and our own observations, the physical and chemical properties and the biological functions of the plant-derived bioactive ingredient CUR, especially regarding the latest research progress in regulating intestinal health as well as its current development and future application prospects in livestock and poultry as a novel feed additive, so as to provide theoretical and practical references for the further study of the application of CUR as a novel feed additive and a potential new antibiotic substitute, thereby improving the research field of plant-derived bioactive ingredients and promoting the healthy development of livestock and poultry.
A growing number of agents targeting ligand-induced Wnt/β-catenin signaling are being developed for cancer therapy. However, clinical development of these molecules is challenging because of the lack ...of a genetic strategy to identify human tumors dependent on ligand-induced Wnt/β-catenin signaling. Ubiquitin E3 ligase ring finger 43 (RNF43) has been suggested as a negative regulator of Wnt signaling, and mutations of RNF43 have been identified in various tumors, including cystic pancreatic tumors. However, loss of function study of RNF43 in cell culture has not been conducted, and the functional significance of RNF43 mutations in cancer is unknown. Here, we show that RNF43 inhibits Wnt/β-catenin signaling by reducing the membrane level of Frizzled in pancreatic cancer cells, serving as a negative feedback mechanism. Inhibition of endogenous Wnt/β-catenin signaling increased the cell surface level of Frizzled. A panel of 39 pancreatic cancer cell lines was tested for Wnt dependency using LGK974, a selective Porcupine inhibitor being examined in a phase 1 clinical trial. Strikingly, all LGK974-sensitive lines carried inactivating mutations of RNF43 . Inhibition of Wnt secretion, depletion of β-catenin, or expression of wild-type RNF43 blocked proliferation of RNF43 mutant but not RNF43 –wild-type pancreatic cancer cells. LGK974 inhibited proliferation and induced differentiation of RNF43 -mutant pancreatic adenocarcinoma xenograft models. Our data suggest that mutational inactivation of RNF43 in pancreatic adenocarcinoma confers Wnt dependency, and the presence of RNF43 mutations could be used as a predictive biomarker for patient selection supporting the clinical development of Wnt inhibitors in subtypes of cancer.
Dietary supplementation of butyrate can prevent diet-induced obesity through increasing mitochondrial function in mice, yet the up-stream signaling pathway remains elusive. In this study, weaned mice ...were divided into two groups, fed control (CON) and high-fat diet (HF, 45% energy from fat), respectively, for 8 weeks. HF-induced obese mice, maintained on HF diet, were then divided into two groups; HFB group was gavaged with 80 mg sodium butyrate (SB) per mice every other day for 10 days, while the HF group received vehicle. It was shown that five gavage doses of SB significantly alleviated HF diet-induced obesity and restored plasma glucose, insulin and leptin to control levels. Muscle contents of ADP and AMP were significantly increased, which was associated with enhanced mitochondrial oxidative phosphorylation and up-regulated expression of fatty acid oxidation enzymes and uncoupling proteins, UCP2 and UCP3 in the skeletal muscle. SB significantly enhanced the expression of adiponectin receptors (adipoR1/2) and AMP kinase (AMPK), while diminished the expression of histone deacetylase 1 (HDAC1). Higher H3K9Ac, a gene activation histone mark, was detected on the promoter of Adipor1/2, Ucp2 and Ucp3 genes that were activated in the muscle of SB-treated obese mice. Our results indicate that short-term oral administration of SB can alleviate diet-induced obesity and insulin resistance in mice through activation of adiponectin-mediated pathway and stimulation of mitochondrial function in the skeletal muscle.
Wnt signaling is one of the key oncogenic pathways in multiple cancers, and targeting this pathway is an attractive therapeutic approach. However, therapeutic success has been limited because of the ...lack of therapeutic agents for targets in the Wnt pathway and the lack of a defined patient population that would be sensitive to a Wnt inhibitor. We developed a screen for small molecules that block Wnt secretion. This effort led to the discovery of LGK974, a potent and specific small-molecule Porcupine (PORCN) inhibitor. PORCN is a membrane-bound O-acyltransferase that is required for and dedicated to palmitoylation of Wnt ligands, a necessary step in the processing of Wnt ligand secretion. We show that LGK974 potently inhibits Wnt signaling in vitro and in vivo, including reduction of the Wnt-dependent LRP6 phosphorylation and the expression of Wnt target genes, such as AXIN2 . LGK974 is potent and efficacious in multiple tumor models at well-tolerated doses in vivo, including murine and rat mechanistic breast cancer models driven by MMTV–Wnt1 and a human head and neck squamous cell carcinoma model (HN30). We also show that head and neck cancer cell lines with loss-of-function mutations in the Notch signaling pathway have a high response rate to LGK974. Together, these findings provide both a strategy and tools for targeting Wnt-driven cancers through the inhibition of PORCN.
