Editor’s Choice Articles

Parkinson’s Disease (PD) is a highly prevalent neurodegenerative disease among older adults. PD neuropathology is marked by the progressive loss of the dopaminergic neurons of the substantia nigra pars compacta and the widespread accumulation of misfolded intracellular α-synuclein (α-syn). Genetic mutations and post-translational modifications, such as α-syn phosphorylation, have been identified among the multiple factors supporting α-syn accrual during PD. A decline in the clearance capacity of the ubiquitin-proteasome and the autophagy-lysosomal systems, together with mitochondrial dysfunction, have been indicated as major pathophysiological mechanisms of PD neurodegeneration. The accrual of misfolded α-syn aggregates into soluble oligomers, and the generation of insoluble fibrils composing the core of intraneuronal Lewy bodies and Lewy neurites observed during PD neurodegeneration, are ignited by the overproduction of reactive oxygen species (ROS). The ROS activate the α-syn aggregation cascade and, together with the Lewy bodies, promote neurodegeneration. However, the molecular pathways underlying the dynamic evolution of PD remain undeciphered. These gaps in knowledge, together with the clinical heterogeneity of PD, have hampered the identification of the biomarkers that may be used to assist in diagnosis, treatment monitoring, and prognostication. Herein, we illustrate the main pathways involved in PD pathogenesis and discuss their possible exploitation for biomarker discovery. Full article

Telomeres are protective structures at the ends of linear chromosomes. Shortened telomere lengths (TL) are an indicator of premature biological aging and have been associated with a wide spectrum of disorders, including multiple sclerosis (MS). MS is a chronic inflammatory, demyelinating and neurodegenerative disease of the central nervous system. The exact cause of MS is still unclear. Here, we provide an overview of genetic, environmental and lifestyle factors that have been described to influence TL and to contribute to susceptibility to MS and possibly disease severity. We show that several early-life factors are linked to both reduced TL and higher risk of MS, e.g., adolescent obesity, lack of physical activity, smoking and vitamin D deficiency. This suggests that the mechanisms underlying the disease are connected to cellular aging and senescence promoted by increased inflammation and oxidative stress. Additional prospective research is needed to clearly define the extent to which lifestyle changes can slow down disease progression and prevent accelerated telomere loss in individual patients. It is also important to further elucidate the interactions between shared determinants of TL and MS. In future, cell type-specific studies and advanced TL measurement methods could help to better understand how telomeres may be causally involved in disease processes and to uncover novel opportunities for improved biomarkers and therapeutic interventions in MS. Full article

Osteogenesis Imperfecta (OI) is a group of connective tissue disorders with a broad range of phenotypes characterized primarily by bone fragility. The prevalence of OI ranges from about 1:15,000 to 1:20,000 births. Five types of the disease are commonly distinguished, ranging from a mild (type I) to a lethal one (type II). Types III and IV are severe forms allowing survival after the neonatal period, while type V is characterized by a mild to moderate phenotype with calcification of interosseous membranes. In most cases, there is a reduction in the production of normal type I collagen (col I) or the synthesis of abnormal collagen as a result of mutations in col I genes. Moreover, mutations in genes involved in col I synthesis and processing as well as in osteoblast differentiation have been reported. The currently available treatments try to prevent fractures, control symptoms and increase bone mass. Commonly used medications in OI treatment are bisphosphonates, Denosumab, synthetic parathyroid hormone and growth hormone for children therapy. The main disadvantages of these therapies are their relatively weak effectiveness, lack of effects in some patients or cytotoxic side effects. Experimental approaches, particularly those based on stem cell transplantation and genetic engineering, seem to be promising to improve the therapeutic effects of OI. Full article

Humans have evolved a series of DNA double-strand break (DSB) repair pathways to efficiently and accurately rejoin nascently formed pairs of double-stranded DNA ends (DSEs). In G0/G1-phase cells, non-homologous end joining (NHEJ) and alternative end joining (A-EJ) operate to support covalent rejoining of DSEs. While NHEJ is predominantly utilized and collaborates extensively with the DNA damage response (DDR) to support pairing of DSEs, much less is known about A-EJ collaboration with DDR factors when NHEJ is absent. Non-cycling lymphocyte progenitor cells use NHEJ to complete V(D)J recombination of antigen receptor genes, initiated by the RAG1/2 endonuclease which holds its pair of targeted DSBs in a synapse until each specified pair of DSEs is handed off to the NHEJ DSB sensor complex, Ku. Similar to designer endonuclease DSBs, the absence of Ku allows for A-EJ to access RAG1/2 DSEs but with random pairing to complete their repair. Here, we describe recent insights into the major phases of DSB end joining, with an emphasis on synapsis and tethering mechanisms, and bring together new and old concepts of NHEJ vs. A-EJ and on RAG2-mediated repair pathway choice. Full article

Signal transduction pathways transmit the information received from external and internal cues and generate a response that allows the cell to adapt to changes in the surrounding environment. Signaling pathways trigger rapid responses by changing the activity or localization of existing molecules, as well as long-term responses that require the activation of gene expression programs. All steps involved in the regulation of gene expression, from transcription to processing and utilization of new transcripts, are modulated by multiple signal transduction pathways. This review provides a broad overview of the post-translational regulation of factors involved in RNA processing events by signal transduction pathways, with particular focus on the regulation of pre-mRNA splicing, cleavage and polyadenylation. The effects of several post-translational modifications (i.e., sumoylation, ubiquitination, methylation, acetylation and phosphorylation) on the expression, subcellular localization, stability and affinity for RNA and protein partners of many RNA-binding proteins are highlighted. Moreover, examples of how some of the most common signal transduction pathways can modulate biological processes through changes in RNA processing regulation are illustrated. Lastly, we discuss challenges and opportunities of therapeutic approaches that correct RNA processing defects and target signaling molecules. Full article

Parasitic nematodes infect almost all forms of life. In the human context, parasites are one of the major causative factors for physical and intellectual growth retardation in the developing world. In the agricultural setting, parasites have a great economic impact through a reduction in livestock performance or control cost. The main method of controlling these devastating conditions is the use of anthelmintic drugs. Unfortunately, there are only a few anthelmintic drug classes available in the market and significant resistance has developed in most of the parasitic species of livestock. Therefore, development of new anthelmintics with different modes of action is critical for sustainable parasitic control in the future. The drug development pipeline is broadly limited to two types of molecules, namely synthetic compounds and natural plant products. Compared to synthetic compounds, natural products are highly diverse, and many have historically proven valuable in folk medicine to treat various gastrointestinal ailments. This review focus on the use of traditional knowledge-based plant extracts in the development of new therapeutic leads, the approaches used as screening techniques, and common bottlenecks and opportunities in plant-based anthelmintic drug discovery. Full article

