Questioning Established Theories and Treatment Methods Related to Iron and Other Metal Metabolic Changes, Affecting All Major Diseases and Billions of Patients.

The medical and scientific literature is dominated by highly cited historical theories and findings [...].

Modelling bioactivities of combinations of whole extracts of edibles with a simplified theoretical framework reveals the statistical role of molecular diversity and system complexity in their mode of action and their nearly certain safety.

Network pharmacology and polypharmacology are emerging as novel drug discovery paradigms. The many discovery, safety and regulatory issues they raise may become tractable with polypharmacological combinations of natural compounds found in whole extracts of edible and mixes thereof. The primary goal of this work is to get general insights underlying the innocuity and the emergence of beneficial and toxic activities of combinations of many compounds in general and of edibles in particular. A simplified model of compounds' interactions with an organism and of their desired and undesired effects is constructed by considering the departure from equilibrium of interconnected biological features. This model allows to compute the scaling of the probability of significant effects relative to nutritional diversity, organism complexity and synergy resulting from mixing compounds and edibles. It allows also to characterize massive indirect perturbation mode of action drugs as a potential novel multi-compound-multi-target pharmaceutical class, coined Ediceuticals when based on edibles. Their mode of action may readily target differentially organisms' system robustness as such based on differential complexity for discovering nearly certainly safe novel antimicrobials, antiviral and anti-cancer treatments. This very general model provides also a theoretical framework to several pharmaceutical and nutritional observations. In particular, it characterizes two classes of undesirable effects of drugs, and may question the interpretation of undesirable effects in healthy subjects. It also formalizes nutritional diversity as such as a novel statistical supra-chemical parameter that may contribute to guide nutritional health intervention. Finally, it is to be noted that a similar formalism may be further applicable to model whole ecosystems in general.

The exposome and health: Where chemistry meets biology.

Despite extensive evidence showing that exposure to specific chemicals can lead to disease, current research approaches and regulatory policies fail to address the chemical complexity of our world. To safeguard current and future generations from the increasing number of chemicals polluting our environment, a systematic and agnostic approach is needed. The "exposome" concept strives to capture the diversity and range of exposures to synthetic chemicals, dietary constituents, psychosocial stressors, and physical factors, as well as their corresponding biological responses. Technological advances such as high-resolution mass spectrometry and network science have allowed us to take the first steps toward a comprehensive assessment of the exposome. Given the increased recognition of the dominant role that nongenetic factors play in disease, an effort to characterize the exposome at a scale comparable to that of the human genome is warranted.

Epitranscriptomic systems regulate the translation of reactive oxygen species detoxifying and disease linked selenoproteins.

Here we highlight the role of epitranscriptomic systems in post-transcriptional regulation, with a specific focus on RNA modifying writers required for the incorporation of the 21st amino acid selenocysteine during translation, and the pathologies linked to epitranscriptomic and selenoprotein defects. Epitranscriptomic marks in the form of enzyme-catalyzed modifications to RNA have been shown to be important signals regulating translation, with defects linked to altered development, intellectual impairment, and cancer. Modifications to rRNA, mRNA and tRNA can affect their structure and function, while the levels of these dynamic tRNA-specific epitranscriptomic marks are stress-regulated to control translation. The tRNA for selenocysteine contains five distinct epitranscriptomic marks and the ALKBH8 writer for the wobble uridine (U) has been shown to be vital for the translation of the glutathione peroxidase (GPX) and thioredoxin reductase (TRXR) family of selenoproteins. The reactive oxygen species (ROS) detoxifying selenocysteine containing proteins are a prime examples of how specialized translation can be regulated by specific tRNA modifications working in conjunction with distinct codon usage patterns, RNA binding proteins and specific 3' untranslated region (UTR) signals. We highlight the important role of selenoproteins in detoxifying ROS and provide details on how epitranscriptomic marks and selenoproteins can play key roles in and maintaining mitochondrial function and preventing disease.

Autophagy-dependent secretion: mechanism, factors secreted, and disease implications.

Although best understood as a degradative pathway, recent evidence demonstrates pronounced involvement of the macroautophagic/autophagic molecular machinery in cellular secretion. With either overexpression or inhibition of autophagy mediators, dramatic alterations in the cellular secretory profile occur. This affects secretion of a plethora of factors ranging from cytokines, to granule contents, and even viral particles. Encompassing a wide range of secreted factors, autophagy-dependent secretion is implicated in diseases ranging from cancer to neurodegeneration. With a growing body of evidence shedding light onto the molecular mediators, this review delineates the molecular machinery involved in selective targeting of the autophagosome for either degradation or secretion. In addition, we summarize the current understanding of factors and cargo secreted through this unconventional route, and describe the implications of this pathway in both health and disease. Abbreviations: BECN1, beclin 1; CAF, cancer associated fibroblast; CUPS, compartment for unconventional protein secretion; CXCL, C-X-C motif chemokine ligand; ER, endoplasmic reticulum; FGF2, fibroblast growth factor 2; HMGB1, high mobility group box 1; IDE, insulin degrading enzyme; IL, Interleukin; MAP1LC3/LC3, microtubule associated protein 1 light chain 3; MAPS, misfolding associated protein secretion; MEF, mouse embryonic fibroblast; MTORC1, MTOR complex I; PtdIns, phosphatidyl inositol; SEC22B, SEC22 homolog B, vesicle trafficking protein (gene/pseudogene); SFV, Semliki forest virus; SNCA, synuclein alpha; SQSTM1, sequestosome 1; STX, Syntaxin; TASCC, TOR-associated spatial coupling compartment; TGFB, transforming growth factor beta; TRIM16, tripartite motif containing 16; UPS, unconventional protein secretion; VWF, von Willebrand factor.

