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Frontiers in Microbiology 2021Injudicious use of antibiotics has been the main driver of severe bacterial non-susceptibility to commonly available antibiotics (known as drug resistance or... (Review)
Review
Injudicious use of antibiotics has been the main driver of severe bacterial non-susceptibility to commonly available antibiotics (known as drug resistance or antimicrobial resistance), a global threat to human health and healthcare. There is an increase in the incidence and levels of resistance to antibacterial drugs not only in nosocomial settings but also in community ones. The drying pipeline of new and effective antibiotics has further worsened the situation and is leading to a potentially "post-antibiotic era." This requires novel and effective therapies and therapeutic agents for combating drug-resistant pathogenic microbes. Nanomaterials are emerging as potent antimicrobial agents with both bactericidal and potentiating effects reported against drug-resistant microbes. Among them, the photothermally active nanomaterials (PANs) are gaining attention for their broad-spectrum antibacterial potencies driven mainly by the photothermal effect, which is characterized by the conversion of absorbed photon energy into heat energy by the PANs. The current review capitalizes on the importance of using PANs as an effective approach for overcoming bacterial resistance to drugs. Various PANs leveraging broad-spectrum therapeutic antibacterial (both bactericidal and synergistic) potentials against drug-resistant pathogens have been discussed. The review also provides deeper mechanistic insights into the mechanisms of the action of PANs against a variety of drug-resistant pathogens with a critical evaluation of efflux pumps, cell membrane permeability, biofilm, and quorum sensing inhibition. We also discuss the use of PANs as drug carriers. This review also discusses possible cytotoxicities related to the therapeutic use of PANs and effective strategies to overcome this. Recent developments, success stories, challenges, and prospects are also presented.
PubMed: 34867863
DOI: 10.3389/fmicb.2021.747019 -
Nanomaterials (Basel, Switzerland) Nov 2022Graphene (GN)-related nanomaterials such as graphene oxide, reduced graphene oxide, quantum dots, etc., and their composites have attracted significant interest owing to... (Review)
Review
Graphene (GN)-related nanomaterials such as graphene oxide, reduced graphene oxide, quantum dots, etc., and their composites have attracted significant interest owing to their efficient antimicrobial properties and thus newer GN-based composites are being readily developed, characterized, and explored for clinical applications by scientists worldwide. The GN offers excellent surface properties, i.e., a large surface area, pH sensitivity, and significant biocompatibility with the biological system. In recent years, GN has found applications in tissue engineering owing to its impressive stiffness, mechanical strength, electrical conductivity, and the ability to innovate in two-dimensional (2D) and three-dimensional (3D) design. It also offers a photothermic effect that potentiates the targeted killing of cells via physicochemical interactions. It is generally synthesized by physical and chemical methods and is characterized by modern and sophisticated analytical techniques such as NMR, Raman spectroscopy, electron microscopy, etc. A lot of reports show the successful conjugation of GN with existing repurposed drugs, which improves their therapeutic efficacy against many microbial infections and also its potential application in drug delivery. Thus, in this review, the antimicrobial potentialities of GN-based nanomaterials, their synthesis, and their toxicities in biological systems are discussed.
PubMed: 36432288
DOI: 10.3390/nano12224002 -
MBio Jul 2020Active efflux of antibiotics preventing their accumulation to toxic intracellular concentrations contributes to clinically relevant multidrug resistance. Inhibition of...
