Migraine and Sleep—An Unexplained Association?

Migraine and sleep disorders are common chronic diseases in the general population, with significant negative social and economic impacts. The association between both of these phenomena has been observed by clinicians for years and is confirmed by many epidemiological studies. Despite this, the nature of this relationship is still not fully understood. In recent years, there has been rapid progress in understanding the common anatomical structures of and pathogenetic mechanism between sleep and migraine. Based on a literature review, the authors present the current view on this topic as well as ongoing research in this field, with reference to the key points of the biochemical and neurophysiological processes responsible for both these disorders. In the future, a better understanding of these mechanisms will significantly expand the range of treatment options.     

Rlip76: An Unexplored Player in Neurodegeneration and Alzheimer’s Disease?

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and is the most common cause of dementia in older people. AD is associated with the loss of synapses, oxidative stress, mitochondrial structural and functional abnormalities, microRNA deregulation, inflammatory responses, neuronal loss, accumulation of amyloid-beta (Aβ) and phosphorylated tau (p-tau). AD occurs in two forms: early onset, familial AD and late-onset, sporadic AD. Causal factors are still unknown for a vast majority of AD patients. Genetic polymorphisms are proposed to contribute to late-onset AD via age-dependent increases in oxidative stress and mitochondrial abnormalities. Recent research from our lab revealed that reduced levels of Rlip76 induce oxidative stress, mitochondrial dysfunction and synaptic damage, leading to molecular and behavioral phenotypes resembling late-onset AD. Rlip76 is a multifunctional 76 kDa protein encoded by the RALBP1 gene, located on chromosome 18. Rlip is a stress-protective ATPase of the mercapturic acid pathway that couples clathrin-dependent endocytosis with the efflux of glutathione–electrophile conjugates. Rlip is evolutionarily highly conserved across species and is ubiquitously expressed in all tissues, including AD-affected brain regions, the cerebral cortex and hippocampus, where highly active neuronal metabolisms render the cells highly susceptible to intracellular oxidative damage. In the current article, we summarize molecular and cellular features of Rlip and how depleted Rlip may exacerbate oxidative stress, mitochondrial dysfunction and synaptic damage in AD. We also discuss the possible role of Rlip in aspects of learning and memory via axonal growth, dendritic remodeling, and receptor regulation. We conclude with a discussion of the potential for the contribution of genetic polymorphisms in Rlip to AD progression and the potential for Rlip-based therapies.     

Exercise-Induced Adipose Tissue Thermogenesis and Browning: How to Explain the Conflicting Findings?

Brown adipose tissue (BAT) has been widely studied in targeting against metabolic diseases such as obesity, type 2 diabetes and insulin resistance due to its role in nutrient metabolism and energy regulation. Whether exercise promotes adipose tissue thermogenesis and browning remains controversial. The results from human and rodent studies contradict each other. In our opinion, fat thermogenesis or browning promoted by exercise should not be a biomarker of health benefits, but an adaptation under the stress between body temperature regulation and energy supply and expenditure of multiple organs. In this review, we discuss some factors that may contribute to conflicting experimental results, such as different thermoneutral zones, gender, training experience and the heterogeneity of fat depots. In addition, we explain that a redox state in cells potentially causes thermogenesis heterogeneity and different oxidation states of UCP1, which has led to the discrepancies noted in previous studies. We describe a network by which exercise orchestrates the browning and thermogenesis of adipose tissue with total energy expenditure through multiple organs (muscle, brain, liver and adipose tissue) and multiple pathways (nerve, endocrine and metabolic products), providing a possible interpretation for the conflicting findings.     

Ion-doped hydroxyapatite: An impasse or the road to follow?

