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PubMed2026

A voyage of reprogrammable metabolic bioengineering reshapes plant defense: from editing tools to synthetic systems.

Metabolic bioengineering has emerged as a transformative approach for reshaping plant defense by targeting intrinsic biosynthetic pathways to enhance immunity in modern agriculture. Moving beyond proof-of-concept metabolomics to broad-spectrum programmable pathway engineering addresses gaps in plant rational design and optimizes resilience in response to diverse environmental cues. This review aims to comprehensively highlight the transition of innovative approaches to phenolics, alkaloids, flavonoids, terpenoids, and benzoxazinoids, inferring adaptive reprogramming that mediates the growth-defense balance and functions as molecular sentinels in plants. Furthermore, decoding the volatile metabolome reveals a dynamic signaling interface that influences defense responses and stress-induced plant-microbe interactions, with the shikimate, jasmonate, and salicylate pathways functioning as central hubs for microbial deterrence and priming immune memory. Recent developments in multi-scalar genome-editing strategies, including CRISPR-driven combinatorial edits, enzyme orthogonalization, fluxomics, and spatially resolved multi-omics, reconfigure central and specialized metabolic fluxes toward improved defense function and regulation. Additionally, emerging tools, such as WUSCHEL2 and BABY BOOM transcriptional modules, and artificial engineering strategies integrating deep learning model-driven predictions facilitate rapid development of synthetic genetic circuits and support a predictive engineering of plants. Moreover, Mass spectrometry imaging (MSI) in spatial metabolomics enables to obtain structures and locations of unidentified endogenous metabolites within cells and tissues. Overall, this review emphasizes a diverse array of primary and secondary metabolites, spanning molecular concepts to recent advances in plant immune mechanisms. It also illustrates new frontiers in programmable metabolic engineering that accelerate the understanding of plant-microbe-metabolite cross-talks, offering strategies to improve plant resistance and advance sustainable agricultural solutions.

metabolic bioengineering↗
PubMed2026

The anaerobic fungus Caecomyces churrovis produces H2 via a non-bifurcating NADH-dependent enzyme complex.

UNLABELLED: Hydrogenosomes are mitochondrion-derived organelles that produce ATP and H2 to support energy metabolism in anaerobic eukaryotes. H2 production allows reoxidation of reduced cofactors generated during fermentative metabolism; however, the metabolic mechanisms for H2 production in anaerobic eukaryotes remain incompletely understood. In particular, it remains unclear whether anaerobic fungi (AF) hydrogenosomes use a ferredoxin-dependent pathway or a distinct mechanism to regenerate NAD(P)+ and link electron transfer to H2 formation. Here, by combining genomic search, proteomic analysis, and enzymology, we reveal the molecular mechanism for H2 production in the AF Caecomyces churrovis. Our enzyme assays on the organelle fraction of C. churrovis revealed the activity of H2:NAD+ oxidoreductase but not pyruvate:ferredoxin oxidoreductase, which is usually linked to H2 formation. We identified genes encoding [FeFe] hydrogenase (Hyd) and NADH dehydrogenase subunits E and F (NuoE and NuoF) in C. churrovis and confirmed their expression in the isolated hydrogenosomal fractions by proteomic analysis. Combining the individually purified enzymes, we found Hyd and NuoEF proteins formed H2 directly from NADH independently of ferredoxin, functioning as a non-bifurcating NADH-dependent enzyme rather than an electron-bifurcating enzyme known from anaerobic prokaryotes. We identified homologs of hydrogenosomal NuoE, NuoF, and Hyd in many other AF, indicating this pathway is commonly shared among the AF. This work demonstrates the existence of a non-bifurcating NADH-dependent enzyme complex for H2 production in eukaryotes. Moreover, this complex could potentially be exploited as a target for controlling AF H2 production and altering fungal metabolism. IMPORTANCE: H2 production is a prominent feature of anaerobic energy metabolism, yet our understanding of eukaryotic mechanisms remains limited. Anaerobic fungi (AF) are key decomposers of lignocellulose and contribute to hydrogen flux in anaerobic environments. Although it has been more than 40 years since the H2 production in Neocallimastix was first reported, the molecular mechanism for hydrogenosomal H2 production and redox balance remains unclear. We demonstrate that AF produce H2 from NADH utilizing a non-bifurcating NADH-dependent enzyme complex rather than an electron-bifurcating, ferredoxin-dependent variant. We show that this enzyme complex is conserved across multiple AF lineages and thus demonstrate the occurrence of a non-bifurcating NADH-dependent enzyme in eukaryotes. This discovery expands our understanding of eukaryotic hydrogenosomal metabolism, reveals a previously unknown strategy for redox balancing, and highlights potential targets for manipulating H2 production. These insights have broad implications for microbial energy metabolism, anaerobic ecosystems, and bioengineering of H2-producing systems.

