The metabolic signature of cardiorespiratory fitness: a protocol for a systematic review and meta-analysis

IntroductionA low cardiorespiratory fitness (CRF) is a strong and independent predictor of cardiometabolic, cancer and all-cause mortality. To date, the mechanisms linking CRF with reduced mortality remain largely unknown. Metabolomics, which is a powerful metabolic phenotyping technology to unravel molecular mechanisms underlying complex phenotypes, could elucidate how CRF fosters human health.Methods and analysisThis study aims at systematically reviewing and meta-analysing the literature on metabolites of any human tissue sample, which are positively or negatively associated with CRF. Studies reporting estimated CRF will not be considered. No restrictions will be placed on the metabolomics technology used to measure metabolites. PubMed, Web of Science and EMBASE will be searched for relevant articles published until the date of the last search. Two authors will independently screen full texts of selected abstracts. References and citing articles of included articles will be screened for additional relevant publications. Data regarding study population, tissue samples, analytical technique, quality control, data processing, metabolites associated to CRF, cardiopulmonary exercise test protocol and exercise exhaustion criteria will be extracted. Methodological quality will be assessed using a modified version of QUADOMICS. Narrative synthesis as well as tabular/charted presentation of the extracted data will be included. If feasible, meta-analyses will be used to investigate the associations between identified metabolites and CRF. Potential sources of heterogeneity will be explored in meta-regressions.Ethics and disseminationNo ethics approval is required. The results will be published in a peer-reviewed journal and as conference presentation.PROSPERO registration numberCRD42020214375.

β-amyloid redirects norepinephrine signaling to activate the pathogenic GSK3β/tau cascade

The brain noradrenergic system is critical for normal cognition and is affected at early stages in Alzheimer’s disease (AD). Here, we reveal a previously unappreciated direct role of norepinephrine signaling in connecting β-amyloid (Aβ) and tau, two key pathological components of AD pathogenesis. Our results show that Aβ oligomers bind to an allosteric site on α2A adrenergic receptor (α2AAR) to redirect norepinephrine-elicited signaling to glycogen synthase kinase 3β (GSK3β) activation and tau hyperphosphorylation. This norepinephrine-dependent mechanism sensitizes pathological GSK3β/tau activation in response to nanomolar accumulations of extracellular Aβ, which is 50- to 100-fold lower than the amount required to activate GSK3β by Aβ alone. The significance of our findings is supported by in vivo evidence in two mouse models, human tissue sample analysis, and longitudinal clinical data. Our study provides translational insights into mechanisms underlying Aβ proteotoxicity, which might have strong implications for the interpretation of Aβ clearance trial results and future drug design and for understanding the selective vulnerability of noradrenergic neurons in AD.

Studies on the Tissue Localization of HKDC1, a Putative Novel Fifth Hexokinase, in Humans

Hexokinase domain component 1 (HKDC1) is a recently discovered novel protein, which is being promoted as a putative fifth hexokinase. Although the exact role HKDC1 plays in physiology is still unclear, it has been shown to be important during pregnancy in the regulation of glucose homeostasis. In this study, we have comprehensively studied the expression pattern of HKDC1 in the human body. Using human tissue sample, immunohistochemistry imaging was performed. Our studies indicate that the tissues with highest HKDC1 expression were the brush border epithelium of the intestines, parts of the pancreas, and lung alveolar macrophages. Future directions will be to understand the role of this fifth hexokinase in these tissues, with a focus on its relative function as compared with other endogenously expressed hexokinases.

Ethical Issues in Molecular Pathology

Recent advances in molecular pathology and molecular genetics have created new concerns about the use of human biologic materials in research. Since researchers now have the ability to extract and amplify DNA from minuscule archived samples, virtually any human tissue sample can potentially become the template for a test that provides information that may relate to the inherited genes of an individual. Researchers using human biologic materials should follow the 3 basic principles that have been defined for all ethical human subjects research: respect for persons, beneficence, and justice. Institutional Review Boards are responsible for providing review of the risks and benefits of research proposals to safeguard the rights and welfare of human subjects. Currently, there is considerable debate concerning the role of informed consent procedures and the Institutional Review Board oversight process in situations when researchers use human biologic materials that have been anonymized or coded. In 1999, the National Bioethics Advisory Commission is expected to make recommendations to President Clinton and the National Science and Technology Council that are expected to clarify the balance between respect for personal autonomy and the societal need to pursue biomedical research to improve the health and welfare of all individuals.