Doping hydroxyapatite (HAp) with foreign ions has been increasing in popularity as a chemical approach to augment the existing and impart new properties to it. However, it is uncertain whether this approach can elicit properties strong enough to make HAp competitive for commercial applications in biomedicine and elsewhere. In particular, material properties, such as grain size, morphology, surface charge, porosity, topology and others may prove to be more effective in controlling properties of HAp than the dopant choice and concentration. This study tackles this question through a meta-analysis of the dependence of selected materials properties on dopant concentrations reported across the literature, showing that doping is a convenient way of controlling some, but not all properties in HAp and should be implemented ideally in combination with other structural and compositional factors of influence. This meta-analysis is coupled to a bibliographic analysis of the evolution of trends in terms of the type, frequency and concurrency of dopants in HAp, covering the entire Periodic Table, all 72 elements incorporated into HAp so far and the 1990 – 2019 period split into successive lustra. The study demonstrates a continuously ascending trend in popularity of certain elements, such as Sr, Ce and Se, and a continuously declining trend of others in the past two decades, including F, Y, I, Ti and most lanthanides. For the fourth period transition metals a trend of constancy was observed and for yet other elements, including Ag and Mg, a period of ascent was succeeded by a steady decline, the onset of which coincided in the case of Ag with the peak in the airing of the concerns over its cytotoxicity by the scientific community. Reasons for these trends with respect to most elements are explained and connected with trends governing broader realms of materials science. It is shown that the choice of ions as dopants in HAp is largely driven by broader trends in materials science, rendering the doped HAp a mirror to view these existing and past trends in. Theoretically, by following the historic progression of these trends, a gaze in this mirror could assist in extrapolation of future trends, which normally come at the cost extinguishing some of the existing ones. This immersion in more general developments in materials science opened the path toward drawing connections between the bibliographically assessed geopolitical trends in doped HAp and in broader aspects of the scientific community, including the growing gap between the rich and the poor pervading it. The analysis reported here is conceptually novel and could be applied to numerous other materials.     

Valorisation of protein waste: An enzymatic approach to make commodity chemicals? ?

Protein-rich waste is an abundantly available resource that is currently used mainly as animal feed and fertilizers. Valorisation of protein waste to higher value products, particularly commodity chemicals such as precursors for polymers, has attracted significant research efforts. Enzyme-based approaches, being environmentally-friendly compared to their chemical counterparts, promise sustainable processes for conversion of protein waste to valuable chemicals. This review provides a general overview on valorisation of protein waste and then further summarises the use of enzymes in different stages of the valorisation process—protein extraction and hydrolysis, separation of individual amino acids and their ultimate conversion into chemicals. Case studies of enzymatic conversion are presented for different amino acids including glutamic acid, lysine, phenylalanine, tyrosine, arginine and aspartic acid. The review compares the different enzyme reactors and operation modes for amino acid conversion. The emerging opportunities and challenges in the field are discussed: engineering powerful enzymes and integrating innovative processes for industrial application at a low cost.     

Functional Precision Oncology: The Next Frontier to Improve Glioblastoma Outcome?

Glioblastoma remains the most malignant and intrinsically resistant brain tumour in adults. Despite intensive research over the past few decades, through which numerous potentially druggable targets have been identified, virtually all clinical trials of the past 20 years have failed to improve the outcome for the vast majority of GBM patients. The observation that small subgroups of patients displayed a therapeutic response across several unsuccessful clinical trials suggests that the GBM patient population probably consists of multiple subgroups that probably all require a distinct therapeutic approach. Due to extensive inter- and intratumoral heterogeneity, assigning the right therapy to each patient remains a major challenge. Classically, bulk genetic profiling would be used to identify suitable therapies, although the success of this approach remains limited due to tumor heterogeneity and the absence of direct relationships between mutations and therapy responses in GBM. An attractive novel strategy aims at implementing methods for functional precision oncology, which refers to the evaluation of treatment efficacies and vulnerabilities of (ex vivo) living tumor cells in a highly personalized way. Such approaches are currently being implemented for other cancer types by providing rapid, translatable information to guide patient-tailored therapeutic selections. In this review, we discuss the current state of the art of transforming technologies, tools and challenges for functional precision oncology and how these could improve therapy selection for GBM patients.     

The Role of Leptin in Childhood Immune Thrombocytopenia (ITP): An Anti-Inflammatory Agent?

To investigate the effect of leptin in childhood ITP, we measured plasma leptin in 39 children with acute ITP, after treatment and in remission, and in 33 healthy age/BMI-matched controls. We also cultured ITP and control peripheral blood mononuclear cells (PBMCs) with recombinant leptin to assess its direct effect on pro/anti-inflammatory cytokine gene expression. A significant increase in leptin was observed in children with active disease compared to controls. A significant inverse correlation of leptin with platelet count was also observed in children with acute ITP. Leptin remained high after treatment with IVIg, whereas steroid treatment lowered leptin below control levels. In remission, leptin was in the control range. Cytokine gene expression was significantly increased in children with acute ITP compared with controls, with highest expression for IFN-γ and IL-10. IVIg/steroid treatment significantly decreased IFN-γ and IL-10 expression. In remission, IFN-γ and IL-10 expression remained low. Addition of leptin to PBMCs isolated from patients in remission resulted in a significant increase in IL-10 gene expression compared to controls. Further experiments with purified T-cells and monocytes identified monocytes as the source of leptin-induced IL-10. We suggest that leptin acts as an active anti-inflammatory agent in childhood ITP by promoting IL-10 secretion by monocytes.     

