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Metabolic disorders, such as lipid accumulation, insulin resistance, and inflammation, have been implicated in the pathogenesis of NAFLD/NASH. Both innate and recruited immune cells mediate the development of insulin resistance and NASH. Oxidative stress is also pivotal for the progression of NASH. Astaxanthin is a natural carotenoid mainly derived from microorganisms and marine organisms. Due to its special chemical structure, astaxanthin has strong antioxidant activity. β-Cryptoxanthin is a xanthophyll carotenoid specifically found in the Satsuma mandarin. β-Cryptoxanthin is readily absorbed and relatively abundant in human plasma, together with α-carotene, β-carotene, lycopene, lutein, and zeaxanthin. Calcitriol solubility dmso Considering the unique chemical properties of astaxanthin and β-cryptoxanthin and the complex pathogenic mechanism of NASH, astaxanthin and β-cryptoxanthin are regarded as a considerable compound for the prevention and treatment of NASH. This chapter comprehensively describes the mechanism of the application for astaxanthin and β-cryptoxanthin on the prevention and treatment of NASH from the aspects, including antioxidative stress, inhibition of inflammation and promotion of M2 macrophage polarization, improvement of mitochondrial oxidative respiration, amelioration of insulin resistance, and suppression of fibrosis.Nonalcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases worldwide and has garnered increasing attention in recent decades. NAFLD is characterized by a wide range of liver changes, from simple steatosis to nonalcoholic steatohepatitis (NASH), cirrhosis, and hepatocellular carcinoma. The pathogenesis of NAFLD/NASH is very complicated and involves lipid accumulation, insulin resistance, inflammation, and fibrogenesis. In addition, NAFLD is closely associated with complications such as obesity, dyslipidemia, and type 2 diabetes. In particular, the clinical spectrum, pathophysiology, and therapeutic options of NAFLD share many things in common with diabetes. Insulin resistance is an underlying basis for the pathogenesis of diabetes and NAFLD. This chapter focuses on the molecular mechanism involved in the pathogenesis of insulin resistance, diabetes, and NASH/NAFLD including those that drive disease progression such as oxidative stress, genetic and epigenetic mechanisms, adiponectin, cytokines, and immune cells.All the organisms that belong to the animal kingdom had been believed not to synthesize carotenoids de novo. However, several groups of arthropods, which contain aphids, spider mites, and flies belonging to the family Cecidomyiidae, have been unexpectedly shown to possess carotenoid biosynthesis genes of fungal origin since 2010. On the other hand, few reports have shown direct evidence corroborating the catalytic functions of the enzymes that the carotenogenic genes encode. In the present review, we want to overview the carotenoid biosynthetic pathway of the pea aphid (Acyrthosiphon pisum), which was elucidated through functional analysis of carotenogenic genes that exist on its genome using Escherichia coli that accumulates carotenoid substrates, in addition to carotenoid biosynthesis in the other carotenogenic arthropods.The intestines of insects are assumed to be the niche of various microbial groups, and a unique microflora could be formed under environmental conditions different from mammalian intestinal tracts. This chapter describes the bacterial flora formed in the intestines of two dragonfly species, "akatombo" (the red dragonfly; Sympetrum frequens) and "usubaki-tombo" (Pantala flavescens), which fly over a long distance, and carotenoid-producing microorganisms isolated from this flora. C30 carotenoids, which were produced by a bacterium Kurthia gibsonii isolated from S. frequens, were structurally determined.Among isoprenoids, carotenoids were the first group of compounds which were synthesized from foreign genes in non-carotenogenic Escherichia coli as a heterologous host. A great variety of carotenoids have been shown to be produced in E. coli due to the introduction of combinations of carotenoid biosynthesis genes, which were isolated from carotenogenic organisms. Carotenoids that have been produced in E. coli are mostly cyclic carotenoids that retain carbon 40 (C40) basic structure, except for acyclic carotene lycopene. On the other hand, acyclic carotenoids, which can also be produced in E. coli, comprise a group of carotenoids with diverse chain lengths, i.e., with C20, C30, C40, or C50 basic skeleton. As for acyclic C30, C40, and C50 carotenoids, carotenogenic genes of bacterial origin were needed, while a cleavage dioxygenase gene of higher-plant origin was utilized for the synthesis of acyclic C20 carotenoids. The present chapter is a review on the biosynthesis of such diverse acyclic carotenoids at the gene level.The biosynthesis of commercialized carotenoids (e.g., lycopene, β-carotene, zeaxanthin, and astaxanthin) using recombinant microorganisms is one of the reasonable and cost-effective alternatives to extraction from natural sources and chemical synthesis. Among heterologous hosts, Escherichia coli is one of the most useful and manageable. To date, many approaches using recombinant E. coli are available to produce various carotenoids. Here we outline the latest carotenoid production research using recombinant E. coli produced through pathway engineering and its future prospects.Nowadays, carotenoid biosynthetic pathways are sufficiently elucidated at gene levels in bacteria, fungi, and higher plants. Also, in pathway engineering for isoprenoid (terpene) production, carotenoids have been one of the most studied targets. However, in 1988 when the author started carotenoid research, almost no carotenoid biosynthesis genes were identified. It was because carotenogenic enzymes are easily inactivated when extracted from their organism sources, indicating that their purification and the subsequent cloning of the corresponding genes were infeasible or difficult. On the other hand, natural product chemistry of