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The Journal of Physiology Jul 19731. The after-effects of repetitive stimulation of the perforant path fibres to the dentate area of the hippocampal formation have been examined with extracellular...
1. The after-effects of repetitive stimulation of the perforant path fibres to the dentate area of the hippocampal formation have been examined with extracellular micro-electrodes in rabbits anaesthetized with urethane.2. In fifteen out of eighteen rabbits the population response recorded from granule cells in the dentate area to single perforant path volleys was potentiated for periods ranging from 30 min to 10 hr after one or more conditioning trains at 10-20/sec for 10-15 sec, or 100/sec for 3-4 sec.3. The population response was analysed in terms of three parameters: the amplitude of the population excitatory post-synaptic potential (e.p.s.p.), signalling the depolarization of the granule cells, and the amplitude and latency of the population spike, signalling the discharge of the granule cells.4. All three parameters were potentiated in 29% of the experiments; in other experiments in which long term changes occurred, potentiation was confined to one or two of the three parameters. A reduction in the latency of the population spike was the commonest sign of potentiation, occurring in 57% of all experiments. The amplitude of the population e.p.s.p. was increased in 43%, and of the population spike in 40%, of all experiments.5. During conditioning at 10-20/sec there was massive potentiation of the population spike (;frequency potentiation'). The spike was suppressed during stimulation at 100/sec. Both frequencies produced long-term potentiation.6. The results suggest that two independent mechanisms are responsible for long-lasting potentiation: (a) an increase in the efficiency of synaptic transmission at the perforant path synapses; (b) an increase in the excitability of the granule cell population.
Topics: Action Potentials; Anesthesia, Intravenous; Animals; Electric Stimulation; Electrophysiology; Evoked Potentials; Female; Hippocampus; Male; Microelectrodes; Neurons; Rabbits; Synapses; Time Factors
PubMed: 4727084
DOI: 10.1113/jphysiol.1973.sp010273 -
PLoS Pathogens Aug 2023Fungal infections are rising, with over 1.5 billion cases and more than 1 million deaths recorded each year. Among these, Candida infections are frequent in at-risk...
Fungal infections are rising, with over 1.5 billion cases and more than 1 million deaths recorded each year. Among these, Candida infections are frequent in at-risk populations and the rapid development of drug resistance and tolerance contributes to their clinical persistence. Few antifungal drugs are available, and their efficacy is declining due to the environmental overuse and the expansion of multidrug-resistant species. One way to prolong their utility is by applying them in combination therapy. Here, we highlight recently described azole potentiators belonging to different categories: natural, repurposed, or novel compounds. We showcase examples of molecules and discuss their identified or proposed mode of action. We also emphasise the challenges in azole potentiator development, compounded by the lack of animal testing, the overreliance on Candida albicans and Candida auris, as well as the limited understanding of compound efficacy.
Topics: Animals; Candida; Candida albicans; Candidiasis; Antifungal Agents; Azoles
PubMed: 37651385
DOI: 10.1371/journal.ppat.1011583 -
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 -
MedChemComm Feb 2018Vaccines show great potential for both prophylactic and therapeutic use in infections, cancer, and other diseases. With the rapid development of bio-technologies and... (Review)
Review
Vaccines show great potential for both prophylactic and therapeutic use in infections, cancer, and other diseases. With the rapid development of bio-technologies and materials sciences, nanomaterials are playing essential roles in novel vaccine formulations and can boost antigen effectiveness by operating as delivery systems to enhance antigen processing and/or as immune-potentiating adjuvants to induce or potentiate immune responses. The effect of nanoparticles in vaccinology showed enhanced antigen stability and immunogenicity as well as targeted delivery and slow release. However, obstacles remain due to the lack of fundamental knowledge on the detailed molecular working mechanism and bio-effects of nanoparticles. This review provides a broad overview of the current improvements in nanoparticles in vaccinology. Modern nanoparticle vaccines are classified by the nanoparticles' action based on either delivery system or immune potentiator approaches. The mechanisms of interaction of nanoparticles with the antigens and the immune system are discussed. Nanoparticle vaccines approved for use are also listed. A fundamental understanding of the bio-distribution and the fate of nanoparticles will accelerate the rational design of new nanoparticles comprising vaccines in the future.
PubMed: 30108916
DOI: 10.1039/c7md00158d -
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 -
BioRxiv : the Preprint Server For... Mar 2024The cystic fibrosis transmembrane conductance regulator (CFTR) is a crucial ion channel whose loss of function leads to cystic fibrosis, while its hyperactivation leads...
The cystic fibrosis transmembrane conductance regulator (CFTR) is a crucial ion channel whose loss of function leads to cystic fibrosis, while its hyperactivation leads to secretory diarrhea. Small molecules that improve CFTR folding (correctors) or function (potentiators) are clinically available. However, the only potentiator, ivacaftor, has suboptimal pharmacokinetics and inhibitors have yet to be clinically developed. Here we combine molecular docking, electrophysiology, cryo-EM, and medicinal chemistry to identify novel CFTR modulators. We docked ~155 million molecules into the potentiator site on CFTR, synthesized 53 test ligands, and used structure-based optimization to identify candidate modulators. This approach uncovered novel mid-nanomolar potentiators as well as inhibitors that bind to the same allosteric site. These molecules represent potential leads for the development of more effective drugs for cystic fibrosis and secretory diarrhea, demonstrating the feasibility of large-scale docking for ion channel drug discovery.
