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Frontiers in Pharmacology 2022Paclitaxel (PTX) has been the first-line treatment for lung cancer; however, its clinical use is limited due to multidrug resistance (MDR) and adverse effects. Thus,...
Paclitaxel (PTX) has been the first-line treatment for lung cancer; however, its clinical use is limited due to multidrug resistance (MDR) and adverse effects. Thus, there is an urgent need to explore agents that can enhance the anticancer efficacy of PTX by reducing drug resistance and adverse reactions. Jiegeng decoction (JG) was used as the meridian guide drug and adjuvant drug in treatment of lung cancer. However, the mechanism of adjuvant effect was unclear. The aim of this study was to determine whether JG could potentiate the anticancer effect of PTX. Tissue distribution of PTX was detected using HPLC-MS/MS. The anti-lung cancer effect of the combination of PTX and JG in Lewis lung cancer C57BL/6J mice was evaluated based on the body weight and tumor-inhibition rate. PTX concentration in tumors was determined using HPLC-MS and imaging. Biochemical indices were detected using biochemical analyzer and ELISA. The anticancer mechanism of the PTX-JG combination in A549/PTX cells was elucidated based on cell proliferation, annexin V-FITC apoptosis assay, and western blotting. Tissue distribution analysis showed that the distribution of PTX increased in the lungs, liver, and heart upon administering the combination of PTX and JG. JG remarkably enhanced the anticancer effect of PTX by increasing the red blood cell and platelet counts; increasing hemoglobin, interleukin (IL)-2, and tumor necrosis factor-α levels; increasing CD4+T cells and the CD4+/CD8+ ratio; and decreasing IL-10 levels. JG administration led to the increased distribution of PTX at the tumor lesion sites and also potentiated the anticancer effect of PTX by inhibiting tumor cell proliferation and promoting apoptosis. Moreover, JG reversed PTX resistance by inhibiting the expression of lung resistance-related proteins, multiresistance protein 1, P-glycoprotein, and breast cancer-resistant protein. Furthermore, the combination of JG and PTX decreased alanine aminotransferase and aspartate aminotransferase levels and did not affect creatine kinase-MB levels. Therefore, our discovery suggests that JG increased the anticancer effect of PTX by downregulating the MDR-related protein and demonstrated a synergistic enhancement of immunity. Thus, the combination of PTX with JG shows potential in the management of lung cancer owing to its synergistic and detoxifying effects.
PubMed: 35281908
DOI: 10.3389/fphar.2022.827520 -
Epilepsia May 2020The antiepileptic drug candidate, padsevonil, is the first in a novel class of drugs designed to interact with both presynaptic and postsynaptic therapeutic targets:...
OBJECTIVE
The antiepileptic drug candidate, padsevonil, is the first in a novel class of drugs designed to interact with both presynaptic and postsynaptic therapeutic targets: synaptic vesicle 2 proteins and γ-aminobutyric acid type A receptors (GABA Rs), respectively. Functional aspects of padsevonil at the postsynaptic target, GABA Rs, were characterized in experiments reported here.
METHODS
The effect of padsevonil on GABA-mediated Cl currents was determined by patch clamp on recombinant human GABA Rs (α1β2γ2) stably expressed in a CHO-K1 cell line and on native GABA Rs in cultured rat primary cortical neurons. Padsevonil selectivity for GABA R subtypes was evaluated using a two-electrode voltage clamp on recombinant human GABA Rs (α1-5/β2/γ2) in Xenopus oocytes.
RESULTS
In recombinant GABA Rs, padsevonil did not evoke Cl currents in the absence of the agonist GABA. However, when co-administered with GABA at effective concentration (EC) , padsevonil potentiated GABA responses by 167% (EC 138 nmol/L) and demonstrated a relative efficacy of 41% compared with zolpidem, a reference benzodiazepine site agonist. Similarly, padsevonil demonstrated GABA-potentiating activity at native GABA Rs (EC 208 nmol/L) in cultured rat cortical neurons. Padsevonil also potentiated GABA (EC ) responses in GABA Rs expressed in oocytes, with higher potency at α1- and α5-containing receptors (EC 295 and 281 nmol/L) than at α2- and α3-containing receptors (EC 1737 and 2089 nmol/L). Compared with chlordiazepoxide-a nonselective, full GABA R agonist-the relative efficacy of padsevonil was 60% for α1β2γ2, 26% for α2β2γ2, 56% for α3β2γ2, and 41% for α5β2γ2; no activity was observed at benzodiazepine-insensitive α4β2γ2 receptors.