carotenoids had advanced a great deal. Thus, those days, carotenoid biosynthetic pathways had been proposed based mainly on the chemical structures of carotenoids without findings on relevant enzymes and genes. This chapter shows what happened on carotenoid research, when carotenoid biosynthesis genes met non-carotenogenic Escherichia coli around 1990, followed by subsequent developments.Actinobacteria is the phylum that has the biggest genome in the Bacteria domain and includes many colored species. Their pigment analysis revealed that structurally diverse carotenoids are responsible for their pigmentation. This chapter reviews the biosynthesis of the diverse carotenoids of Actinobacteria. Its carotenoids belong to three different types 1) carotenoid of C50 chain length, 2) carotenoids with aromatic end groups, and 3) keto carotenoid like canthaxanthin (β,β-carotene-4,4'-dione) or monocyclic keto-γ-carotene derivatives. Species from the genus Rhodococcus are the only known Actinobacteria with a simultaneous pathway to aromatic and to keto carotenoids.Haloarchaea are halophilic microorganisms belonging to the Archaea domain that inhabit salty environments (mainly soils and water) all around the world. Most of the genera included in this group are able to produce carotenoids at significant concentrations (even wild-type strains). The major carotenoid produced by the cells is bacterioruberin (and its derivatives), which is only produced by this kind of microbes. Nevertheless, the understanding of carotenoid metabolism in haloarchaea, its regulation, and the roles of carotenoid derivatives in this group of extreme microorganisms remains mostly unrevealed. Besides, potential biotechnological uses of haloarchaeal pigments are poorly explored. This work summarizes what it has been described so far about carotenoid production by haloarchaea, haloarchaeal carotenoid production at large scale, as well as the potential uses of haloarchaeal pigments in biotechnology and biomedicine.Oleaginous yeasts, Yarrowia lipolytica and Lipomyces starkeyi, can synthesize more than 20% of lipids per dry cell weight from a wide variety of substrates. This feature is attractive for cost-efficient production of industrial biodiesel fuel. These yeasts are also very promising hosts for the efficient production of more value-added lipophilic compound carotenoids, e.g., lycopene and astaxanthin, although they cannot naturally biosynthesize carotenoids. Here, we review recent progress in researches on carotenoid production by oleaginous yeasts, which include red yeasts that naturally produce carotenoids, e.g., Rhodotorula glutinis and Xanthophyllomyces dendrorhous. Our new results on pathway engineering of L. starkeyi for lycopene production are also revealed in the present review.Xanthophyllomyces dendrorhous (with Phaffia rhodozyma as its anamorphic state) is a basidiomycetous, moderately psychrophilic, red yeast belonging to the Cystofilobasidiales. Its red pigmentation is caused by the accumulation of astaxanthin, which is a unique feature among fungi. The present chapter reviews astaxanthin biosynthesis and acetyl-CoA metabolism in X. dendrorhous and describes the construction of a versatile platform for the production of carotenoids, such as astaxanthin, and other acetyl-CoA-derived compounds including fatty acids by using this fungus.Eukaryotic microalgae and prokaryotic cyanobacteria are diverse photosynthetic organisms that produce various useful compounds. Due to their rapid growth and efficient biomass production from carbon dioxide and solar energy, microalgae and cyanobacteria are expected to become cost-effective, sustainable bioresources in the future. These organisms also abundantly produce various carotenoids, but further improvement in carotenoid productivity is needed for a successful commercialization. Metabolic engineering via genetic manipulation and mutational breeding is a powerful tool for generating carotenoid-rich strains. This chapter focuses on carotenoid production in microalgae and cyanobacteria, as well as strategies and potential target genes for metabolic engineering. Recent achievements in metabolic engineering that improved carotenoid production in microalgae and cyanobacteria are also reviewed.In higher plants, there are many studies on carotenoid biosynthetic pathways and their relevant genes. On the other hand, few researches exist on carotenoid biosynthesis in early-land plants containing liverworts, mosses, and ferns. Thus, the evolutionary history of carotenoid biosynthesis genes in land plants has remained unclear. A liverwort Marchantia polymorpha is thought to be one of the first land plants, since this plant remains a primitive figure. Moreover, this liverwort is regarded as the model plant of bryophytes due to several reasons. In this chapter, we review carotenoid biosynthesis in liverworts and discuss the functional evolution and evolutionary history of carotenogenic genes in land plants.Multi-gene transformation methods need to be able to introduce multiple transgenes into plants in order to reconstitute a transgenic locus where the introduced genes express in a coordinated manner and do not segregate in subsequent generations. This simultaneous multiple gene transfer enables the study and modulation of the entire metabolic pathways and the elucidation of complex genetic control circuits and regulatory hierarchies. We used combinatorial nuclear transformation to produce multiplex-transgenic maize plants. In proof of principle experiments, we co-expressed five carotenogenic genes in maize endosperm. The resulting combinatorial transgenic maize plant population, equivalent to a "mutant series," allowed us to identify and complement rate-limiting steps in the extended endosperm carotenoid pathway and to recover corn plants with extraordinary levels of β-carotene and other nutritionally important carotenoids. We then introgressed the induced (transgenic) carotenoid pathway in a transgenic line accumulating high levels of nutritionally important carotenoids into a wild-type yellow-endosperm variety with a high βε ratio.