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Heliyon Jan 2020Chaff (the outermost protective layer of rice grain) in nano and ground sized particles was bio-assessed to explore its insecticidal effects against the greater wax...
Chaff (the outermost protective layer of rice grain) in nano and ground sized particles was bio-assessed to explore its insecticidal effects against the greater wax moth, (Lepidoptera: Pyralidae). These particles induced remarkable disturbances in the biological patterns of the greater wax moth. These were cleared as they exhibited insecticidal impact on both juvenile and adult stages, their impacts on larval, pupal and adult death, the formation of morphogenetic features (permanent larvae and larval-pupal intermediates), their negative influence on the adult emergence and the potentialities of the applied concentrations to hinder the larval weight gain. The recorded LC values proved more larvicidal potency of the nano-sized particle than that of the ground rice chaff one. The transverse sections in the midgut of the 20 days old larvae (both treated and untreated ones) confirmed the histopathological deformations of the examined particles. The high siliceous content of the chaff particle may be responsible for such recorded disturbances.
PubMed: 32021937
DOI: 10.1016/j.heliyon.2020.e03277 -
Biomedicine & Pharmacotherapy =... Oct 2023Hemostasis is a crucial process that quickly forms clots at injury sites to prevent bleeding and infections. Dysfunctions in this process can lead to hemorrhagic...
Hemostasis is a crucial process that quickly forms clots at injury sites to prevent bleeding and infections. Dysfunctions in this process can lead to hemorrhagic disorders, such as hemophilia and thrombocytopenia purpura. While hemostatic agents are used in clinical treatments, there is still limited knowledge about potentiators targeting coagulation factors. Recently, LCTx-F2, a procoagulant spider-derived peptide, was discovered. This study employed various methods, including chromogenic substrate analysis and dynamic simulation, to investigate how LCTx-F2 enhances the activity of thrombin and FXIIa. Our findings revealed that LCTx-F2 binds to thrombin and FXIIa in a similar manner, with the N-terminal penetrating the active-site cleft of the enzymes and the intermediate section reinforcing the peptide-enzyme connection. Interestingly, the C-terminal remained at a considerable distance from the enzymes, as evidenced by the retention of affinity for both enzymes using truncated peptide T-F2. Furthermore, results indicated differences in the bonding relationship of critical residues between thrombin and FXIIa, with His13 facilitating binding to thrombin and Arg7 being required for binding to FXIIa. Overall, our study sheds light on the molecular mechanism by which LCTx-F2 potentiates coagulation factors, providing valuable insights that may assist in designing drugs targeting procoagulation factors.
Topics: Animals; Thrombin; Blood Coagulation Factors; Hemostatics; Peptides; Spiders
PubMed: 37660649
DOI: 10.1016/j.biopha.2023.115421 -
Applied and Environmental Microbiology Apr 2021The emergence and spread of extended-spectrum β-lactamases (ESBLs), metallo-β-lactamases (MBLs), or variant low-affinity penicillin-binding proteins (PBPs) pose a...
The emergence and spread of extended-spectrum β-lactamases (ESBLs), metallo-β-lactamases (MBLs), or variant low-affinity penicillin-binding proteins (PBPs) pose a major threat to our ability to treat bacterial infection using β-lactam antibiotics. Although combinations of β-lactamase inhibitors with β-lactam agents have been clinically successful, there are no MBL inhibitors in current therapeutic use. Furthermore, recent clinical use of new-generation cephalosporins targeting PBP2a, an altered PBP, has led to the emergence of resistance to these antimicrobial agents. Previous work shows that natural polyphenols such as cranberry-extracted proanthocyanidins (cPAC) can potentiate non-β-lactam antibiotics against Gram-negative bacteria. This study extends beyond previous work by investigating the effect of cPAC in overcoming ESBL-, MBL-, and PBP2a-mediated β-lactam resistance. The results show that cPAC exhibit variable potentiation of different β-lactams against β-lactam-resistant clinical isolates as well as ESBL- and MBL-producing We also discovered that cPAC have broad-spectrum inhibitory properties on the activity of different classes of β-lactamases, including CTX-M3 ESBL and IMP-1 MBL. Furthermore, we observe that cPAC selectively potentiate oxacillin and carbenicillin against methicillin-resistant but not methicillin-sensitive staphylococci, suggesting that cPAC also interfere with PBP2a-mediated resistance. This study motivates the need for future work to identify the most bioactive compounds in cPAC and to evaluate their antibiotic-potentiating efficacy The emergence of β-lactam-resistant and staphylococci compromises the effectiveness of β-lactam-based therapy. By acquisition of ESBLs, MBLs, or PBPs, it is highly likely that bacteria may become completely resistant to the most effective β-lactam agents in the near future. In this study, we described a natural extract rich in proanthocyanidins which exerts adjuvant properties by interfering with two different resistance mechanisms. By their broad-spectrum inhibitory ability, cranberry-extracted proanthocyanidins could have the potential to enhance the effectiveness of existing β-lactam agents.