Hydrogen↗
PubMed2025

Robust and highly efficient transformation method for a minimal mycoplasma cell.

UNLABELLED: Mycoplasmas have been widely investigated for their pathogenicity, as well as for genomics and synthetic biology. Conventionally, transformation of mycoplasmas was not highly efficient, and due to the low transformation efficiency, large amounts of DNA and recipient cells were required for that purpose. Here, we report a robust and highly efficient transformation method for the minimal cell JCVI-syn3B, which was created through streamlining the genome of Mycoplasma mycoides. When the growth states of JCVI-syn3B were examined in detail by focusing on such factors as pH, color, absorbance, colony forming unit, and transformation efficiency, it was found that the growth phase after the lag phase can be divided into three distinct phases, of which the highest transformation efficiency was observed during the early exponential growth phase. Notably, the transformation efficiency of up to 4.4 × 10-2 transformants per cell per microgram of plasmid DNA was obtained. A method to obtain several hundred to several thousand transformants with less than 0.2 mL of culture with approximately 1 × 107-108 cells and 10 ng of plasmid DNA was developed. Moreover, a transformation method using a frozen stock of transformation-ready cells was established. These procedures and information could simplify and enhance the transformation process of minimal cells, facilitating advanced genetic engineering and biological research using minimal cells. IMPORTANCE: Mycoplasmas are parasitic and pathogenic bacteria for many animals. They are also useful bacteria to understand the cellular process of life and for bioengineering because of their simple metabolism, small genomes, and cultivability. Genetic manipulation is crucial for these purposes, but transformation efficiency in mycoplasmas is typically quite low. Here, we report a highly efficient transformation method for the minimal genome mycoplasma JCVI-syn3B. Using this method, transformants can be obtained with only 10 ng of plasmid DNA, which is around one-thousandth of the amount required for traditional mycoplasma transformations. Moreover, a convenient method using frozen stocks of transformation-ready cells was established. These improved methods play a crucial role in further studies using minimal cells.

Transformation, Bacterial↗
PubMed2026

Design, expression, purification, and application of novel recombinant miR-491 molecules to define the biogenesis and function of miR-491-3p versus -5p in posttranscriptional regulation of UDP-glucuronosyltransferase 1A1.

Interindividual variations in drug metabolism involve various factors, including posttranscriptional gene regulation mechanisms controlled by microRNAs (miRNAs or miRs) derived from the genome. The aim of this study was to use RNA bioengineering technology to produce novel recombinant human miR-491-5p, miR-491-3p, and pre-miR-491 molecules, namely BioRNA/miR-491-5p, BioRNA/miR-491-3p, and BioRNA/pre-miR-491, respectively, and define their functional difference in regulating UDP-glucuronosyltransferase 1A1 (UGT1A1) expression and drug-metabolizing capacity. All 6 BioRNAs were heterologously overexpressed in Escherichia coli (>30% of total RNA) and isolated by fast protein liquid chromatography to high purity (>97%). As BioRNA/pre-miR-491 agents were processed to both 5p and 3p strands in Hep3B and HepG2 cells, BioRNA/miR-491-5p and -3p were selectively processed to 5p and 3p, respectively, and each accumulated to greater levels. Immunoblotting and immunofluorescence studies demonstrated the efficacy of BioRNA/miR-491-3p to suppress UGT1A1 protein levels in Hep3B and HepG2 cells, localized on the endoplasmic reticulum, exhibiting monomeric (∼55 kDa) and oligomeric (∼150 kDa) bands under different conditions, whereas BioRNA/pre-miR-491 and miR-491-5p had no effects. Using a fluorescent substrate, N-butyl-4-(4-hydroxyphenyl)-1,8-naphthalimide, lower UGT1A1 drug-metabolizing capacities were found in cells treated with BioRNA/miR-491-3p. In addition, liquid chromatography-tandem mass spectrometry analysis revealed a 45% reduction of estradiol 3-glucuronidation activity by BioRNA/miR-491-3p in Hep3B cells, whereas formation of estradiol 17-glucuronidation mediated by other UGTs was unchanged. Together, these results underline the role of miR-491-3p in regulating UGT1A1 and its impact on cellular drug-metabolizing capacity while demonstrating the applications of recombinant miRNA agents to delineating the importance of posttranscriptional gene regulation in drug metabolism. SIGNIFICANT STATEMENT: Research on posttranscriptional gene regulation mainly uses miRNA mimics chemically synthesized in vitro. This study successfully produced 6 novel recombinant miR-491 molecules through in vivo fermentation with transfer RNA scaffold and transfer RNA-fused pre-miRNA carrier-based technologies, which were further utilized to delineate the biogenesis and function of miR-491-3p versus -5p in modulating UDP-glucuronosyltransferase 1A1 protein levels and drug-metabolizing capacity. The findings demonstrate the role of miR-491-3p in regulating UDP-glucuronosyltransferase 1A1 and value of recombinant miRNA agents for studying drug metabolism.