Vitamin D status and its management for achieving optimal health benefits in the elderly.

INTRODUCTION: Vitamin D deficiency is common, world-wide, but vitamin D repletion throughout life, and into older age, has accepted health benefits for bone. Many mechanisms through which vitamin D also benefits soft tissues are understood, and clinical evidence of such benefits is now accumulating, especially following re-analyses of trial data, which are revealing previously missed health benefits with correction of deficiency. AREAS COVERED: The sources of vitamin D, its activation, mechanistic effects; problems of trials of supplementation for reducing health risks, the benefits shown for mortality, cardiovascular disease, infection and cancer; the global problem of vitamin D deficiency; age-related reductions in vitamin D efficacy, and currently recommended intakes. EXPERT COMMENTARY: High prevalence of vitamin D deficiency and insufficiency worldwide have proven ill-effects on health. Governmental efforts to improve population repletion by recommending minimal daily intakes does benefit some but is not effective at the population-level. However, food fortification with vitamin D3, already implemented in some countries, can solve this highly avoidable problem cost-effectively and is probably the best way to abolish vitamin D inadequacy, allowing public health benefits to emerge over time, thereby allowing future research on vitamin D to be directed at emerging issues on vitamin D.

Compositional analyses of white, brown and germinated forms of popular Malaysian rice to offer insight into the growing diet-related diseases.

Diet-related metabolic diseases, and especially obesity, are metabolic disorders with multifactorial aetiologies. Diet has been a cornerstone in both the aetiology and management of this metabolic disorders. Rice, a staple food for over half of the world's population, could be exploited as part of the solution to check this menace which has been skyrocketing in the last decade. The present study investigated nine forms of rice from three widely grown Malaysian rice cultivars for in vitro and in vivo (glycaemic index and load) properties that could translate clinically into a lower predisposition to diet-related diseases. The germinated brown forms of MRQ 74 and MR 84 rice cultivars had high amylose content percentages (25.7% and 25.0%), high relative percentage antioxidant scavenging abilities of 85.0% and 91.7%, relatively low glycaemic indices (67.6 and 64.3) and glycaemic load (32.3 and 30.1) values, and modest glucose uptake capabilities of 33.69% and 31.25%, respectively. The results show that all things being equal, rice cultivars that are germinated and high in amylose content when compared to their white and low amylose counterparts could translate into a lower predisposition to diet-related diseases from the dietary point of view in individuals who consume this cereal as a staple food.

Data-intensive drug development in the information age: applications of Systems Biology/Pharmacology/Toxicology.

Pharmaceutical companies continuously face challenges to deliver new drugs with true medical value. R&D productivity of drug development projects depends on 1) the value of the drug concept and 2) data and in-depth knowledge that are used rationally to evaluate the drug concept's validity. A model-based data-intensive drug development approach is a key competitive factor used by innovative pharmaceutical companies to reduce information bias and rationally demonstrate the value of drug concepts. Owing to the accumulation of publicly available biomedical information, our understanding of the pathophysiological mechanisms of diseases has developed considerably; it is the basis for identifying the right drug target and creating a drug concept with true medical value. Our understanding of the pathophysiological mechanisms of disease animal models can also be improved; it can thus support rational extrapolation of animal experiment results to clinical settings. The Systems Biology approach, which leverages publicly available transcriptome data, is useful for these purposes. Furthermore, applying Systems Pharmacology enables dynamic simulation of drug responses, from which key research questions to be addressed in the subsequent studies can be adequately informed. Application of Systems Biology/Pharmacology to toxicology research, namely Systems Toxicology, should considerably improve the predictability of drug-induced toxicities in clinical situations that are difficult to predict from conventional preclinical toxicology studies. Systems Biology/Pharmacology/Toxicology models can be continuously improved using iterative learn-confirm processes throughout preclinical and clinical drug discovery and development processes. Successful implementation of data-intensive drug development approaches requires cultivation of an adequate R&D culture to appreciate this approach.

[The new paradigm of the developmental origin of health and diseases (DOHaD)--Epigenetics and environment: evidence and missing links]. / Le nouveau paradigme de l'origine développementale de la santé et des maladies (DOHaD)--Épigénétique, environnement: preuves et chaînons manquants.