Active efflux of antibiotics preventing their accumulation to toxic intracellular concentrations contributes to clinically relevant multidrug resistance. Inhibition of active efflux potentiates antibiotic activity, indicating that efflux inhibitors could be used in combination with antibiotics to reverse drug resistance. Expression of by serovar Typhimurium increases in response to efflux inhibition, irrespective of the mode of inhibition. We hypothesized that measuring promoter activity could act as a reporter of efflux inhibition. A rapid, inexpensive, and high-throughput green fluorescent protein (GFP) screen to identify efflux inhibitors was developed, validated, and implemented. Two chemical compound libraries were screened for compounds that increased GFP production. Fifty of the compounds in the 1,200-compound Prestwick chemical library were identified as potential efflux inhibitors, including the previously characterized efflux inhibitors mefloquine and thioridazine. There were 107 hits from a library of 47,168 proprietary compounds from L. Hoffmann La Roche; 45 were confirmed hits, and a dose response was determined. Dye efflux and accumulation assays showed that 40 Roche and three Prestwick chemical library compounds were efflux inhibitors. Most compounds had specific efflux-inhibitor-antibiotic combinations and/or species-specific synergy in antibiotic disc diffusion and checkerboard assays performed with , , , and Typhimurium. These data indicate that both narrow-spectrum and broad-spectrum combinations of efflux inhibitors with antibiotics can be found. Eleven novel efflux inhibitor compounds potentiated antibiotic activities against at least one species of Gram-negative bacteria, and data revealing an mutant with loss of AcrB function suggested that these are AcrB inhibitors. Multidrug-resistant Gram-negative bacteria pose a serious threat to human and animal health. Molecules that inhibit multidrug efflux offer an alternative approach to resolving the challenges caused by antibiotic resistance, by potentiating the activity of old, licensed, and new antibiotics. We have developed, validated, and implemented a high-throughput screen and used it to identify efflux inhibitors from two compound libraries selected for their high chemical and pharmacological diversity. We found that the new high-throughput screen is a valuable tool to identify efflux inhibitors, as evidenced by the 43 new efflux inhibitors described in this study.
Topics: Anti-Bacterial Agents; Bacterial Proteins; Biological Transport; Drug Discovery; Drug Resistance, Multiple, Bacterial; Gram-Negative Bacteria; High-Throughput Screening Assays; Membrane Transport Proteins; Microbial Sensitivity Tests; Multidrug Resistance-Associated Proteins; Salmonella enterica; Small Molecule Libraries; Trans-Activators
PubMed: 32665275
DOI: 10.1128/mBio.01340-20 -
Acta Biochimica Et Biophysica Sinica Jun 2023Glucocorticoid-induced osteoporosis (GIOP), one of the most common and serious adverse effects associated with glucocorticoid administration, manifests as decreased bone...
Glucocorticoid-induced osteoporosis (GIOP), one of the most common and serious adverse effects associated with glucocorticoid administration, manifests as decreased bone formation and increased bone resorption, eventually culminating in bone loss. Galangin (GAL) is a flavonoid extracted from the medicinal herbal galangal that possesses a variety of pharmacological activities and can inhibit osteoclastogenesis. However, the effects of GAL on GIOP remain unclear. Our study aims to explore the effects of GAL on GIOP in mice and the underlying mechanism. Our results show that GAL markedly mitigates the severity of dexamethasone (Dex)-induced osteoporosis in mice and potentiates osteogenic differentiation in mouse bone marrow-derived mesenchymal stem cells (BMSCs). Furthermore, GAL also significantly counteracts Dex-mediated suppression of osteogenic differentiation and autophagy in human BMSCs. GAL augments PKA/CREB-mediated autophagic flux in BMSCs and the bones of osteoporotic mice. GAL-mediated osteogenic differentiation in Dex-treated BMSCs is significantly decreased by the PKA inhibitor H89 and autophagy inhibitor 3-methyladenine. Collectively, our data indicate that GAL can ameliorate GIOP, partly by augmenting the mineralization of BMSCs by potentiating PKA/CREB-mediated autophagic flux, highlighting its potential therapeutic use in treating glucocorticoid-related osteoporosis.
Topics: Humans; Mice; Animals; Glucocorticoids; Osteogenesis; Osteoporosis; Flavonoids; Signal Transduction; Cell Differentiation; Autophagy
PubMed: 37365870
DOI: 10.3724/abbs.2023063 -
Micromachines Aug 2021Active walls such as cilia and bacteria carpets generate background flows that can influence the trajectories of microswimmers moving nearby. Recent advances in...
Active walls such as cilia and bacteria carpets generate background flows that can influence the trajectories of microswimmers moving nearby. Recent advances in artificial magnetic cilia carpets offer the potentiality to use a similar wall-generated background flow to steer bio-hybrid microrobots. In this paper, we provide some ground theoretical and numerical work assessing the viability of this novel means of swimmer guidance by setting up a simple model of a spherical swimmer in an oscillatory flow and analysing it from the control theory viewpoint. We show a property of local controllability around the reference free trajectories and investigate the bang-bang structure of the control for time-optimal trajectories, with an estimation of the minimal time for suitable objectives. By direct simulation, we have demonstrated that the wall actuation can improve the wall-following transport by nearly 50%, which can be interpreted by synchronous flow structure. Although an open-loop control with a periodic bang-bang actuation loses some robustness and effectiveness, a feedback control is found to improve its robustness and effective transport, even with hydrodynamic wall-swimmer interactions. The results shed light on the potentialities of flow control and open the way to future experiments on swimmer guidance.