SIGNIFICANCE
Results of functional investigations on recombinant and native neuronal GABA Rs show that padsevonil acts as a positive allosteric modulator of these receptors, with a partial agonist profile at the benzodiazepine site. These properties may confer better tolerability and lower potential for tolerance development compared with classic benzodiazepines currently used in the clinic.
Topics: Animals; Anticonvulsants; CHO Cells; Cricetulus; Female; Humans; Imidazoles; Neurons; Oocytes; Patch-Clamp Techniques; Pyrrolidinones; Rats, Wistar; Receptors, GABA-A; Receptors, Presynaptic; Recombinant Proteins; Synaptic Potentials; Thiadiazoles; Xenopus laevis
PubMed: 32297665
DOI: 10.1111/epi.16497 -
European Journal of Medicinal Chemistry Jan 2021We previously identified a spiro [piperidine-4,1-pyrido [3,4-b]indole] class of co-potentiators that function in synergy with existing CFTR potentiators such as VX-770...
We previously identified a spiro [piperidine-4,1-pyrido [3,4-b]indole] class of co-potentiators that function in synergy with existing CFTR potentiators such as VX-770 or GLGP1837 to restore channel activity of a defined subset of minimal function cystic fibrosis transmembrane conductance regulator (CFTR) mutants. Here, structure-activity studies were conducted to improve their potency over the previously identified compound, 20 (originally termed CP-A01). Targeted synthesis of 37 spiro [piperidine-4,1-pyrido [3,4-b]indoles] was generally accomplished using versatile two or three step reaction protocols with each step having high efficiency. Structure-activity relationship studies established that analog 2i, with 6'-methoxyindole and 2,4,5-trifluorobenzyl substituents, had the greatest potency for activation of N1303K-CFTR, with EC ∼600 nM representing an ∼17-fold improvement over the original compound identified in a small molecule screen.
Topics: Aminophenols; Animals; Cell Line; Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Indoles; Models, Molecular; Mutation; Piperidines; Quinolones; Rats; Structure-Activity Relationship
PubMed: 33092904
DOI: 10.1016/j.ejmech.2020.112888 -
Acta Naturae 2017The interaction of TRPV1-receptors agonists (capsaicin and protons) has been studied on cultured CHO cells transfected by TRPV1-receptors. Using the whole-cell...
The interaction of TRPV1-receptors agonists (capsaicin and protons) has been studied on cultured CHO cells transfected by TRPV1-receptors. Using the whole-cell patch-clamp approach, it was shown that summation of the currents induced by agonist application was dependent on the membrane potential. The TRPV1-mediated currents induced by the pH and Capsaicin demonstrated arithmetical summation at potentials between 40--40 mV, while they were potentiated at potentials below -40 mV. Currents induced by the pH and Capsaicin combined were higher in comparison with the arithmetic sum of the currents induced by the pH and Capsaicin applied separately at such potentials. Such a potential dependence seems to be a base of the sensitization that is induced by inflammation or pain, when concentrations of proinflammatory mediators acting as TRPV1 agonists are increasing. Further depolarization induced by TRPV1 activation doesn't generate potentiation, which might serve as a protective mechanism to restrict their activity.
PubMed: 28461977
DOI: No ID Found -
Cell Reports Sep 2016The homeostatic modulation of neurotransmitter release, termed presynaptic homeostatic potentiation (PHP), is a fundamental type of neuromodulation, conserved from...
