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Vitamin K 2 (menaquinone, VK 2 , MK) is an essential lipid-soluble vitamin that plays critical roles in inhibiting cell ferroptosis, improving blood clotting, and preventing osteoporosis. The increased global demand for VK 2 has inspired interest in novel production strategies. In this review, various novel metabolic regulation strategies, including static and dynamic metabolic regulation, are summarized and discussed. Furthermore, the advantages and disadvantages of both strategies are analyzed in-depth to highlight the bottlenecks facing microbial VK 2 production on an industrial scale. Finally, advanced metabolic engineering biotechnology for future microbial VK 2 production will also be discussed. In summary, this review provides in-depth information and offers an outlook on metabolic engineering strategies for VK 2 production.

Most tumor cells still exhibit active glucose uptake and glycolysis under aerobic conditions, a phenomenon known as the Warburg effect or aerobic glycolysis. Pyruvate kinase, one of the key enzymes in the cell glycolysis pathway, can promote the conversion of glucose to pyruvate and produce energy. Pyruvate kinase M2 (PKM2), a competitive PK subtype, is an important regulator of the aerobic glycolysis pathway in tumor cells and plays a direct role in gene expression and cell cycle regulation. Human papillomavirus (HPV) persistence is the main risk factor for cervical cancer. In recent years, it has been discovered that HPV plays an important role in malignant anal tumors and oral cancer. HPV oncoprotein E7 can promote the Warburg effect and produce a large amount of ATP, which may meet the energy requirements of cancer cell division. There appears to be a regulatory relationship between HPV E7 and PKM2, but the specific mechanism is mostly unknown. The present review article discusses the role of HPV E7 in transcriptional regulation, enzyme activity regulation, protein kinase activity regulation, post-translational modification and the immune microenvironment of PKM2 in the occurrence and development of cervical cancer.

Drought and salinity are among the most important environmental factors that hampered agricultural productivity worldwide. Both stresses can induce several morphological, physiological, biochemical, and metabolic alterations through various mechanisms, eventually influencing plant growth, development, and productivity. The responses of plants to these stress conditions are highly complex and depend on other factors, such as the species and genotype, plant age and size, the rate of progression as well as the intensity and duration of the stresses. These factors have a strong effect on plant response and define whether mitigation processes related to acclimation will occur or not. In this review, we summarize how drought and salinity extensively affect plant growth in agriculture ecosystems. In particular, we focus on the morphological, physiological, biochemical, and metabolic responses of plants to these stresses. Moreover, we discuss mechanisms underlying plant-microbe interactions that confer abiotic stress tolerance.

Hypoxia-inducible factors (HIFs), a family of transcription factors activated by hypoxia, consist of three α-subunits (HIF1α, HIF2α and HIF3α) and one β-subunit (HIF1β), which serves as a heterodimerization partner of the HIFα subunits. HIFα subunits are stabilized from constitutive degradation by hypoxia largely through lowering the activity of the oxygen-dependent prolyl hydroxylases that hydroxylate HIFα, leading to their proteolysis. HIF1α and HIF2α are expressed in different tissues and regulate target genes involved in angiogenesis, cell proliferation and inflammation, and their expression is associated with different disease states. HIFs have been widely studied because of their involvement in cancer, and HIF2α-specific inhibitors are being investigated in clinical trials for the treatment of kidney cancer. Although cancer has been the major focus of research on HIF, evidence has emerged that this pathway has a major role in the control of metabolism and influences metabolic diseases such as obesity, type 2 diabetes mellitus and non-alcoholic fatty liver disease. Notably increased HIF1α and HIF2α signalling in adipose tissue and small intestine, respectively, promotes metabolic diseases in diet-induced disease models. Inhibition of HIF1α and HIF2α decreases the adverse diet-induced metabolic phenotypes, suggesting that they could be drug targets for the treatment of metabolic diseases.

