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1.
Life Sci ; 354: 122984, 2024 Oct 01.
Article in English | MEDLINE | ID: mdl-39151883

ABSTRACT

AIMS: Advanced glycation end-products (AGEs) are implicated in the age-related decline of renal function, exacerbated by conditions, such as hyperglycemia and oxidative stress. The accumulation of AGEs in the kidneys contributes to the progressive decline in renal function observed with aging. However, the precise role and mechanisms of AGEs in the age-related decline of renal function remain unclear. In this study, we investigated the impact and potential mechanisms of AGEs on aging kidneys in naturally aging mice. MATERIALS AND METHODS: Male C57BL/6 mice were divided into three groups: 6-, 57-, and 107-week-old. First, the 6- and 107-week-old mice were euthanized. The remaining mice were divided into young (6 weeks) and old (57 weeks) groups. The 57-week-old mice were orally administered aminoguanidine (100 mg/kg/day), an AGEs inhibitor, or vehicle for 13 weeks, resulting in a final age of 70 weeks. The serum and kidney tissues were collected for biochemical measurement, histological examination, immunohistochemistry staining, and immunoblotting analysis. KEY FINDINGS: Our findings revealed a notable accumulation of AGEs in both serum and kidney tissue specimens and renal dysfunction in naturally aging mice. Aminoguanidine not only reversed AGEs accumulation but also ameliorated renal dysfunction. Additionally, aminoguanidine attenuated the upregulation of fibrosis markers (phosphorylated p38/α-SMA and C/EBP homologous protein, CHOP), senescence markers (p53 and p21), and oxidative stress marker (4-HNE) in the aging kidneys. SIGNIFICANCE: These findings underscore the critical role of AGEs in age-related renal dysfunction and highlight the therapeutic potential of aminoguanidine in mitigating fibrosis and senescence, offering prospective avenues for combating age-associated renal ailments.


Subject(s)
Aging , Glycation End Products, Advanced , Guanidines , Kidney , Mice, Inbred C57BL , Oxidative Stress , Animals , Glycation End Products, Advanced/metabolism , Male , Aging/metabolism , Mice , Kidney/metabolism , Kidney/pathology , Oxidative Stress/drug effects , Guanidines/pharmacology , Kidney Diseases/metabolism , Kidney Diseases/pathology , Fibrosis/metabolism
2.
Cell Rep ; 43(8): 114566, 2024 Aug 27.
Article in English | MEDLINE | ID: mdl-39088320

ABSTRACT

Novel insecticides were recently introduced to counter pyrethroid resistance threats in African malaria vectors. To prolong their effectiveness, potential cross-resistance from promiscuous pyrethroid metabolic resistance mechanisms must be elucidated. Here, we demonstrate that the duplicated P450s CYP6P9a/-b, proficient pyrethroid metabolizers, reduce neonicotinoid efficacy in Anopheles funestus while enhancing the potency of chlorfenapyr. Transgenic expression of CYP6P9a/-b in Drosophila confirmed that flies expressing both genes were significantly more resistant to neonicotinoids than controls, whereas the contrasting pattern was observed for chlorfenapyr. This result was also confirmed by RNAi knockdown experiments. In vitro expression of recombinant CYP6P9a and metabolism assays established that it significantly depletes both clothianidin and chlorfenapyr, with metabolism of chlorfenapyr producing the insecticidally active intermediate metabolite tralopyril. This study highlights the risk of cross-resistance between pyrethroid and neonicotinoid and reveals that chlorfenapyr-based control interventions such as Interceptor G2 could remain efficient against some P450-based resistant mosquitoes.


Subject(s)
Anopheles , Cytochrome P-450 Enzyme System , Guanidines , Insecticide Resistance , Insecticides , Malaria , Neonicotinoids , Pyrethrins , Thiazoles , Animals , Thiazoles/pharmacology , Guanidines/pharmacology , Insecticide Resistance/genetics , Anopheles/drug effects , Anopheles/genetics , Pyrethrins/pharmacology , Pyrethrins/metabolism , Neonicotinoids/pharmacology , Insecticides/pharmacology , Cytochrome P-450 Enzyme System/metabolism , Cytochrome P-450 Enzyme System/genetics , Substrate Specificity , Mosquito Vectors/drug effects , Mosquito Vectors/genetics , Insect Proteins/metabolism , Insect Proteins/genetics
3.
Zhejiang Da Xue Xue Bao Yi Xue Ban ; 53(4): 509-518, 2024 Aug 25.
Article in English, Chinese | MEDLINE | ID: mdl-39183056

