Microbial metabolism encompasses the biochemical networks that enable cells to convert nutrients into the energy and biosynthetic precursors necessary for cellular function. Understanding microbial metabolism is crucial for ecology, microbiology, and applications in biotechnology, agriculture, and medicine, as it underpins the biological processes that sustain life in various environments. Microbial metabolic products can be broadly classified as primary or secondary metabolites. Primary metabolites, such as amino acids, carbohydrates, organic acids, and alcohols, are essential for energy generation, biosynthesis, and cellular maintenance, typically accumulating during the exponential growth phase. In contrast, secondary metabolites, including compounds such as antibiotics, toxins, and alkaloids, are predominantly synthesised during the stationary growth phase and are not essential for basic cellular functions. However, they are often involved in ecological interactions and may provide adaptive advantages to the organisms. This distinction emphasises the dual function of microbial metabolism in supporting life and influencing ecological processes. The regulation of microbial metabolite biosynthesis is influenced by nutrient availability, environmental stresses, and intricate genetic networks. Advances in metabolic engineering, synthetic biology, and CRISPR-based technologies have enabled the redirection of central carbon fluxes to enhance the yield of both primary and secondary metabolites. Multi-omics approaches and computational modeling now provide deeper insights into metabolic regulation, pathway optimization, and the discovery of novel bioactive molecules. In conclusion, microbial metabolites are an invaluable resource for biotechnological innovation. While primary metabolites are essential for metabolic physiology, secondary metabolites offer unique bioactivities that have transformed pharmaceutical development, sustainable agriculture and industrial microbiology. Research focusing on uncovering new microbial diversity and optimising biosynthetic pathways is expected to continue providing insights that could deliver sustainable strategies and innovative solutions to urgent global challenges such as food security, healthcare, and environmental restoration.
Microbial biotechnology has historically relied heavily on bacteria, both in fundamental science and applied research. Their rapid growth capacity, ease of genetic manipulation, and extraordinary metabolic diversity enable them to offer a wide range of applications across all areas of modern biotechnology. Today, model bacteria such as Escherichia coli, Bacillus subtilis, and Pseudomonas species are at the center of multidimensional research ranging from recombinant protein production to biofuel synthesis, bioremediation, and probiotic therapies. The biotechnological potential of bacteria extends beyond industrial product development to enable the creation of sustainable solutions for global health, food safety, and environmental issues. In the medical field, bacteria serve as cellular factories for the large-scale production of recombinant proteins, including insulin, growth hormones, and monoclonal antibodies. Additionally, bacterial vectors are utilized as platforms in vaccine development and gene therapy applications. Probiotic bacteria are used to regulate the gut microbiota, strengthen the immune system, and prevent infections. In the agricultural sector, bacteria are utilized as biofertilizers, nitrogen-fixing agents (Rhizobium, Azotobacter), and biocontrol agents. They also contribute to reducing chemical fertilizer use by increasing productivity through the production of phytohormones that promote plant growth and by enhancing the availability of nutrients to plants. Bacteria have gained an important place in industrial applications by being used in the production of valuable metabolites such as antibiotics, vitamins, amino acids, and organic acids. With advances in metabolic engineering and synthetic biology, they are also involved in the production of biofuels, biodegradable plastics, and enzymes used in the food and textile industries. In environmental biotechnology, bacteria have a wide range of applications in bioremediation processes. Natural or genetically modified bacteria make important contributions to the degradation or detoxification of petroleum derivatives, heavy metals, and industrial waste. They also play critical roles in wastewater treatment and sustainable environmental management. In conclusion, bacteria serve as biological tools that offer innovative solutions in various areas of biotechnology. Advances in genomics, CRISPR-based gene editing, and systems biology are expanding the biotechnological applications of bacteria, increasing their importance by offering sustainable solutions to global issues such as health, food safety, and environmental protection.