In animals, systemic control of metabolism is conducted by metabolic tissues and relies on the regulated circulation of a plethora of molecules, such as hormones and lipoprotein complexes. MicroRNAs (miRNAs) are a family of post-transcriptional gene repressors that are present throughout the animal kingdom and have been widely associated with the regulation of gene expression in various contexts, including virtually all aspects of systemic control of metabolism. Here we focus on glucose and lipid metabolism and review current knowledge of the role of miRNAs in their systemic regulation. We survey miRNA-mediated regulation of healthy metabolism as well as the contribution of miRNAs to metabolic dysfunction in disease, particularly diabetes, obesity and liver disease. Although most miRNAs act on the tissue they are produced in, it is now well established that miRNAs can also circulate in bodily fluids, including their intercellular transport by extracellular vesicles, and we discuss the role of such extracellular miRNAs in systemic metabolic control and as potential biomarkers of metabolic status and metabolic disease.MicroRNAs widely regulate systemic metabolism, prominently that of glucose and lipids. Consequently, microRNA misexpression can lead to metabolic diseases such as diabetes and atherosclerosis. MicroRNAs are therefore emerging as potential therapeutic targets to control metabolism and, owing to their secretion in extracellular vesicles, as metabolic biomarkers.

The prevalence of cardiovascular and metabolic disease coupled with kidney dysfunction is increasing worldwide. This triad of disorders is associated with considerable morbidity and mortality as well as a substantial economic burden. Further understanding of the underlying pathophysiological mechanisms is important to develop novel preventive or therapeutic approaches. Among the proposed mechanisms, compromised nitric oxide (NO) bioactivity associated with oxidative stress is considered to be important. NO is a short-lived diatomic signalling molecule that exerts numerous effects on the kidneys, heart and vasculature as well as on peripheral metabolically active organs. The enzymatic l-arginine-dependent NO synthase (NOS) pathway is classically viewed as the main source of endogenous NO formation. However, the function of the NOS system is often compromised in various pathologies including kidney, cardiovascular and metabolic diseases. An alternative pathway, the nitrate–nitrite–NO pathway, enables endogenous or dietary-derived inorganic nitrate and nitrite to be recycled via serial reduction to form bioactive nitrogen species, including NO, independent of the NOS system. Signalling via these nitrogen species is linked with cGMP-dependent and independent mechanisms. Novel approaches to restoring NO homeostasis during NOS deficiency and oxidative stress have potential therapeutic applications in kidney, cardiovascular and metabolic disorders.Nitric oxide (NO) has important roles in the regulation of kidney, cardiovascular and metabolic functions. This Review discusses the physiological roles of NO and its effects on kidney function, as well as its association with cardiometabolic complications and novel approaches to restoring NO homeostasis.

New knowledge about the gut microbiota and its interaction with the host’s metabolic regulation has emerged during the last few decades. Several factors may affect the composition of the gut microbiota, including dietary fiber. Dietary fiber is not hydrolyzed by human digestive enzymes, but it is acted upon by gut microbes, and metabolites like short-chain fatty acids are produced. The short-chain fatty acids may be absorbed into the circulation and affect metabolic regulation in the host or be a substrate for other microbes. Some studies have shown improved insulin sensitivity, weight regulation, and reduced inflammation with increases in gut-derived short-chain fatty acids, all of which may reduce the risk of developing metabolic diseases. To what extent a dietary intervention with fiber may affect the human gut microbiota and hence metabolic regulation, is however, currently not well described. The aim of the present review is to summarize recent research on human randomized, controlled intervention studies investigating the effect of dietary fiber on gut microbiota and metabolic regulation. Metabolic regulation is discussed with respect to markers relating to glycemic regulation and lipid metabolism. Taken together, the papers on which the current review is based, suggest that dietary fiber has the potential to change the gut microbiota and alter metabolic regulation. However, due to the heterogeneity of the studies, a firm conclusion describing the causal relationship between gut microbiota and metabolic regulation remains elusive.