Protein signaling networks are formed from diverse and inter-connected cell signaling pathways converging into webs of function and regulation. These signaling pathways both receive and conduct molecular messages, often by a series of post-translation modifications such as phosphorylation or through protein–protein interactions via intrinsic motifs. The mitogen activated protein kinases (MAPKs) are components of kinase cascades that transmit signals through phosphorylation. There are several MAPK subfamilies, and one subfamily is the stress-activated protein kinases, which in mammals is the p38 family. The p38 enzymes mediate a variety of cellular outcomes including DNA repair, cell survival/cell fate decisions, and cell cycle arrest. The cell cycle is itself a signaling system that precisely controls DNA replication, chromosome segregation, and cellular division. Another indispensable cell function influenced by the p38 stress response is programmed cell death (apoptosis). As the regulators of cell survival, the BCL2 family of proteins and their dynamics are exquisitely sensitive to cell stress. The BCL2 family forms a protein–protein interaction network divided into anti-apoptotic and pro-apoptotic members, and the balance of binding between these two sides determines cell survival. Here, we discuss the intersections among the p38 MAPK, cell cycle, and apoptosis signaling pathways. Full article

High Mobility Group Box (HMGB) proteins are small architectural DNA binding proteins that regulate multiple genomic processes such as DNA damage repair, nucleosome sliding, telomere homeostasis, and transcription. In doing so they control both normal cellular functions and impact a myriad of disease states, including cancers and autoimmune diseases. HMGB proteins bind to DNA and nucleosomes to modulate the local chromatin environment, which facilitates the binding of regulatory protein factors to the genome and modulates higher order chromosomal organization. Numerous studies over the years have characterized the structure and function of interactions between HMGB proteins and DNA, both biochemically and inside cells, providing valuable mechanistic insight as well as evidence these interactions influence pathological processes. This review highlights recent studies supporting the roles of HMGB1 and HMGB2 in global organization of the genome, as well as roles in transcriptional regulation and telomere maintenance via interactions with G-quadruplex structures. Moreover, emerging models for how HMGB proteins function as RNA binding proteins are presented. Nuclear HMGB proteins have broad regulatory potential to impact numerous aspects of cellular metabolism in normal and disease states. Full article

Over the years, multiple biomarkers have been used to aid in disease screening, diagnosis, prognosis, and response to therapy. As of late, protein biomarkers are gaining strength in their role for early disease diagnosis and prognosis in part due to the advancements in identification and characterization of a distinct functional pool of proteins known as proteoforms. Proteoforms are defined as all of the different molecular forms of a protein derived from a single gene caused by genetic variations, alternative spliced RNA transcripts and post-translational modifications. Monitoring the structural changes of each proteoform of a particular protein is essential to elucidate the complex molecular mechanisms that guide the course of disease. Clinical proteomics therefore holds the potential to offer further insight into disease pathology, progression, and prevention. Nevertheless, more technologically advanced diagnostic methods are needed to improve the reliability and clinical applicability of proteomics in preventive medicine. In this manuscript, we review the use of immunoaffinity capillary electrophoresis (IACE) as an emerging powerful diagnostic tool to isolate, separate, detect and characterize proteoform biomarkers obtained from liquid biopsy. IACE is an affinity capture-separation technology capable of isolating, concentrating and analyzing a wide range of biomarkers present in biological fluids. Isolation and concentration of target analytes is accomplished through binding to one or more biorecognition affinity ligands immobilized to a solid support, while separation and analysis are achieved by high-resolution capillary electrophoresis (CE) coupled to one or more detectors. IACE has the potential to generate rapid results with significant accuracy, leading to reliability and reproducibility in diagnosing and monitoring disease. Additionally, IACE has the capability of monitoring the efficacy of therapeutic agents by quantifying companion and complementary protein biomarkers. With advancements in telemedicine and artificial intelligence, the implementation of proteoform biomarker detection and analysis may significantly improve our capacity to identify medical conditions early and intervene in ways that improve health outcomes for individuals and populations. Full article

Pyrroloquinoline quinone (PQQ) is associated with biological processes such as mitochondriogenesis, reproduction, growth, and aging. In addition, PQQ attenuates clinically relevant dysfunctions (e.g., those associated with ischemia, inflammation and lipotoxicity). PQQ is novel among biofactors that are not currently accepted as vitamins or conditional vitamins. For example, the absence of PQQ in diets produces a response like a vitamin-related deficiency with recovery upon PQQ repletion in a dose-dependent manner. Moreover, potential health benefits, such as improved metabolic flexibility and immuno-and neuroprotection, are associated with PQQ supplementation. Here, we address PQQ’s role as an enzymatic cofactor or accessory factor and highlight mechanisms underlying PQQ’s actions. We review both large scale and targeted datasets demonstrating that a neonatal or perinatal PQQ deficiency reduces mitochondria content and mitochondrial-related gene expression. Data are reviewed that suggest PQQ’s modulation of lactate acid and perhaps other dehydrogenases enhance NAD+-dependent sirtuin activity, along with the sirtuin targets, such as PGC-1$\mathsf{\alpha }$, NRF-1, NRF-2 and TFAM; thus, mediating mitochondrial functions. Taken together, current observations suggest vitamin-like PQQ has strong potential as a potent therapeutic nutraceutical. Full article

Obesity represents a major public health problem with a prevalence increasing at an alarming rate worldwide. Continuous intensive efforts to elucidate the complex pathophysiology and improve clinical management have led to a better understanding of biomolecules like gut hormones, antagonists of orexigenic signals, stimulants of fat utilization, and/or inhibitors of fat absorption. In this article, we will review the pathophysiology and pharmacotherapy of obesity including intersection points to the new generation of antidiabetic drugs. We provide insight into the effectiveness of currently approved anti-obesity drugs and other therapeutic avenues that can be explored. Full article

Cannabis (Cannabis sativa), popularly known as marijuana, is the most commonly used psychoactive substance and is considered illicit in most countries worldwide. However, a growing body of research has provided evidence of the therapeutic properties of chemical components of cannabis known as cannabinoids against several diseases including Alzheimer’s disease (AD), multiple sclerosis (MS), Parkinson’s disease, schizophrenia and glaucoma; these have prompted changes in medicinal cannabis legislation. The relaxation of legal restrictions and increased socio-cultural acceptance has led to its increase in both medicinal and recreational usage. Several biochemically active components of cannabis have a range of effects on the biological system. There is an urgent need for more research to better understand the molecular and biochemical effects of cannabis at a cellular level, to understand fully its implications as a pharmaceutical drug. Proteomics technology is an efficient tool to rigorously elucidate the mechanistic effects of cannabis on the human body in a cell and tissue-specific manner, drawing conclusions associated with its toxicity as well as therapeutic benefits, safety and efficacy profiles. This review provides a comprehensive overview of both in vitro and in vivo proteomic studies involving the cellular and molecular effects of cannabis and cannabis-derived compounds. Full article