Lead (Pb) is a toxic heavy metal pollutants and can damage male reproductive function. Selenium (Se) possesses an ability of antagonizing Pb toxicity. However, biological events in the process of Pb ...toxicity and mitigative effect of Se are not well understood. The aim of present research was to investigate potential mechanism of Se against Pb toxicity from the perspective of oxidative stress, heat shock response and autophagy in the spermatogonia and Leydig cell of chicken. The cells from one-day-old male Hyline chickens were treated with Se (0.5 μmol/L) and/or Pb (20 μmol/L) for 24 h, respectively. Cell viability, cell ultrastucture, Pb and Se concentrations, testosterone level, oxidative stress indicators and relative expression of heat shock proteins (HSPs) and autophagy-related genes were measured. The results showed that spermatogonia was more tolerant to Pb than Leydig cell; cell injury was confirmed via histological assessment, cell viability and testosterone level; oxidative stress was further indicated by the decrease of catalase, glutathione peroxidase, glutathione-s-transferase and superoxide dismutase activities and the increase of malondialdehyde and reactive oxygen species contents. Pb increased expression of HSPs (27, 40, 60, 70 and 90). Meanwhile Pb induced autophagy through up-regulation of autophagy-related proteins 5, Beclin 1, Dynein, light chain 3 (LC3)-I and LC3-II and down-regulation of mammalian target of rapamycin in two type cells of chicken. However, Se intervention mitigated the aforementioned alterations caused by Pb. In conclusion, Pb led to oxidative stress, which triggered heat shock response and autophagy; Se administration mitigated reproductive toxicity of Pb through strengthening antioxidant defense in the spermatogonia and Leydig cell of chicken.
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•Spermatogonia has higher tolerance to Pb and Se than Leydig cell.•Pb causes spermatogonia and Leydig cell injury and reduces testosterone secretion of Leydig cell.•Pb induces heat shock response and autophagy under burden of oxidative stress.•Se alleviates Pb-induced germ cell toxicity through relieving oxidative stress.
The misuse and abuse of antibiotics in livestock and poultry seriously endanger both human health and the continuously healthy development of the livestock and poultry breeding industry. ...Plant-derived bioactive compounds (curcumin, capsaicin, quercetin, resveratrol, catechin, lignans, etc.) have been widely studied in recent years, due to their extensive pharmacological functions and biological activities, such as anti-inflammatory, antioxidant, antistress, antitumor, antiviral, lowering blood glucose and lipids, and improving insulin sensitivity. Numerous studies have demonstrated that plant-derived bioactive compounds are able to enhance the host's ability to resist or diminish diseases by regulating the abundance of its gut microbiota, achieving great potential as a substitute for antibiotics. Recent developments in both humans and animals have also highlighted the major contribution of gut microbiota to the host's nutrition, metabolism, immunity, and neurological functions. Changes in gut microbiota composition are closely related to the development of obesity and can lead to numerous metabolic diseases. Mounting evidence has also demonstrated that plant-derived bioactive compounds, especially curcumin, can improve intestinal barrier function by regulating intestinal flora. Furthermore, bioactive constituents can be also directly metabolized by intestinal flora and further produce bioactive metabolites by the interaction between the host and intestinal flora. This largely enhances the protective effect of bioactive compounds on the host intestinal and whole body health, indicating that the bidirectional regulation between bioactive compounds and intestinal flora has great application potential in maintaining the host's intestinal health and preventing or treating various diseases. This review mainly summarizes the latest research progress in the bioregulation between gut microbiota and plant-derived bioactive compounds, together with its application potential in humans and animals, so as to provide theoretical support for the application of plant-derived bioactive compounds as new feed additives and potential substitutes for antibiotics in the livestock and poultry breeding industry. Overall, based on this review, it can be concluded that plant-derived bioactive compounds, by modulating gut microbiota, hold great promise toward the healthy development of both humans and animal husbandry.