PubMed: 37745391
DOI: 10.1101/2023.09.09.557002 -
Cell Reports Oct 2023The amygdala, cholinergic basal forebrain, and higher-order auditory cortex (HO-AC) regulate brain-wide plasticity underlying auditory threat learning. Here, we perform...
The amygdala, cholinergic basal forebrain, and higher-order auditory cortex (HO-AC) regulate brain-wide plasticity underlying auditory threat learning. Here, we perform multi-regional extracellular recordings and optical measurements of acetylcholine (ACh) release to characterize the development of discriminative plasticity within and between these brain regions as mice acquire and recall auditory threat memories. Spiking responses are potentiated for sounds paired with shock (CS+) in the lateral amygdala (LA) and optogenetically identified corticoamygdalar projection neurons, although not in neighboring HO-AC units. Spike- or optogenetically triggered local field potentials reveal enhanced corticofugal-but not corticopetal-functional coupling between HO-AC and LA during threat memory recall that is correlated with pupil-indexed memory strength. We also note robust sound-evoked ACh release that rapidly potentiates for the CS+ in LA but habituates across sessions in HO-AC. These findings highlight a distributed and cooperative plasticity in LA inputs as mice learn to reappraise neutral stimuli as possible threats.
Topics: Mice; Animals; Acoustic Stimulation; Learning; Basolateral Nuclear Complex; Amygdala; Acetylcholine; Cholinergic Agents
PubMed: 37742187
DOI: 10.1016/j.celrep.2023.113167 -
Frontiers in Microbiology 2022Antimicrobial resistance in clinically important microbes has emerged as an unmet challenge in global health. Extensively drug-resistant bacterial pathogens have cropped... (Review)
Review
Antimicrobial resistance in clinically important microbes has emerged as an unmet challenge in global health. Extensively drug-resistant bacterial pathogens have cropped up lately defying the action of even the last resort of antibiotics. This has led to a huge burden in the health sectors and increased morbidity and mortality rate across the world. The dwindling antibiotic discovery pipeline and rampant usage of antibiotics has set the alarming bells necessitating immediate actions to combat this looming threat. Various alternatives to discovery of new antibiotics are gaining attention such as reversing the antibiotic resistance and hence reviving the arsenal of antibiotics in hand. Antibiotic resistance reversal is mainly targeted against the antibiotic resistance mechanisms, which potentiates the effective action of the antibiotic. Such compounds are referred to as resistance breakers or antibiotic adjuvants/potentiators that work in conjunction with antibiotics. Many studies have been conducted for the identification of compounds, which decrease the permeability barrier, expression of efflux pumps and the resistance encoding enzymes. Compounds targeting the stability, inheritance and dissemination of the mobile genetic elements linked with the resistance genes are also potential candidates to curb antibiotic resistance. In pursuit of such compounds various natural sources and synthetic compounds have been harnessed. The activities of a considerable number of compounds seem promising and are currently at various phases of clinical trials. This review recapitulates all the studies pertaining to the use of antibiotic potentiators for the reversal of antibiotic resistance and what the future beholds for their usage in clinical settings.
PubMed: 35847117
DOI: 10.3389/fmicb.2022.887251 -
Plants (Basel, Switzerland) May 2022The secondary metabolites of endemic plants from the Rutaceae family, such as Burkillanthusmalaccensis (Ridl.) Swingle from the rainforest of Malaysia, has not been...
The secondary metabolites of endemic plants from the Rutaceae family, such as Burkillanthusmalaccensis (Ridl.) Swingle from the rainforest of Malaysia, has not been studied. Burkillanthusmalaccensis (Ridl.) Swingle may produce antibacterial and antibiotic-potentiating secondary metabolites. Hexane, chloroform, and methanol extracts of leaves, bark, wood, pericarps, and endocarps were tested against bacteria by broth microdilution assay and their antibiotic-potentiating activities. Chromatographic separations of hexane extracts of seeds were conducted to investigate effective phytochemicals and their antibacterial activities. Molecular docking studies of werneria chromene and dihydroxyacidissiminol against SARS-CoV-2 virus infection were conducted using AutoDock Vina. The methanol extract of bark inhibited the growth of Staphylococcusaureus, Escherichiacoli, and Pseudomonasaeruginosa with the minimum inhibitory concentration of 250, 500, and 250 µg/mL, respectively. The chloroform extract of endocarps potentiated the activity of imipenem against imipenem-resistant Acinetobacterbaumannii. The hexane extract of seeds increased the sensitivity of P. aeruginosa against ciprofloxacin and levofloxacin. The hexane extract of seeds and chloroform extract of endocarps were chromatographed, yielding werneria chromene and dihydroxyacidissiminol. Werneria chromene was bacteriostatic for P.aeruginosa and P.putida, with MIC/MBC values of 1000 > 1000 µg/mL. Dihydroxyacidissiminol showed the predicted binding energies of −8.1, −7.6, −7.0, and −7.5 kcal/mol with cathepsin L, nsp13 helicase, SARS-CoV-2 main protease, and SARS-CoV-2 spike protein receptor-binding domain S-RBD. Burkillanthusmalaccensis (Ridl.) Swingle can be a potential source of natural products with antibiotic-potentiating activity and that are anti-SARS-CoV-2.
PubMed: 35684161
DOI: 10.3390/plants11111388 -
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