The homeostatic modulation of neurotransmitter release, termed presynaptic homeostatic potentiation (PHP), is a fundamental type of neuromodulation, conserved from Drosophila to humans, that stabilizes information transfer at synaptic connections throughout the nervous system. Here, we demonstrate that α2δ-3, an auxiliary subunit of the presynaptic calcium channel, is required for PHP. The α2δ gene family has been linked to chronic pain, epilepsy, autism, and the action of two psychiatric drugs: gabapentin and pregabalin. We demonstrate that loss of α2δ-3 blocks both the rapid induction and sustained expression of PHP due to a failure to potentiate presynaptic calcium influx and the RIM-dependent readily releasable vesicle pool. These deficits are independent of α2δ-3-mediated regulation of baseline calcium influx and presynaptic action potential waveform. α2δ proteins reside at the extracellular face of presynaptic release sites throughout the nervous system, a site ideal for mediating rapid, transsynaptic homeostatic signaling in health and disease.
Topics: Action Potentials; Animals; Archaeal Proteins; Calcium; Calcium Channels; Drosophila Proteins; Drosophila melanogaster; Egtazic Acid; Epistasis, Genetic; Excitatory Postsynaptic Potentials; Homeostasis; Ion Channel Gating; Mutation; Neuronal Plasticity; Presynaptic Terminals; Signal Transduction; Synaptic Transmission; Synaptic Vesicles; rab3 GTP-Binding Proteins
PubMed: 27626659
DOI: 10.1016/j.celrep.2016.08.030 -
Journal of Cystic Fibrosis : Official... Sep 2021Trikafta, the combination of elexacaftor (VX-445), tezacaftor (VX-661) and ivacaftor (VX-770), was approved for therapy of cystic fibrosis (CF) patients with at least...
Trikafta, the combination of elexacaftor (VX-445), tezacaftor (VX-661) and ivacaftor (VX-770), was approved for therapy of cystic fibrosis (CF) patients with at least one allele of the CFTR mutation F508del. While the corrector function of VX-445 is well established, here we investigated the putative potentiator activity of VX-445 alone and in combination with VX-770. Acute addition of VX-445 increased the VX-770-potentiated F508del- and G551D-CFTR current by ~24% and >70%, respectively, in human bronchial and nasal epithelia. Combinatorial profiling and cluster analysis of G551D- and G1244E-CFTR channel activation with potentiator pairs indicated a distinct VX-445 mechanism of action that is, at least, additive to previously identified potentiator classes, including the VX-770. Since VX-770 only partially normalizes the G551D-CFTR channel function and adult G551D patients still experience progressive loss of lung function, VX-445+VX-770 combination therapy could provide clinical benefit to CF patients with the G551D and other dual potentiator responsive mutants.
Topics: Cells, Cultured; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Genotype; Humans; Mutation; Nasal Mucosa; Pyrazoles; Pyridines; Pyrrolidines
PubMed: 33775603
DOI: 10.1016/j.jcf.2021.03.011 -
Brain Sciences Aug 2020The progress of technology has increased research on neuropsychological emotion and attention with virtual reality (VR). However, direct comparisons between conventional...
The progress of technology has increased research on neuropsychological emotion and attention with virtual reality (VR). However, direct comparisons between conventional two-dimensional (2D) and VR stimulations are lacking. Thus, the present study compared electroencephalography (EEG) correlates of explicit task and implicit emotional attention between 2D and VR stimulation. Participants ( = 16) viewed angry and neutral faces with equal size and distance in both 2D and VR, while they were asked to count one of the two facial expressions. For the main effects of emotion (angry vs. neutral) and task (target vs. nontarget), established event related potentials (ERP), namely the late positive potential (LPP) and the target P300, were replicated. VR stimulation compared to 2D led to overall bigger ERPs but did not interact with emotion or task effects. In the frequency domain, alpha/beta-activity was larger in VR compared to 2D stimulation already in the baseline period. Of note, while alpha/beta event related desynchronization (ERD) for emotion and task conditions were seen in both VR and 2D stimulation, these effects were significantly stronger in VR than in 2D. These results suggest that enhanced immersion with the stimulus materials enabled by VR technology can potentiate induced brain oscillation effects to implicit emotion and explicit task effects.