Protein aggregation is now a common hallmark of numerous human diseases, most of which involve cytosolic aggregates including Aβ (AD) and ⍺-synuclein (PD) in Alzheimer's disease and Parkinson's disease. However, it is also evident that protein aggregation can also occur in the lumen of the endoplasmic reticulum (ER) that leads to specific diseases due to loss of protein function or detrimental effects on the host cell, the former is inherited in a recessive manner where the latter are dominantly inherited. However, the mechanisms of protein aggregation, disaggregation and degradation in the ER are not well understood. Here we provide an overview of factors that cause protein aggregation in the ER and how the ER handles aggregated proteins. Protein aggregation in the ER can result from intrinsic properties of the protein (hydrophobic residues in the ER), oxidative stress or nutrient depletion. The ER has quality control mechanisms [chaperone functions, ER-associated protein degradation (ERAD) and autophagy] to ensure only correctly folded proteins exit the ER and enter the cis-Golgi compartment. Perturbation of protein folding in the ER activates the unfolded protein response (UPR) that evolved to increase ER protein folding capacity and efficiency and degrade misfolded proteins. Accumulation of misfolded proteins in the ER to a level that exceeds the ER-chaperone folding capacity is a major factor that exacerbates protein aggregation. The most significant ER resident protein that prevents protein aggregation in the ER is the heat shock protein 70 (HSP70) homologue, BiP/GRP78, which is a peptide-dependent ATPase that binds unfolded/misfolded proteins and releases them upon ATP binding. Since exogenous factors can also reduce protein misfolding and aggregation in the ER, such as chemical chaperones and antioxidants, these treatments have potential therapeutic benefit for ER protein aggregation-associated diseases.
The origin of life on Earth is a profound biological question, with Bacteria and Archaea-the two principal prokaryotic lineages-central to the inquiry. Together, they represent microbial diversity and offer insights into Earth's earliest biosphere and evolutionary history. Microorganisms are of significant relevance to humanity, not only as disease agents for some infections but also due to their indispensable contributions to ecosystem functioning, primarily because of their involvement in biogeochemical cycling in various habitats. They influence soil fertility, plant growth, and the overall stability of biological communities across different habitats by mediating the turnover of energy and matter through processes such as decomposition, nutrient cycling, and regulating atmospheric gases. The fields of microbial evolution and systematics are mainly concerned with elucidating the origins, diversification, and classification of these two domains of life. These disciplines are fundamental for comprehending the extensive diversity of life on Earth and the evolutionary mechanisms that have shaped it. Notably, horizontal gene transfer, recombination, mutation, and selection are key evolutionary mechanisms driving genetic innovation and ecological differentiation in microbial populations, influencing phylogeny, function, and ecosystem dynamics. Advances in genomics and bioinformatics have transformed microbial systematics by enhancing polyphasic taxonomy through the integration of phenotypic and phylogenetic data, and have also provided valuable tools to gain deep insight into microbial evolution. This chapter examines the evolutionary history of microorganisms in the context of Bacteria and Archaea, the mechanisms underlying their evolution, the modern methodologies employed in microbial systematics, and the broader implications of these studies for science and society.
With an aging population, the presence of aging-associated pathologies is expected to increase within the next decades. Regrettably, we still do not have any valid pharmacological or non-pharmacological tools to prevent, revert, or cure these pathologies. The absence of therapeutical approaches against aging-associated pathologies can be at least partially explained by the relatively lack of knowledge that we still have regarding the molecular mechanisms underlying them, as well as by the complexity of their etiopathology. In fact, a complex number of changes in the physiological function of the cell has been described in all these aging-associated pathologies, including neurodegenerative disorders. Based on multiple scientific manuscripts produced by us and others, it seems clear that mitochondria are dysfunctional in many of these aging-associated pathologies. For example, mitochondrial dysfunction is an early event in the etiopathology of all the main neurodegenerative disorders, and it could be a trigger of many of the other deleterious changes which are present at the cellular level in these pathologies. While mitochondria are complex organelles and their regulation is still not yet entirely understood, inorganic polyphosphate (polyP) could play a crucial role in the regulation of some mitochondrial processes, which are dysfunctional in neurodegeneration. PolyP is a well-preserved biopolymer; it has been identified in every organism that has been studied. It is constituted by a series of orthophosphates connected by highly energetic phosphoanhydride bonds, comparable to those found in ATP. The literature suggests that the role of polyP in maintaining mitochondrial physiology might be related, at least partially, to its effects as a key regulator of cellular bioenergetics. However, further research needs to be conducted to fully elucidate the molecular mechanisms underlying the effects of polyP in the regulation of mitochondrial physiology in aging-associated pathologies, including neurodegenerative disorders. With a significant lack of therapeutic options for the prevention and/or treatment of neurodegeneration, the search for new pharmacological tools against these conditions has been continuous in past decades, even though very few therapeutic approaches have shown potential in treating these pathologies. Therefore, increasing our knowledge about the molecular mechanisms underlying the effects of polyP in mitochondrial physiology as well as its metabolism could place this polymer as a promising and innovative pharmacological target not only in neurodegeneration, but also in a wide range of aging-associated pathologies and conditions where mitochondrial dysfunction has been described as a crucial component of its etiopathology, such as diabetes, musculoskeletal disorders, and cardiovascular disorders.
