-
Brain Research Sep 2015The goal of this essay is to link the regulation of actin dynamics to the idea that the synaptic changes that support long-term potentiation and memory evolve in... (Review)
Review
The goal of this essay is to link the regulation of actin dynamics to the idea that the synaptic changes that support long-term potentiation and memory evolve in temporally overlapping stages-generation, stabilization, and consolidation. Different cellular/molecular processes operate at each stage to change the spine cytoarchitecture and, in doing so, alter its function. Calcium-dependent processes that degrade the actin cytoskeleton network promote a rapid insertion of AMPA receptors into the post synaptic density, which increases a spine's capacity to express a potentiated response to glutamate. Other post-translation events then begin to stabilize and expand the actin cytoskeleton by increasing the filament actin content of the spine and reorganizing it to be resistant to depolymerizing events. Disrupting actin polymerization during this stabilization period is a terminal event-the actin cytoskeleton shrinks and potentiated synapses de-potentiate and memories are lost. Late-arriving, new proteins may consolidate changes in the actin cytoskeleton. However, to do so requires a stabilized actin cytoskeleton. The now enlarged spine has properties that enable it to capture other newly transcribed mRNAs or their protein products and thus enable the synaptic changes that support LTP and memory to be consolidated and maintained. This article is part of a Special Issue entitled SI: Brain and Memory.
Topics: Actin Cytoskeleton; Animals; Brain; Dendritic Spines; Humans; Long-Term Potentiation; Memory; Receptors, AMPA; Synapses
PubMed: 25498985
DOI: 10.1016/j.brainres.2014.12.007 -
International Journal of Molecular... Apr 2022Advances in aging studies brought about by heterochronic parabiosis suggest that agingmight be a reversable process that is affected by changes in the systemic milieu of... (Review)
Review
Advances in aging studies brought about by heterochronic parabiosis suggest that agingmight be a reversable process that is affected by changes in the systemic milieu of organs andcells. Given the broadness of such a systemic approach, research to date has mainly questioned theinvolvement of "shared organs" versus "circulating factors". However, in the absence of a clearunderstanding of the chronological development of aging and a unified platform to evaluate thesuccesses claimed by specific rejuvenation methods, current literature on this topic remains scattered.Herein, aging is assessed from an engineering standpoint to isolate possible aging potentiators via ajuxtaposition between biological and mechanical systems. Such a simplification provides a generalframework for future research in the field and examines the involvement of various factors in aging.Based on this simplified overview, the kidney as a filtration organ is clearly implicated, for the firsttime, with the aging phenomenon, necessitating a re-evaluation of current rejuvenation studies tountangle the extent of its involvement and its possible role as a potentiator in aging. Based on thesefindings, the review concludes with potential translatable and long-term therapeutics for aging whileoffering a critical view of rejuvenation methods proposed to date.
Topics: Immunotherapy; Parabiosis; Rejuvenation
PubMed: 35457154
DOI: 10.3390/ijms23084338 -
Restorative Neurology and Neuroscience 2019The cholinergic system is a potent neuromodulator system that plays a critical role in cortical plasticity, attention, and learning. Recently, it was found that boosting... (Review)
Review
BACKGROUND
The cholinergic system is a potent neuromodulator system that plays a critical role in cortical plasticity, attention, and learning. Recently, it was found that boosting this system during perceptual learning robustly enhances sensory perception in rodents. In particular, pairing cholinergic activation with visual stimulation increases neuronal responses, cue detection ability, and long-term facilitation in the primary visual cortex. The mechanisms of cholinergic enhancement are closely linked to attentional processes, long-term potentiation, and modulation of the excitatory/inhibitory balance. Some studies currently examine this effect in humans.
OBJECTIVE
The present article reviews the research from our laboratory, examining whether potentiating the central cholinergic system could help visual perception and restoration.
METHODS
Electrophysiological or pharmacological enhancement of the cholinergic system are administered during a visual training. Electrophysiological responses and perceptual learning performance are investigated before and after the training in rats and humans. This approach's ability to restore visual capacities following a visual deficit induced by a partial optic nerve crush is also investigated in rats.
RESULTS
The coupling of visual training to cholinergic stimulation improved visual discrimination and visual acuity in rats, and improved residual vision after a deficit. These changes were due to muscarinic and nicotinic transmissions and were associated with a functional improvement of evoked potentials. In humans, potentiation of cholinergic transmission with 5 mg of donepezil showed improved learning and ocular dominance plasticity, although this treatment was ineffective in augmenting the perceptual threshold and electroencephalography.
CONCLUSIONS
Potential therapeutic outcomes ought to facilitate vision restoration using commercially available cholinergic agents combined with visual stimulation in order to prevent irreversible vision loss in patients. This approach has the potential to help a large population of visually impaired individuals.
