-
RSC Advances Jul 2022Zorifertinib (AZD-3759; ZFB) is a potent, novel, oral, small molecule used for the treatment of non-small cell lung cancer (NSCLC). ZFB is Epidermal Growth Factor...
Zorifertinib (AZD-3759; ZFB) is a potent, novel, oral, small molecule used for the treatment of non-small cell lung cancer (NSCLC). ZFB is Epidermal Growth Factor Receptor (EGFR) inhibitor that is characterized by good permeability of the blood-brain barrier for (NSCLC) patients with EGFR mutations. The present research reports the profiling of , and reactive metabolites of ZFB. Prediction of vulnerable metabolic sites and reactivity pathways (cyanide and GSH) of ZFB were performed by WhichP450™ module (StarDrop software package) and XenoSite reactivity model (XenoSite Web Predictor-Home), respectively. ZFB metabolites were done by incubation with isolated perfused rat liver hepatocytes and rat liver microsomes (RLMs). Extraction of ZFB and its related metabolites from the incubation matrix was done by protein precipitation. metabolism was performed by giving ZFB (10 mg kg) through oral gavage to Sprague Dawley rats that were housed in metabolic cages. Urine was collected at specific time intervals (0, 6, 12, 18, 24, 48, 72, 96 and 120 h) from ZFB dosing. The collected urine samples were filtered then stored at -70 °C. -Methyl piperazine ring of ZFB undergoes phase I metabolism forming iminium intermediates that were stabilized using potassium cyanide as a trapping agent. Incubation of ZFB with RLMs were performed in the presence of 1.0 mM KCN and 1.0 mM glutathione to check reactive intermediates as it is may be responsible for toxicities associated with ZFB usage. For metabolites there were six phase I metabolites, three phase II metabolites, seven reactive intermediates (four GSH conjugates and three cyano adducts) of ZFB were detected by LC-IT-MS. For metabolites there were six phase I and three phase II metabolites of ZFB were detected by LC-IT-MS. and phase I metabolic pathways were -demethylation, -demethylation, hydroxylation, reduction, defluorination and dechlorination. phase II metabolic reaction was direct sulphate and glucuronic acid conjugation with ZFB.
PubMed: 35919181
DOI: 10.1039/d2ra02848d -
Marine Pollution Bulletin Sep 2022
Topics: Animals; Embryo, Nonmammalian; Potassium Cyanide; Sea Urchins
PubMed: 35872477
DOI: 10.1016/j.marpolbul.2022.113965 -
Journal of Hypertension Jul 2022The carotid body has been implicated as an important mediator and putative target for hypertension. Previous studies have indicated an important role for angiotensin II...
OBJECTIVE
The carotid body has been implicated as an important mediator and putative target for hypertension. Previous studies have indicated an important role for angiotensin II in mediating carotid body function via angiotensin type-1 receptors (AT1R); however, their role in modulating carotid body function during hypertension is unclear.
METHODS
Using a large preclinical ovine model of renovascular hypertension, we hypothesized that acute AT1R blockade would lower blood pressure and decrease carotid body-mediated increases in arterial pressure. Adult ewes underwent either unilateral renal artery clipping or sham surgery. Two weeks later, flow probes were placed around the contralateral renal and common carotid arteries.
RESULTS
In both hypertensive and sham animals, carotid body stimulation using potassium cyanide caused dose-dependent increases in mean arterial pressure but a reduction in renal vascular conductance. These responses were not different between groups. Infusion of angiotensin II led to an increase in arterial pressure and reduction in renal blood flow. The sensitivity of the renal vasculature to angiotensin II was significantly attenuated in hypertension compared with the sham animals. Systemic inhibition of the AT1R did not alter blood pressure in either group. Interestingly carotid body-evoked arterial pressure responses were attenuated by AT1R blockade in renovascular hypertension but not in shams.
