A re-appraisal of pathogenic mechanisms bridging wet and dry age-related macular degeneration leads to reconsider a role for phytochemicals

Which pathogenic mechanisms underlie age-related macular degeneration (AMD)? Are they different for dry and wet variants, or do they stem from common metabolic alterations? Where shall we look for altered metabolism? Is it the inner choroid, or is it rather the choroid–retinal border? Again, since cell-clearing pathways are crucial to degrade altered proteins, which metabolic system is likely to be the most implicated, and in which cell type? Here we describe the unique clearing activity of the retinal pigment epithelium (RPE) and the relevant role of its autophagy machinery in removing altered debris, thus centering the RPE in the pathogenesis of AMD. The cell-clearing systems within the RPE may act as a kernel to regulate the redox homeostasis and the traffic of multiple proteins and organelles toward either the choroid border or the outer segments of photoreceptors. This is expected to cope with the polarity of various domains within RPE cells, with each one owning a specific metabolic activity. A defective clearance machinery may trigger unconventional solutions to avoid intracellular substrates’ accumulation through unconventional secretions. These components may be deposited between the RPE and Bruch’s membrane, thus generating the drusen, which remains the classic hallmark of AMD. These deposits may rather represent a witness of an abnormal RPE metabolism than a real pathogenic component. The empowerment of cell clearance, antioxidant, anti-inflammatory, and anti-angiogenic activity of the RPE by specific phytochemicals is here discussed

Results of a national UK physician reported survey of COVID-19 infection in patients with a myeloproliferative neoplasm

Funder: Cancer Research UK (CRUK); doi: https://doi.org/10.13039/501100000289Funder: DH | National Institute for Health Research (NIHR); doi: https://doi.org/10.13039/50110000027

Psychological aspects of transitive verbs

It has previously been shown that transitive verbs are more difficult to recall than intransitive. Experiment I replicated this finding. Experiment II examined the associations to, and response latencies of, transitive and intransitive verbs. Latencies of responses did not differ, but the form class of responses was significantly different. Transitive verbs elicited more noun responses. It is suggested that the lexical entry provided for transitive verbs by Chomsky is psychologically real and will account for the observed differences.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/32688/1/0000055.pd

Lactoferrin protects against methamphetamine toxicity by modulating autophagy and mitochondrial status

Lactoferrin (LF) was used at first as a vehicle to deliver non‐soluble active compounds to the body, including the central nervous system (CNS). Nonetheless, it soon became evident that, apart from acting as a vehicle, LF itself owns active effects in the CNS. In the present study, the effects of LF are assessed both in baseline conditions, as well as to counteract methamphetamine (METH)‐induced neurodegeneration by assessing cell viability, cell phenotype, mitochondrial status, and specific autophagy steps. In detail, cell integrity in baseline conditions and following METH administration was carried out by using H&E staining, Trypan blue, Fluoro Jade B, and WST‐1. Western blot and immuno‐fluorescence were used to assess the expression of the neurofilament marker βIII‐tubulin. Mitochondria were stained using Mito Tracker Red and Green and were further detailed and quantified by using transmission electron microscopy. Autophagy markers were analyzed through immuno‐fluorescence and electron microscopy. LF counteracts METH‐induced degeneration. In detail, LF significantly attenuates the amount of cell loss and mitochondrial alterations produced by METH; and mitigates the dissipation of autophagy‐related proteins from the autophagy compartment, which is massively induced by METH. These findings indicate a protective role of LF in the molecular mechanisms of neurodegeneration

Phytochemicals bridging autophagy induction and alpha-synuclein degradation in parkinsonism

Among nutraceuticals, phytochemical-rich compounds represent a source of naturally-derived bioactive principles, which are extensively studied for potential beneficial effects in a variety of disorders ranging from cardiovascular and metabolic diseases to cancer and neurodegeneration. In the brain, phytochemicals produce a number of biological effects such as modulation of neurotransmitter activity, growth factor induction, antioxidant and anti-inflammatory activity, stem cell modulation/neurogenesis, regulation of mitochondrial homeostasis, and counteracting protein aggregation through modulation of protein-folding chaperones and the cell clearing systems autophagy and proteasome. In particular, the ability of phytochemicals in restoring proteostasis through autophagy induction took center stage in recent research on neurodegenerative disorders such as Parkinson’s disease (PD). Indeed, autophagy dysfunctions and α-syn aggregation represent two interdependent downstream biochemical events, which concur in the parkinsonian brain, and which are targeted by phytochemicals administration. Therefore, in the present review we discuss evidence about the autophagy-based neuroprotective effects of specific phytochemical-rich plants in experimental parkinsonism, with a special focus on their ability to counteract alpha-synuclein aggregation and toxicity. Although further studies are needed to confirm the autophagy-based effects of some phytochemicals in parkinsonism, the evidence discussed here suggests that rescuing autophagy through natural compounds may play a role in preserving dopamine (DA) neuron integrity by counteracting the aggregation, toxicity, and prion-like spreading of α-syn, which remains a hallmark of PD

Binding Strength and Dynamics of Invariant Natural Killer Cell T Cell Receptor/CD1d-Glycosphingolipid Interaction on Living Cells by Single Molecule Force Spectroscopy*

Invariant natural killer T (iNKT) cells are a population of T lymphocytes that play an important role in regulating immunity to infection and tumors by recognizing endogenous and exogenous CD1d-bound lipid molecules. Using soluble iNKT T cell receptor (TCR) molecules, we applied single molecule force spectroscopy for the investigation of the iNKT TCR affinity for human CD1d molecules loaded with glycolipids differing in the length of the phytosphingosine chain using either recombinant CD1d molecules or lipid-pulsed THP1 cells. In both settings, the dissociation of the iNKT TCR from human CD1d molecules loaded with the lipid containing the longer phytosphingosine chain required higher unbinding forces compared with the shorter phytosphingosine lipid. Our findings are discussed in the context of previous results obtained by surface plasmon resonance measurements. We present new insights into the energy landscape and the kinetic rate constants of the iNKT TCR/human CD1d-glycosphingolipid interaction and emphasize the unique potential of single molecule force spectroscopy on living cells