Topics: Acetylcholine; Animals; Cholinergic Agents; Donepezil; Evoked Potentials, Visual; Humans; Neuronal Plasticity; Rats; Rodentia; Vision Disorders; Visual Cortex; Visual Perception
PubMed: 31839615
DOI: 10.3233/RNN-190947 -
Spike frequency-dependent inhibition and excitation of neural activity by high-frequency ultrasound.The Journal of General Physiology Nov 2020Ultrasound can modulate action potential firing in vivo and in vitro, but the mechanistic basis of this phenomenon is not well understood. To address this problem, we...
Ultrasound can modulate action potential firing in vivo and in vitro, but the mechanistic basis of this phenomenon is not well understood. To address this problem, we used patch-clamp recording to quantify the effects of focused, high-frequency (43 MHz) ultrasound on evoked action potential firing in CA1 pyramidal neurons in acute rodent hippocampal brain slices. We find that ultrasound can either inhibit or potentiate firing in a spike frequency-dependent manner: at low (near-threshold) input currents and low firing frequencies, ultrasound inhibits firing, while at higher input currents and higher firing frequencies, ultrasound potentiates firing. The net result of these two competing effects is that ultrasound increases the threshold current for action potential firing, the slope of frequency-input curves, and the maximum firing frequency. In addition, ultrasound slightly hyperpolarizes the resting membrane potential, decreases action potential width, and increases the depth of the after-hyperpolarization. All of these results can be explained by the hypothesis that ultrasound activates a sustained potassium conductance. According to this hypothesis, increased outward potassium currents hyperpolarize the resting membrane potential and inhibit firing at near-threshold input currents but potentiate firing in response to higher-input currents by limiting inactivation of voltage-dependent sodium channels during the action potential. This latter effect is a consequence of faster action potential repolarization, which limits inactivation of voltage-dependent sodium channels, and deeper (more negative) after-hyperpolarization, which increases the rate of recovery from inactivation. Based on these results, we propose that ultrasound activates thermosensitive and mechanosensitive two-pore-domain potassium (K2P) channels through heating or mechanical effects of acoustic radiation force. Finite-element modeling of the effects of ultrasound on brain tissue suggests that the effects of ultrasound on firing frequency are caused by a small (<2°C) increase in temperature, with possible additional contributions from mechanical effects.
Topics: Action Potentials; Animals; CA1 Region, Hippocampal; In Vitro Techniques; Membrane Potentials; Patch-Clamp Techniques; Pyramidal Cells; Rodentia; Ultrasonics
PubMed: 33074301
DOI: 10.1085/jgp.202012672 -
Biomaterials Mar 2022Immunotherapy has emerged as a promising cancer treatment modality. Despite the rapid progress in cancer immunotherapy, the therapeutic efficiency and clinical... (Review)
Review
Immunotherapy has emerged as a promising cancer treatment modality. Despite the rapid progress in cancer immunotherapy, the therapeutic efficiency and clinical translation of immunotherapy are not as satisfactory as expected, especially for the patients with immune-cold tumors. Immunogenic cell death (ICD) represents a particular form of tumor cell death accompanied by the production of tumor-specific antigens, which facilitates the infiltration of effector T cells and potentiates immune response in solid tumors. Thus, ICD contributes to stimulating immune-cold tumors to immune-hot ones. Increasing evidence shows that photodynamic therapy (PDT) is able to effectively induce ICD. Recently, a variety of photodynamic nanotherapeutics have been developed to induce ICD and to potentiate cancer immunotherapy. Herein, this review outlines the recent advances in the field at the intersection of PDT, nanotechnology and ICD, including PDT-induced ICD, PDT-based synergistic induction of ICD, and multimodal immunotherapy in basis of PDT-induced ICD. Finally, the prospects and challenges of these photodynamic nanotherapeutics in ICD induction-based cancer immunotherapy are discussed.
Topics: Cell Death; Cell Line, Tumor; Humans; Immunogenic Cell Death; Immunotherapy; Neoplasms; Photochemotherapy
PubMed: 35202933
DOI: 10.1016/j.biomaterials.2022.121433 -
Journal of Bone and Mineral Research :... May 2023The development of Wnt-based osteoanabolic agents has progressed rapidly in recent years, given the potent effects of Wnt modulation on bone homeostasis. Simultaneous...