Topics: Ampicillin; Anti-Bacterial Agents; Bacteria; Cefotaxime; Drug Synergism; Proanthocyanidins; Vaccinium macrocarpon; beta-Lactam Resistance
PubMed: 33712420
DOI: 10.1128/AEM.00127-21 -
The Journal of General Physiology Dec 2017Cystic fibrosis (CF) is a channelopathy caused by loss-of-function mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which encodes a...
Cystic fibrosis (CF) is a channelopathy caused by loss-of-function mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which encodes a phosphorylation-activated and adenosine triphosphate (ATP)-gated chloride channel. In the past few years, high-throughput drug screening has successfully realized the first US Food and Drug Administration-approved therapy for CF, called ivacaftor (or VX-770). A more recent CFTR potentiator, GLPG1837 (-(3-carbamoyl-5,5,7,7-tetramethyl-4,7-dihydro-5-thieno[2,3-]pyran-2-yl)-1-pyrazole-3-carboxamide), has been shown to exhibit a higher efficacy than ivacaftor for the G551D mutation, yet the underlying mechanism of GLPG1837 remains unclear. Here we find that despite their differences in potency and efficacy, GLPG1837 and VX-770 potentiate CFTR gating in a remarkably similar manner. Specifically, they share similar effects on single-channel kinetics of wild-type CFTR. Their actions are independent of nucleotide-binding domain (NBD) dimerization and ATP hydrolysis, critical steps controlling CFTR's gate opening and closing, respectively. By applying the two reagents together, we provide evidence that GLPG1837 and VX-770 likely compete for the same site, whereas GLPG1837 and the high-affinity ATP analogue 2'-deoxy--(2-phenylethyl)-adenosine-5'--triphosphate (dPATP) work synergistically through two different sites. We also find that the apparent affinity for GLPG1837 is dependent on the open probability of the channel, suggesting a state-dependent binding of the drug to CFTR (higher binding affinity for the open state than the closed state), which is consistent with the classic mechanism for allosteric modulation. We propose a simple four-state kinetic model featuring an energetic coupling between CFTR gating and potentiator binding to explain our experimental results.
Topics: Aminophenols; Animals; Binding Sites; CHO Cells; Chloride Channel Agonists; Cricetinae; Cricetulus; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Ion Channel Gating; Protein Binding; Quinolones
PubMed: 29079713
DOI: 10.1085/jgp.201711886 -
Antimicrobial Agents and Chemotherapy May 2018kills more people than any other bacterial pathogen and is becoming increasingly untreatable due to the emergence of resistance. Verapamil, an FDA-approved calcium...
