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  • Enzymes revolutionize the bioproduction of value-added compounds: From enzyme discovery to special applications
    Biotechnol. Adv. (IF 12.831) Pub Date : 2020-01-23
    Birgit Wiltschi; Tomislav Cernava; Alexander Dennig; Meritxell Galindo; Martina Geier; Steffen Gruber; Marianne Haberbauer; Petra Heidinger; Enrique Herrero Acero; Regina Kratzer; Christiane Luley-Goedl; Christina A. Müller; Julia Pitzer; Doris Ribitsch; Michael Sauer; Katharina Schmölzer; Wolfgang Schnitzhofer; Christoph W. Sensen; Tamara Wriessnegger

    Competitive sustainable production in industry demands new and better biocatalysts, optimized bioprocesses and cost-effective product recovery. Our review sheds light on the progress made for the individual steps towards these goals, starting with the discovery of new enzymes and their corresponding genes. The enzymes are subsequently engineered to improve their performance, combined in reaction cascades to expand the reaction scope and integrated in whole cells to provide an optimal environment for the bioconversion. Strain engineering using synthetic biology methods tunes the host for production, reaction design optimizes the reaction conditions and downstream processing ensures the efficient recovery of commercially viable products. Selected examples illustrate how modified enzymes can revolutionize future-oriented applications ranging from the bioproduction of bulk-, specialty- and fine chemicals, active pharmaceutical ingredients and carbohydrates, over the conversion of the greenhouse-gas CO2 into valuable products and biocontrol in agriculture, to recycling of synthetic polymers and recovery of precious metals.

  • Molecular farming – The slope of enlightenment
    Biotechnol. Adv. (IF 12.831) Pub Date : 2020-01-16
    Rainer Fischer; Johannes F. Buyel

    Molecular farming can be defined as the use of plants to produce recombinant protein products. The technology is now >30 years old. The early promise of molecular farming was based on three perceived advantages: the low costs of growing plants, the immense scalability of agricultural production, and the inherent safety of plants as hosts for the production of pharmaceuticals. This resulted in a glut of research publications in which diverse proteins were expressed in equally diverse plant-based systems, and numerous companies were founded hoping to commercialize the new technology. There was a moderate degree of success for companies producing non-pharmaceutical proteins, but in the pharmaceutical sector the anticipation raised by promising early research was soon met by the cold hard reality of industrial pragmatism. Plants did not have a track record of success in pharmaceutical protein manufacturing, lacked a regulatory framework, and did not perform as well as established industry platforms. Negative attitudes towards genetically modified plants added to the mix. By the early 2000s, major industry players started to lose interest and pharmaceutical molecular farming fell from a peak of expectation into a trough of disillusionment, just as predicted by the Gartner hype cycle. But many of the pioneers of molecular farming have refocused their activities and have worked to address the limitations that hampered the first generation of technologies. The field has now consolidated around a smaller number of better-characterized platforms and has started to develop standardized methods and best practices, mirroring the evolution of more mature industry sectors. Likewise, attention has turned from proof-of-principle studies to realistic techno-economic modeling to capture significant niche markets, replicating the success of the industrial molecular farming sector. Here we argue that these recent developments signify that pharmaceutical molecular farming is now climbing the slope of enlightenment and will soon emerge as a mature technology.

  • Mapping and refactoring pathway control through metabolic and protein engineering: The hexosamine biosynthesis pathway
    Biotechnol. Adv. (IF 12.831) Pub Date : 2020-01-15
    Pieter Coussement; David Bauwens; Gert Peters; Jo Maertens; Marjan De Mey

    Microorganisms possess a plethora of regulatory mechanisms to tightly control the flux through their metabolic network, allowing optimal behaviour in response to environmental conditions. However, these mechanisms typically counteract metabolic engineering efforts to rewire the metabolism with a view to overproduction. Hence, overcoming flux control is key in the development of microbial cell factories, illustrated in this contribution using the strictly controlled hexosamine biosynthesis pathway. The hexosamine biosynthesis pathway has recently garnered attention as gateway for the industrial biotechnological production of numerous mono-, oligo- and polysaccharidic compounds, composed of, i.a., glucosamine, N-acetylglucosamine, and neuraminic acid and with a vast application potential in the health, comsetics, and agricultural sector. First, the various alternative pathways in eukaryotes and prokaryotes are discussed. Second, the main regulatory mechanisms on transcriptional, translational and post-translational control, and the strategies to circumvent these pathway bottlenecks are highlighted. These efforts can serve as an inspiration to tackle regulatory control when optimizing any microbial cell factory.

  • Expanding the chemical diversity through microorganisms co-culture: Current status and outlook
    Biotechnol. Adv. (IF 12.831) Pub Date : 2020-01-15
    Divya Arora; Prasoon Gupta; Sundeep Jaglan; Catherine Roullier; Olivier Grovel; Samuel Bertrand

    Natural products (NPs) are considered as a cornerstone for the generation of bioactive leads in drug discovery programs. However, one of the major limitations of NP drug discovery program is “rediscovery” of known compounds, thereby hindering the rate of drug discovery efficiency. Therefore, in recent years, to overcome these limitations, a great deal of attention has been drawn towards understanding the role of microorganisms’ co-culture in inducing novel chemical entities. Such induction could be related to activation of genes which might be silent or expressed at very low levels (below detection limit) in pure-strain cultures under normal laboratory conditions. In this review, chemical diversity of compounds isolated from microbial co-cultures, is discussed. For this purpose, chemodiversity has been represented as a chemical-structure network based on the “Tanimoto Structural Similarity Index”. This highlights the huge structural diversity induced by microbial co-culture. In addition, the current trends in microbial co-culture research are highlighted. Finally, the current challenges (1 - induction monitoring, 2 - reproducibility, 3 - growth time effect and 4 - up-scaling for isolation purposes) are discussed. The information in this review will support researchers to design microbial co-culture strategies for future research efforts. In addition, guidelines for co-culture induction reporting are also provided to strengthen future reporting in this NP field.

  • Controlling biofilms using synthetic biology approaches
    Biotechnol. Adv. (IF 12.831) Pub Date : 2020-01-15
    Kuili Fang; Oh-Jin Park; Seok Hoon Hong
  • Cyanobacterial sigma factors: Current and future applications for biotechnological advances
    Biotechnol. Adv. (IF 12.831) Pub Date : 2020-01-13
    Amit Srivastava; Michael L. Summers; Roman Sobotka

    A sigma (σ) factor is a constituent of bacterial RNA polymerase that guides the holoenzyme to promoter sequences and initiates transcription. In addition to a primary housekeeping σ factor, bacteria contain a number of alternative σ factors which recognize a specific set of promoters. By replacing the primary σ factor with alternative variants, the cell controls transcription of the whole sets of genes, typically to acclimate to changes in the environment. As key regulatory elements, σ factors are frequent targets of genetic manipulation aimed at the improvement of bacterial stress tolerance and capacity for bioproduction. Cyanobacteria are a phylum of bacteria capable of oxygenic photosynthesis and there is a great interest to employ them as biochemical and biofuel production hosts. Engineering of σ factor genes has become an important strategy to improve robustness and suitability of cyanobacteria for the production of high-value metabolites such as polyhydroxybutyrate, succinate, sucrose or hydrogen. Here, we summarize the current knowledge about the regulatory role of different σ factor classes in cyanobacteria, highlighting their biotechnological potential.

  • Whole-cell biocatalysis using cytochrome P450 monooxygenases for biotransformation of sustainable bioresources (fatty acids, fatty alkanes, and aromatic amino acids)
    Biotechnol. Adv. (IF 12.831) Pub Date : 2020-01-08
    HyunA Park; Gyuyeon Park; Wooyoung Jeon; Jung-Oh Ahn; Yung-Hun Yang; Kwon-Young Choi

    Cytochrome P450s (CYPs) are heme-thiolated enzymes that catalyze the oxidation of CH bonds in a regio and stereoselective manner. Activation of the non-activated carbon atom can be further enhanced by multistep chemo-enzymatic reactions; moreover, several useful chemicals can be synthesized to provide alternative organic synthesis routes. Given their versatile functionality, CYPs show promise in a number of biotechnological fields. Recently, various CYPs, along with their sequences and functionalities, have been identified owing to rapid developments in sequencing technology and molecular biotechnology. In addition to these discoveries, attempts have been made to utilize CYPs to industrially produce biochemicals from available and sustainable bioresources such as oil, amino acids, carbohydrates, and lignin. Here, these accomplishments, particularly those involving the use of CYP enzymes as whole-cell biocatalysts for bioresource biotransformation, will be reviewed. Further, recently developed biotransformation pathways that result in gram-scale yields of fatty acids and fatty alkanes as well as aromatic amino acids, which depend on the hosts used for CYP expression, and the nature of the multistep reactions will be discussed. These pathways are similar regardless of whether the hosts are CYP-producing or non-CYP-producing; the limitations of these methods and the ways to overcome them are reviewed here.

  • Molecular priming as an approach to induce tolerance against abiotic and oxidative stresses in crop plants
    Biotechnol. Adv. (IF 12.831) Pub Date : 2019-12-31
    Pavel Kerchev; Tom van der Meer; Neerakkal Sujeeth; Arno Verlee; Christian V. Stevens; Frank Van Breusegem; Tsanko Gechev

    Abiotic stresses, including drought, salinity, extreme temperature, and pollutants, are the main cause of crop losses worldwide. Novel climate-adapted crops and stress tolerance-enhancing compounds are needed increasingly to counteract the negative effects of unfavorable stressful environments. A number of natural products and synthetic chemicals can protect model and crop plants against abiotic stresses through the ectopic induction of molecular and physiological defense mechanisms, a process known as molecular priming. In addition to their stress-protective effect, some of these compounds can also stimulate plant growth. Here, we provide an overview of the known physiological and molecular mechanisms behind the compounds that induce molecular priming, together with a survey of approaches to discover and functionally study new stress-alleviating chemicals.