ABSTRACT

OBJECTIVES: To synthesize new bakuchiol aminoguanidine derivatives and test their effect on viability and apoptosis of human triple-negative breast cancer (TNBC) cells. METHODS: Two bakuchiol derivatives 1 and 2 were obtained by formylation and Shiff base reaction of bakuchol. The structures of derivatives 1 and 2 were identified by 1H-NMR, 13C-NMR, and high-resolution electrospray ionization mass spectrometry (HR-ESI-MS) analysis. Human TNBC MDA-MB-231 cells were treated with bakuchiol and its derivatives and cell viability was measured by MTT assay. Apoptosis was detected by fluorescence microscopy and flow cytometry with Annexin V-FITC/PI staining. The expressions of apoptosis-related proteins were analyzed with Western blotting. The JC-1 and reactive oxygen species (ROS) assay kits were used to determine the effect of new bakuchiol derivatives on mitochondrial function. RESULTS: Based on spectroscopic analysis, a new bakuchiol schiff base derivative was elucidated as 2-{(E)-5-[(S, E)-3, 7-dimethyl-3-vinylocta-1, 6-dien-1-yl]-2-hydroxylbenzylidene} hydrazine-1-carboximidamide (derivative 2). Bakuchiol and its derivatives 1 and 2 all showed cytotoxic activity against the MDA-MB-231 cells. Derivative 2 exhibited the most potent cytotoxic activity to MDA-MB-231 cell with IC50 of (13.11±1.09), (6.91±1.78), and (2.23±1.32) µmol/L after 24, 48, and 72 h. It had low toxicity to normal mouse liver (AML-12) cells with IC50 of (31.23±1.58) µmol/L at 72 h. Fluorescence microscopy and flow cytometry demonstrated apoptosis in breast cancer cells after treating with derivative 2 in a concentration dependent manner. Western blotting showed that after derivative 2 treatment, the expression of apoptosis-related proteins cytochrome C, cleaving caspase-3 and Bax/Bcl-2 radio in MDA-MB-231 cells increased; in addition, apoptosis was associated with the decreased mitochondrial membrane potential and increased reactive oxygen species accumulation. CONCLUSIONS: The novel bakuchiol aminoguanidine derivative (derivative 2) is capable of inducing apoptosis in MDA-MB-231 cells, but has low toxicity to normal liver cells, suggesting that it may be used as a lead compound for an anti-TNBC agent.


Subject(s)
Apoptosis , Guanidines , Phenols , Reactive Oxygen Species , Triple Negative Breast Neoplasms , Humans , Apoptosis/drug effects , Triple Negative Breast Neoplasms/pathology , Triple Negative Breast Neoplasms/drug therapy , Cell Line, Tumor , Female , Phenols/pharmacology , Guanidines/pharmacology , Reactive Oxygen Species/metabolism , Cell Survival/drug effects
4.
Biochim Biophys Acta Mol Basis Dis ; 1870(7): 167450, 2024 Oct.
Article in English | MEDLINE | ID: mdl-39111631

ABSTRACT

Defense against intracellular acidification of breast cancer tissue depends on net acid extrusion via Na+,HCO3--cotransporter NBCn1/Slc4a7 and Na+/H+-exchanger NHE1/Slc9a1. NBCn1 is increasingly recognized as breast cancer susceptibility protein and promising therapeutic target, whereas evidence for targeting NHE1 is discordant. Currently, selective small molecule inhibitors exist against NHE1 but not NBCn1. Cellular assays-with some discrepancies-link NHE1 activity to proliferation, migration, and invasion; and disrupted NHE1 expression can reduce triple-negative breast cancer growth. Studies on human breast cancer tissue associate high NHE1 expression with reduced metastasis and-in some molecular subtypes-improved patient survival. Here, we evaluate Na+/H+-exchange and therapeutic potential of the NHE1 inhibitor cariporide/HOE-642 in murine ErbB2-driven breast cancer. Ex vivo, cariporide inhibits net acid extrusion in breast cancer tissue (IC50 = 0.18 µM) and causes small decreases in steady-state intracellular pH (pHi). In vivo, we deliver cariporide orally, by osmotic minipumps, and by intra- and peritumoral injections to address the low oral bioavailability and fast metabolism. Prolonged cariporide administration in vivo upregulates NBCn1 expression, shifts pHi regulation towards CO2/HCO3--dependent mechanisms, and shows no net effect on the growth rate of ErbB2-driven primary breast carcinomas. Cariporide also does not influence proliferation markers in breast cancer tissue. Oral, but not parenteral, cariporide elevates serum glucose by ∼1.5 mM. In conclusion, acute administration of cariporide ex vivo powerfully inhibits net acid extrusion from breast cancer tissue but lowers steady-state pHi minimally. Prolonged cariporide administration in vivo is compensated via NBCn1 and we observe no discernible effect on growth of ErbB2-driven breast carcinomas.