CONCLUSION
Taken together, our findings indicate a decrease in vascular reactivity of the non-clipped kidney to angiotensin II in hypertension. The CB-evoked increase in blood pressure in hypertension is mediated in part, by the AT1R. These findings indicate a differential role of the AT1R in the carotid body versus the renal vasculature.
Topics: Angiotensin II; Animals; Carotid Body; Female; Hypertension, Renovascular; Kidney; Receptor, Angiotensin, Type 1; Renal Artery; Sheep
PubMed: 35762481
DOI: 10.1097/HJH.0000000000003173 -
Scientific Reports Jun 2022Mucormycosis is a fungal infection caused by Mucorales, with a high mortality rate. However, only a few virulence factors have been described in these organisms. This...
Mucormycosis is a fungal infection caused by Mucorales, with a high mortality rate. However, only a few virulence factors have been described in these organisms. This study showed that deletion of rfs, which encodes the enzyme for the biosynthesis of rhizoferrin, a siderophore, in Mucor lusitanicus, led to a lower virulence in diabetic mice and nematodes. Upregulation of rfs correlated with the increased toxicity of the cell-free supernatants of the culture broth (SS) obtained under growing conditions that favor oxidative metabolism, such as low glucose levels or the presence of HO in the culture, suggesting that oxidative metabolism enhances virulence through rhizoferrin production. Meanwhile, growing M. lusitanicus in the presence of potassium cyanide, N-acetylcysteine, a higher concentration of glucose, or exogenous cAMP, or the deletion of the gene encoding the regulatory subunit of PKA (pkaR1), correlated with a decrease in the toxicity of SS, downregulation of rfs, and reduction in rhizoferrin production. These observations indicate the involvement of the cAMP-PKA pathway in the regulation of rhizoferrin production and virulence in M. lusitanicus. Moreover, rfs upregulation was observed upon macrophage interaction or during infection with spores in mice, suggesting a pivotal role of rfs in M. lusitanicus infection.
Topics: Animals; Diabetes Mellitus, Experimental; Ferric Compounds; Glucose; Hydrogen Peroxide; Mice; Mucor; Siderophores; Virulence
PubMed: 35739200
DOI: 10.1038/s41598-022-14515-0 -
Acta Physiologica (Oxford, England) Aug 2022Stimulation of peripheral chemoreceptors, as during hypoxia, increases breathing and respiratory-related sympathetic bursting. Activation of catecholaminergic C1...
AIMS
Stimulation of peripheral chemoreceptors, as during hypoxia, increases breathing and respiratory-related sympathetic bursting. Activation of catecholaminergic C1 neurones induces sympathoexcitation, while its ablation reduces the chemoreflex sympathoexcitatory response. However, no study has determined the respiratory phase(s) in which the pre-sympathetic C1 neurones are recruited by peripheral chemoreceptor and whether C1 neurone activation affects all phases of respiratory modulation of sympathetic activity. We addressed these unknowns by testing the hypothesis that peripheral chemoreceptor activation excites pre-sympathetic C1 neurones during inspiration and expiration.
METHODS
Using the in situ preparation of rat, we made intracellular recordings from baroreceptive pre-sympathetic C1 neurones during peripheral chemoreflex stimulation. We optogenetically activated C1 neurones selectively and compared any respiratory-phase-related increases in sympathetic activity with that which occurs following stimulation of the peripheral chemoreflex.
RESULTS
Activation of peripheral chemoreceptors using cytotoxic hypoxia (potassium cyanide) increased the firing frequency of C1 neurones and both the frequency and amplitude of their excitatory post-synaptic currents during the phase of expiration only. In contrast, optogenetic stimulation of C1 neurones activates inspiratory neurones, which secondarily inhibit expiratory neurones, but produced comparable increases in sympathetic activity across all phases of respiration.
CONCLUSION
Our data reveal that the peripheral chemoreceptor-mediated expiratory-related sympathoexcitation is mediated through excitation of expiratory neurones antecedent to C1 pre-sympathetic neurones; these may be found in the Kölliker-Fuse nucleus. Despite peripheral chemoreceptor excitation of inspiratory neurones, these do not trigger C1 neurone-mediated increases in sympathetic activity. These studies provide compelling novel insights into the functional organization of respiratory-sympathetic neural networks.
