Search

The gut microbiome plays a key role in influencing several pathways and functions involved in human health, including metabolism, protection against infection, and immune regulation. Perturbation of the gut microbiome is recognised as a pathogenic factor in several gastrointestinal and extraintestinal disorders, and is increasingly considered as a therapeutic target in these conditions. Faecal microbiota transplantation (FMT) is the transfer of the microbiota from healthy screened stool donors into the gut of affected patients, and is a well-established and highly effective treatment for recurrent Clostridioides difficile infection. Despite the mechanisms of efficacy of FMT not being fully understood, it has been investigated in several chronic noncommunicable disorders, with variable results. This review aims to give an overview of mechanisms of efficacy of FMT in chronic noncommunicable disorders, and to paint the current landscape of its investigation in these medical conditions, including inflammatory bowel disease (IBD), chronic liver disorders, and also extraintestinal autoimmune conditions., Competing Interests: Declaration of competing interest B·H.M. reports consultancy fees from Finch Therapeutics Group, Ferring Pharmaceuticals, and Summit Therapeutics, outside of the submitted work. A.G. reports personal fees for consultancy from Eisai Srl, 3PSolutions, Real Time Meeting, Fondazione Istituto Danone, SinergieSrl, Board MRGE and Sanofi SpA personal fees for acting as a speaker for Takeda SpA, AbbVie and Sandoz SpA and personal fees for acting on advisory boards for VSL3 and Eisai. G.C. has received personal fees for acting as advisor for Ferring Therapeutics. G.I. has received personal fees for acting as speaker for Biocodex, Danone, Sofar, Malesci, Metagenics and Tillotts Pharma, and for acting as consultant and/or advisor for Ferring Therapeutics, Giuliani, Malesci and Tillotts Pharma. All other authors have no conflicts of interest to disclose., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Arsenite is an important carcinogen and toxic compound, causing various deleterious effects through multiple mechanisms. In this review, we focused on mitochondrial ROS (mitoROS) and discussed on the mechanisms mediating their formation. The metalloid promotes direct effects in mitochondria, resulting in superoxide formation only under conditions of increased mitochondrial Ca 2+ concentration ([Ca 2+ ] m ). In this perspective, the time of exposure and concentration requirements for arsenite were largely conditioned by other effects of the metalloid in specific sites of the endoplasmic reticulum (ER). Arsenite induced a slow and limited mobilization of Ca 2+ from IP 3 R via a saturable mechanism, failing to increase the [Ca 2+ ] m . This effect was however associated with the triggering of an intraluminal crosstalk between the IP 3 R and the ryanodine receptor (RyR), causing a large and concentration dependent release of Ca 2+ from RyR and a parallel increase in [Ca 2+ ] m . Thus, the Ca 2+ -dependent mitoO 2 -. formation appears to be conditioned by the spatial/functional organization of the ER/mitochondria network and RyR expression. We also speculate on the possibility that the ER stress response might regulate the above effects on the intraluminal crosstalk between the IP 3 R and the RyR via oxidation of critical thiols mediated by the H 2 O 2 locally released by oxidoreductin 1α., (Copyright © 2021. Published by Elsevier Ltd.)

