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RSC Advances Aug 2023Nanobiotechnological approaches can provide effective solutions for overcoming food products' contamination and spoilage. The development of rapid and eco-friendly...
Nanobiotechnological approaches can provide effective solutions for overcoming food products' contamination and spoilage. The development of rapid and eco-friendly approaches for synthesizing nanocomposites from chitosan nanoparticles (Cht), Neptune grass "" extract (NG), and NG-mediated selenium nanoparticles (SeNPs) was targeted, with their investigation as potential antimicrobial, antioxidant, and biopreservatives of fresh chicken fillets. SeNPs were biosynthesized with NG, and their conjugates with Cht were composited. Characterization approaches, including infrared analysis, physiognomic analysis, and electron microscopy of synthesized nanomaterials and composites, were applied. The nanomaterials' antibacterial properties were assessed against , , and qualitatively, quantitatively, and with ultrastructure imaging. The antimicrobial and antioxidant potentialities of nanomaterials were employed for preserving chicken fillets, and the sensorial and microbiological parameters were assessed for coated fillets. SeNPs were effectively biosynthesized by NG, with mean diameters of 12.41 nm; the NG/SeNPs had homogenous spherical shapes with good distribution. The prepared Cht/NG/SeNPs nanoconjugates had a mean diameter of 164.61 nm, semi-spherical or smooth structures, and charges of +21.5 mV. The infrared analyses revealed the involvement of biochemical groups in nanomaterial biosynthesis and interactions. The antibacterial actions of nanomaterials were proven against the entire challenged strains; Cht/NG/SeNPs was the most active agent, and was the most susceptible bacteria. Scanning micrographs of Cht/NG/SeNPs-treated and indicate the severe time-dependent destruction of bacterial cells within 8 h of exposure. The antioxidant potentiality of Cht/NG/SeNPs was the highest (91.36%), followed by NG/SeNPs (79.45%). The chicken fillets' coating with Cht, NG, NG/SeNPs, and Cht/NG/SeNPs resulted in a remarkable reduction in microbial group count and raised the sensorial attributes of coated fillets after 14 days of cold storage, with increased potentialities in the order: Cht/NG/SeNPs > NG/SeNPs > NG > Cht > control. The inventive, facile biosynthesis of Cht, NG, and SeNPs could provide effective antimicrobial and antioxidant nanocomposites for prospective applications in food biopreservation.
PubMed: 37664190
DOI: 10.1039/d3ra04288j -
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 -
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 -
BioRxiv : the Preprint Server For... Apr 2024The hexameric AAA+ disaggregase, Hsp104, collaborates with Hsp70 and Hsp40 via its autoregulatory middle domain (MD) to solubilize aggregated protein conformers....
The hexameric AAA+ disaggregase, Hsp104, collaborates with Hsp70 and Hsp40 via its autoregulatory middle domain (MD) to solubilize aggregated protein conformers. However, how ATP- or ADP-specific MD configurations regulate Hsp104 hexamers remains poorly understood. Here, we define an ATP-specific network of interprotomer contacts between nucleotide-binding domain 1 (NBD1) and MD helix L1, which tunes Hsp70 collaboration. Manipulating this network can: (a) reduce Hsp70 collaboration without enhancing activity; (b) generate Hsp104 hypomorphs that collaborate selectively with class B Hsp40s; (c) produce Hsp70-independent potentiated variants; or (d) create species barriers between Hsp104 and Hsp70. Conversely, ADP-specific intraprotomer contacts between MD helix L2 and NBD1 restrict activity, and their perturbation frequently potentiates Hsp104. Importantly, adjusting the NBD1:MD helix L1 rheostat via rational design enables finely tuned collaboration with Hsp70 to safely potentiate Hsp104, minimize off-target toxicity, and counteract FUS proteinopathy in human cells. Thus, we establish important design principles to tailor Hsp104 therapeutics.
PubMed: 38712168
DOI: 10.1101/2024.04.26.591398 -
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 -
Biology Oct 2021Sporadic Alzheimer's Disease (AD) is the most common form of dementia, and its severity is characterized by the progressive formation of tau neurofibrillary tangles... (Review)
Review
Sporadic Alzheimer's Disease (AD) is the most common form of dementia, and its severity is characterized by the progressive formation of tau neurofibrillary tangles along a well-described path through the brain. This spatial progression provides the basis for Braak staging of the pathological progression for AD. Tau protein is a necessary component of AD pathology, and recent studies have found that soluble tau species with selectively, but not extensively, modified epitopes accumulate along the path of disease progression before AD-associated insoluble aggregates form. As such, modified tau may represent a key cellular stressing agent that potentiates selective vulnerability in susceptible neurons during AD progression. Specifically, studies have found that tau phosphorylated at sites such as T181, T231, and S396 may initiate early pathological changes in tau by disrupting proper tau localization, initiating tau oligomerization, and facilitating tau accumulation and extracellular export. Thus, this review elucidates potential mechanisms through which tau post-translational modifications (PTMs) may simultaneously serve as key modulators of the spatial progression observed in AD development and as key instigators of early pathology related to neurodegeneration-relevant cellular dysfunctions.
PubMed: 34681146
DOI: 10.3390/biology10101047 -
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 -
Molecules (Basel, Switzerland) Oct 2019Surface disinfection is of utmost importance in the prevention of bacterial infections. This study aims to assess the ability of ten phytochemicals and related...
Surface disinfection is of utmost importance in the prevention of bacterial infections. This study aims to assess the ability of ten phytochemicals and related derivatives as potentiators of two commonly used biocides-cetyltrimethylammonium bromide (CTAB) and lactic acid (LA). LA in combination with cinnamic, hydrocinnamic, α-methylcinnamic, and α-fluorocinnamic acids had a factional inhibitory concentration index (FICI) ≤ 1 for and . Several phytochemicals/derivatives in combination with biocides improved the biocidal efficacy against early sessile bacteria. The most effective combination was LA with allyl cinnamate (2.98 ± 0.76 log CFU.cm reduction) against . The combination with CTAB was successful for most phytochemicals/derivatives with a maximum bactericidal efficacy against sessile when combined with allyl cinnamate (2.20 ± 0.07 log CFU.cm reduction) and for when combined with α-methylcinnamic acid (1.68 ± 0.30 log CFU.cm reduction). This study highlights the potential of phytochemicals and their derivatives to be used in biocide formulations.
Topics: Bacteria; Cetrimonium; Cinnamates; Disinfectants; Hydrophobic and Hydrophilic Interactions; Lactic Acid; Microbial Sensitivity Tests; Phytochemicals
PubMed: 31671687
DOI: 10.3390/molecules24213918