Topics: Animals; Chemoreceptor Cells; Exhalation; Hypoxia; Medulla Oblongata; Rats; Respiration; Sympathetic Nervous System
PubMed: 35722749
DOI: 10.1111/apha.13853 -
Journal of Bacteriology Jul 2022Staphylococcus aureus Tet38 efflux pump has multiple functions, including conferring resistance to tetracycline and other compounds and enabling internalization and...
Staphylococcus aureus Tet38 efflux pump has multiple functions, including conferring resistance to tetracycline and other compounds and enabling internalization and survival within epithelial cells. In this study, we evaluated the effects of sodium and potassium on expression. These monovalent cations are known to play a role in transport by the related S. aureus TetK and B. subtilis TetL transporters. transcription decreased with increasing sodium concentrations by means of direct repression by the salt stress-dependent KdpD/E regulator. transcription increased 20-fold and tetracycline minimum inhibitory concentration (MIC) increased 4-fold in a Δ mutant. KdpE bound specifically to the promoter. Under extreme salt stress, the survival of S. aureus with intact was reduced compared to that of a Δ mutant. To study the effect of sodium on Tet38 function, we generated constructs overexpressing and and introduced them into Escherichia coli TO114, which is deficient in major sodium transporters. Tet38 tetracycline efflux was directly demonstrated in a fluorescence assay, and tetracycline efflux of both Tet38 and TetK was abolished by the protonophore carbonyl cyanide 3-chlorophenylhydrazone (CCCP). In contrast, NaCl inhibited efflux by Tet38 but not TetK, whereas KCl inhibited efflux by TetK but not Tet38. Cell-associated Na increased with heterologous overexpression of Tet38. These data indicate that S. aureus Tet38 is a tetracycline efflux pump regulated by the KdpD/E regulator. Under salt stress, S. aureus adjusted its survival in part by reducing the expression of through KdpD/E. The mechanisms by which Tet38 is detrimental to salt tolerance in S. aureus and inhibited by sodium remain to be determined. This study shows that S. aureus Tet38 is a tetracycline efflux pump regulated by KdpD/E regulator. These findings are the first direct demonstration of Tet38-mediated tetracycline efflux, which had previously been inferred from its ability to confer tetracycline resistance. Under salt stress, S. aureus adjusts its survival in part by reducing the expression of through KdpD/E. We demonstrated the differences in the respective functions of S. aureus Tet38 and other tetracycline efflux transporters (S. aureus TetK, B. subtilis TetL) regarding their transport of tetracycline and Na/K. Notably, sodium selectively reduced tetracycline efflux by Tet38, and potassium selectively reduced tetracycline efflux by TetK. The multiple functions of Tet38 emphasize its importance in bacterial adaptation to and survival in diverse environments.
Topics: Anti-Bacterial Agents; Bacterial Proteins; Escherichia coli; Escherichia coli Proteins; Membrane Transport Proteins; Microbial Sensitivity Tests; Potassium; Protein Kinases; Salt Stress; Sodium; Staphylococcus aureus; Tetracycline
PubMed: 35699453
DOI: 10.1128/jb.00142-22 -
Chemosphere Oct 2022This sustainable approach was performed to evaluate the bioremediation potential of cyanide resistant bacterial species on sago industry effluents and assess the...
Sustainable bioremediation approach to treat the sago industry effluents and evaluate the possibility of yielded biomass as a single cell protein (SCP) using cyanide tolerant Streptomyces tritici D5.