  • The approved gene therapy drugs worldwide: from 1998 to 2019
    Biotechnol. Adv. (IF 12.831) Pub Date : 2019-12-27
    Cui-Cui Ma; Zhen-Ling Wang; Ting Xu; Zhi-Yao He; Yu-Quan Wei

    With the improvement of gene vectors, the rise of chimeric antigen receptor T cell immunotherapy and breakthroughs in the genome editing technology, gene therapy had once again returned to the central stage of disease treatment. It had brought new choices to clinical therapy of diseases such as tumors and genetic diseases, and had changed the status quo of treatment for monogenic disorders and diffuse large B-cell lymphoma. Until August 2019, 22 gene medicines had been approved by the drug regulatory agencies from various countries, but there were few relevant reviews of combing these drugs systematically. Consequently, this review summarizes the gene therapy drugs approved worldwide from 1998 to 2019 in details, including names, indications, dates of approval, companies, vectors, the applied technologies and mechanisms of gene therapy drugs, etc. Furthermore, the gene therapy drugs were classified and addressed in accordance with the employed vectors. Gene therapy had gradually been accepted by the government and the public since 1980s, and have become a new and important alternative to existing treatments for human diseases in the past few years. Therefore, gene therapy drugs, with safe vectors and advanced biotechnologies, would play a greater role in the prevention and treatment of human diseases in future.

  • Fungal potential for the degradation of petroleum-based polymers: An overview of macro- and microplastics biodegradation
    Biotechnol. Adv. (IF 12.831) Pub Date : 2019-12-20
    Carmen Sánchez

    Petroleum-based plastic materials as pollutants raise concerns because of their impact on the global ecosystem and on animal and human health. There is an urgent need to remove plastic waste from the environment to overcome the environmental crisis of plastic pollution. This review describes the natural and unique ability of fungi to invade substrates by using enzymes that have the capacity to detoxify pollutants and are able to act on nonspecific substrates, the fungal ability to produce hydrophobins for surface coating to attach hyphae to hydrophobic substrates, and hyphal ability to penetrate three dimensional substrates. Fungal studies on macro- and microplastics biodegradation have shown that fungi are able to use these materials as the sole carbon and energy source. Further research is required on novel isolates from plastisphere ecosystems, on the use of molecular techniques to characterize plastic-degrading fungi and enhance enzymatic activity levels, and on the use of omics-based technologies to accelerate plastic waste biodegradation processes. The addition of pro-oxidants species (photosensitizers) and the reduction of biocides and antioxidant stabilizers used in the plastic manufacturing process should also be considered to promote biodegradation. Interdisciplinary research and innovative fungal strategies for plastic waste biodegradation, as well as ecofriendly manufacturing of petroleum-based plastics, may help to reduce the negative impacts of plastic waste pollution in the biosphere.

  • Towards a new avenue for producing therapeutic proteins: Microalgae as a tempting green biofactory
    Biotechnol. Adv. (IF 12.831) Pub Date : 2019-12-18
    Jaber Dehghani; Khosro Adibkia; Ali Movafeghi; Hadi Maleki-Kakelar; Nazli Saeedi; Yadollah Omidi

    Most of the recent approved therapeutic proteins are multi-subunit biologics, which need glycosylation and disulfide bridges for the correct conformation and biological functions. Currently, there exist many protein-based drugs that are mostly produced in the Chinese hamster ovary (CHO) cells. However, this expression system appears to associate with some limitations both in upstream and downstream processing steps, including low growth rate, sensitivity to different stresses and pathogens, and time-consuming purification processes. Some microalgae species offer a suitable expression system for the production of a wide range of recombinant proteins due to their key features such as fast-growing rate, having no common pathogens with the human, being used as the human food, and providing the possibility for the large-scale production in the closed/controlled bioreactors. More importantly, the protein biosynthesis machinery of some microalgae seems to be relatively similar to those of the human and animal cells. In fact, microalgae can assemble fully functional complex proteins that can be safely used in humans. In this review, we provide comprehensive insights into the currently used expression systems for the production of therapeutic proteins and discuss the essential features of the microalgae as a novel protein expression platform.

  • Biotechnological potential and applications of microbial consortia
    Biotechnol. Adv. (IF 12.831) Pub Date : 2019-12-18
    Xiujuan Qian; Lin Chen; Yuan Sui; Chong Chen; Wenming Zhang; Jie Zhou; Weiliang Dong; Min Jiang; Fengxue Xin; Katrin Ochsenreither

    Recent advances in microbial consortia present a valuable approach for expanding the scope of metabolic engineering. Systems biology enable thorough understanding of diverse physiological processes of cells and their interactions, which in turn offers insights into the optimal design of synthetic microbial consortia. Yet, the study of synthetic microbial consortia is still in early infancy, facing many unknowns and challenges in intercellular communication and construction of stable and controllable microbial consortia systems. In this review, we comprehensively discussed the recent application of defined microbial consortia in the fields of human health monitoring and medicine exploitation, valuable compounds synthesis, consolidated bioprocessing of lignocellulosic materials and environmental bioremediation. Moreover, the outstanding challenges and future directions to advance the development of high-efficient, stable and controllable synthetic microbial consortia were highlighted.

  • Sperm selection in assisted reproduction: A review of established methods and cutting-edge possibilities
    Biotechnol. Adv. (IF 12.831) Pub Date : 2019-12-11
    Giuseppina Marzano, Maria Serena Chiriacò, Elisabetta Primiceri, Maria Elena Dell’Aquila, João Ramalho-Santos, Vincenzo Zara, Alessandra Ferramosca, Giuseppe Maruccio

    Male infertility often involves idiopathic or unknown causes, leading to an increasing demand for assisted reproduction technologies (ART). Conventional sperm sorting techniques rely on centrifugation steps that are known to cause oxidative stress and consequently damage cells. Alternative novel techniques have been introduced but offer disadvantages that need to be overcome. These techniques are also employed to increase the number and the quality of subjects in the animal breeding industry, to obtain purebred subjects or to preserve endangered animal species. Microfluidics deals with the manipulation of small amounts of volume within a microdevice known as lab-on-a-chip (LOC), which offers rapid analyses, ease of use, small reagent sample volumes, high-throughput processing and wide reproducibility owing to automation and standardization. As the LOC allows gamete handling within a microenvironment that strictly mimics physiological in vivo conditions and avoids centrifugation steps and long processing time, the use of microfluidics for sperm sorting and selection have been proposed during the last 15 years and is currently under investigation. Moreover, LOC technologies to sort, identify and analyse other kinds of cells could be transferred to sperm selection and analysis, thus opening the way to a novel approach to the sperm cell selection and manipulation. This review describes the techniques routinely performed in human and animal clinical practice for sorting good-quality sperm for in vitro fertilization procedures, and focuses on the positive and negative aspects of each method. Emerging microfluidic devices, recently proposed for sperm selection, are also described and, when possible, compared with standard methods.

  • Cellular engineering strategies toward sustainable omega-3 long chain polyunsaturated fatty acids production: State of the art and perspectives
    Biotechnol. Adv. (IF 12.831) Pub Date : 2019-12-09
    Jinjin Diao, Xinyu Song, Taohong Guo, Fangzhong Wang, Lei Chen, Weiwen Zhang

    Long-chain polyunsaturated fatty acids (LC-PUFAs) especially ω-3 fatty acids provide significant health benefits for human beings. However, ω-3 LC-PUFAs cannot be synthesized de novo in mammals. Traditionally, ω-3 LC-PUFAs are extracted from marine fish, and their production depends on sea fishing, which has not met ever-increasing global demand. To address the challenges, innovative cellular engineering strategies need to be developed. In nature, many fungi and microalgae are rich in ω-3 LC-PUFAs, representing promising sources of ω-3 LC-PUFAs. The latest progress in developing new cellular engineering strategies toward sustainable ω-3 LC-PUFAs production using fungi and microalga has demonstrated that they can to some extent address the supply shortage. In this review, we critically summarize the recent progress in enhancing the productivity in various ω-3 LC-PUFAs-producing organisms, as well as the latest efforts of biosynthesizing PUFAs in heterogenous biosystems. In addition, we also provide future perspectives in developing genetic toolkits for LC-PUFAs producing microbes so that cut-edging biotechnology such as gene stacking and genome editing can be further applied to increase the productivity of ω-3 LC-PUFAs.

  • Biological and conventional food processing modifications on food proteins: Structure, functionality, and bioactivity
    Biotechnol. Adv. (IF 12.831) Pub Date : 2019-11-20
    Di Wu, Maolin Tu, Zhenyu Wang, Chao Wu, Cuiping Yu, Maurizio Battino, Hesham R. El-Seedi, Ming Du

    Food proteins are important nutrients for human health and thus make significant contributions to the unique functions of different foods. The modification of proteins through physical and biological processing could improve the functional and nutritional properties of food products; these changes can be attributed to modifications in particle size, solubility, emulsion stability, secondary structure, as well as the bioactivities of the proteins. Physical processing treatments might promote physical phenomena, such as combined friction, collision, shear forces, turbulence, and cavitation of particles, and lead to changes in the particle sizes of proteins. The objective of this review is to illustrate the effect of physical and biological processing on the structure, and physical and chemical properties of food-derived proteins and provide insights into the mechanism underlying structural changes. Many studies have suggested that physical and biological processes, such as ultrasound treatment, high pressure homogenization, ball mill treatment, and enzymatic hydrolysis could affect the structure, physical properties, and chemical properties of food-derived proteins. Some important applications of food-derived proteins are also discussed based on the relationships between their physical, chemical, and functional properties. Perspectives from fundamental or practical research are also brought in to provide a complete picture of the currently available relevant data.