kills more people than any other bacterial pathogen and is becoming increasingly untreatable due to the emergence of resistance. Verapamil, an FDA-approved calcium channel blocker, potentiates the effect of several antituberculosis (anti-TB) drugs and This potentiation is widely attributed to inhibition of the efflux pumps of , resulting in intrabacterial drug accumulation. Here, we confirmed and quantified verapamil's synergy with several anti-TB drugs, including bedaquiline (BDQ) and clofazimine (CFZ), but found that the effect is not due to increased intrabacterial drug accumulation. We show that, consistent with its potentiating effects on anti-TB drugs that target or require oxidative phosphorylation, the cationic amphiphile verapamil disrupts membrane function and induces a membrane stress response similar to those seen with other membrane-active agents. We recapitulated these activities using inverted mycobacterial membrane vesicles, indicating a direct effect of verapamil on membrane energetics. We observed bactericidal activity against nonreplicating "persister" that was consistent with such a mechanism of action. In addition, we demonstrated a pharmacokinetic interaction whereby human-equivalent doses of verapamil caused a boost of rifampin exposure in mice, providing a potential explanation for the observed treatment-shortening effect of verapamil in mice receiving first-line drugs. Our findings thus elucidate the mechanistic basis for verapamil's potentiation of anti-TB drugs and and highlight a previously unrecognized role for the membrane of as a pharmacologic target.
Topics: Animals; Antitubercular Agents; Calcium Channel Blockers; Cell Membrane; Clofazimine; Diarylquinolines; Drug Synergism; Female; Humans; Mice; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Verapamil
PubMed: 29463541
DOI: 10.1128/AAC.02107-17 -
International Journal of Molecular... Apr 2020TMEM16A is a Ca activated Cl channel with important functions in airways, intestine, and other epithelial organs. Activation of TMEM16A is proposed as a therapy in...
TMEM16A is a Ca activated Cl channel with important functions in airways, intestine, and other epithelial organs. Activation of TMEM16A is proposed as a therapy in cystic fibrosis (CF) to reinstall airway Cl secretion and to enhance airway surface liquid (ASL). This CFTR-agnostic approach is thought to improve mucociliary clearance and lung function in CF. This could indeed improve ASL, however, mucus release and airway contraction may also be induced by activators of TMEM16A, particularly in inflamed airways of patients with asthma, COPD, or CF. Currently, both activators and inhibitors of TMEM16A are developed and examined in different types of tissues. Here we compare activation and inhibition of endogenous and overexpressed TMEM16A and analyze potential off-target effects. The three well-known blockers benzbromarone, niclosamide, and Ani9 inhibited both TMEM16A and ATP-induced Ca increase by variable degrees, depending on the cell type. Niclosamide, while blocking Ca activated TMEM16A, also induced a subtle but significant Ca store release and inhibited store-operated Ca influx. Niclosamide, benzbromarone and Ani9 also affected TMEM16F whole cell currents, indicating limited specificity for these inhibitors. The compounds Eact, cinnamaldehyde, and melittin, as well as the phosphatidylinositol diC8-PIP are the reported activators of TMEM16A. However, the compounds were unable to activate endogenous TMEM16A in HT colonic epithelial cells. In contrast, TMEM16A overexpressed in HEK293 cells was potently stimulated by these activators. We speculate that overexpressed TMEM16A might have a better accessibility to intracellular Ca, which causes spontaneous activity even at basal intracellular Ca concentrations. Small molecules may therefore potentiate pre-stimulated TMEM16A currents, but may otherwise fail to activate silent endogenous TMEM16A.
Topics: Animals; Anoctamin-1; Asthma; Calcium; Cell Line; Cell Line, Tumor; Chloride Channels; Cystic Fibrosis; Epithelial Cells; HEK293 Cells; HT29 Cells; Humans; Mice; Mice, Knockout
PubMed: 32272686
DOI: 10.3390/ijms21072557 -
International Journal of Molecular... Mar 2020The concept that increasing airway hydration leads to improvements in mucus clearance and lung function in cystic fibrosis has been clinically validated with osmotic... (Review)
Review
The concept that increasing airway hydration leads to improvements in mucus clearance and lung function in cystic fibrosis has been clinically validated with osmotic agents such as hypertonic saline and more convincingly with cystic fibrosis transmembrane conductance regulator (CFTR) repair therapies. Although rapidly becoming the standard of care in cystic fibrosis (CF), current CFTR modulators do not treat all patients nor do they restore the rate of decline in lung function to normal levels. As such, novel approaches are still required to ensure all with CF have effective therapies. Although CFTR plays a fundamental role in the regulation of fluid secretion across the airway mucosa, there are other ion channels and transporters that represent viable targets for future therapeutics. In this review article we will summarise the current progress with CFTR-independent approaches to restoring mucosal hydration, including epithelial sodium channel (ENaC) blockade and modulators of SLC26A9. A particular emphasis is given to modulation of the airway epithelial calcium-activated chloride channel (CaCC), TMEM16A, as there is controversy regarding whether it should be positively or negatively modulated. This is discussed in light of a recent report describing for the first time bona fide TMEM16A potentiators and their positive effects upon epithelial fluid secretion and mucus clearance.
