Do airborne biogenic chemicals interact with the PI3K/Akt/mTOR cell signalling pathway to benefit human health and wellbeing in rural and coastal environments?

Living and taking recreation in rural and coastal environments promote health and wellbeing, although the causal factors involved are unclear. It has been proposed that such environments provide a counter to the stresses of everyday living, leading to enhanced mental and physical health. Living in natural environments will result in airborne exposure to a wide range of biogenic chemicals through inhalation and ingestion of airborne microbiota and particles. The “biogenics” hypothesis formulated here is that regular exposure to low concentrations of mixtures of natural compounds and toxins in natural environments confers pleiotropic health benefits by inhibiting the activities of interconnected cell signalling systems, particularly PI3K/Akt/mTORC1. When overactive, Akt and mTOR (mTORC1) can lead to many pathological processes including cancers, diabetes, inflammation, immunosuppression, and neurodegenerative diseases. There is a substantial body of evidence that many natural products (i.e., from bacteria, algae, fungi and higher plants) inhibit the activities of these protein kinases. Other mTOR-related interconnected metabolic control “switches” (e.g., PTEN & NF-κB), autophagy and other cytoprotective processes are also affected by natural products. The “biogenics” hypothesis formulated here is that regular intermittent exposure to a mixture of airborne biogenic compounds in natural environments confers pleiotropic health benefits by inhibiting activities of the highly interconnected PI3K/Akt/mTORC1 system. It is proposed that future experimental exposures to biogenic aerosols in animal models coupled with epidemiology, should target the activities of the various kinases in the PI3K/Akt/mTORC1 systems and related physiological processes for selected urban, rural and coastal populations in order to test this hypothesis

Quantitative Cytochemical Effects Of 3 Metal-Ions On A Lysosomal Hydrolase Of A Hydroid

The quantitative effects of Cu8+, Cd2+ and Hg2+ on the cytochemical staining reaction for lysosomal N-acetyl-/?-D-glucosaminidase have been determined and related to the inhibitory effects of the metals on colonial growth rate in the experimentally cultured hydroid Campanularia flexuosa. Cytochemical threshold concentrations are comparable to known environmental levels and are about one order of magnitude lower than those obtained by measuring colony growth rates. Pretreatment of colonies with Cuz+ gave no indication of tolerance adaptation, although there is evidence of the cumulative toxicity of Cu2+ and the possible sequestration of this metal in endodermal cell lysosomes. There is also an indication that the Cu2+ may exert its toxic effect by decreasing the stability of the lysosomal membranes, thus increasing the level of free glucosaminidase activity

Mode of action of Cr(VI) in immunocytes of earthworms: Implications for animal health

Chromium (Cr) is one of the major and most detrimental pollutant, widely present in the environment as a result of several anthropogenic activities. In mammalian cells, Cr(VI) is known to enhance reactive oxygen species (ROS) production and to cause toxic and genotoxic effects. Less commonly investigated are the effects and mode of action of this contaminant in invertebrates, particularly in soil organisms. In this work, earthworms of the species Eisenia andrei were exposed for 1 and 3 days to various sublethal concentrations of Cr(VI) (2, 15, 30 µg mL−1) using the paper contact toxicity test. In amoeboid leukocytes we investigated intracellular ROS and lipoperoxide production, oxidative DNA damage, and the effects on different cell functions. The analysis of the results shows that Cr(VI) triggered severe adverse reactions; the first events were an increase of intracellular ROS levels, generating in the cells oxidative stress conditions leading to membrane lipid peroxidation and oxidative DNA damage. Lysosomes showed relevant changes such as a strong membrane destabilization, which was accompanied by an increased catabolism of cytoplasmic proteins and accumulation of lipofuscin. With an increase in the dose and/or time of exposure, the physiological status of intracellular organelles (such as lysosomes, nucleus and mitochondria) showed further impairment and amoebocyte immune functions were adversely affected, as shown by the decrease of the phagocytic activity. By mapping the responses of the different parameters evaluated, diagnostic of (oxidative) stress events, against lysosomal membrane stability, a “health status” indicator (able to describe the stress syndrome from its early phase to pathology), we have shown that this biomarker is suitable as a prognostic test for health of earthworms. This is viewed as a crucial step toward the derivation of explanatory frameworks for prediction of pollutant impact on animal health

Effects of PAHs and dioxins on the earthworm Eisenia andrei: a multivariate approach for biomarker interpretation.