  • Biocatalytic derivatization of proteinogenic amino acids for fine chemicals
    Biotechnol. Adv. (IF 12.831) Pub Date : 2019-11-19
    Wei Song, Xiulai Chen, Jing Wu, Jianzhong Xu, Weiguo Zhang, Jia Liu, Jian Chen, Liming Liu

    Amino acids (AAs), which contain various functional groups including α-amino group, α-carboxyl group, and certain specific side-chains, exhibit a wide range of chemical properties. The derivatization of these functional groups of AAs via biocatalysis represents a sustainable approach for producing various chemicals, such as α-keto acids, α-hydroxyl acids, non-proteinogenic AAs, amines, peptides, higher alcohols, and phenylpropanoids, that are valuable in the pharmaceutical, chemical synthesis, cosmetic, and food industries. Here, we review recent advances in the derivatization of AAs to describe the design of derivatization reactions, how to overcome technical bottlenecks, and the potential range of chemicals that may be obtained. Furthermore, we highlight future prospects and address the challenges that remain in the derivatization of AAs for the production of fine chemicals.

  • Genetic transformation of Triticeae cereals – Summary of almost three-decade's development
    Biotechnol. Adv. (IF 12.831) Pub Date : 2019-11-18
    Goetz Hensel

    Triticeae cereals are among the most important crop plants grown worldwide and being used for animal feed, food and beverages. Although breeding efforts evolved over the last ten thousand years our today's crop plants, biotechnological methods would help to speed up the process and incorporate traits impossible by conventional breeding. The main research topics were related to cover the future demand on our agricultural practices to supply sufficient food for a growing world population. Target traits are resistances against viral and fungal diseases, improvement of water and nitrogen use efficiency, to tackle plant architecture, both below and aboveground and to develop varieties that could grow on dry or salty locations. Other applications are considering accumulation of useful compounds or decreasing allergenicity. This review will summarize methods to generate the material including a section how genome engineering using gRNA/Cas (CRISPR/Cas) technology could further improve the methodology and will give an overview about recent and future applications.

  • Triterpenoid-biosynthetic UDP-glycosyltransferases from plants
    Biotechnol. Adv. (IF 12.831) Pub Date : 2019-05-09
    Shadi Rahimi, Jaewook Kim, Ivan Mijakovic, Ki-Hong Jung, Giltsu Choi, Sun-Chang Kim, Yu-Jin Kim

    Triterpenoid saponins are naturally occurring structurally diverse glycosides of triterpenes that are widely distributed among plant species. Great interest has been expressed by pharmaceutical and agriculture industries for the glycosylation of triterpenes. Such modifications alter their taste and bio-absorbability, affect their intra−/extracellular transport and storage in plants, and induce novel biological activities in the human body. Uridine diphosphate (UDP)-glycosyltransferases (UGTs) catalyze glycosylation using UDP sugar donors. These enzymes belong to a multigene family and recognize diverse natural products, including triterpenes, as the acceptor molecules. For this review, we collected and analyzed all of the UGT sequences found in Arabidopsis thaliana as well as 31 other species of triterpene-producing plants. To identify potential UGTs with novel functions in triterpene glycosylation, we screened and classified those candidates based on similarity with UGTs from Panax ginseng, Glycine max, Medicago truncatula, Saponaria vaccaria, and Barbarea vulgaris that are known to function in glycosylate triterpenes. We highlight recent findings on UGT inducibility by methyl jasmonate, tissue-specific expression, and subcellular localization, while also describing their catalytic activity in terms of regioselectivity for potential key UGTs dedicated to triterpene glycosylation in plants. Discovering these new UGTs expands our capacity to manipulate the biological and physicochemical properties of such valuable molecules.

  • A comparison between the homocyclic aromatic metabolic pathways from plant-derived compounds by bacteria and fungi
    Biotechnol. Adv. (IF 12.831) Pub Date : 2019-05-07
    Ronnie J.M. Lubbers, Adiphol Dilokpimol, Jaap Visser, Miia R. Mäkelä, Kristiina S. Hildén, Ronald P. de Vries

    Aromatic compounds derived from lignin are of great interest for renewable biotechnical applications. They can serve in many industries e.g. as biochemical building blocks for bioplastics or biofuels, or as antioxidants, flavor agents or food preservatives. In nature, lignin is degraded by microorganisms, which results in the release of homocyclic aromatic compounds. Homocyclic aromatic compounds can also be linked to polysaccharides, tannins and even found freely in plant biomass. As these compounds are often toxic to microbes already at low concentrations, they need to be degraded or converted to less toxic forms. Prior to ring cleavage, the plant- and lignin-derived aromatic compounds are converted to seven central ring-fission intermediates, i.e. catechol, protocatechuic acid, hydroxyquinol, hydroquinone, gentisic acid, gallic acid and pyrogallol through complex aromatic metabolic pathways and used as energy source in the tricarboxylic acid cycle. Over the decades, bacterial aromatic metabolism has been described in great detail. However, the studies on fungal aromatic pathways are scattered over different pathways and species, complicating a comprehensive view of fungal aromatic metabolism. In this review, we depicted the similarities and differences of the reported aromatic metabolic pathways in fungi and bacteria. Although both microorganisms share the main conversion routes, many alternative pathways are observed in fungi. Understanding the microbial aromatic metabolic pathways could lead to metabolic engineering for strain improvement and promote valorization of lignin and related aromatic compounds.

  • From lignocellulosic residues to market: Production and commercial potential of xylooligosaccharides
    Biotechnol. Adv. (IF 12.831) Pub Date : 2019-05-07
    Cláudia Amorim, Sara C. Silvério, Kristala L.J. Prather, Lígia R. Rodrigues

    The updated definition of prebiotic expands the range of potential applications in which emerging xylooligosaccharides (XOS) can be used. It has been demonstrated that XOS exhibit prebiotic effects at lower amounts compared to others, making them competitively priced prebiotics. As a result, the industry is focused on developing alternative approaches to improve processes efficiency that can meet the increasing demand while reducing costs. Recent advances have been made towards greener and more efficient processes, by applying process integration strategies to produce XOS from costless lignocellulosic residues and using genetic engineering to create microorganisms that convert these residues to XOS. In addition, collecting more in vivo data on their performance will be key to achieve regulatory claims, greatly increasing XOS commercial value.

  • Microbial production of cyanophycin: From enzymes to biopolymers
    Biotechnol. Adv. (IF 12.831) Pub Date : 2019-05-13
    Jikun Du, Li Li, Shining Zhou

    Cyanophycin is an attractive biopolymer with chemical and material properties that are suitable for industrial applications in the fields of food, medicine, cosmetics, nutrition, and agriculture. For efficient production of cyanophycin, considerable efforts have been exerted to characterize cyanophycin synthetases (CphAs) and optimize fermentations and downstream processes. In this paper, we review the characteristics of diverse CphAs from cyanobacteria and non-cyanobacteria. Furthermore, strategies for cyanophycin production in microbial strains, including Escherichia coli, Pseudomonas putida, Ralstonia eutropha, Rhizopus oryzae, and Saccharomyces cerevisiae, heterologously expressing different cphA genes are reviewed. Additionally, chemical and material properties of cyanophycin and its derivatives produced through biological or chemical modifications are reviewed in the context of their industrial applications. Finally, future perspectives on microbial production of cyanophycin are provided to improve its cost-effectiveness.

  • 更新日期:2019-11-18
  • Modular design: Implementing proven engineering principles in biotechnology
    Biotechnol. Adv. (IF 12.831) Pub Date : 2019-06-07
    Sergio Garcia, Cong T. Trinh

    Modular design is at the foundation of contemporary engineering, enabling rapid, efficient, and reproducible construction and maintenance of complex systems across applications. Remarkably, modularity has recently been discovered as a governing principle in natural biological systems from genes to proteins to complex networks within a cell and organism communities. The convergent knowledge of natural and engineered modular systems provides a key to drive modern biotechnology to address emergent challenges associated with health, food, energy, and the environment. Here, we first present the theory and application of modular design in traditional engineering fields. We then discuss the significance and impact of modular architectures on systems biology and biotechnology. Next, we focus on the very recent theoretical and experimental advances in modular cell engineering that seeks to enable rapid and systematic development of microbial catalysts capable of efficiently synthesizing a large space of useful chemicals. We conclude with an outlook towards theoretical and practical opportunities for a more systematic and effective application of modular cell engineering in biotechnology.

  • Production of fuels and chemicals from renewable resources using engineered Escherichia coli
    Biotechnol. Adv. (IF 12.831) Pub Date : 2019-06-04
    Chunhua Zhao, Yanping Zhang, Yin Li

    Biotechnological production of fuels and chemicals from renewable resources is an appealing way to move from the current petroleum-based economy to a biomass-based green economy. Recently, the feedstocks that can be used for bioconversion or fermentation have been expanded to plant biomass, microbial biomass, and industrial waste. Several microbes have been engineered to produce chemicals from renewable resources, among which Escherichia coli is one of the best studied. Much effort has been made to engineer E. coli to produce fuels and chemicals from different renewable resources. In this paper, we focused on E. coli and systematically reviewed a range of fuels and chemicals that can be produced from renewable resources by engineered E. coli. Moreover, we proposed how can we further improve the efficiency for utilizing renewable resources by engineered E. coli, and how can we engineer E. coli for utilizing alternative renewable feedstocks. e.g. C1 gases and methanol. This review will help the readers better understand the current progress in this field and provide insights for further metabolic engineering efforts in E. coli.