PubMed: 32784990
DOI: 10.3390/brainsci10080537 -
Antibiotics (Basel, Switzerland) Jul 2023Metal ions, including Fe, affect the target site binding of some antibiotics and control the porin- and siderophore-mediated uptake of antibiotics. Amphiphilic...
Metal ions, including Fe, affect the target site binding of some antibiotics and control the porin- and siderophore-mediated uptake of antibiotics. Amphiphilic tobramycins are an emerging class of antibiotic potentiators capable of synergizing with multiple classes of antibiotics against Gram-negative bacteria, including . To study how the antibiotic-potentiating effect of amphiphilic tobramycins is affected by the presence of intermolecular iron chelators, we conjugated the FDA-approved iron chelator deferiprone (DEF) to tobramycin (TOB). Three TOB-DEF conjugates differing in the length of the carbon tether were prepared and tested for antibacterial activity and synergistic relationships with a panel of antibiotics against clinical isolates of . While all TOB-DEF conjugates were inactive against , the TOB-DEF conjugates strongly synergized with outer-membrane-impermeable antibiotics, such as novobiocin and rifampicin. Among the three TOB-DEF conjugates, containing a C tether showed a remarkable and selective potentiating effect to improve the susceptibility of multidrug-resistant isolates to tetracyclines when compared with other antibiotics. However, the antibacterial activity and antibiotic-potentiating effect of the optimized conjugate was not enhanced under iron-depleted conditions, indicating that the function of the antibiotic potentiator is not affected by the Fe concentration.
PubMed: 37627681
DOI: 10.3390/antibiotics12081261 -
Molecules (Basel, Switzerland) Feb 2022The burkholdines are a family of cyclic lipopeptides reported to exhibit antifungal activity. We synthesized a series of 18 burkholdine analogues in good yield by...
The burkholdines are a family of cyclic lipopeptides reported to exhibit antifungal activity. We synthesized a series of 18 burkholdine analogues in good yield by conventional Fmoc-SPPS followed by cyclization with DIPCI/HOBt in the solution phase. Although none of the synthesized peptides exhibited antifungal activity, several did potentiate the antibiotic effect of the antibiotic G418, including the Thr-bearing Bk analogue () and the tartaramide-bearing Bk analogue (). This work exemplifies the potential of burkholdine analogues as potentiating agents.
Topics: Antifungal Agents; Hydrophobic and Hydrophilic Interactions; Lipopeptides
PubMed: 35208979
DOI: 10.3390/molecules27041191 -
Mutation Research. Reviews in Mutation... Jul 2017Hydrogen peroxide (HO) is unique among general toxins, because it is stable in abiotic environments at ambient temperature and neutral pH, yet rapidly kills any type of... (Review)
Review
Hydrogen peroxide (HO) is unique among general toxins, because it is stable in abiotic environments at ambient temperature and neutral pH, yet rapidly kills any type of cells by producing highly-reactive hydroxyl radicals. This life-specific reactivity follows the distribution of soluble iron, Fe(II) (which combines with HO to form the famous Fenton's reagent),Fe(II) is concentrated inside cells, but is virtually absent outside them. Because of the immediate danger of HO, all cells have powerful HO scavengers, the equally famous catalases, which enable cells to survive thousand-fold higher concentrations of HO and, in combination with adequate movement of HO across membranes, make the killing HO concentrations virtually impractical to generate in vivo. And yet, low concentrations of HO are somehow used as an efficient biological weapon. Here we review several examples of how cells potentiate HO toxicity with other chemicals. At first, these potentiators were thought to simply inhibit catalases, but recent findings with cyanide suggest that potentiators mostly promote the other side of Fenton's reaction, recruiting iron from cell depots into stable DNA-iron complexes that, in the presence of elevated HO, efficiently break duplex DNA, pulverizing the chromosome. This multifaceted potentiation of HO toxicity results in robust and efficient killing.
Topics: Animals; Bacteria; Catalase; DNA; Humans; Hydrogen Peroxide; Hydrogen-Ion Concentration; Iron
PubMed: 28927535
DOI: 10.1016/j.mrrev.2016.08.006