The repair of alveolar cleft defects remains a formidable challenge in craniofacial surgery, with implications for dental arch continuity, tooth eruption, speech, and facial aesthetics. Traditional bone grafting methods (especially iliac crest autografts) have remained the gold standard, yet donor-site morbidity, graft resorption, and limitations in large defects drive the search for more advanced strategies. In recent years, developments in biomaterials, stem cell-based tissue engineering, and computer-aided surgery have opened new conceptual and practical pathways for alveolar cleft repair. This chapter reviews the embryology and pathophysiology of alveolar clefts, the structural and functional sequelae, and conventional surgical approaches. It then delves into advances in scaffold design, growth factor delivery, mesenchymal stem cell therapies, and 3D bioprinting strategies, highlighting preclinical and early clinical findings. Additionally, the role of CBCT, CAD/CAM, and custom surgical guides is examined in improving graft placement, reducing surgical error, and optimizing outcomes. Clinical successes and persistent challenges are analyzed, including graft integration, long-term stability, tooth eruption, and ethical/regulatory issues. We conclude by identifying key research gaps and proposing future directions-such as scaffold-free regeneration, AI-driven planning, and patient-specific regenerative protocols-that may transform alveolar cleft management in the coming decade.
Global food security has become one of the greatest challenges of the twenty-first century due to the rapidly growing world population's food demands and environmental threats such as climate change, soil erosion, and the depletion of freshwater resources. The extensive use of chemical fertilizers and pesticides throughout conventional agriculture has increased productivity significantly, but it has additionally resulted in major ecological and socioeconomic problems, such as soil acidity, groundwater resource pollution, and decreased biodiversity. In this regard, microbial biotechnology is a particularly noteworthy technique that improves agricultural production while promoting environmental sustainability, maintaining ecological balance, and making effective use of resources. This application makes use of microorganisms to enhance soil health and structure, promote plant growth, and minimize both abiotic and biotic stresses. Microbial applications include nitrogen fixation, as well as biofertilizers that reduce the dependency on synthetic materials and biopesticides. Microbial consortia and biostimulants that improve plant physiology by producing phytohormones produce more dependable and durable consequences in the field. Metagenomics and metabolomics are the two types of omic technologies used in these areas of study that provide a thorough description of the variety and roles of microorganisms. Furthermore, the intentional production of microbes targeted at specific organisms has been made practical via synthetic biology and gene editing techniques. In-depth case studies performed in several countries reveal that microbial technologies significantly reduced expenses and improved soil production, advancing the sustainable development goals. Nevertheless, there are several barriers to the widespread use of microbial biotechnology in agriculture. These include unpredictable conditions in the fields, strict regulations, especially related to genetically modified organisms' problems with product quality, and farmers' insufficient understanding. Microbial biotechnology aims to accomplish its full potential as an advancement in technology and as an essential aspect of resource-efficient and environmentally friendly agricultural systems via responsible innovation, adaptable regulations, and worldwide cooperation.