The transient receptor potential (TRP) cation channel superfamily comprises more than 50 channels that play crucial roles in physiological processes. TRP channels are responsive to several exogenous and endogenous biomolecules, with aldehydes emerging as a TRP channel trigger contributing to a cellular cascade that can lead to disease pathophysiology. The body is not only exposed to exogenous aldehydes via tobacco products or alcoholic beverages, but also to endogenous aldehydes triggered by lipid peroxidation. In response to lipid peroxidation from inflammation or organ injury, polyunsaturated fatty acids undergo lipid peroxidation to aldehydes, such as 4-hydroxynonenal. Reactive aldehydes activate TRP channels via aldehyde-induced protein adducts, leading to the release of pro-inflammatory mediators driving the pathophysiology caused by cellular injury, including inflammatory pain and organ reperfusion injury. Recent studies have outlined how aldehyde dehydrogenase 2 protects against aldehyde toxicity through the clearance of toxic aldehydes, indicating that targeting the endogenous aldehyde metabolism may represent a novel treatment strategy. An addition approach can involve targeting specific TRP channel regions to limit the triggering of a cellular cascade induced by aldehydes. In this review, we provide a comprehensive summary of aldehydes, TRP channels, and their interactions, as well as their role in pathological conditions and the different therapeutical treatment options. Full article

Epstein-Barr virus (EBV) is typically found in a latent, asymptomatic state in immunocompetent individuals. Perturbations of the host immune system can stimulate viral reactivation. Furthermore, there are a myriad of EBV-associated illnesses including various cancers, post-transplant lymphoproliferative disease, and autoimmune conditions. A thorough understanding of this virus, and the interplay between stress and the immune system, is essential to establish effective treatment. This review will provide a summary of the interaction between both psychological and cellular stressors resulting in EBV reactivation. It will examine mechanisms by which EBV establishes and maintains latency and will conclude with a brief overview of treatments targeting EBV. Full article

Rab proteins are small GTPases that act as molecular switches for intracellular vesicle trafficking. Although their function is mainly regulated by regulatory proteins such as GTPase-activating proteins and guanine nucleotide exchange factors, recent studies have shown that some Rab proteins are physiologically phosphorylated in the switch II region by Rab kinases. As the switch II region of Rab proteins undergoes a conformational change depending on the bound nucleotide, it plays an essential role in their function as a ‘switch’. Initially, the phosphorylation of Rab proteins in the switch II region was shown to inhibit the association with regulatory proteins. However, recent studies suggest that it also regulates the binding of Rab proteins to effector proteins, determining which pathways to regulate. These findings suggest that the regulation of the Rab function may be more dynamically regulated by phosphorylation than just through the association with regulatory proteins. In this review, we summarize the recent findings and discuss the physiological and pathological roles of Rab phosphorylation. Full article

Abnormal accumulation of the protein α- synuclein (α-syn) into proteinaceous inclusions called Lewy bodies (LB) is the neuropathological hallmark of Parkinson’s disease (PD) and related disorders. Interestingly, a growing body of evidence suggests that LB are also composed of other cellular components such as cellular membrane fragments and vesicular structures, suggesting that dysfunction of the endolysosomal system might also play a role in LB formation and neuronal degeneration. Yet the link between α-syn aggregation and the endolysosomal system disruption is not fully elucidated. In this review, we discuss the potential interaction between α-syn and the endolysosomal system and its impact on PD pathogenesis. We propose that the accumulation of monomeric and aggregated α-syn disrupt vesicles trafficking, docking, and recycling, leading to the impairment of the endolysosomal system, notably the autophagy-lysosomal degradation pathway. Reciprocally, PD-linked mutations in key endosomal/lysosomal machinery genes (LRRK2, GBA, ATP13A2) also contribute to increasing α-syn aggregation and LB formation. Altogether, these observations suggest a potential synergistic role of α-syn and the endolysosomal system in PD pathogenesis and represent a viable target for the development of disease-modifying treatment for PD and related disorders. Full article

Amylomaltases (4-α-glucanotransferases, E.C. 2.4.1.25) are enzymes which can perform a double-step catalytic process, resulting in a transglycosylation reaction. They hydrolyse glucosidic bonds of α-1,4′-d-glucans and transfer the glucan portion with the newly available anomeric carbon to the 4′-position of an α-1,4′-d-glucan acceptor. The intramolecular reaction produces a cyclic α-1,4′-glucan. Amylomaltases can be found only in prokaryotes, where they are involved in glycogen degradation and maltose metabolism. These enzymes are being studied for possible biotechnological applications, such as the production of (i) sugar substitutes; (ii) cycloamyloses (molecules larger than cyclodextrins), which could potentially be useful as carriers and encapsulating agents for hydrophobic molecules and also as effective protein chaperons; and (iii) thermoreversible starch gels, which could be used as non-animal gelatin substitutes. Extremophilic prokaryotes have been investigated for the identification of amylomaltases to be used in the starch modifying processes, which require high temperatures or extreme conditions. The aim of this article is to present an updated overview of studies on amylomaltases from extremophilic Bacteria and Archaea, including data about their distribution, activity, potential industrial application and structure. Full article

The majority of critically ill intensive care unit (ICU) patients with severe sepsis develop ICU-acquired weakness (ICUAW) characterized by loss of muscle mass, reduction in myofiber size and decreased muscle strength leading to persisting physical impairment. This phenotype results from a dysregulated protein homeostasis with increased protein degradation and decreased protein synthesis, eventually causing a decrease in muscle structural proteins. The ubiquitin proteasome system (UPS) is the predominant protein-degrading system in muscle that is activated during diverse muscle atrophy conditions, e.g., inflammation. The specificity of UPS-mediated protein degradation is assured by E3 ubiquitin ligases, such as atrogin-1 and MuRF1, which target structural and contractile proteins, proteins involved in energy metabolism and transcription factors for UPS-dependent degradation. Although the regulation of activity and function of E3 ubiquitin ligases in inflammation-induced muscle atrophy is well perceived, the contribution of the proteasome to muscle atrophy during inflammation is still elusive. During inflammation, a shift from standard- to immunoproteasome was described; however, to which extent this contributes to muscle wasting and whether this changes targeting of specific muscular proteins is not well described. This review summarizes the function of the main proinflammatory cytokines and acute phase response proteins and their signaling pathways in inflammation-induced muscle atrophy with a focus on UPS-mediated protein degradation in muscle during sepsis. The regulation and target-specificity of the main E3 ubiquitin ligases in muscle atrophy and their mode of action on myofibrillar proteins will be reported. The function of the standard- and immunoproteasome in inflammation-induced muscle atrophy will be described and the effects of proteasome-inhibitors as treatment strategies will be discussed. Full article