In this study, respiration-proficient (RP) and -deficient (RD) cells were exposed to 2.5 or 10 μM arsenite to generate superoxide (O 2 -. ) respectively in the mitochondrial respiratory chain or via NADPH oxidase activation. These treatments, while causing similar, although mitochondrial permeability transition-dependent (RP-cells) or independent (RD-cells), delayed apoptosis, surprisingly generated identical kinetics and levels of dihydrorhodamine oxidation, indicative of O 2 -. formation. These similarities were attributable to the involvement of a common upstream event resulting in activation of the two O 2 -. -generating systems, and to intrinsic features of the cells. Both mechanisms required an initial and sequential mobilization of Ca 2+ from the inositol-1,4,5-trisphosphate receptor and the ryanodine receptor (RyR), with however different implications. The close contacts existing between the RyR and the mitochondria created optimal conditions for the Ca 2+ clearance, and the ensuing formation of O 2 -. in RP-cell mitochondria. Exposure to low concentrations of l-ascorbic acid (AA) transported by high affinity mechanisms in cells and mitochondria, suppressed O 2 -. formation. Much more Ca 2+ , and hence more arsenite, was necessary to promote NADPH oxidase activation in RD-cells, as a consequence of the cytosolic dilution and mitochondrial clearance of Ca 2+ . For the same reasons, an exposure to high concentrations of AA was required to suppress O 2 -. formation under these conditions., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Arsenite toxicity is in numerous cellular systems dependent on the formation of reactive oxygen and or nitrogen species. This is also true in U937 cells in which the metalloid selectively promotes the formation of mitochondrial superoxide (mitoO 2 - ) rapidly converted to diffusible H 2 O 2 . We tested the hypothesis that, under the same conditions, mitoO 2 - also mediates the triggering of a parallel survival signaling. We found that a low concentration of the metalloid causes an early activation of nuclear factor erythroid 2 p45-related factor 2 (Nrf2), and a downstream signaling leading to enhanced GSH biosynthesis, via a mechanism sensitive to various treatments/strategies selectively preventing mitoO 2 - formation. Under the same conditions, the toxic effects mediated by arsenite, leading to delayed mitochondrial permeability transition (MPT)-dependent apoptosis, were also prevented. Additional studies revealed remarkable similarities in the kinetics of mitoO 2 - formation, MPT induction, Nrf2 activation and GSH biosynthesis, prior to the onset of apoptosis in a small portion of the cells. Importantly, mitoO 2 - formation, as well as the ensuing toxic events, were significantly potentiated and anticipated under conditions associated with inhibition of de novo GSH biosynthesis triggered by the metalloid through Nrf2 activation. We conclude that, in the arsenite toxicity paradigm under investigation, mitoO 2 - represents the only trigger of two opposite pathways leading to activation of the Nrf2 signaling and/or to a MPT-dependent apoptotic death. The first pathway, through enhanced GSH biosynthesis, mitigates the extent of further mitoO 2 - formation, thereby limiting and delaying an otherwise rapid and massive apoptotic death., (Copyright © 2018 Elsevier Inc. All rights reserved.)

We herein report the results from a comparative study of arsenite toxicity in respiration-proficient (RP) and -deficient (RD) U937 cells. An initial characterization of these cells led to the demonstration that the respiration-deficient phenotype is not associated with apparent changes in mitochondrial mass and membrane potential. In addition, similar levels of superoxide (O2(.-)) were generated by RP and RD cells in response to stimuli specifically triggering respiratory chain-independent mitochondrial mechanisms or extramitochondrial, NADPH-oxidase dependent, mechanisms. At the concentration of 2.5μM, arsenite elicited selective formation of O2(.-) in the respiratory chain of RP cells, with hardly any contribution of the above mechanisms. Under these conditions, O2(.-) triggered downstream events leading to endoplasmic reticulum (ER) stress, autophagy and apoptosis. RD cells challenged with similar levels of arsenite failed to generate O2(.-) because of the lack of a functional respiratory chain and were therefore resistant to the toxic effects mediated by the metalloid. Their resistance, however, was lost after exposure to four fold greater concentrations of arsenite, coincidentally with the release of O2(.-) mediated by NADPH oxidase. Interestingly, extramitochondrial O2(.-) triggered the same downstream events and an identical mode of death previously observed in RP cells. Taken together, the results obtained in this study indicate that arsenite toxicity is strictly dependent on O2(.-) availability that, regardless of whether generated in the mitochondrial or extramitochondrial compartments, triggers similar downstream events leading to ER stress, autophagy and apoptosis., (Copyright © 2016 Elsevier Inc. All rights reserved.)

To investigate the contribution of feedback circuits from area V4 to the receptive-field properties of V2 neurons, we used tungsten microelectrodes to record extracellular single units in these visual areas, before and after pressure injections of a solution of 0.25 mol/L of GABA in two anesthetized and paralyzed Cebus apella monkeys. The visual stimulus consisted of a single bar moving in one of eight directions. Using a device made of four stainless steel pipettes and one central tungsten electrode, we inactivated, with different amounts of GABA, topographically corresponding areas of V4, while studying V2 neurons. We studied a total of 36 V2 neurons during six sessions of GABA injections into area V4. GABA inactivation of visual area V4 produced a general decrease in the excitability of the neurons, which included a decrease in spontaneous and driven activities, followed by changes in direction selectivity. The changes in selectivity were toward an increase in directional selectivity and decrease in orientation selectivity. Thus, feedback connections arising from V4, an area of the ventral steams of visual information processing, are capable of not only modulating the spontaneous and driven activity of V2 neurons, but also of modifying V2 receptive field properties, such as its direction and/or orientation selectivity., (Published by Elsevier Inc.)