Humans↗
PubMed2026

Beyond Earth: Recent Advancements in Microgravity Biomedical and Genetic Research in Saudi Arabia.

Microgravity research has emerged as a rapidly evolving field at the intersection of space medicine, genomics, biotechnology, and precision medicine. Exposure to the space environment induces complex physiological and molecular adaptations that affect multiple biological systems, including immune regulation, metabolism, musculoskeletal function, and gene expression. Recent advances in genomics, multi-omics technologies, artificial intelligence, and bioengineering have substantially improved our understanding of biological adaptation to spaceflight and expanded opportunities for translational biomedical research. This review summarizes recent advances in genetic and biomedical research under microgravity conditions, with particular emphasis on molecular mechanisms, omics technologies, genome editing, microbiome research, regenerative medicine, and personalized healthcare approaches. Major experimental platforms, landmark spaceflight studies, and translational applications in infectious diseases, cancer biology, aging, tissue engineering, and pharmaceutical development are discussed. The review also highlights Saudi Arabia's emerging contributions to genomic medicine and space biosciences through initiatives such as the Saudi Human Genome Program, the Saudi Pangenome Project, the Saudi Space Agency, and the BioGravity Initiative. Recent Saudi participation in human spaceflight and microgravity-associated biomedical research is discussed within the context of Vision 2030 and national investments in biotechnology and precision medicine. Collectively, advances in microgravity research are expected to contribute to the advancement of precision medicine and facilitate the development of innovative diagnostic and therapeutic strategies with significant implications for both human space exploration and terrestrial healthcare.

Humans↗
PubMed2025

Genome editing in the green alga Chlamydomonas: past, present practice and future prospects.

The green alga Chlamydomonas is an important and versatile model organism for research topics ranging from photosynthesis and metabolism, cilia, and basal bodies to cellular communication and the cellular cycle and is of significant interest for green bioengineering processes. The genome in this unicellular green alga is contained in 17 haploid chromosomes and codes for 16 883 protein coding genes. Functional genomics, as well as biotechnological applications, rely on the ability to remove, add, and change these genes in a controlled and efficient manner. In this review, the history of gene editing in Chlamydomonas is put in the context of the wider developments in genetics to demonstrate how many of the key developments to engineer these algae follow the global trends and the availability of technology. Building on this background, an overview of the state of the art in Chlamydomonas engineering is given, focusing primarily on the practical aspects while giving examples of recent applications. Commonly encountered Chlamydomonas-specific challenges, recent developments, and community resources are presented, and finally, a comprehensive discussion on the emergence and evolution of CRISPR/Cas-based precision gene editing is given. An outline of possible future paths for gene editing based on current global trends in genetic engineering and tools for gene editing is presented.

Gene Editing↗
PubMed2024

Genetic modification of the shikimate pathway to reduce lignin content in switchgrass (Panicum virgatum L.) significantly impacts plant microbiomes.