The development of Wnt-based osteoanabolic agents has progressed rapidly in recent years, given the potent effects of Wnt modulation on bone homeostasis. Simultaneous pharmacologic inhibition of the Wnt antagonists sclerostin and Dkk1 can be optimized to create potentiated effects in the cancellous bone compartment. We looked for other candidates that might be co-inhibited along with sclerostin to potentiate the effects in the cortical compartment. Sostdc1 (Wise), like sclerostin and Dkk1, also binds and inhibits Lrp5/6 coreceptors to impair canonical Wnt signaling, but Sostdc1 has greater effects in the cortical bone. To test this concept, we deleted Sostdc1 and Sost from mice and measured the skeletal effects in cortical and cancellous compartments individually. Sost deletion alone produced high bone mass in all compartments, whereas Sostdc1 deletion alone had no measurable effects on either envelope. Mice with codeletion of Sostdc1 and Sost had high bone mass and increased cortical properties (bone mass, formation rates, mechanical properties), but only among males. Combined administration of sclerostin antibody and Sostdc1 antibody in wild-type female mice produced potentiation of cortical bone gain despite no effect of Sostdc1 antibody alone. In conclusion, Sostdc1 inhibition/deletion can work in concert with sclerostin deficiency to improve cortical bone properties. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
Topics: Male; Female; Animals; Mice; Intercellular Signaling Peptides and Proteins; Glycoproteins; Bone and Bones; Cortical Bone; Cancellous Bone; Adaptor Proteins, Signal Transducing
PubMed: 36891756
DOI: 10.1002/jbmr.4798 -
American Journal of Respiratory Cell... May 2021Premature-termination codons (PTCs) in CFTR (cystic fibrosis [CF] transmembrane conductance regulator) result in nonfunctional CFTR protein and are the proximate cause...
Premature-termination codons (PTCs) in CFTR (cystic fibrosis [CF] transmembrane conductance regulator) result in nonfunctional CFTR protein and are the proximate cause of ∼11% of CF-causing alleles, for which no treatments exist. The CFTR corrector lumacaftor and the potentiator ivacaftor improve CFTR function with terminal PTC mutations and enhance the effect of readthrough agents. Novel correctors GLPG2222 (corrector 1 [C1]), GLPG3221 (corrector 2 [C2]), and potentiator GLPG1837 compare favorably with lumacaftor and ivacaftor . Here, we evaluated the effect of correctors C1a and C2a (derivatives of C1 and C2) and GLPG1837 alone or in combination with the readthrough compound G418 on CFTR function using heterologous Fischer rat thyroid (FRT) cells, the genetically engineered human bronchial epithelial (HBE) 16HBE14o cell lines, and primary human cells with PTC mutations. In FRT lines pretreated with G418, GLPG1837 elicited dose-dependent increases in CFTR activity that exceeded those from ivacaftor in FRT-W1282X and FRT-R1162X cells. A three-mechanism strategy consisting of G418, GLPG1837, and two correctors (C1a + C2a) yielded the greatest functional improvements in FRT and 16HBE14o PTC variants, noting that correction and potentiation without readthrough was sufficient to stimulate CFTR activity for W1282X cells. GLPG1837 + C1a + C2a restored substantial function in G542X/F508del HBE cells and restored even more function for W1282X/F508del cells, largely because of the corrector/potentiator effect, with no additional benefit from G418. In G542X/R553X or R1162X/R1162X organoids, enhanced forskolin-induced swelling was observed with G418 + GLPG1837 + C1a + C2a, although GLPG1837 + C1a + C2a alone was sufficient to improve forskolin-induced swelling in W1282X/W1282X organoids. Combination of CFTR correctors, potentiators, and readthrough compounds augments the functional repair of CFTR nonsense mutations, indicating the potential for novel correctors and potentiators to restore function to truncated W1282X CFTR.
Topics: Aminophenols; Aminopyridines; Animals; Benzoates; Benzodioxoles; Benzopyrans; Cell Line; Chlorides; Codon, Nonsense; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Epithelial Cells; Humans; Ion Transport; Protein Biosynthesis; Pyrans; Pyrazoles; Quinolones; Rats; Recovery of Function; Thyroid Epithelial Cells
PubMed: 33616476
DOI: 10.1165/rcmb.2019-0291OC -
Therapeutic Advances in Chronic Disease 2022Cystic fibrosis (CF), a life-limiting chronic disease caused by mutations in the cystic fibrosis transmembrane regulator (CFTR) gene, affects more than 90,000 people... (Review)
Review
Cystic fibrosis (CF), a life-limiting chronic disease caused by mutations in the cystic fibrosis transmembrane regulator (CFTR) gene, affects more than 90,000 people worldwide. Until recently, the only available treatments were directed to symptom control, but they failed to change the course of the disease. New drugs developed in the last decade have the potential to change the expression, function, and stability of CFTR protein, targeting the basic molecular defect. The authors seek to provide an update on the new drugs, with a special focus on the most promising clinical trials that have been carried out to date. These newly approved drugs that target specific mutations are mainly divided into two main groups of CFTR modulators: potentiators and correctors. New therapies have opened the door for potentially disease-modifying, personalized treatments for patients with CF.