Orthogonal engineering strategies spanning genetic information, metabolic pathways, energy, and regulation unlock cell factory functionalities and extend the repertoire of microbial synthetic biology.Orthogonal genetic information systems operate as in vivo ‘virtual machines’ that independently process genetic information while minimizing host constraints, thereby enabling programmable reconstruction and advanced functions.Orthogonal metabolic pathways isolate product-forming routes at the network and spatial levels, thereby reducing interference with host metabolism and enabling dedicated metabolic flux allocation with higher yields.Constructing an orthogonal energetic system can overcome the constraints of limited native energy pools and dissipative distribution, analogous to an insulated cable supplying power directly to a synthetic module.Orthogonal regulatory systems pave the way for complex information processing in synthetic microbial consortia, with potential applications in biocomputing, biosensing, and biomanufacturing. Microbial synthetic biology focuses on the application of rational engineering strategies to reprogram microbial cells, thereby providing them with novel functions to meet different requirements. However, this engineering process inherently disrupts natural metabolism, leading to increased complexity and unpredictability within the metabolic system. To address these challenges, a series of orthogonal strategies has been developed and implemented in the construction of orthogonal genetic systems, metabolic pathways, energy systems, and regulatory systems. This review summarizes recent advances and applications of orthogonal strategies in microbial synthetic biology. Finally, future research directions in orthogonal microbial synthetic biology are explored, aiming to provide new insights for future studies. Microbial synthetic biology focuses on the application of rational engineering strategies to reprogram microbial cells, thereby providing them with novel functions to meet different requirements. However, this engineering process inherently disrupts natural metabolism, leading to increased complexity and unpredictability within the metabolic system. To address these challenges, a series of orthogonal strategies has been developed and implemented in the construction of orthogonal genetic systems, metabolic pathways, energy systems, and regulatory systems. This review summarizes recent advances and applications of orthogonal strategies in microbial synthetic biology. Finally, future research directions in orthogonal microbial synthetic biology are explored, aiming to provide new insights for future studies.

Peroxisome proliferator-activated receptor-α (PPARα), PPARδ and PPARγ are transcription factors that regulate gene expression following ligand activation. PPARα increases cellular fatty acid uptake, esterification and trafficking, and regulates lipoprotein metabolism genes. PPARδ stimulates lipid and glucose utilization by increasing mitochondrial function and fatty acid desaturation pathways. By contrast, PPARγ promotes fatty acid uptake, triglyceride formation and storage in lipid droplets, thereby increasing insulin sensitivity and glucose metabolism. PPARs also exert antiatherogenic and anti-inflammatory effects on the vascular wall and immune cells. Clinically, PPARγ activation by glitazones and PPARα activation by fibrates reduce insulin resistance and dyslipidaemia, respectively. PPARs are also physiological master switches in the heart, steering cardiac energy metabolism in cardiomyocytes, thereby affecting pathological heart failure and diabetic cardiomyopathy. Novel PPAR agonists in clinical development are providing new opportunities in the management of metabolic and cardiovascular diseases.Novel peroxisome proliferator-activated receptor (PPAR) agonists are providing new opportunities in the management of metabolic and cardiovascular diseases. In this Review, Staels and colleagues discuss the physiological regulation and actions of the PPAR family and their modulation of the atherogenic lipid profile, atherosclerosis and cardiac remodelling.

Macrophages exposed to inflammatory stimuli including LPS undergo metabolic reprogramming to facilitate macrophage effector function. This metabolic reprogramming supports phagocytic function, cytokine release, and ROS production that are critical to protective inflammatory responses. The Krebs cycle is a central metabolic pathway within all mammalian cell types. In activated macrophages, distinct breaks in the Krebs cycle regulate macrophage effector function through the accumulation of several metabolites that were recently shown to have signaling roles in immunity. One metabolite that accumulates in macrophages because of the disturbance in the Krebs cycle is itaconate, which is derived from cis-aconitate by the enzyme cis-aconitate decarboxylase (ACOD1), encoded by immunoresponsive gene 1 (Irg1). This Review focuses on itaconate's emergence as a key immunometabolite with diverse roles in immunity and inflammation. These roles include inhibition of succinate dehydrogenase (which controls levels of succinate, a metabolite with multiple roles in inflammation), inhibition of glycolysis at multiple levels (which will limit inflammation), activation of the antiinflammatory transcription factors Nrf2 and ATF3, and inhibition of the NLRP3 inflammasome. Itaconate and its derivatives have antiinflammatory effects in preclinical models of sepsis, viral infections, psoriasis, gout, ischemia/reperfusion injury, and pulmonary fibrosis, pointing to possible itaconate-based therapeutics for a range of inflammatory diseases. This intriguing metabolite continues to yield fascinating insights into the role of metabolic reprogramming in host defense and inflammation.