  • A critical review on use of Agrobacterium rhizogenes and their associated binary vectors for plant transformation
    Biotechnol. Adv. (IF 12.831) Pub Date : 2019-06-08
    Bahman Bahramnejad, Mohammad Naji, Rahul Bose, Sumita Jha

    Agrobacterium rhizogenes, along with A. tumefaciens, has been used to affect genetic transformation in plants for many years. Detailed studies conducted in the past have uncovered the basic mechanism of foreign gene transfer and the implication of Ri/Ti plasmids in this process. A number of reviews exist describing the usage of binary vectors with A. tumefaciens, but no comprehensive account of the numerous binary vectors employed with A. rhizogenes and their successful applications has been published till date. In this review, we recollect a brief history of development of Ri-plasmid/Ri-T-DNA based binary vectors systems and their successful implementation with A. rhizogenes for different applications. The modification of native Ri plasmid to introduce foreign genes followed by development of binary vector using Ri plasmid and how it facilitated rapid and feasible genetic manipulation, earlier impossible with native Ri plasmid, have been discussed. An important milestone was the development of inducible plant expressing promoter systems which made expression of toxic genes in plant systems possible. The successful application of binary vectors in conjunction with A. rhizogenes in gene silencing and genome editing studies which are relatively newer developments, demonstrating the amenability and adaptability of hairy roots systems to make possible studying previously intractable research areas have been summarized in the present review.

  • Multi-enzyme systems and recombinant cells for synthesis of valuable saccharides: Advances and perspectives
    Biotechnol. Adv. (IF 12.831) Pub Date : 2019-06-11
    Jiangang Yang, Tong Zhang, Chaoyu Tian, Yueming Zhu, Yan Zeng, Yan Men, Peng Chen, Yuanxia Sun, Yanhe Ma

    Saccharides have recently attracted considerable attention because of their biological functions and potential applications in the pharmaceutical, cosmetic and food industries. Over the decades, a large amount of enzymes involved in saccharide synthesis have been discovered and characterised with the aid of available genome sequences. The advancement of metabolic engineering and synthetic biology strategies facilitated the artificial pathway design and construction for production of multiple sugars in vitro and in vivo based on those characterized enzymes. This review presented a panoramic view of enzymes related to saccharide synthesis and gave the detailed information. Furthermore, we provide an extensive overview of the recent advances in the construction of cell-free reaction systems and engineering of microbial cells for the production of natural or unnatural saccharides. In addition, the future trends in the synthesis of sugars with high structural diversity through the combination of multiple pathways are presented and evaluated.

  • Microbial production of short and medium chain esters: Enzymes, pathways, and applications
    Biotechnol. Adv. (IF 12.831) Pub Date : 2019-06-11
    Aleksander J. Kruis, Anna C. Bohnenkamp, Constantinos Patinios, Youri M. van Nuland, Mark Levisson, Astrid E. Mars, Corjan van den Berg, Servé W.M. Kengen, Ruud A. Weusthuis

    Sustainable production of bulk chemicals is one of the major challenges in the chemical industry, particularly due to their low market prices. This includes short and medium chain esters, which are used in a wide range of applications, for example fragrance compounds, solvents, lubricants or biofuels. However, these esters are produced mainly through unsustainable, energy intensive processes. Microbial conversion of biomass-derived sugars into esters may provide a sustainable alternative. This review provides a broad overview of natural ester production by microorganisms. The underlying ester-forming enzymatic mechanisms are discussed and compared, with particular focus on alcohol acyltransferases (AATs). This large and versatile group of enzymes condense an alcohol and an acyl-CoA to form esters. Natural production of esters typically cannot compete with existing petrochemical processes. Much effort has therefore been invested in improving in vivo ester production through metabolic engineering. Identification of suitable AATs and efficient alcohol and acyl-CoA supply are critical to the success of such strategies and are reviewed in detail. The review also focusses on the physical properties of short and medium chain esters, which may simplify downstream processing, while limiting the effects of product toxicity. Furthermore, the esters could serve as intermediates for the synthesis of other compounds, such as alcohols, acids or diols. Finally, the perspectives and major challenges of microorganism-derived ester synthesis are presented.

  • Classification and enzyme kinetics of formate dehydrogenases for biomanufacturing via CO2 utilization
    Biotechnol. Adv. (IF 12.831) Pub Date : 2019-06-12
    Christian Førgaard Nielsen, Lene Lange, Anne S. Meyer

    The reversible interconversion of formate (HCOO−) and carbon dioxide (CO2) is catalyzed by formate dehydrogenase (FDH, EC This enzyme can be used as a first step in the utilization of CO2 as carbon substrate for production of high-in-demand chemicals. However, comparison and categorization of the very diverse group of FDH enzymes has received only limited attention. With specific emphasis on FDH catalyzed CO2 reduction to HCOO−, we present a novel classification scheme for FDHs based on protein sequence alignment and gene organization analysis. We show that prokaryotic FDHs can be neatly divided into six meaningful sub-types. These sub-types are discussed in the context of overall structural composition, phylogeny of the gene segment organization, metabolic role, and catalytic properties of the enzymes. Based on the available literature, the influence of electron donor choice on the efficacy of FDH catalyzed CO2 reduction is quantified and compared. This analysis shows that methyl viologen and hydrogen are several times more potent than NADH as electron donors. Hence, the new FDH classification scheme and the electron donor analysis provide an improved base for developing FDH-facilitated CO2 reduction as a viable step in the utilization of CO2 as carbon source for green production of chemicals.

  • Advances in liquid formulations of parenteral therapeutic proteins
    Biotechnol. Adv. (IF 12.831) Pub Date : 2019-06-27
    Robert J. Falconer

    Liquid formulation of therapeutic proteins is a maturing technology. Demand for products that are easy to use in the clinic or that are amenable to self-administration make a ready to use liquid formulation desirable. Most modern liquid formulations have a simple composition; comprising a buffer, a tonicity modifier, a surfactant, sometimes a stabiliser, the therapeutic protein and water. Recent formulations of monoclonal antibodies often use histidine or acetate as the buffer, sucrose or trehalose as the tonicity modifier and polysorbate 20 or 80 as the surfactant with a pH of 5.7 +/− 0.4. The mechanisms for the behaviour of excipients is still debated by academics so formulation design is still a black art. Fortunately, a statistical approach like design of experiment is suitable for formulation development and has been successful when combined with accelerated stability experimentation. The development of prefilled syringes and pens has added low viscosity and shear resistance to the quality attributes for a successful formulation. To achieve patient compliance for self-administration, formulations that cause minimal pain and tissue damage is also desirable.

  • CAR-T immunotherapies: Biotechnological strategies to improve safety, efficacy and clinical outcome through CAR engineering
    Biotechnol. Adv. (IF 12.831) Pub Date : 2019-06-25
    Theano I. Panagopoulou, Qasim A. Rafiq

    T cells engineered to express a chimeric antigen receptor (CAR) have re-shaped the way hematological malignancies are treated. Despite the overwhelming early clinical success, CAR-T therapies are associated with severe side-effects, disease relapse and often exhibit limited efficacy. In this Review article we summarize the most recent biotechnological advances that have been developed to enhance the efficacy and specificity of CAR-T therapies, as well as to address the key challenges associated with them. We place particular emphasis on the most recent clinical data that indicate which CAR-T populations are the most relevant to clinical success, and indicate how the molecular structure of the CAR receptor can affect clinical outcome. Finally, we outline what we believe is the next generation of immunotherapies.

  • Plant cell-made protein antigens for induction of Oral tolerance
    Biotechnol. Adv. (IF 12.831) Pub Date : 2019-06-26
    Henry Daniell, Michael Kulis, Roland W. Herzog

    The gut associated lymphoid tissue has effective mechanisms in place to maintain tolerance to food antigens. These can be exploited to induce antigen-specific tolerance for the prevention and treatment of autoimmune diseases and severe allergies and to prevent serious immune responses in protein replacement therapies for genetic diseases. An oral tolerance approach for the prevention of peanut allergy in infants proved highly efficacious and advances in treatment of peanut allergy have brought forth an oral immunotherapy drug that is currently awaiting FDA approval. Several other protein antigens made in plant cells are in clinical development. Plant cell-made proteins are protected in the stomach from acids and enzymes after their oral delivery because of bioencapsulation within plant cell wall, but are released to the immune system upon digestion by gut microbes. Utilization of fusion protein technologies facilitates their delivery to the immune system, oral tolerance induction at low antigen doses, resulting in efficient induction of FoxP3+ and latency-associated peptide (LAP)+ regulatory T cells that express immune suppressive cytokines such as IL-10. LAP and IL-10 expression represent potential biomarkers for plant-based oral tolerance. Efficacy studies in hemophilia dogs support clinical development of oral delivery of bioencapsulated antigens to prevent anti-drug antibody formation. Production of clinical grade materials in cGMP facilities, stability of antigens in lyophilized plant cells for several years when stored at ambient temperature, efficacy of oral delivery of human doses in large animal models and lack of toxicity augur well for clinical advancement of this novel drug delivery concept.