To investigate whether the effect of maternal dietary protein on offspring lipid metabolism is mediated by microRNA (miRNA), fourteen Meishan sows were fed either low-protein (LP, half of standard ...protein (SP) level, n 7) or SP (n 7) diets throughout gestation and lactation periods. PPAR-γ and CCAAT/enhancer-binding protein-β (C/EBP-β) protein expression was evaluated. The expression of miRNA predicted to directly target PPAR-γ and C/EBP-β in the subcutaneous fat of offspring at weaning age was determined, and the functions of these potential miRNA were verified. The results showed that piglet body weight and back fat thickness were significantly decreased in the LP group compared with the SP group (P<0·05). The protein level of PPAR-γ was significantly decreased and C/EBP-β protein expression was also decreased, though not significantly (P=0·056), in the subcutaneous fat of the LP group. Furthermore, miRNA expression analysis showed that miR-130b, targeting the PPAR-γ 3'-untranslated region (UTR), and miR-374b, targeting the C/EBP-β 3'-UTR, were significantly increased in the LP group compared with the SP group; other candidate regulatory miRNA were expressed similarly in both groups. Dual luciferase activity assay results indicated that miR-130b directly recognised and bound to the 3'-UTR of PPAR-γ and thereby suppressed PPAR-γ gene expression. Similar results were found for miR-374b and the 3'-UTR of C/EBP-β. The present study showed that miR-130b and miR-374b are involved in the effect of maternal dietary protein on offspring lipid metabolism in pigs. These results shed new light on our understanding of the maternal effect on offspring lipid deposition.
Lead (Pb), a toxic pollutant, is toxic to the testis. However, biological events during testicular Pb poisoning were not well understood. Selenium (Se) has the ability to antagonize Pb toxicity. The ...purpose of this research was to clarify the relief mechanism of Se on testicular toxicity of Pb from the perspective of oxidative stress, inflammation, heat shock response, and autophagy in a chicken model. Sixty male Hyline chickens (7-day-old) were randomly assigned into four groups. The feeding program consisted of a commercial diet, a Se-supplemented diet (1 mg kg
−1
Se), a Pb-supplemented diet (350 mg L
−1
Pb), and a Se- and Pb-supplemented diet, respectively. On the 12th week, serums were collected to measure testosterone level and testes were removed to determine testis weight, histological structure, Pb and Se concentrations, oxidative stress indicators, and mRNA and protein expression of inflammatory cytokines, heat shock proteins, and autophagy-related genes. The results showed that Pb poisoning changed the histological structure of testes; decreased serum testosterone level, testis weight, catalase, glutathione-s-transferase, and total antioxidative capacity activities; increased hydrogen peroxide content; inhibited interleukin (IL)-2 and mammalian target of rapamycin expression; and promoted IL-4, IL-12β, heat shock proteins, Beclin 1, Dynein, autophagy-related proteins 5, light chain 3 (LC3)-I, and LC3-II expression in the testes of chickens. Se intervention mitigated the aforementioned alterations induced by Pb. In conclusion, Pb led to oxidative stress, which triggered inflammation, heat shock response, and autophagy. Se administration mitigated testicular toxicity of Pb mainly by mitigating oxidative stress in male chickens.
Exosomes (EXs) are the major types of extracellular vesicles (EVs) of 30-100 nm diameter that can be secreted by most cells to the extracellular environment. EXs transport endogenous cargoes ...(proteins, lipids, RNAs, etc.) to target cells and thereby triggers the release of these bioactive components, which then play important roles in regulating numerous biological processes under both physiological and pathological conditions. Throughout the studies in recent years, growing evidences have shown that EXs-derived non-coding RNAs (EXs-ncRNAs) are emerging as key players in cell-to-cell communication between adipose tissue and other related tissues in obesity and metabolic diseases. In this review, we will summarize the recent findings about EXs-ncRNAs, especially focus on the following aspects: 1) the biogenesis of EXs and emerging roles of EXs-ncRNAs, 2) the role of EXs-ncRNAs (EXs-miRNAs, EXs-lncRNAs, EXs-circRNAs, etc.) that were secreted by adipose-related tissues in promoting the differentiation of preadipocytes into mature and fully functional adipocytes, and 3) the crosstalk between the adipose tissue derived EXs-ncRNAs and the development of insulin resistance, obesity and various cancers. This review aims to reveal the emerging roles and mechanisms of EXs-ncRNAs in the mutual regulation of adipose tissue and its related tissues in obesity and metabolic diseases, so as to provide references for elucidating the etiology of obesity and related metabolic diseases and screening novel therapeutic targets.
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