The convergence of biology, technology, and medicine has revolutionised healthcare, with microbial biotechnology at the forefront. While many microbes are often considered solely for their infectious properties, many are major producers of natural products, including antimicrobials. Now, not only sources of clinically relevant drugs, they are also being directly engineered for advanced applications such as targeted drug delivery, immune modulation, and precision therapeutics. Microorganisms are key sources of novel antimicrobials, immunomodulatory, and anticancer agents, which synthetic biology and genomics mining can exploit. Bioengineering and exploration of underused microbial taxa offer promising solutions to the problem of rising antimicrobial resistance. Microbes also play crucial roles in modern vaccine development, from live attenuated to recombinant antigen production. The human microbiome has emerged as an interesting player in health, driving innovations in diagnostics and therapies that include next-generation probiotics and microbiota transplants. Furthermore, synthetic biology further empowers the design of 'smart' microbes for in situ therapeutic functions like imaging, biosensing, and targeted treatment. While transformative, these innovations also raise critical ethical and regulatory concerns, including biosafety, ecological impact, data privacy, and equitable access. This chapter explores the multifaceted roles of microbes in medical biotechnology-spanning therapeutics, vaccines, microbiome-based interventions, and engineered systems-underscoring their importance in the evolution of sustainable, personalised healthcare.
Exposure to ionizing radiation can cause severe skin damage, leading to the development of cutaneous radiation syndrome. Wound healing of radiation-induced skin injuries proceeds in defined phases that depend on the intensity and type of radiation exposure. Skin damage caused by ionizing radiation can occur not only through accidental exposure, as in the case of the Chernobyl disaster, but also during radiotherapy of tumor patients. The extent of cell damage by ionizing radiation is greater in the presence of oxygen ("oxygen-effect"), most likely by the generation of reactive oxygen species (ROS), which cause damage to macromolecules (nucleic acids, proteins, lipoproteins, and polymeric carbohydrate compounds). If DNA lesions are not repaired, cells can die by apoptosis. This chapter describes the application of sensitive high-throughput microplate assays to determine the frequency of single- and double-strand DNA breaks in individuals exposed during cleanup work at the Chernobyl reactor ("liquidators"), in personnel who had worked in the destroyed Unit IV of the reactor, and in radiotherapy patients. In addition, new materials based on chitin-glucan-melanin complexes (ChGMC) and melanin-glucan complexes (MGC) or on the regeneratively active polymer inorganic polyphosphate (polyP) are presented to prevent the induction and accelerate the healing of radiation-induced skin damage.
Collagen is a biocompatible, biodegradable, and low-immunogenic protein, making it an ideal candidate for regenerative medicine. Due to ethical/religious concerns and the risk of disease transmission from traditional terrestrial mammal sources (bovine/porcine), scientific interest has increasingly shifted toward the vast marine ecosystem as a sustainable and alternative source. This chapter explores the primary applications of marine-derived collagen in wound healing, detailing its unique biochemical and structural characteristics compared to terrestrial collagen. Collagen, a fibrous protein of the extracellular matrix (ECM), is defined by its triple-helix structure, stabilized by hydroxyproline. Marine collagen shows significant diversity between vertebrates (fish) and invertebrates (Porifera, Cnidaria, Mollusca, Annelida, Echinodermata). For instance, fish collagen, though abundant from fishing industry waste, often has lower thermal stability due to a reduced imino acid content. However, specific invertebrate collagens, such as those from sponges (Chondrosia reniformis) or mollusk byssal threads, exhibit unique mechanical properties and surprising thermal resistance. The chapter comprehensively reviews the latest innovative applications using marine collagen (from fish, jellyfish, sponges, and mollusks) or gelatin in scaffolds, films, and bioactive peptides to promote skin regeneration and wound repair. This highlights the vast, unexplored potential of marine biodiversity for developing more efficient and sustainable biomaterials.