  • Turning food waste to energy and resources towards a great environmental and economic sustainability: An innovative integrated biological approach
    Biotechnol. Adv. (IF 12.831) Pub Date : 2019-06-26
    Yingqun Ma, Yu Liu

    Food waste (FW) management is a global conundrum because of the rapid population growth and growing economic activity. Currently, incineration and landfill are still the main means for FW management, while their environmental sustainability and economic viability have been in question. Recently, the biological processes including anaerobic digestion, aerobic composting, bioethanol fermentation, feed fermentation etc. have attracted increasing interest with the aims for energy and resource recovery from FW. However, these biological approaches have inherent drawbacks, and cannot provide a comprehensive solution for future FW management. Therefore, this review attempts to offer a critical and holistic analysis of current biotechnologies for FW management with the focus on the challenges and solutions forward. The biological approaches towards future FW management should be able to achieve both environmental sustainability and economic viability. In this instance, the concept of zero solid discharge-driven resource recovery has thus been put forward. According to which, several innovative biological processes for FW management are further elucidated with critical analysis on their engineering feasibility and environmental sustainability. It turns out that is an urgent need for turning current single task-orientated bioprocess to an integrated biological process with multiple tasks of concurrent recovery of water, resource and energy together with zero-solid discharge.

  • Biofouling effects on the performance of microbial fuel cells and recent advances in biotechnological and chemical strategies for mitigation
    Biotechnol. Adv. (IF 12.831) Pub Date : 2019-07-22
    Md.T. Noori, M.M. Ghangrekar, C.K. Mukherjee, Booki Min

    The occurrence of biofouling in MFC can cause severe problems such as hindering proton transfer and increasing the ohmic and charge transfer resistance of cathodes, which results in a rapid decline in performance of MFC. This is one of the main reasons why scaling-up of MFCs has not yet been successfully accomplished. The present review article is a wide-ranging attempt to provide insights to the biofouling mechanisms on surfaces of MFC, mainly on proton exchange membranes and cathodes, and their effects on performance of MFC based on theoretical and practical evidence. Various biofouling mitigation techniques for membranes are discussed, including preparation of antifouling composite membranes, modification of the physical and chemical properties of existing membranes, and coating with antifouling agents. For cathodes of MFC, use of Ag nanoparticles, Ag-based composite nanoparticles, and antifouling chemicals is outlined in considerable detail. Finally, prospective techniques for mitigation of biofouling are discussed, which have not been given much previous attention in the field of MFC research. This article will help to enhance understanding of the severity of biofouling issues in MFCs and provides up-to-date solutions. It will be beneficial for scientific communities for further strengthening MFC research and will also help in progressing this cutting-edge technology to scale-up, using the most efficient methods as described here.

  • The potential of microalgae and their biopolymers as structuring ingredients in food: A review
    Biotechnol. Adv. (IF 12.831) Pub Date : 2019-07-21
    Tom M.M. Bernaerts, Lore Gheysen, Imogen Foubert, Marc E. Hendrickx, Ann M. Van Loey

    Microalgae are considered promising functional food ingredients due to their balanced composition, containing multiple nutritional and health-beneficial components. However, their functionality in food products is not limited to health aspects, since microalgae can also play a structuring role in food, for instance as a texturizing ingredient. Photoautotrophic microalgae are actually rich in structural biopolymers such as proteins, storage polysaccharides, and cell wall related polysaccharides, and their presence might possibly alter the rheological properties of the enriched food product. A first approach to benefit from these structural biopolymers consists of isolating the cell wall related polysaccharides for use as food hydrocolloids. The potential of extracted cell wall polysaccharides as food hydrocolloids has only been shown for a few microalgae species, mainly due to an enormous diversity in molecular structure and composition. Nevertheless, with intrinsic viscosities comparable or higher than those of commercial thickening agents, extracellular polysaccharides of red microalgae and cyanobacteria could be a promising source of novel food hydrocolloids. A more sustainable approach would be to incorporate the whole microalgal biomass into food products, to combine health benefits with potential structuring benefits, i.e. providing desired rheological properties of the enriched food product. If microalgal biomass would act as a thickening agent, this would actually reduce the need for additional texturizing ingredients. Even though only limitedly studied so far, food processing operations have been proven successful in establishing desired microstructural and rheological properties. In fact, the use of cell disruption techniques allows the release of intracellular compounds, which become available to create strong particle aggregates resulting in an improved viscosity and network structure. Food processing operations might not only be favorable in terms of rheological properties, but also for enhancing the bioaccessibility of several bioactive compounds. However, this research area is only very scarcely explored, and there is a demand for more standardized research studies to draw conclusions on the effect of processing on the nutritional quality of food products enriched with microalgae. Even though considered as promising food ingredients, some major scientific challenges have been pointed out throughout this review paper for the successful design of microalgal based food products.

  • Biocatalysis in ionic liquids for lignin valorization: Opportunities and recent developments
    Biotechnol. Adv. (IF 12.831) Pub Date : 2019-07-18
    Joseph C. Stevens, Jian Shi

    Lignin holds tremendous potential as a renewable feedstock for upgrading to a number of high-value chemicals and products that are derived from the petroleum industry at present. Since lignin makes up a significant fraction of lignocellulosic biomass, co-utilization of lignin in addition to cellulose and hemicelluloses is vital to the economic viability of cellulosic biorefineries. The recalcitrant nature of lignin, originated from the molecule's compositional and structural heterogeneity, however, poses great challenges toward effective and selective lignin depolymerization and valorization. Ionic liquid (IL) is a powerful solvent that has demonstrated high efficiency in fractionating lignocellulosic biomass into sugar streams and a lignin stream of reduced molecular weight. Compared to thermochemical methods, biological lignin deconstruction takes place at mild temperature and pressure while product selectivity can be potentially improved via the specificity of biocatalysts (lignin degrading enzymes, LDEs). This review focuses on a lignin valorization strategy by harnessing the biomass fractionating capabilities of ILs and the substrate and product selectivity of LDEs. Recent advances in elucidating enzyme-IL interactions as well as strategies for improving enzyme activity in IL are discussed, with specific emphases on biocompatible ILs, thermostable and IL-tolerant enzymes, enzyme immobilization, and surface charge engineering. Also reviewed is the protein engineering toolsets (directed evolution and rational design) to improve the biocatalysts' activity, stability and product selectivity in IL systems. The alliance between IL and LDEs offers a great opportunity for developing a biocatalytic route for lignin valorization.

  • Diatom isoprenoids: Advances and biotechnological potential
    Biotechnol. Adv. (IF 12.831) Pub Date : 2019-07-18
    Anastasia Athanasakoglou, Sotirios C. Kampranis

    Diatoms are among the most productive and ecologically important groups of microalgae in contemporary oceans. Due to their distinctive metabolic and physiological features, they offer exciting opportunities for a broad range of commercial and industrial applications. One such feature is their ability to synthesize a wide diversity of isoprenoid compounds. However, limited understanding of how these molecules are synthesized have until recently hindered their exploitation. Following comprehensive genomic and transcriptomic analysis of various diatom species, the biosynthetic mechanisms and regulation of the different branches of the pathway are now beginning to be elucidated. In this review, we provide a summary of the recent advances in understanding diatom isoprenoid synthesis and discuss the exploitation potential of diatoms as chassis for high-value isoprenoid synthesis.

  • Artificial humification of lignin architecture: Top-down and bottom-up approaches
    Biotechnol. Adv. (IF 12.831) Pub Date : 2019-07-16
    Jeong Gu Lee, Ho Young Yoon, Joon-Yung Cha, Woe-Yeon Kim, Pil Joo Kim, Jong-Rok Jeon

    Humic substances readily identifiable in the environment are involved in several biotic and abiotic reactions affecting carbon turnover, soil fertility, plant nutrition and stimulation, xenobiotic transformation and microbial respiration. Inspired by natural roles of humic substances, several applications of these substances, including crop stimulants, redox mediators, anti-oxidants, human medicines, environmental remediation and fish feeding, have been developed. The annual market for humic substances has grown rapidly for these reasons and due to eco-conscious features, but there is a limited supply of natural coal-related resources such as lignite and leonardite from which humic substances are extracted in bulk. The structural similarity between humic substances and lignin suggests that lignocellulosic refinery resulting in lignin residues as a by-product could be a potential candidate for a bulk source of humic-like substances, but structural differences between the two polymeric materials indicate that additional transformation procedures allowing lignin architecture to fully mimic commercial humic substances are required. In this review, we introduce the emerging concept of artificial humification of lignin-related materials as a promising strategy for lignin valorization. First, the core structural features of humic substances and the relationship between these features and the physicochemical properties, natural functions and versatile applications of the substances are described. In particular, the mechanism by which humic substances stimulate the growth of plants and hence can improve crop productivity is highlighted. Second, top-down and bottom-up transformation pathways for scalable humification of small lignin-derived phenols, technical lignins and lignin-containing plant residues are described in detail. Finally, future directions are suggested for research and development of artificial lignin humification to achieve alternative ways of producing customized analogues of humic substances.

  • Vector-related stratagems for enhanced monoclonal antibody production in mammalian cells
    Biotechnol. Adv. (IF 12.831) Pub Date : 2019-07-03
    Kritika Gupta, Mruganka Parasnis, Ratnesh Jain, Prajakta Dandekar
  • Betulin and its derivatives as novel compounds with different pharmacological effects
    Biotechnol. Adv. (IF 12.831) Pub Date : 2019-06-18
    Shayan Amiri, Sanaz Dastghaib, Mazaher Ahmadi, Parvaneh Mehrbod, Forough Khadem, Hamid Behrouj, Mohamad-Reza Aghanoori, Filip Machaj, Mahdi Ghamsari, Jakub Rosik, Andrzej Hudecki, Abbas Afkhami, Mohammad Hashemi, Marek J. Los, Pooneh Mokarram, Tayyebeh Madrakian, Saeid Ghavami

    Betulin (B) and Betulinic acid (BA) are natural pentacyclic lupane-structure triterpenoids which possess a wide range of pharmacological activities. Recent evidence indicates that B and BA have several properties useful for the treatment of metabolic disorders, infectious diseases, cardiovascular disorders, and neurological disorders. In the current review, we discuss B and BA structures and derivatives and then comprehensively explain their pharmacological effects in relation to various diseases. We also explain antiviral, antibacterial and anti-cancer effects of B and BA. Finally, we discuss the delivery methods, in which these compounds most effectively target different systems.