This sustainable approach was performed to evaluate the bioremediation potential of cyanide resistant bacterial species on sago industry effluents and assess the possibility of using the yielded biomass as single cell protein (SCP). The predominant cyanide tolerant bacterium enumerated from muddy soil was identified as Streptomyces tritici D5 through 16S rRNA sequencing. The identified S. tritici D5 strains showed excellent resistant and degradation potential at 100 mM concentration of potassium cyanide. Furthermore, the physicochemical properties analysis of sago industry effluents results revealed that the most of the parameters were crossing the permissible limits of Pollution control board of India. The bioremediation process was performed at various temperatures at 25 °C, 35 °C, and 45 °C for a period of 30 days of continuous bioremediation process with the aid of an aerator. Surprisingly, the best organic pollutant reduction was found at 35 °C and 45 °C, with 25 °C following close behind. Remarkably, the dissolved oxygen (DO) level was gradually increased from 2.24 to 12.04 mg L at 35 °C in 30 days of the remediation process. The pH and ammonia were also significantly increased during the bioremediation process in 30 days of treatment. Similarly, at 35 °C of bioremediation process the S. tritici D5 yielded maximum dried biomass (6.9 g L) with the total crude protein (SCP) as 4.8 g L (69.56%) in 30 days of growth. These findings stated that S. tritici D5 can treat sago industry effluents and that the biomass produced may be considered SCP after some in-vitro and in-vivo analyses.
Topics: Biodegradation, Environmental; Biomass; Cyanides; Dietary Proteins; RNA, Ribosomal, 16S; Streptomyces
PubMed: 35679978
DOI: 10.1016/j.chemosphere.2022.135248 -
Molecules (Basel, Switzerland) May 2022Coumestrol (3,9-dihydroxy-6-benzofuran [3,2-c] chromenone) as a phytoestrogen and polyphenolic compound is a member of the Coumestans family and is quite common in...
Coumestrol (3,9-dihydroxy-6-benzofuran [3,2-c] chromenone) as a phytoestrogen and polyphenolic compound is a member of the Coumestans family and is quite common in plants. In this study, antiglaucoma, antidiabetic, anticholinergic, and antioxidant effects of Coumestrol were evaluated and compared with standards. To determine the antioxidant activity of coumestrol, several methods-namely N,N-dimethyl-p-phenylenediamine dihydrochloride radical (DMPD)-scavenging activity, 2,2'-azinobis-(3-ethylbenzothiazoline-6-sulphonate) radical (ABTS)-scavenging activity, 1,1-diphenyl-2-picrylhydrazyl radical (DPPH)-scavenging activity, potassium ferric cyanide reduction ability, and cupric ion (Cu)-reducing activity-were performed. Butylated hydroxyanisole (BHA), Trolox, α-Tocopherol, and butylated hydroxytoluene (BHT) were used as the reference antioxidants for comparison. Coumestrol scavenged the DPPH radical with an IC value of 25.95 μg/mL (r: 0.9005) while BHA, BHT, Trolox, and α-Tocopherol demonstrated IC values of 10.10, 25.95, 7.059, and 11.31 μg/mL, respectively. When these results evaluated, Coumestrol had similar DPPH-scavenging effect to BHT and lower better than Trolox, BHA and α-tocopherol. In addition, the inhibition effects of Coumestrol were tested against the metabolic enzymes acetylcholinesterase (AChE), butyrylcholinesterase (BChE), carbonic anhydrase II (CA II), and α-glycosidase, which are associated with some global diseases such as Alzheimer's disease (AD), glaucoma, and diabetes. Coumestrol exhibited K values of 10.25 ± 1.94, 5.99 ± 1.79, 25.41 ± 1.10, and 30.56 ± 3.36 nM towards these enzymes, respectively.
Topics: Acetylcholinesterase; Antioxidants; Butylated Hydroxyanisole; Butylated Hydroxytoluene; Butyrylcholinesterase; Carbonic Anhydrases; Coumestrol; Free Radical Scavengers; Glycoside Hydrolases; alpha-Tocopherol
PubMed: 35630566
DOI: 10.3390/molecules27103091 -
Life (Basel, Switzerland) May 2022Periodontitis is an inflammatory lesion in the periodontal tissue. The behavior of human periodontal ligament stem cells (hPDLSCs), which play an important role in...