Inorganic polyphosphate (polyP), a linear polymer of orthophosphoric acid residues, is essential for living cells from bacteria to humans. It forms complexes with metal ions, DNA, and polyhydroxybutyrate. The interaction of polyP with proteins includes polyphosphorylation at lysine and histidine residues, as well as participation in amyloid formation. The enzymes of polyP metabolism are polyfunctional, and their substrates include second messenger compounds and nucleoside phosphates. PolyP is a universal regulatory compound and plays an important role in bone tissue development, thrombosis and inflammation, signal transmission in nerve cells, carcinogenesis, and amyloid formation. PolyP participates in biofilm formation and other processes occurring during the interaction of pathogenic microorganisms with the host. PolyP of the gut microbiome is involved in maintaining intestinal functions. PolyP and the enzymes of its metabolism are promising targets for developing drugs against infections and novel approaches to treat bone, cardiovascular, and neurodegenerative diseases.
Bacteria exhibit extraordinary evolutionary and ecological diversity. They range from dominant, well-characterized phyla to rare lineages that are known only through environmental sequencing. This chapter reviews four key bacterial phyla, including Pseudomonadota, Bacillota, Actinomycetota, and Bacteroidota. These phyla are widely distributed, metabolically versatile, and play a central role in ecosystem functioning and human health. We discuss unique phyla within the PVC superphylum (Planctomycetota, Verrucomicrobiota, Chlamydiota) for their unusual cell biology, compartmentalization, and host associations. We also highlight hyperthermophilic phyla, such as Thermotogota, Aquificota, and Thermodesulfobacteriota, that thrive in geothermal ecosystems and drive sulfur and carbon cycling. We consider less-cultivated lineages, including Deinococcota, Acidobacteriota, Nitrospirota, Fusobacteriota, Fibrobacterota, Synergistota, Deferribacterota, and Chrysiogenota, in terms of their ecological niches, metabolic specializations, and roles in biogeochemical cycles, symbiosis, and disease. Collectively, these examples demonstrate the remarkable metabolic flexibility and ecological impact of bacteria, ranging from host-associated commensals and pathogens to free-living autotrophs in extreme environments. Despite advances in genomics and cultivation-independent methods, vast portions of bacterial diversity remain uncultured and poorly understood. Continued exploration of both dominant phyla and rare lineages promises to refine bacterial taxonomy, expand our understanding of microbial evolution, and reveal novel metabolic pathways with implications for ecology, medicine, and biotechnology.
The unfolded protein response (UPR) is an evolutionarily conserved adaptive regulatory pathway that alleviates protein-folding defects in the endoplasmic reticulum (ER). Physiological demands, environmental perturbations and pathological conditions can cause accumulation of unfolded proteins in the ER and the stress signal is transmitted to the nucleus to turn on a series of genes to respond the challenge. In metazoan, the UPR pathways consisted of IRE1/XBP1, PEK-1 and ATF6, which function in parallel and downstream transcriptional activation triggers the proteostasis networks consisting of molecular chaperones, protein degradation machinery and other stress response pathways ((Labbadia J, Morimoto RI, F1000Prime Rep 6:7, 2014); (Shen X, Ellis RE, Lee K, Annu Rev Biochem 28:893-903, 2014)). The integrated responses act on to resolve the ER stress by increasing protein folding capacity, attenuating ER-loading translation, activating ER-associated proteasomal degradation (ERAD), and regulating IRE1-dependent decay of mRNA (RIDD). Therefore, the effective UPR to internal and external causes is linked to the multiple pathophysiological conditions such as aging, immunity, and neurodegenerative diseases. Recent development in the research of the UPR includes cell-nonautonomous features of the UPR, interplay between the UPR and other stress response pathways, unconventional UPR inducers, and noncanonical UPR independent of the three major branches, originated from multiple cellular and molecular machineries in addition to ER. Caenorhabditis elegans model system has critically contributed to these unprecedented aspects of the ER UPR and broadens the possible therapeutic targets to treat the ER-stress associated human disorders and time-dependent physiological deterioration of aging.