  • Soft and flexible material-based affinity sensors
    Biotechnol. Adv. (IF 12.831) Pub Date : 2019-05-06
    Lingyin Meng, Anthony P.F. Turner, Wing Cheung Mak

    Recent advances in biosensors and point-of-care (PoC) devices are poised to change and expand the delivery of diagnostics from conventional lateral-flow assays and test strips that dominate the market currently, to newly emerging wearable and implantable devices that can provide continuous monitoring. Soft and flexible materials are playing a key role in propelling these trends towards real-time and remote health monitoring. Affinity biosensors have the capability to provide for diagnosis and monitoring of cancerous, cardiovascular, infectious and genetic diseases by the detection of biomarkers using affinity interactions. This review tracks the evolution of affinity sensors from conventional lateral-flow test strips to wearable/implantable devices enabled by soft and flexible materials. Initially, we highlight conventional affinity sensors exploiting membrane and paper materials which have been so successfully applied in point-of-care tests, such as lateral-flow immunoassay strips and emerging microfluidic paper-based devices. We then turn our attention to the multifarious polymer designs that provide both the base materials for sensor designs, such as PDMS, and more advanced functionalised materials that are capable of both recognition and transduction, such as conducting and molecularly imprinted polymers. The subsequent content discusses wearable soft and flexible material-based affinity sensors, classified as flexible and skin-mountable, textile materials-based and contact lens-based affinity sensors. In the final sections, we explore the possibilities for implantable/injectable soft and flexible material-based affinity sensors, including hydrogels, microencapsulated sensors and optical fibers. This area is truly a work in progress and we trust that this review will help pull together the many technological streams that are contributing to the field.

  • Anti-cancer effects of polyphenols via targeting p53 signaling pathway: updates and future directions
    Biotechnol. Adv. (IF 12.831) Pub Date : 2019-04-18
    Haroon Khan, Marcella Reale, Hammad Ullah, Antoni Sureda, Silvia Tejada, Ying Wang, Zhang-Jin Zhang, Jianbo Xiao

    The anticancer effects of polyphenols are ascribed to several signaling pathways including the tumor suppressor gene tumor protein 53 (p53). Expression of endogenous p53 is silent in various types of cancers. A number of polyphenols from a wide variety of dietary sources could upregulate p53 expression in several cancer cell lines through distinct mechanisms of action. The aim of this review is to focus the significance of p53 signaling pathways and to provide molecular intuitions of dietary polyphenols in chemoprevention by monitoring p53 expression that have a prominent role in tumor suppression.

  • Advances in phytochemical delivery systems for improved anticancer activity
    Biotechnol. Adv. (IF 12.831) Pub Date : 2019-04-09
    Ricardo Lagoa, João Silva, Joaquim Rui Rodrigues, Anupam Bishayee

    Natural compounds have significant anticancer pharmacological activities, but often suffer from low bioavailability and selectivity that limit therapeutic use. The present work critically analyzes the latest advances on drug delivery systems designed to enhance pharmacokinetics, targeting, cellular uptake and efficacy of anticancer phytoconstituents. Various phytochemicals, including flavonoids, resveratrol, celastrol, curcumin, berberine and camptothecins, carried by liposomes, nanoparticles, nanoemulsions and films showed promising results. Strategies to avoid drug metabolism, overcome physiological barriers and achieve higher concentration at cancer sites through skin, buccal, nasal, vaginal, pulmonary and colon targeted delivery are presented. Current limitations, challenges and future research directions are also discussed.

  • Neural tissue engineering with structured hydrogels in CNS models and therapies
    Biotechnol. Adv. (IF 12.831) Pub Date : 2019-03-19
    Julian George, Chia-Chen Hsu, Linh Thuy Ba Nguyen, Hua Ye, Zhanfeng Cui

    The development of techniques to create and use multiphase microstructured hydrogels (granular hydrogels or microgels) has enabled the generation of cultures with more biologically relevant architecture and use of structured hydrogels is especially pertinent to the development of new types of central nervous system (CNS) culture models and therapies. We review material choice and the customisation of hydrogel structure, as well as the use of hydrogels in developmental models. Combining the use of structured hydrogel techniques with developmentally relevant tissue culture approaches will enable the generation of more relevant models and treatments to repair damaged CNS tissue architecture.

  • Sowing seeds for the future: The need for on-site plant diagnostics
    Biotechnol. Adv. (IF 12.831) Pub Date : 2019-02-23
    Arabelle Cassedy, Ewen Mullins, Richard O'Kennedy

    Point-of-care technology is a term used to describe any treatment given at the “site-of-need”. The span of point-of-care has broadened, growing from its current dominant usage in clinical settings to encompass many sectors, such as water and food testing. This review focuses on applications of point-of-care/use technology in phytodiagnostics, a field which requires accurate diagnostic systems with increasing urgency due to the demands of global food needs in conjunction with persistent crop loss due to pathogens and increased awareness of the environmental impacts of extensive agrochemical usage.

  • Harmonization of immunoassays for biomarkers in diabetes mellitus
    Biotechnol. Adv. (IF 12.831) Pub Date : 2019-02-23
    Sebastian Hörber, Peter Achenbach, Erwin Schleicher, Andreas Peter

    Harmonization of biomarkers is important for the comparability of laboratory results as it allows the definition of universal reference values and clinical decision limits. In diabetology, immunoassays are widely used to determine HbA1c, C-peptide, insulin, and autoantibodies to beta cell proteins, which are essential biomarkers for the diagnosis and classification of diabetes mellitus. Furthermore, as large clinical studies have identified HbA1c as a predictor for the development of diabetic complications, HbA1c has evolved as the general treatment target. For decades, the use of non-harmonized assays caused confusion. After the standardization of HbA1c, the worldwide comparability improved and increased the confidence in this laboratory biomarker. Insulin and C-peptide are not only valuable biomarkers to assess beta-cell function, but may also be used to evaluate insulin resistance, a metabolic feature of type 2 diabetes often occurring before its manifestation. Long-lasting efforts led to substantial improvements in the harmonization process of C-peptide assays, but harmonization of insulin assays is still ongoing. Therefore, C-peptide is now sometimes used as a surrogate biomarker for insulin. Furthermore, autoantibodies against beta cell components are important biomarkers for the accurate differentiation of type 1, type 2, and other special types of diabetes. Owing to the heterogeneity of these autoantibodies against beta cell proteins, harmonization is very difficult to achieve. International efforts are in progress to harmonize the current assays, as the presence of autoantibodies against beta cell proteins predicts the development of type 1 diabetes in early life. In conclusion, clinical studies linking diagnosis, classification, prediction, and treatment to laboratory values of the respective biomarkers need to be harmonized to avoid misdiagnosis and incorrect clinical decisions, thus improving patient care and safety.

  • Biomaterializing the promise of cardiac tissue engineering
    Biotechnol. Adv. (IF 12.831) Pub Date : 2019-02-20
    Jordan E. Pomeroy, Abbigail Helfer, Nenad Bursac

    During an average individual's lifespan, the human heart pumps nearly 200 million liters of blood delivered by approximately 3 billion heartbeats. Therefore, it is not surprising that native myocardium under this incredible demand is extraordinarily complex, both structurally and functionally. As a result, successful engineering of adult-mimetic functional cardiac tissues is likely to require utilization of highly specialized biomaterials representative of the native extracellular microenvironment. There is currently no single biomaterial that fully recapitulates the architecture or the biochemical and biomechanical properties of adult myocardium. However, significant effort has gone toward designing highly functional materials and tissue constructs that may one day provide a ready source of cardiac tissue grafts to address the overwhelming burden of cardiomyopathic disease. In the near term, biomaterial-based scaffolds are helping to generate in vitro systems for querying the mechanisms underlying human heart homeostasis and disease and discovering new, patient-specific therapeutics. When combined with advances in minimally-invasive cardiac delivery, ongoing efforts will likely lead to scalable cell and biomaterial technologies for use in clinical practice. In this review, we describe recent progress in the field of cardiac tissue engineering with particular emphasis on use of biomaterials for therapeutic tissue design and delivery.

  • Curcumin, the golden spice in treating cardiovascular diseases
    Biotechnol. Adv. (IF 12.831) Pub Date : 2019-02-01
    Hong Li, Antoni Sureda, Hari Prasad Devkota, Valeria Pittalà, Davide Barreca, Ana Sanches Silva, Devesh Tewari, Suowen Xu, Seyed Mohammad Nabavi

    Cardiovascular diseases (CVDs) cause the largest mortality worldwide, and much attention has been focused to unravel the mechanisms and optimize the treatment regimens. Curcumin is an important bioactive component of turmeric that has been widely applied as traditional medicine to prevent and treat various diseases in some countries. Recent studies have demonstrated its potent activities in modulating multiple signaling pathways associated with cellular growth, proliferation, survival, inflammation and oxidative stress. The cardiovascular protective properties of curcumin in CVDs have been fully illustrated in numerous studies. In this review, we first briefly introduce the medicinal history of curcumin. Secondly, we systematically analyze the preclinical studies of curcumin in CVDs such as cardiac hypertrophy, heart failure, drug-induced cardiotoxicity, myocardial infarction, atherosclerosis, abdominal aortic aneurysm, stroke and diabetic cardiovascular complications. The potential molecular targets of curcumin are also summarized. Thirdly, the clinical trials of curcumin in CVDs are overviewed and discussed. Finally, we discuss the therapeutic utility of derivatives of curcumin, and highlight existing problems of curcumin as an effective drug lead in treating CVDs.