Carcinogenesis is a multifactorial process with the input and interactions of environmental, genetic, and metabolic factors. During cancer development, a significant remodeling of the extracellular matrix (ECM) is evident. Proteoglycans (PGs), such as lumican, are glycosylated proteins that participate in the formation of the ECM and are established biological mediators. Notably, lumican is involved in cellular processes associated with tumorigeneses, such as EMT (epithelial-to-mesenchymal transition), cellular proliferation, migration, invasion, and adhesion. Furthermore, lumican is expressed in various cancer tissues and is reported to have a positive or negative correlation with tumor progression. This review focuses on significant advances achieved regardingthe role of lumican in the tumor biology. Here, the effects of lumican on cancer cell growth, invasion, motility, and metastasis are discussed, as well as the repercussions on autophagy and apoptosis. Finally, in light of the available data, novel roles for lumican as a cancer prognosis marker, chemoresistance regulator, and cancer therapy target are proposed. Full article

Stem cell transplantation with rehabilitation therapy presents an effective stroke treatment. Here, we discuss current breakthroughs in stem cell research along with rehabilitation strategies that may have a synergistic outcome when combined together after stroke. Indeed, stem cell transplantation offers a promising new approach and may add to current rehabilitation therapies. By reviewing the pathophysiology of stroke and the mechanisms by which stem cells and rehabilitation attenuate this inflammatory process, we hypothesize that a combined therapy will provide better functional outcomes for patients. Using current preclinical data, we explore the prominent types of stem cells, the existing theories for stem cell repair, rehabilitation treatments inside the brain, rehabilitation modalities outside the brain, and evidence pertaining to the benefits of combined therapy. In this review article, we assess the advantages and disadvantages of using stem cell transplantation with rehabilitation to mitigate the devastating effects of stroke. Full article

Organoids are three-dimensional in vitro cell constructs that recapitulate organ properties and structure to a significant extent. They constitute particularly useful models to study unapproachable states in humans, such as embryonic and fetal development, or early disease progression in adults. In recent years organoids have been implemented to model a wide range of different organs and disease conditions. However, the technology for their fabrication and application to cardiovascular studies has been lagging significantly when compared to other organoid types (e.g., brain, pancreas, kidney, intestine). This is a surprising fact since cardiovascular disease (CVD) and congenital heart disease (CHD) constitute the leading cause of mortality and morbidity in the developed world, and the most common birth defect in humans, respectively, and collectively constitute one of the largest unmet medical needs in the modern world. There is a critical need to establish in vitro models of the human heart that faithfully recapitulate its biology and function, thus enabling basic and translational studies to develop new therapeutics. Generating heart organoids that truly resemble the heart has proven difficult due to its complexity, but significant progress has been made recently to overcome this obstacle. In this review, we will discuss progress in novel heart organoid generation methods, the advantages and disadvantages of each approach, and their translational applications for advancing cardiovascular studies and the treatment of heart disorders. Full article

Several studies reported that metformin, the most widely used drug for type 2 diabetes, might affect cancer aggressiveness. The biguanide seems to directly impair cancer energy asset, with the consequent phosphorylation of AMP-activated protein kinase (AMPK) inhibiting cell proliferation and tumor growth. This action is most often attributed to a well-documented blockage of oxidative phosphorylation (OXPHOS) caused by a direct interference of metformin on Complex I function. Nevertheless, several other pleiotropic actions seem to contribute to the anticancer potential of this biguanide. In particular, in vitro and in vivo experimental studies recently documented that metformin selectively inhibits the uptake of 2-[18F]-Fluoro-2-Deoxy-D-Glucose (FDG), via an impaired catalytic function of the enzyme hexose-6P-dehydrogenase (H6PD). H6PD triggers a still largely uncharacterized pentose-phosphate pathway (PPP) within the endoplasmic reticulum (ER) that has been found to play a pivotal role in feeding the NADPH reductive power for both cellular proliferation and antioxidant responses. Regardless of its exploitability in the clinical setting, this metformin action might configure the ER metabolism as a potential target for innovative therapeutic strategies in patients with solid cancers and potentially modifies the current interpretative model of FDG uptake, attributing PET/CT capability to predict cancer aggressiveness to the activation of H6PD catalytic function. Full article

Because of their abilities to catalyze generation of toxic free radical species, free concentrations of the redox reactive metals iron and copper are highly regulated. Importantly, desired neurobiological effects of these redox reactive metal cations occur within very narrow ranges of their local concentrations. For example, synaptic release of free copper acts locally to modulate NMDA receptor-mediated neurotransmission. Moreover, within the developing brain, iron is critical to hippocampal maturation and the differentiation of parvalbumin-expressing neurons, whose soma and dendrites are surrounded by perineuronal nets (PNNs). The PNNs are a specialized component of brain extracellular matrix, whose polyanionic character supports the fast-spiking electrophysiological properties of these parvalbumin-expressing GABAergic interneurons. In addition to binding cations and creation of the Donnan equilibrium that support the fast-spiking properties of this subset of interneurons, the complex architecture of PNNs also binds metal cations, which may serve a protective function against oxidative damage, especially of these fast-spiking neurons. Data suggest that pathological disturbance of the population of fast-spiking, parvalbumin-expressing GABAergic inhibitory interneurons occur in at least some clinical presentations, which leads to disruption of the synchronous oscillatory output of assemblies of pyramidal neurons. Increased expression of the GluN2A NMDA receptor subunit on parvalbumin-expressing interneurons is linked to functional maturation of both these neurons and the perineuronal nets that surround them. Disruption of GluN2A expression shows increased susceptibility to oxidative stress, reflected in redox dysregulation and delayed maturation of PNNs. This may be especially relevant to neurodevelopmental disorders, including autism spectrum disorder. Conceivably, binding of metal redox reactive cations by the perineuronal net helps to maintain safe local concentrations, and also serves as a reservoir buffering against second-to-second fluctuations in their concentrations outside of a narrow physiological range. Full article