Topics: Animals; Anions; Anoctamin-1; Antiporters; Cystic Fibrosis; Drug Discovery; Epithelial Sodium Channels; Humans; Neoplasm Proteins; Respiratory Mucosa; Sulfate Transporters
PubMed: 32235608
DOI: 10.3390/ijms21072386 -
Chemical Science Nov 2021Quantum-chemistry simulations based on potential energy surfaces of molecules provide invaluable insight into the physicochemical processes at the atomistic level and...
Quantum-chemistry simulations based on potential energy surfaces of molecules provide invaluable insight into the physicochemical processes at the atomistic level and yield such important observables as reaction rates and spectra. Machine learning potentials promise to significantly reduce the computational cost and hence enable otherwise unfeasible simulations. However, the surging number of such potentials begs the question of which one to choose or whether we still need to develop yet another one. Here, we address this question by evaluating the performance of popular machine learning potentials in terms of accuracy and computational cost. In addition, we deliver structured information for non-specialists in machine learning to guide them through the maze of acronyms, recognize each potential's main features, and judge what they could expect from each one.
PubMed: 34880991
DOI: 10.1039/d1sc03564a -
Pain Feb 2020Low levels of catechol-O-methyltransferase (COMT), an enzyme that metabolizes catecholamines, and stress, which potentiates catecholamine release from sympathetic...
Low levels of catechol-O-methyltransferase (COMT), an enzyme that metabolizes catecholamines, and stress, which potentiates catecholamine release from sympathetic nerves, are fundamental to chronic functional pain syndromes and comorbid depression, which predominantly affect females. Here, we sought to examine the independent and joint contributions of low COMT and stress to chronic functional pain and depression at the behavioral and molecular level. Male and female C57BL/6 mice received sustained systemic delivery of the COMT inhibitor OR486 over 14 days and underwent a swim stress paradigm on days 8 to 10. Pain and depressive-like behavior were measured over 14 days, and brain-derived neurotrophic factor (BDNF; a factor involved in nociception and depression) and glucocorticoid receptor (GR; a stress-related receptor) expression were measured on day 14. We found that stress potentiates the effect of low COMT on functional pain and low COMT potentiates the effect of stress on depressive-like behavior. The joint effects of low COMT and stress on functional pain and depressive-like behavior were significantly greater in females vs males. Consistent with behavioral data, we found that stress potentiates COMT-dependent increases in spinal BDNF and low COMT potentiates stress-dependent decreases in hippocampal BDNF in females, but not males. Although low COMT increases spinal GR and stress increases hippocampal GR expression, these increases are not potentiated in the OR486 + stress group and are not sex-specific. These results suggest that genetic and environmental factors that enhance catecholamine bioavailability cause abnormalities in BDNF signaling and increase risk of comorbid functional pain and depression, especially among females.
Topics: Animals; Behavior, Animal; Brain-Derived Neurotrophic Factor; Catechol O-Methyltransferase; Catechol O-Methyltransferase Inhibitors; Catechols; Chronic Pain; Depression; Disease Models, Animal; Female; Hippocampus; Male; Mice; Mice, Inbred C57BL; Receptors, Glucocorticoid; Sex Factors; Spinal Cord; Stress, Psychological
PubMed: 31972854
DOI: 10.1097/j.pain.0000000000001734 -
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