  • Collateral sensitivity of natural products in drug-resistant cancer cells
    Biotechnol. Adv. (IF 12.831) Pub Date : 2019-01-29
    Thomas Efferth, Mohamed E.M. Saeed, Onat Kadioglu, Ean-Jeong Seo, Samira Shirooie, Armelle T. Mbaveng, Seyed Mohammad Nabavi, Victor Kuete

    Cancer chemotherapy is frequently hampered by drug resistance. Concepts to combine anticancer drugs with different modes of action to avoid the development of resistance did not provide the expected success in the past, because tumors can be simultaneously non-responsive to many drugs (e.g. the multidrug resistance phenotype). However, tumors may be specifically hypersensitive to other drugs – a phenomenon also termed collateral sensitivity. This seems to be a general biological mechanism, since it also occurs in drug-resistant Escherichia coli and Saccharomyces cerevisiae. Here, we give a timely and comprehensive overview on hypersensitivity in resistant cancer cells towards natural products and their derivatives. Since the majority of clinically established anticancer drugs are natural products or are in one way or another derived from them, it is worth hypothesizing that natural products may deliver promising lead compounds for the development of collateral sensitive anticancer drugs. Hypersensitivity occurs not only in classical ABC transporter-mediated multidrug resistance, but also in many other resistance phenotypes. Resistant cancers can be hypersensitive to natural compounds from diverse classes and origins (i.e. mitotic spindle poisons, DNA topoisomerase 1 and 2 inhibitors, diverse phytochemicals isolated from medicinal plants, (semi)synthetic derivatives of phytochemicals, antibiotics, marine drugs, recombinant therapeutic proteins and others). Molecular mechanisms of collateral sensitivity include (1) increased ATP hydrolysis and reactive oxygen species production by futile cycling during ABC transporter-mediated drug efflux, (2) inhibition of ATP production, and (3) alterations of drug target proteins (e.g. increased expression of topoisomerases and heat shock proteins, inhibition of Wnt/β-catenin pathway, mutations in β-tubulin). The phenomenon of hypersensitivity needs to be exploited for clinical oncology by the development of (1) novel combination protocols that include collateral sensitive drugs and (2) novel drugs that specifically exhibit high degrees of hypersensitivity in resistant tumors.

  • Harnessing cells to deliver nanoparticle drugs to treat cancer
    Biotechnol. Adv. (IF 12.831) Pub Date : 2019-01-11
    Bijay Singh, Samir Mitragotri

    Clinical translation of nanoparticle drug (nanodrug) delivery systems for cancer therapy is primarily hindered by short half-life of nanodrugs in blood circulation and their poor ability of tumor targeting and penetration in vivo. Circulatory cells have garnered much attention in cancer therapy as drug delivery vehicles due to their biocompatibility, high mobility, biodegradability, tissue targeting capability, high drug loading capacity, ability to cross biological barriers and inherent ability to remain in blood circulation long enough to accumulate within the tumors. Here, we review the progress and potential of circulatory cells as nanodrug delivery vehicles, especially for cancer therapy.

  • Concise review: The challenges and opportunities of employing mesenchymal stromal cells in the treatment of acute pancreatitis
    Biotechnol. Adv. (IF 12.831) Pub Date : 2019-01-09
    Robbie R. Goodman, Madelaine K. Jong, John E. Davies

    To date only small animal models have been employed to assess the effect of mesenchymal stromal cell (MSC) therapy on acute pancreatitis (AP), the most common cause of hospitalization for gastrointestinal diseases worldwide. We outline the challenges inherent in the small animal models of AP. We also point to specific benefits afforded by the adoption of larger animal models. The potential for MSC therapeutics in the treatment of AP was recognized over a decade ago. With sharper focus on the form of AP and development of new MSC delivery routes in larger animals, we believe the challenge can be engaged.

  • Current status and contemporary approaches to the discovery of antitumor agents from higher plants
    Biotechnol. Adv. (IF 12.831) Pub Date : 2019-01-08
    Garima Agarwal, Peter J. Blanco Carcache, Ermias Mekuria Addo, A. Douglas Kinghorn

    Higher plant constituents have afforded clinically available anticancer drugs. These include both chemically unmodified small molecules and their synthetic derivatives currently used or those in clinical trials as antineoplastic agents, and an updated summary is provided. In addition, botanical dietary supplements, exemplified by mangosteen and noni constituents, are also covered as potential cancer chemotherapeutic agents. Approaches to metabolite purification, rapid dereplication, and biological evaluation including analytical hyphenated techniques, molecular networking, and advanced cellular and animal models are discussed. Further, enhanced and targeted drug delivery systems for phytochemicals, including micelles, nanoparticles and antibody drug conjugates (ADCs) are described herein.

  • Dietary phytochemicals in colorectal cancer prevention and treatment: A focus on the molecular mechanisms involved
    Biotechnol. Adv. (IF 12.831) Pub Date : 2018-11-23
    Sadia Afrin, Francesca Giampieri, Massimiliano Gasparrini, Tamara Y. Forbes-Hernández, Danila Cianciosi, Patricia Reboredo-Rodriguez, Jiaojiao Zhang, Piera Pia Manna, Maria Daglia, Atanas Georgiev Atanasov, Maurizio Battino

    Worldwide, colorectal cancer (CRC) remains a major cancer type and leading cause of death. Unfortunately, current medical treatments are not sufficient due to lack of effective therapy, adverse side effects, chemoresistance and disease recurrence. In recent decades, epidemiologic observations have highlighted the association between the ingestion of several phytochemical-enriched foods and nutrients and the lower risk of CRC. According to preclinical studies, dietary phytochemicals exert chemopreventive effects on CRC by regulating different markers and signaling pathways; additionally, the gut microbiota plays a role as vital effector in CRC onset and progression, therefore, any dietary alterations in it may affect CRC occurrence. A high number of studies have displayed a key role of growth factors and their signaling pathways in the pathogenesis of CRC. Indeed, the efficiency of dietary phytochemicals to modulate carcinogenic processes through the alteration of different molecular targets, such as Wnt/β-catenin, PI3K/Akt/mTOR, MAPK (p38, JNK and Erk1/2), EGFR/Kras/Braf, TGF-β/Smad2/3, STAT1-STAT3, NF-кB, Nrf2 and cyclin-CDK complexes, has been proven, whereby many of these targets also represent the backbone of modern drug discovery programs. Furthermore, epigenetic analysis showed modified or reversed aberrant epigenetic changes exerted by dietary phytochemicals that led to possible CRC prevention or treatment. Therefore, our aim is to discuss the effects of some common dietary phytochemicals that might be useful in CRC as preventive or therapeutic agents. This review will provide new guidance for research, in order to identify the most studied phytochemicals, their occurrence in foods and to evaluate the therapeutic potential of dietary phytochemicals for the prevention or treatment of CRC by targeting several genes and signaling pathways, as well as epigenetic modifications. In addition, the results obtained by recent investigations aimed at improving the production of these phytochemicals in genetically modified plants have been reported. Overall, clinical data on phytochemicals against CRC are still not sufficient and therefore the preventive impacts of dietary phytochemicals on CRC development deserve further research so as to provide additional insights for human prospective studies.

  • Flavonoid biosynthetic pathways in plants: Versatile targets for metabolic engineering
    Biotechnol. Adv. (IF 12.831) Pub Date : 2018-11-17
    Seyed Mohammad Nabavi, Dunja Šamec, Michał Tomczyk, Luigi Milella, Daniela Russo, Solomon Habtemariam, Ipek Suntar, Luca Rastrelli, Maria Daglia, Jianbo Xiao, Francesca Giampieri, Maurizio Battino, Eduardo Sobarzo-Sanchez, Seyed Fazel Nabavi, Bahman Yousefi, Philippe Jeandet, Suowen Xu, Samira Shirooie

    Plants, fungi, and microorganisms are equipped with biosynthesis machinery for producing thousands of secondary metabolites. These compounds have important functions in nature as a defence against predators or competitors as well as other ecological significances. The full utilization of these compounds for food, medicine, and other purposes requires a thorough understanding of their structures and the distinct biochemical pathways of their production in cellular systems. In this review, flavonoids as classical examples of secondary metabolites are employed to highlight recent advances in understanding how valuable compounds can be regulated at various levels. With extensive diversity in their chemistry and pharmacology, understanding the metabolic engineering of flavonoids now allows us to fine-tune the eliciting of their production, accumulation, and extraction from living systems. More specifically, recent advances in the shikimic acid and acetate biosynthetic pathways of flavonoids production from metabolic engineering point of view, from genes expression to multiple principles of regulation, are addressed. Specific examples of plants and microorganisms as the sources of flavonoids-based compounds with particular emphasis on therapeutic applications are also discussed.

  • Advances in nanoparticle and microparticle delivery systems for increasing the dispersibility, stability, and bioactivity of phytochemicals
    Biotechnol. Adv. (IF 12.831) Pub Date : 2018-08-04
    David Julian McClements

    Application of bioactive phytochemicals in foods, supplements, and pharmaceuticals is often limited because of their poor solubility, stability, and bioavailability. Phytochemical oral delivery systems (PODS), consisting of phytochemical-loaded nanoparticles or microparticles, can overcome these challenges. PODS can be produced in liquid, gel, paste, or solid forms. They must be carefully formulated to be compatible with the product matrix, economical, robust, and maintain phytochemical bioactivity. This review evaluates recent advances in the development of PODS, including microemulsions, nanoemulsions, emulsions, solid lipid nanoparticles, liposomes, and biopolymer microgels. Properly designed PODS will increase phytochemical applications in commercial products.