The Future of Aminoglycosides: The End or Renaissance?

Although aminoglycosides have been used as antibacterials for decades, their use has been hindered by their inherent toxicity and the resistance that has emerged to these compounds. It seems that such issues have relegated a formerly front‐line class of antimicrobials to the proverbial back shelf. However, recent advances have demonstrated that novel aminoglycosides have a potential to overcome resistance as well as to be used to treat HIV‐1 and even human genetic disorders, with abrogated toxicity. It is not the end for aminoglycosides, but rather, the challenges faced by researchers have led to ingenuity and a change in how we view this class of compounds, a renaissance.     

The mbocayá palm: An economic oil plant of paraguay

Summary The mbocayá palm (Acrocomia totai Mart.) is one of a number of oil palms found in Latin America which is exploited for its pulp and kernel oils. Since the products of many of these palms are consumed locally or are exported to neighboring countries or Europe, they are little known in the United States. The mbocayá is one of these palms which has been exploited commercially for its kernel oil for about 50 years and for a lesser time for its pulp oil. The kernel oil is similar in composition to that of other American oil palms but is unique in being more unsaturated and having a lower melting point which clearly reflects the more temperate environment in which this palm thrives. Paraguay contains 6 to 7 million of these palms which produce annually an estimated 55,000 to 120,000 metric tons of fruit, only a part of which is processed for oil. In recent years production of kernel oil has varied between 2,000 and 2,700 metric tons and pulp oil between 500 and 1,100 metric tons, all of which has been consumed locally or exported to Argentina. Processing mbocayá fruit presents many difficulties not encountered with most oilseeds but which are similar to those encountered in processing most American oil palm fruits. This is the first comprehensive report in English on the mbocayá palm and its economic importance. Vegetable Oil Specialist, United States of America Operations Mission to Brazil, Foregin Operations Administration.     

The ionic substituted octacalcium phosphate for biomedical applications: A new pathway to follow?

Numerous studies have found that octacalcium phosphate possesses promising biological properties applicable to bone tissue regeneration. To further improve the osteogenic and regenerative properties of octacalcium phosphate, substitutions with Sr²⁺, Zn²⁺, Mg²⁺, Fe³⁺, Na⁺, F^? and CO₃^2? ions have been investigated in recent years. Despite that, hydroxyapatite is still considered the most promising calcium phosphate for bioactive bone grafts due to its biocompatibility, physicochemical similarity to biological apatite, osteoconductivity and strong bonding with the surrounding tissue. However, better biological properties of octacalcium phosphate in vivo as well as a larger volume of regenerated bone tissue, compared to hydroxyapatite, were confirmed by many studies. This review summarizes recent and relevant studies on cationic and anionic substitutions in the crystal lattice of octacalcium phosphate and its in vitro biological performance. It also discusses future challenges and prospects for the use of substituted octacalacium phosphate.     

Graphite: An active or an inactive anode?

Positive polarization of a graphite anode in aqueous solution functionalizes the surface and releases soluble organic carbon to the solution concurrent with the electrolysis of water. Mineralization of the anode occurs at more positive potentials, and can be explained as a repetitive sequence involving functionalization, oxidation to carboxyl, and Kolbe decarboxylation, without recourse to hydroxyl radicals. Other lines of evidence against the intermediacy of hydroxyl radicals include the resistance of p-benzoquinone towards oxidation at graphite – i.e., graphite does not function as an inactive anode towards the oxidation of added substrates. A direct electron transfer mechanism operates for substrates that are oxidizable in the range of water stability, such as acetaminophen and sulfide ion. In the potential range of oxygen evolution we propose that graphite behaves as a modified active anode, at which the oxygen atom to be transferred to an oxidizable substrate first becomes bonded to the previously functionalized surface.     

Breast Cancer and Microcalcifications: An Osteoimmunological Disorder?