In this study, a battery of biomarkers was utilised to evaluate the stress syndrome induced in the earthworm Eisenia andrei by exposure to environmentally realistic concentrations of benzo[a]pyrene (B[a]P) and 2,3,7,8-tetrachlorodibenzo-para-dioxin (TCDD) in OECD soil. The set of tests was then employed to assess the toxicity of field soils contaminated with organic xenobiotic compounds (such as PAHs, dioxins and PCBs). Biomarker responses (comprising biomarkers of stress and of genotoxicity) varied depending on chemicals, dose and time of exposure; and among the different polluted field soils. The results highlighted an impairment of immune and metabolic functions and genotoxic damage in worms exposed also to lower bioavailable concentrations of toxic chemicals. Multivariate analysis of biomarker data showed that all different contaminated soils had a detrimental effect on the earthworms; control animals being clearly separated from the treated ones. A separation between temporal and concentration factors were also evident for B[a]P and TCDD treatments; and field contaminated soils were further differentiated reflecting a diverse contamination. Multivariate analysis also demonstrated that lysosomal membrane stability can be considered as a predictive tool of the adverse effects on worm health status provoked by increasing bioavailable concentrations of toxic chemicals

Anti-oxidative cellular protection effect of fasting-induced autophagy as a mechanism for hormesis

The aim of this investigation was to test the hypothesis that fasting-induced augmented lysosomal autophagic turnover of cellular proteins and organelles will reduce potentially harmful lipofuscin (age-pigment) formation in cells by more effectively removing oxidatively damaged proteins. An animal model (marine snail - common periwinkle, Littorina littorea) was used to experimentally test this hypothesis. Snails were deprived of algal food for 7 days to induce an augmented autophagic response in their hepatopancreatic digestive cells (hepatocyte analogues). This treatment resulted in a 25% reduction in the cellular content of lipofuscin in the digestive cells of the fasting animals in comparison with snails fed ad libitum on green alga (Ulva lactuca). Similar findings have previously been observed in the digestive cells of marine mussels subjected to copper-induced oxidative stress. Additional measurements showed that fasting significantly increased cellular health based on lysosomal membrane stability, and reduced lipid peroxidation and lysosomal/cellular triglyceride. These findings support the hypothesis that fasting-induced augmented autophagic turnover of cellular proteins has an anti-oxidative cytoprotective effect by more effectively removing damaged proteins, resulting in a reduction in the formation of potentially harmful proteinaceous aggregates such as lipofuscin. The inference from this study is that autophagy is important in mediating hormesis. An increase was demonstrated in physiological complexity with fasting, using graph theory in a directed cell physiology network (digraph) model to integrate the various biomarkers. This was commensurate with increased health status, and supportive of the hormesis hypothesis. The potential role of enhanced autophagic lysosomal removal of damaged proteins in the evolutionary acquisition of stress tolerance in intertidal molluscs is discussed and parallels are drawn with the growing evidence for the involvement of autophagy in hormesis and anti-ageing processes

Environmental health impacts of natural and man-made chemicals

Humans have been exposed to naturally occurring toxic chemicals and materials over the course of their existence as a species. These materials include various metals, the metalloid arsenic, and atmospheric combustion particulates, as well as bacterial, fungal, algal, and plant toxins. They have also consumed plants that contain a host of phytochemicals, many of which are believed to be beneficial, such as plant polyphenols. People are exposed to these various substances from a number of sources. The pathways of exposure include air, water, groundwater, soil (including via plants grown in toxic soils), and various foods, such as vegetables, fruit, fungi, seafood and fish, eggs, wild birds, marine mammals, and farmed animals. An overview of the various health benefits, hazards and risks relating to the risks reveals the very wide variety of chemicals and materials that are present in the natural environment and can interact with human biology, to both its betterment and detriment. The major naturally occurring toxic materials that impact human health include metals, metalloids (e.g., arsenic), and airborne particulates. The Industrial Revolution is a major event that increased ecosystem degradation and the various types and duration of exposure to toxic materials. The explosions in new organic and organometallic products that were and still are produced over the past two centuries have introduced new toxicities and associated pathologies. The prevalence in the environment of harmful particulates from motor-vehicle exhaust emissions, road dust and tire dust, and other combustion processes must also be considered in the broader context of air pollution. Natural products, such as bacterial, fungal, algal, and plant toxins, can also have adverse effects on health. At the same time, plant-derived phytochemicals (i.e., polyphenols, terpenoids, urolithins, and phenolic acids, etc.) also have beneficial and potential beneficial effects, particularly with regard to their anti-inflammatory effects. Because inflammation is associated with most disease processes, phytochemicals that have antioxidant and anti-inflammatory properties are of great interest as potential nutraceuticals. These potentially beneficial compounds may help to combat various cancers; autoimmune conditions; neurodegenerative diseases, including dementias; and psychotic conditions, such as depression, and are also essential micronutrients that promote health and well-being. The cellular and molecular mechanisms in humans that phytochemicals modulate, or otherwise interact with, to improve human health are now known. In the early 21st century, some of the current pollution issues are legacy problems from past industrialization, such as mercury and persistent organic pollutants (POPs). These POPs include many organochlorine compounds (e.g., polychlorinated biphenyls, pesticides, polychlorinated and polybrominated dibenzo-dioxans and -furans), as well as polycyclic aromatic hydrocarbons (PAHs), nitro-PAHs, and others. The toxicity of chemical mixtures is still a largely unknown problem, particularly with regard to possible synergies. The continuing development of new organic chemicals and nanomaterials is an important environmental health issue; and the need for vigilance with respect to their possible health hazards is urgent. Nanomaterials, in particular, pose potential novel problems in the context of their chemical properties; humans have not previously been exposed to these types of materials, which may well be able to exploit gaps in our existing cellular protection mechanisms. Hopefully, future advances in knowledge emerging from combinatorial chemistry, molecular modeling, and predictive quantitative structure-activity relationships (QSARs), will enable improved identification of the potential toxic properties of novel industrial organic chemicals, pharmaceuticals, and nanomaterials before they are released into the natural environment, and thus prevent a repetition of past disastrous events