The endoplasmic reticulum (ER) is an organelle that mediates the proper folding and assembly of proteins destined for the cell surface, the extracellular space and subcellular compartments such as the lysosomes. The ER contains a wide range of molecular chaperones to handle the folding requirements of a diverse set of proteins that traffic through this compartment. The lectin-like chaperones calreticulin and calnexin are an important class of structurally-related chaperones relevant for the folding and assembly of many N-linked glycoproteins. Despite the conserved mechanism of action of these two chaperones in nascent protein recognition and folding, calreticulin has unique functions in cellular calcium signaling and in the immune response. The ER-related functions of calreticulin in the assembly of major histocompatibility complex (MHC) class I molecules are well-studied and provide many insights into the modes of substrate and co-chaperone recognition by calreticulin. Calreticulin is also detectable on the cell surface under some conditions, where it induces the phagocytosis of apoptotic cells. Furthermore, mutations of calreticulin induce cell transformation in myeloproliferative neoplasms (MPN). Studies of the functions of the mutant calreticulin in cell transformation and immunity have provided many insights into the normal biology of calreticulin, which are discussed.
Chronic wounds, pathological states failing to heal promptly, are especially prevalent among the elderly. This impaired healing in the senescent tissue is predominately attributed to the accumulation of senescent cells and a concomitant decline in energy metabolism, ultimately leading to functional impairment. Existing clinical practices-including debridement, hyperbaric oxygen, antibiotics, and wound dressings-cannot fundamentally resolve this cellular decline. In this context, advanced biomaterials designed to enhance cellular energy metabolism emerge as a viable strategy. This chapter details strategies by which biomaterials enhance skin wound healing in aging environments by modulating energy metabolism. It explains that delayed healing primarily stems from age-associated metabolic and mitochondrial dysregulation, which compromises cellular repair functions. Furthermore, it reviews advanced biomaterial-based approaches that promote healing by delivering metabolites, restoring mitochondrial function, and indirectly modulating stem cells. By targeting energy metabolism to reverse the low-energy state of aged skin, these approaches fundamentally address cellular functional decline and actively foster tissue regeneration. Therefore, this chapter outlines design principles for energy metabolism-modulating biomaterials to aid wound healing in aged skin and highlights recent advances in this field.
Ageing is a complex and multifactorial process driven by genetic, environmental and stochastic factors that lead to the progressive decline of biological systems. Mechanisms of ageing have been extensively investigated in various model organisms and systems generating fundamental advances. Notably, studies on yeast ageing models have made numerous and relevant contributions to the progress in the field. Different longevity factors and pathways identified in yeast have then been shown to regulate molecular ageing in invertebrate and mammalian models. Currently the best candidates for anti-ageing drugs such as spermidine and resveratrol or anti-ageing interventions such as caloric restriction were first identified and explored in yeast. Yeasts have also been instrumental as models to study the cellular and molecular effects of proteins associated with age-related diseases such as Parkinson's, Huntington's or Alzheimer's diseases. In this chapter, a review of the advances on ageing and age-related diseases research in yeast models will be made. Particular focus will be placed on key longevity factors, ageing hallmarks and interventions that slow ageing, both yeast-specific and those that seem to be conserved in multicellular organisms. Their impact on the pathogenesis of age-related diseases will be also discussed.
The human microbiota represents a complex and dynamic ecosystem composed of microorganisms from various taxonomic groups, including bacteria, viruses, fungi, archaea, and protozoa. These microorganisms inhabit different anatomical regions of the human body, such as the genitourinary system, the gastrointestinal tract, the oral cavity, the skin, and the respiratory tract, exhibiting distinct densities, compositions, and functional characteristics, and interact reciprocally with the host organism. The term microbiota not only defines the diversity and abundance of microorganisms but also encompasses their functional influence on host physiology. At this point, the concept of the microbiome becomes relevant. The microbiome refers to the collective genomic content of all microorganisms comprising the microbiota, that is, their genetic material and the potential biological functions encoded by their genes. Therefore, microbiome analysis enables not only the assessment of microbial diversity, but also of metabolic capacity, signal transduction, immune regulation, and other host-microbe interactions. The microbiota and microbiome play important roles in preserving human health and homeostatic balance. A healthy microbial composition promotes immune system development, aids digestion and nutrient absorption, reduces pathogenic microorganism colonization, and contributes to the integrity of the mucosal barrier. In contrast, dysbiosis, or disruption of microbial equilibrium, has been linked to a variety of pathophysiological illnesses, including inflammatory diseases, metabolic disorders, neurodegenerative diseases, and some neoplasms. Today, microbiome research is not only essential for understanding health and disease mechanisms but also forms the foundation for innovative future medical applications.