High-Intensity Red Light-Emitting Diode Irradiation Suppresses the Inflammatory Response of Human Periodontal Ligament Stem Cells by Promoting Intracellular ATP Synthesis.
Periodontitis is an inflammatory lesion in the periodontal tissue. The behavior of human periodontal ligament stem cells (hPDLSCs), which play an important role in periodontal tissue regeneration, is restricted by the influence of inflammatory mediators. Photobiomodulation therapy exerts anti-inflammatory effects. The purpose of this study was to investigate the effects of light-emitting diode (LED) irradiation on the inflammatory responses of hPDLSCs. The light source was a red LED (peak wavelength: 650 nm), and the total absolute irradiance was 400 mW/cm. The inflammatory response in hPDLSCs is induced by tumor necrosis factor (TNF)-α. Adenosine triphosphate (ATP) levels and pro-inflammatory cytokine (interleukin [IL]-6 and IL-8) production were measured 24 h after LED irradiation, and the effects of potassium cyanide (KCN) were investigated. LED irradiation at 6 J/cm significantly increased the ATP levels and reduced TNF-α-induced IL-6 and IL-8 production. Furthermore, the inhibitory effect of LED irradiation on the production of pro-inflammatory cytokines was inhibited by KCN treatment. The results of this study showed that high-intensity red LED irradiation suppressed the TNF-α-stimulated pro-inflammatory cytokine production in hPDLSCs by promoting ATP synthesis. These results suggest that high-intensity red LED is a useful tool for periodontal tissue regeneration in chronically inflamed tissues.
PubMed: 35629403
DOI: 10.3390/life12050736 -
Journal of Applied Microbiology Sep 2022Agriculture faces challenges to fulfil the rising food demand due to shortage of arable land and various environmental stressors. Traditional farming technologies help... (Review)
Review
Agriculture faces challenges to fulfil the rising food demand due to shortage of arable land and various environmental stressors. Traditional farming technologies help in fulfilling food demand but they are harmful to humans and environmental sustainability. The food production along with agro-environmental sustainability could be achieved by encouraging farmers to use agro-environmental sustainable products such as biofertilizers and biopesticides consisting of live microbes or plant extract instead of chemical-based inputs. The eco-friendly formulations play a significant role in plant growth promotion, crop yield and repairing degraded soil texture and fertility sustainably. Mineral solubilizing microbes that provide vital nutrients like phosphorus, potassium, zinc and selenium are essential for plant growth and development and could be developed as biofertilizers. These microbes could be plant associated (rhizospheric, endophytic and phyllospheric) or inhabit the bulk soil and diverse extreme habitats. Mineral solubilizing microbes from soil, extreme environments, surface and internal parts of the plant belong to diverse phyla such as Ascomycota, Actinobacteria, Basidiomycota, Bacteroidetes, Chlorobi, Cyanobacteria, Chlorophyta, Euryarchaeota, Firmicutes, Gemmatimonadetes, Mucoromycota, Proteobacteria and Tenericutes. Mineral solubilizing microbes (MSMs) directly or indirectly stimulate plant growth and development either by releasing plant growth regulators; solubilizing phosphorus, potassium, zinc, selenium and silicon; biological nitrogen fixation and production of siderophores, ammonia, hydrogen cyanide, hydrolytic enzymes and bioactive compound/secondary metabolites. Biofertilizer developed using mineral solubilizing microbes is an eco-friendly solution to the sustainable food production system in many countries worldwide. The present review deals with the biodiversity of mineral solubilizing microbes, and potential roles in crop improvement and soil well-being for agricultural sustainability.
Topics: Agriculture; Bacteria; Fertilizers; Humans; Microbiota; Phosphorus; Plants; Potassium; Selenium; Soil; Soil Microbiology; Zinc
PubMed: 35588278
DOI: 10.1111/jam.15627