The presence of microcalcifications in the breast microenvironment, combined with the growing evidences of the possible presence of osteoblast-like or osteoclast-like cells in the breast, suggest the existence of active processes of calcification in the breast tissue during a woman’s life. Furthermore, much evidence that osteoimmunological disorders, such as osteoarthritis, rheumatoid arthritis, or periodontitis influence the risk of developing breast cancer in women exists and vice versa. Antiresorptive drugs benefits on breast cancer incidence and progression have been reported in the past decades. More recently, biological agents targeting pro-inflammatory cytokines used against rheumatoid arthritis also demonstrated benefits against breast cancer cell lines proliferation, viability, and migratory abilities, both in vitro and in vivo in xenografted mice. Hence, it is tempting to hypothesize that breast carcinogenesis should be considered as a potential osteoimmunological disorder. In this review, we compare microenvironments and molecular characteristics in the most frequent osteoimmunological disorders with major events occurring in a woman’s breast during her lifetime. We also highlight what the use of bone anabolic drugs, antiresorptive, and biological agents targeting pro-inflammatory cytokines against breast cancer can teach us.     

Organometallic Compounds: An Opportunity for Chemical Biology?

Organometallic compounds are renowned for their remarkable applications in the field of catalysis, but much less is known about their potential in chemical biology. Indeed, such compounds have long been considered to be either unstable under physiological conditions or cytotoxic. As a consequence, little attention has been paid to their possible utilisation for biological purposes. Because of their outstanding physicochemical properties, which include chemical stability, structural diversity and unique photo- and electrochemical properties, however, organometallic compounds have the ability to play a leading role in the field of chemical biology. Indeed, remarkable examples of the use of such compounds-notably as enzyme inhibitors and as luminescent agents-have recently been reported. Here we summarise recent advances in the use of organometallic compounds for chemical biology purposes, an area that we define as "organometallic chemical biology". We also demonstrate that these recent discoveries are only a beginning and that many other organometallic complexes are likely to be found useful in this field of research in the near future.     

How to conceptualize catalytic cycles? The energetic span model

A computational study of a catalytic cycle generates state energies (the E-representation), whereas experiments lead to rate constants (the k-representation). Based on transition state theory (TST), these are equivalent representations. Nevertheless, until recently, there has been no simple way to calculate the efficiency of a catalytic cycle, that is, its turnover frequency (TOF), from a theoretically obtained energy profile. In this Account, we introduce the energetic span model that enables one to evaluate TOFs in a straightforward manner and in affinity with the Curtin-Hammett principle. As shown herein, the model implies a change in our kinetic concepts. Analogous to Ohm's law, the catalytic chemical current (the TOF) can be defined by a chemical potential (independent of the mechanism) divided by a chemical resistance (dependent on the mechanism and the nature of the catalyst). This formulation is based on Eyring's TST and corresponds to a steady-state regime. In many catalytic cycles, only one transition state and one intermediate determine the TOF. We call them the TOF-determining transition state (TDTS) and the TOF-determining intermediate (TDI). These key states can be located, from among the many states available to a catalytic cycle, by assessing the degree of TOF control (X(TOF)); this last term resembles the structure-reactivity coefficient in classical physical organic chemistry. The TDTS-TDI energy difference and the reaction driving force define the energetic span (δE) of the cycle. Whenever the TDTS appears after the TDI, δE is the energy difference between these two states; when the opposite is true, we must also add the driving force to this difference. Having δE, the TOF is expressed simply in the Arrhenius-Eyring fashion, wherein δE serves as the apparent activation energy of the cycle. An important lesson from this model is that neither one transition state nor one reaction step possess all the kinetic information that determines the efficiency of a catalyst. Additionally, the TDI and TDTS are not necessarily the highest and lowest states, nor do they have to be adjoined as a single step. As such, we can conclude that a change in the conceptualization of catalytic cycles is in order: in catalysis, there are no rate-determining steps, but rather rate-determining states. We also include a study on the effect of reactant and product concentrations. In the energetic span approximation, only the reactants or products that are located between the TDI and TDTS accelerate or inhibit the reaction. In this manner, the energetic span model creates a direct link between experimental quantities and theoretical results. The versatility of the energetic span model is demonstrated with several catalytic cycles of organometallic reactions.     

The role of the solvent in TS-1 chemistry: active or passive? An early study revisited

The oxidation of n-hexane with hydrogen peroxide, catalyzed by TS-1 in various solvents, is reported. The initial rate of reaction decreases in the order: t-butanol > t-butanol/water > methanol acetonitrile water, whereas the reverse trend was observed for the adsorption of n-hexane in the catalyst. A dual function is postulated for the solvent in relation to its effects on kinetics. It assists the sorption/desorption of reagents/products in TS-1 (passive role) and participates in the catalytic cycle, through interactions with polar species involved in it (active role). A mechanistic pathway for the hydroxylation of paraffinic and aromatic C–H bonds is suggested.