According to the new paradigm of the Developpemental Origins of Health and Disease (DOHaD), the environmental factors to which an individual is exposed throughout his life can leave an epigenetic footprint on the genome. A crucial period is the early development, where the epigenome is particularly sensitive to the effects of the environment, and during which the individual builds up his health capital that will enable him to respond more or less well to the vagaries of life. The research challenge is to decipher the modes of action and the epigenetic mechanisms put into play by environmental factors that lead to increased disease susceptibility or resilience. The challenge for health is to translate these scientific discoveries into action through, among others, the establishment of preventive recommendations to slow down the growing incidence of non communicable diseases.

Use of complementary and alternative medicine in patients with health complaints attributed to former dental amalgam fillings.

BACKGROUND: The dental filling material amalgam is generally well tolerated. However, a small proportion of dental patients experience health complaints which they attribute to amalgam. The symptom pattern is often similar to patients with medically unexplained physical symptoms (MUPS) and the health complaints may persist after amalgam removal. Among patients with MUPS, the use of complementary and alternative medicine (CAM) seems to be high. The aim of this survey was to describe the prevalence and range of CAM use among people with health complaints attributed to dental amalgam fillings in which the health problems persist after the removal of all amalgam fillings. Specific attention was paid to (1) self-reported effects of CAM, (2) differences in CAM use dependent on self-reported health, and (3) gender differences in self-reported CAM use. METHODS: A survey was distributed to all members of The Norwegian dental patient association (NDPA) (n = 999), the response rate was 36.4%. The anonymous questionnaire asked for socio-demographic data, health complaints related to former amalgam fillings, subjectively perceived health status, symptoms, and experience with therapeutic interventions, mostly from the spectrum of CAM. Only participants who had all their fillings removed, which was the vast majority, were analysed. RESULTS: A total of 88.9% of included respondents had used at least one CAM modality, with a higher proportion of men (95.7%) compared to women (86.2%, p = 0.015). The most frequently used therapies were dietary supplements, vitamins and minerals recommended by a therapist (used by 66.7%) followed by self-prescribed dietary supplements, vitamins and minerals (59.0%), homeopathy (54.0%), acupuncture (48.8%) and special diets (47.5%). Use of CAM was similar for participants reporting normal to good health compared to participants reporting poor health. For all but two CAM modalities, the self-reported treatment effect was better in the group reporting normal to good health compared to the group reporting poor health. CONCLUSIONS: CAM was widely used by participants in our study, a finding similar to findings from studies of MUPS patients. To date, health problems associated with the use of dental amalgam is not an accepted diagnosis in the healthcare system. Consequently, people suffering from such complaints experience a lack of adequate treatment and support within conventional health care, which might have contributed to the high number of CAM users in this study.

[Guidance of volume transmission theory on treatment of "bipolar lesions"].

As the key organ of human, the brain has projection area corresponding to every part of the body, indicating that the damage on human body will locate a corresponding projection area in the brain. The primary injury on the distal end will produce secondary lesion in the projection area of brain, featuring as "bipolar lesions". The volume transmission (VT) theory and propagated sensation along meridians (PSAM) in TCM provide core guidance for the treatment of "bipolar lesions". The tendency to lesion of PSAM is achieved through volume transmission, which is also called "propagated sensation tendency to lesion of VT". From three aspects, VT can treat bipolar lesions, formatting a ring closed path. With VT as main treatment and wiring transmission as supplemented treatment, it has a more comprehensive guidance for treatment, and this theory may play an essential guiding role in the future treatment development for diseases.

Framework negotiations: diagnostic insights among alternative medical practitioners participating in integrative medicine case conferences.

Medical anthropology concerns itself with cultural interpretations of health and illness in complex pluralistic societies whose members incorporate multiple strategies to address health issues. This research explored the variety of complementary and alternative medicine (CAM) topics introduced into biomedically structured clinical evaluation. A field study of routine case conferences held within a clinical fellowship program in integrative medicine (IM) provided the ideal setting to explore contrasting conceptualizations of disease. Study results yielded five core sources of information sought by CAM practitioners, typically not addressed in biomedicine: social relations history within family of origin, emotional health, energetic health, spiritual health, and in-depth nutritional evaluation.

An integrated approach to defining genetic and environmental determinants for major clinical outcomes involving vitamin D.

There is substantial genetic and epidemiological evidence implicating vitamin D in the pathogenesis of many common diseases. A number of studies have sought to define an association for disease with sequence variation in the VDR gene, encoding the ligand-activated nuclear hormone receptor for vitamin D. The results of such studies have been difficult to replicate and are likely to need to account for specific environmental exposures. Here, we review recent work that has begun to study the interactions between VDR gene polymorphisms, vitamin D blood levels, and complex disease susceptibility, notably in the context of major clinical outcomes. We highlight the challenges moving forward in this area and its importance for effective clinical translation of current research.