High levels of histamine and histamine receptors (HRs), including H1R~H4R, are found in many different types of tumor cells and cells in the tumor microenvironment, suggesting their involvement in tumor progression. This review summarizes the latest evidence demonstrating the pathophysiological roles of histamine and its cognate receptors in cancer biology. We also discuss the novel therapeutic approaches of selective HR ligands and their potential prognostic values in cancer treatment. Briefly, histamine is highly implicated in cancer development, growth, and metastasis through interactions with distinct HRs. It also regulates the infiltration of immune cells into the tumor sites, exerting an immunomodulatory function. Moreover, the effects of various HR ligands, including H1R antagonists, H2R antagonists, and H4R agonists, on tumor progression in many different cancer types are described. Interestingly, the expression levels of HR subtypes may serve as prognostic biomarkers in several cancers. Taken together, HRs are promising targets for cancer treatment, and HR ligands may offer novel therapeutic potential, alone or in combination with conventional therapy. However, due to the complexity of the pathophysiological roles of histamine and HRs in cancer biology, further studies are warranted before HR ligands can be introduced into clinical settings. Full article

Chalcones belong to the flavonoid class of phenolic compounds. They form one of the largest groups of bioactive natural products. The potential anticancer, anti-inflammatory, antimicrobial, antioxidant, and antiparasitic properties of naturally occurring chalcones, and their unique chemical structural features inspired the synthesis of numerous chalcone derivatives. In fact, structural features of chalcones are easy to construct from simple aromatic compounds, and it is convenient to perform structural modifications to generate functionalized chalcone derivatives. Many of these synthetic analogs were shown to possess similar bioactivities as their natural counterparts, but often with an enhanced potency and reduced toxicity. This review article aims to demonstrate how bioinspired synthesis of chalcone derivatives can potentially introduce a new chemical space for exploitation for new drug discovery, justifying the title of this article. However, the focus remains on critical appraisal of synthesized chalcones and their derivatives for their bioactivities, linking to their interactions at the biomolecular level where appropriate, and revealing their possible mechanisms of action. Full article

All proteins are subject to quality control processes during or soon after their synthesis, and these cellular quality control pathways play critical roles in maintaining homeostasis in the cell and in organism health. Protein quality control is particularly vital for those polypeptides that enter the endoplasmic reticulum (ER). Approximately one-quarter to one-third of all proteins synthesized in eukaryotic cells access the ER because they are destined for transport to the extracellular space, because they represent integral membrane proteins, or because they reside within one of the many compartments of the secretory pathway. However, proteins that mature inefficiently are subject to ER-associated degradation (ERAD), a multi-step pathway involving the chaperone-mediated selection, ubiquitination, and extraction (or “retrotranslocation”) of protein substrates from the ER. Ultimately, these substrates are degraded by the cytosolic proteasome. Interestingly, there is an increasing number of native enzymes and metabolite and solute transporters that are also targeted for ERAD. While some of these proteins may transiently misfold, the ERAD pathway also provides a route to rapidly and quantitatively downregulate the levels and thus the activities of a variety of proteins that mature or reside in the ER. Full article

Despite being the most prevalent cause of inherited blindness in children, Stargardt disease is yet to achieve the same clinical trial success as has been achieved for other inherited retinal diseases. With an early age of onset and continual progression of disease over the life course of an individual, Stargardt disease appears to lend itself to therapeutic intervention. However, the aetiology provides issues not encountered with the likes of choroideremia and X-linked retinitis pigmentosa and this has led to a spectrum of treatment strategies that approach the problem from different aspects. These include therapeutics ranging from small molecules and anti-sense oligonucleotides to viral gene supplementation and cell replacement. The advancing development of CRISPR-based molecular tools is also likely to contribute to future therapies by way of genome editing. In this we review, we consider the most recent pre-clinical and clinical trial data relating to the different strategies being applied to the problem of generating a treatment for the large cohort of Stargardt disease patients worldwide. Full article

Pancreatic ductal adenocarcinoma (PDAC) is a malignancy with a poor prognosis and low survival rates. PDAC is characterized by a fibroinflammatory tumor microenvironment enriched by abundant fibroblasts and a variety of immune cells, contributing to its aggressiveness. Neutrophils are essential infiltrating immune cells in the PDAC microenvironment. Recent studies have identified several cellular mechanisms by which neutrophils are recruited to tumor lesion and promote tumorigenesis. This review summarizes the current understanding of the interplay between neutrophils, tumor cells, and other components in the PDAC tumor microenvironment. The prognosis and therapeutic implications of neutrophils in PDAC are also discussed. Full article

Wound healing is an essential process to restore tissue integrity after trauma. Large skin wounds such as burns often heal with hypertrophic scarring and contractures, resulting in disfigurements and reduced joint mobility. Such adverse healing outcomes are less common in the oral mucosa, which generally heals faster compared to skin. Several studies have identified differences between oral and skin wound healing. Most of these studies however focus only on a single stage of wound healing or a single cell type. The aim of this review is to provide an extensive overview of wound healing in skin versus oral mucosa during all stages of wound healing and including all cell types and molecules involved in the process and also taking into account environmental specific factors such as exposure to saliva and the microbiome. Next to intrinsic properties of resident cells and differential expression of cytokines and growth factors, multiple external factors have been identified that contribute to oral wound healing. It can be concluded that faster wound closure, the presence of saliva, a more rapid immune response, and increased extracellular matrix remodeling all contribute to the superior wound healing and reduced scar formation in oral mucosa, compared to skin. Full article

Pregnane X Receptor (PXR) belongs to the nuclear receptors’ superfamily and mainly functions as a xenobiotic sensor activated by a variety of ligands. PXR is widely expressed in normal and malignant tissues. Drug metabolizing enzymes and transporters are also under PXR’s regulation. Antineoplastic agents are of particular interest since cancer patients are characterized by significant intra-variability to treatment response and severe toxicities. Various PXR polymorphisms may alter the function of the protein and are linked with significant effects on the pharmacokinetics of chemotherapeutic agents and clinical outcome variability. The purpose of this review is to summarize the roles of PXR polymorphisms in the metabolism and pharmacokinetics of chemotherapeutic drugs. It is also expected that this review will highlight the importance of PXR polymorphisms in selection of chemotherapy, prediction of adverse effects and personalized medicine. Full article

The eye is at the forefront of developing therapies for genetic diseases. With the FDA approval of the first gene-therapy drug for a form of congenital blindness, numerous studies have been initiated to develop gene therapies for other forms of eye diseases. These examinations have revealed new information about the benefits as well as restrictions to using drug-delivery routes to the different parts of the eye. In this article, we will discuss a brief history of gene therapy and its importance to the eye and ocular delivery landscape that is currently being investigated, and provide insights into their advantages and disadvantages. Efficient delivery routes and vehicle are crucial for an effective, safe, and longer-lasting therapy. Full article