UNLABELLED: Switchgrass (Panicum virgatum L.) is considered a sustainable biofuel feedstock, given its fast-impact growth, low input requirements, and high biomass yields. Improvements in bioenergy conversion efficiency of switchgrass could be made by reducing its lignin content. Engineered switchgrass that expresses a bacterial 3-dehydroshikimate dehydratase (QsuB) has reduced lignin content and improved biomass saccharification due to the rerouting of the shikimate pathway towards the simple aromatic protocatechuate at the expense of lignin biosynthesis. However, the impacts of this QsuB trait on switchgrass microbiome structure and function remain unclear. To address this, wild-type and QsuB-engineered switchgrass were grown in switchgrass field soils, and samples were collected from inflorescences, leaves, roots, rhizospheres, and bulk soils for microbiome analysis. We investigated how QsuB expression influenced switchgrass-associated fungal and bacterial communities using high-throughput Illumina MiSeq amplicon sequencing of ITS and 16S rDNA. Compared to wild-type, QsuB-engineered switchgrass hosted different microbial communities in roots, rhizosphere, and leaves. Specifically, QsuB-engineered plants had a lower relative abundance of arbuscular mycorrhizal fungi (AMF). Additionally, QsuB-engineered plants had fewer Actinobacteriota in root and rhizosphere samples. These findings may indicate that changes in the plant metabolism impact both AMF and Actinobacteriota similarly or potential interactions between AMF and the bacterial community. This study enhances understanding of plant-microbiome interactions by providing baseline microbial data for developing beneficial bioengineering strategies and by assessing nontarget impacts of engineered plant traits on the plant microbiome. IMPORTANCE: Bioenergy crops provide an important strategy for mitigating climate change. Reducing the lignin in bioenergy crops could improve fermentable sugar yields for more efficient conversion into bioenergy and bioproducts. In this study, we assessed how switchgrass engineered for low lignin impacted aboveground and belowground switchgrass microbiome. Our results show unexpected reductions in mycorrhizas and actinobacteria in belowground tissues, raising questions on the resilience and function of genetically engineered plants in agricultural systems.

Panicum↗
PubMed1978

Progress in hemodialysis.

Bioengineering research over the past 16 years has provided clear definition of the design parameters controlling solute transport in dialyzers and resulted in the present dialysis systems which have a broad range of solute transport and ultrafiltration properties with predictable performance. Research into the pathophysiology of uremia has further established the role of protein catabolism in pathogenesis and resulted in information indicating that endocrine metabolic, drug toxicity and immunologic pathogenetic mechanisms may also be operative in this complex syndrome. Average dialysis treatment time has decreased more than 50 percent over the last ten years, but to a considerable extent remains empirically determined. Progress in elucidation of the solute kinetic parameters controlling solute concentration during regular dialysis therapy (RDT) is reviewed and the critical role of mass balance in evaluation of this therapy is discussed. Progress in kinetic modeling to quantify RDT is reviewed, the limitations of current kinetic models are considered and anticipated requirements to develop improved model parameters outlined.

History, 20th Century↗
PubMed2026

Bioengineering and physicochemical optimization of ergothioneine production by Aspergillus oryzae.

Ergothioneine (EGT) is a bioactive, rare variant of histidine with many applications in the medical, pharmaceutical, and food fields. Therefore, we aimed to investigate in this study the impact of genomic and physicochemical factors on EGT production by the industrial filamentous fungus Aspergillus oryzae. Firstly, to facilitate efficient EGT production, we analyzed the subcellular localization of the three EGT biosynthetic enzymes present in A. oryzae. During screening for the most potent producer of EGT among bioengineered transformants, the strain EgtACO overexpressing both AoegtA and AoegtC showed promising EGT production in DPY medium. Five days of incubation was the optimum period, and CZYP medium was the optimum medium for EGT production. Co-cultivation with the nisin Z-producing Lactococcus lactis JCM 7638 yielded EGT production equivalent to that of the EgtACO strain alone. Having broad-spectrum antimicrobial activity without suppressing growth of the EgtACO strain suggested that bacteriocin may help reduce the risk of contamination during long-term cultivation. Moreover, supplementing the production medium with L-methionine or zinc sulfate improved EGT production (1468.5 or 1565 mg/L, respectively). Furthermore, repeated inoculation of the producer strain EgtACO and incubation in blue light were the optimum conditions for EGT production (1895 mg/L). Finally, we achieved cost-effective EGT production using A. oryzae strain EgtACO under the optimal culture conditions using agricultural wastes: potato peel and sweet potato peel (293 and 308 mg/L, respectively).

Aspergillus oryzae↗