Lysosomes, Autophagy, and Hormesis in Cell Physiology, Pathology, and Age-Related Disease

Autophagy has been strongly linked with hormesis, however, it is only relatively recently that the mechanistic basis underlying this association has begun to emerge. Lysosomal autophagy is a group of processes that degrade proteins, protein aggregates, membranes, organelles, segregated regions of cytoplasm, and even parts of the nucleus in eukaryotic cells. These degradative processes are evolutionarily very ancient and provide a survival capability for cells that are stressed or injured. Autophagy and autophagic dysfunction have been linked with many aspects of cell physiology and pathology in disease processes; and there is now intense interest in identifying various therapeutic strategies involving its regulation. The main regulatory pathway for augmented autophagy is the mechanistic target of rapamycin (mTOR) cell signaling, although other pathways can be involved, such as 50adenosine monophosphate-activated protein kinase. Mechanistic target of rapamycin is a key player in the many highly interconnected intracellular signaling pathways and is responsible for the control of cell growth among other processes. Inhibition of mTOR (specifically dephosphorylation of mTOR complex 1) triggers augmented autophagy and the search is on the find inhibitors that can induce hormetic responses that may be suitable for treating many diseases, including many cancers, type 2 diabetes, and age-related neurodegenerative conditions

Seeing Tree Structure from Vibration

Humans recognize object structure from both their appearance and motion; often, motion helps to resolve ambiguities in object structure that arise when we observe object appearance only. There are particular scenarios, however, where neither appearance nor spatial-temporal motion signals are informative: occluding twigs may look connected and have almost identical movements, though they belong to different, possibly disconnected branches. We propose to tackle this problem through spectrum analysis of motion signals, because vibrations of disconnected branches, though visually similar, often have distinctive natural frequencies. We propose a novel formulation of tree structure based on a physics-based link model, and validate its effectiveness by theoretical analysis, numerical simulation, and empirical experiments. With this formulation, we use nonparametric Bayesian inference to reconstruct tree structure from both spectral vibration signals and appearance cues. Our model performs well in recognizing hierarchical tree structure from real-world videos of trees and vessels.Comment: ECCV 2018. The first two authors contributed equally to this work. Project page: http://tree.csail.mit.edu

The biomechanics of amnion rupture: an X-ray diffraction study

Pre-term birth is the leading cause of perinatal and neonatal mortality, 40% of which are attributed to the pre-term premature rupture of amnion. Rupture of amnion is thought to be associated with a corresponding decrease in the extracellular collagen content and/or increase in collagenase activity. However, there is very little information concerning the detailed organisation of fibrillar collagen in amnion and how this might influence rupture. Here we identify a loss of lattice like arrangement in collagen organisation from areas near to the rupture site, and present a 9% increase in fibril spacing and a 50% decrease in fibrillar organisation using quantitative measurements gained by transmission electron microscopy and the novel application of synchrotron X-ray diffraction. These data provide an accurate insight into the biomechanical process of amnion rupture and highlight X-ray diffraction as a new and powerful tool in our understanding of this process

Identification and Correction of Mechanisms Underlying Inherited Blindness in Human iPSC-Derived Optic Cups

Leber congenital amaurosis (LCA) is an inherited retinal dystrophy that causes childhood blindness. Photoreceptors are especially sensitive to an intronic mutation in the cilia-related gene CEP290, which causes missplicing and premature termination, but the basis of this sensitivity is unclear. Here, we generated differentiated photoreceptors in three-dimensional optic cups and retinal pigment epithelium (RPE) from iPSCs with this common CEP290 mutation to investigate disease mechanisms and evaluate candidate therapies. iPSCs differentiated normally into RPE and optic cups, despite abnormal CEP290 splicing and cilia defects. The highest levels of aberrant splicing and cilia defects were observed in optic cups, explaining the retinal-specific manifestation of this CEP290 mutation. Treating optic cups with an antisense morpholino effectively blocked aberrant splicing and restored expression of full-length CEP290, restoring normal cilia-based protein trafficking. These results provide a mechanistic understanding of the retina-specific phenotypes in CEP290 LCA patients and potential strategies for therapeutic intervention