Single-domain antibodies derive from the heavy-chain-only antibodies of Camelidae (camel, dromedary, llama, alpaca, vicuñas, and guananos; i.e., nanobodies) and cartilaginous fishes (i.e., VNARs). Their small size, antigen specificity, plasticity, and potential to recognize unique conformational epitopes represent a diagnostic and therapeutic opportunity for many central nervous system (CNS) pathologies. However, the blood–brain barrier (BBB) poses a challenge for their delivery into the brain parenchyma. Nevertheless, numerous neurological diseases and brain pathologies, including cancer, result in BBB leakiness favoring single-domain antibodies uptake into the CNS. Some single-domain antibodies have been reported to naturally cross the BBB. In addition, different strategies and methods to deliver both nanobodies and VNARs into the brain parenchyma can be exploited when the BBB is intact. These include device-based and physicochemical disruption of the BBB, receptor and adsorptive-mediated transcytosis, somatic gene transfer, and the use of carriers/shuttles such as cell-penetrating peptides, liposomes, extracellular vesicles, and nanoparticles. Approaches based on single-domain antibodies are reaching the clinic for other diseases. Several tailoring methods can be followed to favor the transport of nanobodies and VNARs to the CNS, avoiding the limitations imposed by the BBB to fulfill their therapeutic, diagnostic, and theragnostic promises for the benefit of patients suffering from CNS pathologies. Full article

Plants are constantly threatened by pathogens, so have evolved complex defence signalling networks to overcome pathogen attacks. Post-translational modifications (PTMs) are fundamental to plant immunity, allowing rapid and dynamic responses at the appropriate time. PTM regulation is essential; pathogen effectors often disrupt PTMs in an attempt to evade immune responses. Here, we cover the mechanisms of disease resistance to pathogens, and how growth is balanced with defence, with a focus on the essential roles of PTMs. Alteration of defence-related PTMs has the potential to fine-tune molecular interactions to produce disease-resistant crops, without trade-offs in growth and fitness. Full article

Neuro-muscular disorders include a variety of diseases induced by genetic mutations resulting in muscle weakness and waste, swallowing and breathing difficulties. However, muscle alterations and nerve depletions involve specific molecular and cellular mechanisms which lead to the loss of motor-nerve or skeletal-muscle function, often due to an excessive cell death. Morphological and molecular studies demonstrated that a high number of these disorders seem characterized by an upregulated apoptosis which significantly contributes to the pathology. Cell death involvement is the consequence of some cellular processes that occur during diseases, including mitochondrial dysfunction, protein aggregation, free radical generation, excitotoxicity and inflammation. The latter represents an important mediator of disease progression, which, in the central nervous system, is known as neuroinflammation, characterized by reactive microglia and astroglia, as well the infiltration of peripheral monocytes and lymphocytes. Some of the mechanisms underlying inflammation have been linked to reactive oxygen species accumulation, which trigger mitochondrial genomic and respiratory chain instability, autophagy impairment and finally neuron or muscle cell death. This review discusses the main inflammatory pathways contributing to cell death in neuro-muscular disorders by highlighting the main mechanisms, the knowledge of which appears essential in developing therapeutic strategies to prevent the consequent neuron loss and muscle wasting. Full article

Recent developments have revolutionized the study of biomolecules. Among them are molecular markers, amplification and sequencing of nucleic acids. The latter is classified into three generations. The first allows to sequence small DNA fragments. The second one increases throughput, reducing turnaround and pricing, and is therefore more convenient to sequence full genomes and transcriptomes. The third generation is currently pushing technology to its limits, being able to sequence single molecules, without previous amplification, which was previously impossible. Besides, this represents a new revolution, allowing researchers to directly sequence RNA without previous retrotranscription. These technologies are having a significant impact on different areas, such as medicine, agronomy, ecology and biotechnology. Additionally, the study of biomolecules is revealing interesting evolutionary information. That includes deciphering what makes us human, including phenomena like non-coding RNA expansion. All this is redefining the concept of gene and transcript. Basic analyses and applications are now facilitated with new genome editing tools, such as CRISPR. All these developments, in general, and nucleic-acid sequencing, in particular, are opening a new exciting era of biomolecule analyses and applications, including personalized medicine, and diagnosis and prevention of diseases for humans and other animals. Full article

Lytic polysaccharide monooxygenases (LPMOs) have sparked a lot of research regarding their fascinating mode-of-action. Particularly, their boosting effect on top of the well-known cellulolytic enzymes in lignocellulosic hydrolysis makes them industrially relevant targets. As more characteristics of LPMO and its key role have been elucidated, the need for fast and reliable methods to assess its activity have become clear. Several aspects such as its co-substrates, electron donors, inhibiting factors, and the inhomogeneity of lignocellulose had to be considered during experimental design and data interpretation, as they can impact and often hamper outcomes. This review provides an overview of the currently available methods to measure LPMO activity, including their potential and limitations, and it is illustrated with practical examples. Full article

Brain ischemia is one of the leading causes of disability and mortality worldwide. Nitric oxide (NO^•), a molecule that is involved in the regulation of proper blood flow, vasodilation, neuronal and glial activity constitutes the crucial factor that contributes to the development of pathological changes after stroke. One of the early consequences of a sudden interruption in the cerebral blood flow is the massive production of reactive oxygen and nitrogen species (ROS/RNS) in neurons due to NO^• synthase uncoupling, which leads to neurotoxicity. Progression of apoptotic or necrotic neuronal damage activates reactive astrocytes and attracts microglia or lymphocytes to migrate to place of inflammation. Those inflammatory cells start to produce large amounts of inflammatory proteins, including pathological, inducible form of NOS (iNOS), which generates nitrosative stress that further contributes to brain tissue damage, forming vicious circle of detrimental processes in the late stage of ischemia. S-nitrosylation, hypoxia-inducible factor 1α (HIF-1α) and HIF-1α-dependent genes activated in reactive astrocytes play essential roles in this process. The review summarizes the roles of NO^•-dependent pathways in the early and late aftermath of stroke and treatments based on the stimulation or inhibition of particular NO^• synthases and the stabilization of HIF-1α activity. Full article