  • Medicinal plants used in the treatment of tuberculosis - Ethnobotanical and ethnopharmacological approaches
    Biotechnol. Adv. (IF 12.831) Pub Date : 2017-07-08
    Javad Sharifi-Rad, Bahare Salehi, Zorica Z. Stojanović-Radić, Patrick Valere Tsouh Fokou, Marzieh Sharifi-Rad, Gail B. Mahady, Majid Sharifi-Rad, Mohammad-Reza Masjedi, Temitope O. Lawal, Seyed Abdulmajid Ayatollahi, Javid Masjedi, Razieh Sharifi-Rad, William N. Setzer, Mehdi Sharifi-Rad, Farzad Kobarfard, Atta-ur Rahman, Muhammad Iqbal Choudhary, Athar Ata, Marcello Iriti

    Tuberculosis is a highly infectious disease declared a global health emergency by the World Health Organization, with approximately one third of the world's population being latently infected with Mycobacterium tuberculosis. Tuberculosis treatment consists in an intensive phase and a continuation phase. Unfortunately, the appearance of multi drug-resistant tuberculosis, mainly due to low adherence to prescribed therapies or inefficient healthcare structures, requires at least 20 months of treatment with second-line, more toxic and less efficient drugs, i.e., capreomycin, kanamycin, amikacin and fluoroquinolones. Therefore, there exists an urgent need for discovery and development of new drugs to reduce the global burden of this disease, including the multi-drug-resistant tuberculosis. To this end, many plant species, as well as marine organisms and fungi have been and continue to be used in various traditional healing systems around the world to treat tuberculosis, thus representing a nearly unlimited source of active ingredients. Besides their antimycobacterial activity, natural products can be useful in adjuvant therapy to improve the efficacy of conventional antimycobacterial therapies, to decrease their adverse effects and to reverse mycobacterial multi-drug resistance due to the genetic plasticity and environmental adaptability of Mycobacterium. However, even if some natural products have still been investigated in preclinical and clinical studies, the validation of their efficacy and safety as antituberculosis agents is far from being reached, and, therefore, according to an evidence-based approach, more high-level randomized clinical trials are urgently needed.

  • Strategic enhancement of genetic gain for nutraceutical development in buckwheat: A genomics-driven perspective
    Biotechnol. Adv. (IF 12.831) Pub Date : 2019-11-09
    Dinesh C. Joshi, Kaixuan Zhang, Chenglong Wang, Rahul Chandora, Muhammad Khurshid, Jinbo Li, Ming He, Milen I. Georgiev, Meiliang Zhou

    Buckwheat (Fagopyrum spp.) under the family Polygonaceae is an ancient pseudocereal with stupendous but less studied nutraceutical properties. The gluten free nature of protein, balanced amino acid profile and health promoting bioactive flavonoids make it a golden crop of future. Besides a scanty basic research, not much attention has been paid to the improvement of plant type and breeding of nutraceutical traits. Scanning of scientific literature indicates that adequate genetic variation exists for agronomic and nutritional traits in mainstream and wild gene pool of buckwheat. However, the currently employed conventional approaches together with poorly understood genetic mechanisms restrict effective utilization of the existing genetic variation in nutraceutical breeding of buckwheat. The latest trends in buckwheat genomics, particularly avalilabity of draft genome sequences for both the cultivated species (F. esculentum and F.tataricum) hold immense potential to overcome these limitations. Utilizing the transgenic hairy rot cultures, role of various transcription factors and gene families have been deduced in production and biosynthesis of bioactive flavonoids. Further, the acquisition of high-density genomics data coupled with the next-generation phenotyping will certainly improve our understanding of underlying genetic regulation of nutraceutical traits. The present paper highlights the application of multilayered omics interventions for tailoring a nutrient rich buckwheat cultivar and nutraceutical product development.

  • Strategies for improving the electroactivity and specific metabolic functionality of microorganisms for various microbial electrochemical technologies1
    Biotechnol. Adv. (IF 12.831) Pub Date : 2019-11-07
    P. Chiranjeevi, Sunil A. Patil

    Electroactive microorganisms, which possess extracellular electron transfer (EET) capabilities, are the basis of microbial electrochemical technologies (METs) such as microbial fuel and electrolysis cells. These are considered for several applications ranging from the energy-efficient treatment of waste streams to the production of value-added chemicals and fuels, bioremediation, and biosensing. Various aspects related to the microorganisms, electrodes, separators, reactor design, and operational or process parameters influence the overall functioning of METs. The most fundamental and critical performance-determining factor is, however, the microorganisms-electrode interactions. Modification of the electrode surfaces and microorganisms for optimizing their interactions has therefore been the major MET research focus area over the last decade. In the case of microorganisms, primarily their EET mechanisms and efficiencies along with the biofilm formation capabilities, collectively considered as microbial electroactivity, affect their interactions with the electrodes. In addition to electroactivity, the specific metabolic or biochemical functionality of microorganisms is equally crucial to the target MET application. In this article, we present the major strategies that are used to enhance the electroactivity and specific functionality of microorganisms pertaining to both anodic and cathodic processes of METs. These include simple physical methods based on the use of heat and magnetic field along with chemical, electrochemical, and growth media amendment approaches to the complex procedure-based microbial bioaugmentation, co-culture, and cell immobilization or entrapment, and advanced toolkit-based biofilm engineering, genetic modifications, and synthetic biology strategies. We further discuss the applicability and limitations of these strategies and possible future research directions for advancing the highly promising microbial electrochemistry-driven biotechnology.

  • In depth natural product discovery - Myxobacterial strains that provided multiple secondary metabolites
    Biotechnol. Adv. (IF 12.831) Pub Date : 2019-11-07
    Chantal D. Bader, Fabian Panter, Rolf Müller

    In recognition of many microorganisms ability to produce a variety of secondary metabolites in parallel, Zeeck and coworkers introduced the term “OSMAC” (one strain many compounds) around the turn of the century. Since then, additional efforts focused on the systematic characterization of a single bacterial species ability to form multiple secondary metabolite scaffolds. With the beginning of the genomic era mainly initiated by a dramatic reduction of sequencing costs, investigations of the genome encoded biosynthetic potential and especially the exploitation of biosynthetic gene clusters of undefined function gained attention. This was seen as a novel means to extend range and diversity of bacterial secondary metabolites. Genome analyses showed that even for well-studied bacterial strains, like the myxobacterium Myxococcus xanthus DK1622, many biosynthetic gene clusters are not yet assigned to their corresponding hypothetical secondary metabolites. In contrast to the results from emerging genome and metabolome mining techniques that show the large untapped biosynthetic potential per strain, many newly isolated bacterial species are still used for the isolation of only one target compound class and successively abandoned in the sense that no follow up studies are published from the same species. This work provides an overview about myxobacterial bacterial strains, from which not just one but multiple different secondary metabolite classes were successfully isolated. The underlying methods used for strain prioritization and natural product discovery such as biological characterization of crude extracts against a panel of pathogens, in-silico prediction of secondary metabolite abundance from genome data and state of the art instrumental analytics required for new natural product scaffold discovery in comparative settings are summarized and classified according to their output. Furthermore, for each approach selected studies performed with actinobacteria are shown to underline especially innovative methods used for natural product discovery.

  • Development of reporter gene assays to determine the bioactivity of biopharmaceuticals
    Biotechnol. Adv. (IF 12.831) Pub Date : 2019-11-05
    Lan Wang, Chuanfei Yu, Junzhi Wang

    Complex structure and structure-function relationship of biopharmaceuticals require extensive analytical characterization and appropriate quality control of the products. Despite rapid development of sophisticated physicochemical techniques, biological activity measurement remains the critical role in inferring the high-order structure of biopharmaceuticals. Cell-based biological assays are mostly applied to determine the biological activity of biopharmaceuticals, however, refined biological assays are continually needed to increase their robustness. Reporter gene assays (RGAs) which are mechanism of action (MOA) related, less variable, accurate, precise, and labor-saving are becoming more and more recognized and adopted in the quality control. Here we discuss the importance of bioactivity determination, the strength and weakness of various assay formats with RGAs. We also introduce the mechanism of RGAs, and present a number of examples for RGAs to determine the bioactivity of various biopharmaceuticals, which indicate their extensive use in the screening, characterization, quality control, stability and biosimilarity study. We believe that with the rapid development of biotechnology, new strategies of bioassays based on RGAs will be more widely applied in various fields of biopharmaceuticals.

  • Engineering unnatural methylotrophic cell factories for methanol-based biomanufacturing: Challenges and opportunities
    Biotechnol. Adv. (IF 12.831) Pub Date : 2019-11-05
    Taicheng Zhu, Tongxin Zhao, Olufemi Emmanuel Bankefa, Yin Li

    Methanol is a very promising feedstock alternative to sugar-based raw materials for biomanufacturing because it does not compete with food production, is abundant and potentially sustainable in the future. Although methylotrophic fermentations have been practiced for decades, their applications are limited by technical drawbacks and insufficient knowledge of the physiology and metabolic regulation of native methylotrophs. Synthetic biology offers great opportunities for engineering efficient methylotrophic microbial cell factories by enabling non-methylotrophic model organisms to utilize methanol via the introduction of C1 utilization pathways. This review critically comments C1 metabolism with a focus on comparing different methanol-utilization pathways in light of biomanufacturing, and highlights recent advances in the engineering of synthetic methylotrophs. Most importantly, the unique challenges in the engineering process and possible solutions are also discussed in detail.

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上海纽约大学William Glover