PubMed: 35620188
DOI: 10.1177/20406223221098136 -
MBio Aug 2023Each year, fungi cause more than 1.5 billion infections worldwide and have a devastating impact on human health, particularly in immunocompromised individuals or...
Each year, fungi cause more than 1.5 billion infections worldwide and have a devastating impact on human health, particularly in immunocompromised individuals or patients in intensive care units. The limited antifungal arsenal and emerging multidrug-resistant species necessitate the development of new therapies. One strategy for combating drug-resistant pathogens is the administration of molecules that restore fungal susceptibility to approved drugs. Accordingly, we carried out a screen to identify small molecules that could restore the susceptibility of pathogenic species to azole antifungals. This screening effort led to the discovery of novel 1,4-benzodiazepines that restore fluconazole susceptibility in resistant isolates of , as evidenced by 100-1,000-fold potentiation of fluconazole activity. This potentiation effect was also observed in azole-tolerant strains of and in other pathogenic species. The 1,4-benzodiazepines selectively potentiated different azoles, but not other approved antifungals. A remarkable feature of the potentiation was that the combination of the compounds with fluconazole was fungicidal, whereas fluconazole alone is fungistatic. Interestingly, the potentiators were not toxic to in the absence of fluconazole, but inhibited virulence-associated filamentation of the fungus. We found that the combination of the potentiators and fluconazole significantly enhanced host survival in a model of systemic fungal infection. Taken together, these observations validate a strategy wherein small molecules can restore the activity of highly used anti-infectives that have lost potency. IMPORTANCE In the last decade, we have been witnessing a higher incidence of fungal infections, due to an expansion of the fungal species capable of causing disease (e.g., ), as well as increased antifungal drug resistance. Among human fungal pathogens, species are a leading cause of invasive infections and are associated with high mortality rates. Infections by these pathogens are commonly treated with azole antifungals, yet the expansion of drug-resistant isolates has reduced their clinical utility. In this work, we describe the discovery and characterization of small molecules that potentiate fluconazole and restore the susceptibility of azole-resistant and azole-tolerant isolates. Interestingly, the potentiating 1,4-benzodiazepines were not toxic to fungal cells but inhibited their virulence-associated filamentous growth. Furthermore, combinations of the potentiators and fluconazole decreased fungal burdens and enhanced host survival in a model of systemic fungal infections. Accordingly, we propose the use of novel antifungal potentiators as a powerful strategy for addressing the growing resistance of fungi to clinically approved drugs.
Topics: Humans; Antifungal Agents; Candida; Fluconazole; Azoles; Pharmaceutical Preparations; Microbial Sensitivity Tests; Candida albicans; Mycoses; Drug Resistance, Fungal; Benzodiazepines
PubMed: 37326546
DOI: 10.1128/mbio.00479-23 -
Current Drug Targets 2021Pathogenic microorganisms should be considered as the number one foe of human, as witnessed by recent outbreaks of coronavirus disease (COVID-19) and with bacteria no... (Review)
Review
Pathogenic microorganisms should be considered as the number one foe of human, as witnessed by recent outbreaks of coronavirus disease (COVID-19) and with bacteria no longer sensitive to existing antibiotics. The resistance of pathogenic bacteria and deaths attributable to bacterial infections is increasing exponentially. Bacteria used different mechanisms to counterattack to existing antibiotics, namely (i) enzymatic inhibition, (ii) penicillin-binding protein modification, (iii) porin mutations, (iv) efflux pumps and (v) molecular modifications of antibiotic targets. Developing new antibiotics would be time-consuming to address such a situation, thus one of the promising approaches is by potentiating existing antibiotics. Plants used synergism to naturally defend and protect themselves from microbes. Using the same strategy, several studies have shown that the combinations of natural products and antibiotics could effectively prolong the lifespan of existing antibiotics and minimize the impact and emergence of antibiotic resistance. Combining essential oils constituents, namely uvaol, ferruginol, farnesol and carvacrol, with antibiotics, have proved to be efficient efflux pump inhibitors. Plant-derived compounds such as gallic acid and tannic acid are effective potentiators of various antibiotics, including novobiocin, chlorobiocin, coumermycin, fusidic acid, and rifampicin, resulting in a 4-fold increase in the potencies of these antibiotics. Several lines of research, as discussed in this review, have demonstrated the effectiveness of natural products in potentiating existing antibiotics. For this reason, the search for more efficient combinations should be an ongoing process with the aim to extend the life of the ones that we have and may preserve the life for the ones that are yet to come.
Topics: Anti-Bacterial Agents; Bacteria; Biological Products; COVID-19; Drug Resistance, Multiple, Bacterial; Drug Synergism; Microbial Sensitivity Tests; SARS-CoV-2
PubMed: 32972338
DOI: 10.2174/1389450121666200924113740