PubMed: 34577669
DOI: 10.3390/mi12091025 -
Cellular Signalling Sep 2022Nine mammalian adenylyl cyclases (AC) are pseudoheterodimers with two hexahelical membrane domains, which are isoform-specifically conserved. Previously we proposed that...
Nine mammalian adenylyl cyclases (AC) are pseudoheterodimers with two hexahelical membrane domains, which are isoform-specifically conserved. Previously we proposed that these membrane domains are orphan receptors (https://doi.org/10.7554/eLife.13098; https://doi.org/10.1016/j.cellsig.2020.109538). Lipids extracted from fetal bovine serum at pH 1 inhibited several mAC activities. Guided by a lipidomic analysis we tested glycerophospholipids as potential ligands. Contrary to expectations we surprisingly discovered that 1-stearoyl-2-docosahexaenoyl-phosphatidic acid (SDPA) potentiated Gsα-activated activity of human AC isoform 3 seven-fold. The specificity of fatty acyl esters at glycerol positions 1 and 2 was rather stringent. 1-Stearoyl-2-docosahexaenoyl-phosphatidylserine and 1-stearoyl-2-docosahexaenoyl-phosphatidylethanolamine significantly potentiated several Gsα-activated mAC isoforms to different extents. SDPA appears not interact with forskolin activation of AC isoform 3. SDPA enhanced Gsα-activated AC activities in membranes from mouse brain cortex. The action of SDPA was reversible. Unexpectedly, SDPA did not affect cAMP generation in HEK293 cells stimulated by isoproterenol, PGE and adenosine, virtually excluding a role as an extracellular ligand and, instead, suggesting an intracellular role. In summary, we discovered a new dimension of intracellular AC regulation by chemically defined glycerophospholipids.
Topics: Adenylyl Cyclases; Animals; Colforsin; GTP-Binding Protein alpha Subunits, Gs; Glycerophospholipids; HEK293 Cells; Humans; Mammals; Mice
PubMed: 35787445
DOI: 10.1016/j.cellsig.2022.110396 -
Journal of Cell Communication and... Dec 2022Systemic autoimmune rheumatic diseases (SARDs) are a heterogeneous group of chronic multisystem inflammatory disorders that are thought to have a complex... (Review)
Review
Systemic autoimmune rheumatic diseases (SARDs) are a heterogeneous group of chronic multisystem inflammatory disorders that are thought to have a complex pathophysiology, which is not yet fully understood. Recently, the role of non-coding RNAs, including long non-coding RNA (lncRNA), has been of particular interest in the pathogenesis of SARDs. We aimed to summarize the potential roles of lncRNA in SARDs affecting the skin including, systemic sclerosis (SSc), dermatomyositis (DM) and cutaneous lupus erythematosus (CLE). We conducted a narrative review summarizing original articles published until July 19, 2021, regarding lncRNA associated with SSc, DM, and CLE. Several lncRNAs were hypothesized to play an important role in disease pathogenesis of SSc, DM and CLE. In SSc, Negative Regulator of IFN Response (NRIR) was thought to modulate Interferon (IFN) response in monocytes, anti-sense gene to X-inactivation specific transcript (TSIX) to regulate increased collagen stability, HOX transcript antisense RNA (HOTAIR) to increase numbers of myofibroblasts, OTUD6B-Anti-Sense RNA 1 to decrease fibroblast apoptosis, ncRNA00201 to regulate pathways in SSc pathogenesis and carcinogenesis, H19X potentiating TGF-β-driven extracellular matrix production, and finally PSMB8-AS1 potentiates IFN response. In DM, linc-DGCR6-1 expression was hypothesized to target the USP18 protein, a type 1 IFN-inducible protein that is considered a key regulator of IFN signaling. Additionally, AL136018.1 is suggested to regulate the expression Cathepsin G, which increases the permeability of vascular endothelial cells and the chemotaxis of inflammatory cells in peripheral blood and muscle tissue in DM. Lastly, lnc-MIPOL1-6 and lnc-DDX47-3 in discoid CLE were thought to be associated with the expression of chemokines, which are significant in Th1 mediated disease. In this review, we summarize the key lncRNAs that may drive pathogenesis of these connective tissue diseases and could potentially serve as therapeutic targets in the future.
PubMed: 34346026
DOI: 10.1007/s12079-021-00639-x -
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