As the world develops and population increases, so too does the demand for higher agricultural output with lower resources. Plant biostimulants appear to be one of the more prominent sustainable solutions, given their natural origin and their potential to substitute conventional methods in agriculture. Classified based on their source rather than constitution, biostimulants such as humic substances (HS), protein hydrolysates (PHs), seaweed extracts (SWE) and microorganisms have a proven potential in improving plant growth, increasing crop production and quality, as well as ameliorating stress effects. However, the multi-molecular nature and varying composition of commercially available biostimulants presents challenges when attempting to elucidate their underlying mechanisms. While most research has focused on the broad effects of biostimulants in crops, recent studies at the molecular level have started to unravel the pathways triggered by certain products at the cellular and gene level. Understanding the molecular influences involved could lead to further refinement of these treatments. This review comprises the most recent findings regarding the use of biostimulants in plants, with particular focus on reports of their molecular influence. Full article

Pancreatic cancer is the third leading cause of cancer-related deaths in the United States. Pancreatic ductal adenocarcinoma (PDA) is the most common (90%) and aggressive type of pancreatic cancer. Genomic analyses of PDA specimens have identified the recurrent genetic mutations that drive PDA initiation and progression. However, the underlying mechanisms that further drive PDA metastasis remain elusive. Despite many attempts, no recurrent genetic mutation driving PDA metastasis has been found, suggesting that PDA metastasis is driven by epigenetic fluctuations rather than genetic factors. Therefore, establishing epigenetic mechanisms of PDA metastasis would facilitate the development of successful therapeutic interventions. In this review, we provide a comprehensive overview on the role of epigenetic mechanisms in PDA as a critical contributor on PDA progression and metastasis. In particular, we explore the recent advancements elucidating the role of nucleosome remodeling, histone modification, and DNA methylation in the process of cancer metastasis. Full article

Neutrophil elastase (NE) is a major inflammatory protease released by neutrophils and is present in the airways of patients with cystic fibrosis (CF), chronic obstructive pulmonary disease, non-CF bronchiectasis, and bronchopulmonary dysplasia. Although NE facilitates leukocyte transmigration to the site of infection and is required for clearance of Gram-negative bacteria, it also activates inflammation when released into the airway milieu in chronic inflammatory airway diseases. NE exposure induces airway remodeling with increased mucin expression and secretion and impaired ciliary motility. NE interrupts epithelial repair by promoting cellular apoptosis and senescence and it activates inflammation directly by increasing cytokine expression and release, and indirectly by triggering extracellular trap release and exosome release, which magnify protease activity and inflammation in the airway. NE inhibits innate immune function by digesting opsonins and opsonin receptors, degrading innate immune proteins such as lactoferrin, and inhibiting macrophage phagocytosis. Importantly, NE-directed therapies have not yet been effective in preventing the pathologic sequelae of NE exposure, but new therapies are being developed that offer both direct antiprotease activity and multifunctional anti-inflammatory properties. Full article

Oligodendrocytes, the myelin-making cells of the CNS, regulate the complex process of myelination under physiological and pathological conditions, significantly aided by other glial cell types such as microglia, the brain-resident, macrophage-like innate immune cells. In this review, we summarize how oligodendrocytes orchestrate myelination, and especially myelin repair after damage, and present novel aspects of oligodendroglial functions. We emphasize the contribution of microglia in the generation and regeneration of myelin by discussing their beneficial and detrimental roles, especially in remyelination, underlining the cellular and molecular components involved. Finally, we present recent findings towards human stem cell-derived preclinical models for the study of microglia in human pathologies and on the role of microbiome on glial cell functions. Full article

Aberrant protein folding underpins many neurodegenerative diseases as well as certain myopathies and cancers. Protein misfolding can be driven by the presence of distinctive prion and prion-like regions within certain proteins. These prion and prion-like regions have also been found to drive liquid-liquid phase separation. Liquid-liquid phase separation is thought to be an important physiological process, but one that is prone to malfunction. Thus, aberrant liquid-to-solid phase transitions may drive protein aggregation and fibrillization, which could give rise to pathological inclusions. Here, we review prions and prion-like proteins, their roles in phase separation and disease, as well as potential therapeutic approaches to counter aberrant phase transitions. Full article

Nanomaterial-mediated cancer therapeutics is a fast developing field and has been utilized in potential clinical applications. However, most effective therapies, such as photodynamic therapy (PDT) and radio therapy (RT), are strongly oxygen-dependent, which hinders their practical applications. Later on, several strategies were developed to overcome tumor hypoxia, such as oxygen carrier nanomaterials and oxygen generated nanomaterials. Among these, oxygen species generation on nanozymes, especially catalase (CAT) mimetic nanozymes, convert endogenous hydrogen peroxide (H₂O₂) to oxygen (O₂) and peroxidase (POD) mimetic nanozymes converts endogenous H₂O₂ to water (H₂O) and reactive oxygen species (ROS) in a hypoxic tumor microenvironment is a fascinating approach. The present review provides a detailed examination of past, present and future perspectives of POD mimetic nanozymes for effective oxygen-dependent cancer phototherapeutics. Full article

Mitochondria play key roles in ATP supply, calcium homeostasis, redox balance control and apoptosis, which in neurons are fundamental for neurotransmission and to allow synaptic plasticity. Their functional integrity is maintained by mitostasis, a process that involves mitochondrial transport, anchoring, fusion and fission processes regulated by different signaling pathways but mainly by the peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α). PGC-1α also favors Ca²⁺ homeostasis, reduces oxidative stress, modulates inflammatory processes and mobilizes mitochondria to where they are needed. To achieve their functions, mitochondria are tightly connected to the endoplasmic reticulum (ER) through specialized structures of the ER termed mitochondria-associated membranes (MAMs), which facilitate the communication between these two organelles mainly to aim Ca²⁺ buffering. Alterations in mitochondrial activity enhance reactive oxygen species (ROS) production, disturbing the physiological metabolism and causing cell damage. Furthermore, cytosolic Ca²⁺ overload results in an increase in mitochondrial Ca²⁺, resulting in mitochondrial dysfunction and the induction of mitochondrial permeability transition pore (mPTP) opening, leading to mitochondrial swelling and cell death through apoptosis as demonstrated in several neuropathologies. In summary, mitochondrial homeostasis is critical to maintain neuronal function; in fact, their regulation aims to improve neuronal viability and to protect against aging and neurodegenerative diseases. Full article