In recent years, inorganic polyphosphate (polyP) has attracted increasing attention as a biomedical polymer or biomaterial with a great potential for application in regenerative medicine, in particular in the fields of tissue engineering and repair. The interest in polyP is based on two properties of this physiological polymer that make polyP stand out from other polymers: polyP has morphogenetic activity by inducing cell differentiation through specific gene expression, and it functions as an energy store and donor of metabolic energy, especially in the extracellular matrix or in the extracellular space. No other biopolymer applicable in tissue regeneration/repair is known that is endowed with this combination of properties. In addition, polyP can be fabricated both in the form of a biologically active coacervate and as biomimetic amorphous polyP nano/microparticles, which are stable and are activated by transformation into the coacervate phase after contact with protein/body fluids. PolyP can be used in the form of various metal salts and in combination with various hydrogel-forming polymers, whereby (even printable) hybrid materials with defined porosities and mechanical and biological properties can be produced, which can even be loaded with cells for 3D cell printing or with drugs and support the growth and differentiation of (stem) cells as well as cell migration/microvascularization. Potential applications in therapy of bone, cartilage and eye disorders/injuries and wound healing are summarized and possible mechanisms are discussed.
The corneal epithelium, a stratified squamous non-keratinized layer of 50-60 μm thickness, forms the outermost barrier of the cornea and provides both optical clarity and protection against trauma, infection, and fluid imbalance. It plays a vital role in protecting the eye and maintaining visual clarity. A range of conditions, including trauma, metabolic disorders, microbial infection, and limbal stem cell deficiency, can lead to chronic corneal epithelial defects and subsequent visual impairment. Epithelial renewal is a continuous process, primarily sustained by stem cells located at the limbus. These stem cells give rise to transient amplifying cells, which migrate centripetally and superficially to maintain epithelial integrity. Wound healing follows a highly regulated sequence, superficial cells slide to cover the defect, basal cells proliferate, and corneal nerves realign to support epithelial stratification. This process is orchestrated by cytoskeletal remodeling, integrin-matrix interactions, and growth factor signaling. The epithelium relies on glucose from the corneal stroma, primarily metabolized through glycolysis, while mitochondrial oxidative phosphorylation generates the ATP required for repair. Thus, epithelial regeneration is closely tied to cellular energy availability. Enhancing this process involves supporting mitochondrial function, metabolic signaling pathways, and stem cell activity. Emerging strategies in regenerative ophthalmology include NAD+ replenishment, activation of AMP-activated protein kinase (AMPK), application of growth factors, targeted nanotherapies, and photobiomodulation. This chapter explores these cutting-edge approaches aimed at promoting energy-driven regeneration of the corneal surface.
The lectin chaperones calreticulin (CALR) and calnexin (CANX), together with their co-chaperone PDIA3, are increasingly implicated in studies of human cancers in roles that extend beyond their primary function as quality control facilitators of protein folding within the endoplasmic reticulum (ER). Led by the discovery that cell surface CALR functions as an immunogen that promotes anti-tumour immunity, studies have now expanded to include their potential uses as prognostic markers for cancers, and in regulation of oncogenic signaling that regulate such diverse processes including integrin-dependent cell adhesion and migration, proliferation, cell death and chemotherapeutic resistance. The diversity stems from the increasing recognition that these proteins have an equally diverse spectrum of subcellular and extracellular localization, and which are aberrantly expressed in tumour cells. This review describes key foundational discoveries and highlight recent findings that further our understanding of the plethora of activities mediated by CALR, CANX and PDIA3.