Neurodegenerative disorders affect fifteen percent of the world’s population and pose a significant financial burden to all nations. Cognitive impairment is the seventh leading cause of death throughout the globe. Given the enormous challenges to treat cognitive disorders, such as Alzheimer’s disease, and the inability to markedly limit disease progression, circadian clock gene pathways offer an exciting strategy to address cognitive loss. Alterations in circadian clock genes can result in age-related motor deficits, affect treatment regimens with neurodegenerative disorders, and lead to the onset and progression of dementia. Interestingly, circadian pathways hold an intricate relationship with autophagy, the mechanistic target of rapamycin (mTOR), the silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1), mammalian forkhead transcription factors (FoxOs), and the trophic factor erythropoietin. Autophagy induction is necessary to maintain circadian rhythm homeostasis and limit cortical neurodegenerative disease, but requires a fine balance in biological activity to foster proper circadian clock gene regulation that is intimately dependent upon mTOR, SIRT1, FoxOs, and growth factor expression. Circadian rhythm mechanisms offer innovative prospects for the development of new avenues to comprehend the underlying mechanisms of cognitive loss and forge ahead with new therapeutics for dementia that can offer effective clinical treatments. Full article

The brain–gut–microbiome axis is a bidirectional communication pathway between the gut microbiota and the central nervous system. The growing interest in the gut microbiota and mechanisms of its interaction with the brain has contributed to the considerable attention given to the potential use of probiotics, prebiotics and postbiotics in the prevention and treatment of depressive disorders. This review discusses the up-to-date findings in preclinical and clinical trials regarding the use of pro-, pre- and postbiotics in depressive disorders. Studies in rodent models of depression show that some of them inhibit inflammation, decrease corticosterone level and change the level of neurometabolites, which consequently lead to mitigation of the symptoms of depression. Moreover, certain clinical studies have indicated improvement in mood as well as changes in biochemical parameters in patients suffering from depressive disorders. Full article

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the etiological agent of the coronavirus disease 2019 (COVID-19) pandemic, which has been a topic of major concern for global human health. The challenge to restrain the COVID-19 pandemic is further compounded by the emergence of several SARS-CoV-2 variants viz. B.1.1.7 (Alpha), B.1.351 (Beta), P1 (Gamma) and B.1.617.2 (Delta), which show increased transmissibility and resistance towards vaccines and therapies. Importantly, there is convincing evidence of increased susceptibility to SARS-CoV-2 infection among individuals with dysregulated immune response and comorbidities. Herein, we provide a comprehensive perspective regarding vulnerability of SARS-CoV-2 infection in patients with underlying medical comorbidities. We discuss ongoing vaccine (mRNA, protein-based, viral vector-based, etc.) and therapeutic (monoclonal antibodies, small molecules, plasma therapy, etc.) modalities designed to curb the COVID-19 pandemic. We also discuss in detail, the challenges posed by different SARS-CoV-2 variants of concern (VOC) identified across the globe and their effects on therapeutic and prophylactic interventions. Full article

The cerebral endothelium is an active interface between blood and the central nervous system. In addition to being a physical barrier between the blood and the brain, the endothelium also actively regulates metabolic homeostasis, vascular tone and permeability, coagulation, and movement of immune cells. Being part of the blood–brain barrier, endothelial cells of the brain have specialized morphology, physiology, and phenotypes due to their unique microenvironment. Known cardiovascular risk factors facilitate cerebral endothelial dysfunction, leading to impaired vasodilation, an aggravated inflammatory response, as well as increased oxidative stress and vascular proliferation. This culminates in the thrombo-inflammatory response, an underlying cause of ischemic stroke and cerebral small vessel disease (CSVD). These events are further exacerbated when blood flow is returned to the brain after a period of ischemia, a phenomenon termed ischemia-reperfusion injury. Purinergic signaling is an endogenous molecular pathway in which the enzymes CD39 and CD73 catabolize extracellular adenosine triphosphate (eATP) to adenosine. After ischemia and CSVD, eATP is released from dying neurons as a damage molecule, triggering thrombosis and inflammation. In contrast, adenosine is anti-thrombotic, protects against oxidative stress, and suppresses the immune response. Evidently, therapies that promote adenosine generation or boost CD39 activity at the site of endothelial injury have promising benefits in the context of atherothrombotic stroke and can be extended to current CSVD known pathomechanisms. Here, we have reviewed the rationale and benefits of CD39 and CD39 therapies to treat endothelial dysfunction in the brain. Full article

The oncogenic Transcription Factor EB (TFEB), a member of MITF-TFE family, is known to be the most important regulator of the transcription of genes responsible for the control of lysosomal biogenesis and functions, autophagy, and vesicles flux. TFEB activation occurs in response to stress factors such as nutrient and growth factor deficiency, hypoxia, lysosomal stress, and mitochondrial damage. To reach the final functional status, TFEB is regulated in multimodal ways, including transcriptional rate, post-transcriptional regulation, and post-translational modifications. Post-transcriptional regulation is in part mediated by miRNAs. miRNAs have been linked to many cellular processes involved both in physiology and pathology, such as cell migration, proliferation, differentiation, and apoptosis. miRNAs also play a significant role in autophagy, which exerts a crucial role in cell behaviour during stress or survival responses. In particular, several miRNAs directly recognise TFEB transcript or indirectly regulate its function by targeting accessory molecules or enzymes involved in its post-translational modifications. Moreover, the transcriptional programs triggered by TFEB may be influenced by the miRNA-mediated regulation of TFEB targets. Finally, recent important studies indicate that the transcription of many miRNAs is regulated by TFEB itself. In this review, we describe the interplay between miRNAs with TFEB and focus on how these types of crosstalk affect TFEB activation and cellular functions. Full article

Cardiovascular diseases (CVDs) are the leading cause of death worldwide. The initial stage of CVDs is characterized by endothelial dysfunction, defined as the limited bioavailability of nitric oxide (NO). Thus, any factors that interfere with the synthesis or metabolism of NO in endothelial cells are involved in CVD pathogenesis. It is well established that hypoxia is both the triggering factor as well as the accompanying factor in cardiovascular disease, and diminished tissue oxygen levels have been reported to influence endothelial NO bioavailability. In endothelial cells, NO is produced by endothelial nitric oxide synthase (eNOS) from L-Arg, with tetrahydrobiopterin (BH₄) as an essential cofactor. Here, we discuss the mechanisms by which hypoxia affects NO bioavailability, including regulation of eNOS expression and activity. What is particularly important is the fact that hypoxia contributes to the depletion of cofactor BH₄ and deficiency of substrate L-Arg, and thus elicits eNOS uncoupling—a state in which the enzyme produces superoxide instead of NO. eNOS uncoupling and the resulting oxidative stress is the major driver of endothelial dysfunction and atherogenesis. Moreover, hypoxia induces impairment in mitochondrial respiration and endothelial cell activation; thus, oxidative stress and inflammation, along with the hypoxic response, contribute to the development of endothelial dysfunction. Full article