Subject(s)
Breast Neoplasms , Cell Proliferation , Guanidines , Receptor, ErbB-2 , Sodium-Hydrogen Exchanger 1 , Sulfones , Guanidines/pharmacology , Female , Animals , Receptor, ErbB-2/metabolism , Receptor, ErbB-2/genetics , Receptor, ErbB-2/antagonists & inhibitors , Sodium-Hydrogen Exchanger 1/metabolism , Sodium-Hydrogen Exchanger 1/antagonists & inhibitors , Sodium-Hydrogen Exchanger 1/genetics , Mice , Humans , Sulfones/pharmacology , Cell Proliferation/drug effects , Breast Neoplasms/drug therapy , Breast Neoplasms/pathology , Breast Neoplasms/metabolism , Breast Neoplasms/genetics , Sodium-Bicarbonate Symporters/metabolism , Sodium-Bicarbonate Symporters/genetics , Sodium-Bicarbonate Symporters/antagonists & inhibitors , Cell Line, Tumor , Hydrogen-Ion Concentration
5.
Protein Sci ; 33(9): e5146, 2024 Sep.
Article in English | MEDLINE | ID: mdl-39150147

ABSTRACT

D2 is a structural and cooperative domain of Thermotoga maritima Arginine Binding Protein, that possesses a remarkable conformational stability, with a denaturation temperature of 102.6°C, at pH 7.4. The addition of potassium thiocyanate causes a significant decrease in the D2 denaturation temperature. The interactions of thiocyanate ions with D2 have been studied by means of isothermal titration calorimetry measurements and molecular dynamics simulations. It emerged that: (a) 20-30 thiocyanate ions interact with the D2 surface and are present in its first solvation shell; (b) each of them makes several contacts with protein groups, both polar and nonpolar ones. The addition of guanidinium thiocyanate causes a marked destabilization of the D2 native state, because both the ions are denaturing agents. However, on adding to the solution containing D2 and guanidinium thiocyanate a stabilizing agent, such as TMAO, sucrose or sodium sulfate, a significant increase in denaturation temperature occurs. The present results confirm that counteraction is a general phenomenon for globular proteins.


Subject(s)
Molecular Dynamics Simulation , Protein Stability , Thermotoga maritima , Thiocyanates , Thiocyanates/chemistry , Thermotoga maritima/chemistry , Bacterial Proteins/chemistry , Bacterial Proteins/metabolism , Protein Denaturation/drug effects , Sulfates/chemistry , Methylamines/chemistry , Protein Domains , Guanidines/chemistry
6.
PLoS One ; 19(7): e0305710, 2024.
Article in English | MEDLINE | ID: mdl-38990850

ABSTRACT

There is an urgent unmet need for more targeted and effective treatments for advanced epithelial ovarian cancer (EOC). The emergence of drug resistance is a particular challenge, but small molecule covalent inhibitors have promise for difficult targets and appear less prone to resistance. Michael acceptors are covalent inhibitors that form bonds with cysteines or other nucleophilic residues in the target protein. However, many are categorized as pan-assay interference compounds (PAINS) and considered unsuitable as drugs due to their tendency to react non-specifically. Targeting RPN13/ADRM1-mediated substrate recognition and deubiquitination by the proteasome 19S Regulatory Particle (RP) is a promising treatment strategy. Early candidate RPN13 inhibitors (iRPN13) produced a toxic accumulation of very high molecular weight polyubiquitinated substrates, resulting in therapeutic activity in mice bearing liquid or solid tumor models, including ovarian cancer; however, they were not drug-like (PAINS) because of their central piperidone core. Up284 instead has a central spiro-carbon ring. We hypothesized that adding a guanidine moiety to the central ring nitrogen of Up284 would produce a compound, RA475, with improved drug-like properties and therapeutic activity in murine models of ovarian cancer. RA475 produced a rapid accumulation of high molecular polyubiquitinated proteins in cancer cell lines associated with apoptosis, similar to Up284 although it was 3-fold less cytotoxic. RA475 competed binding of biotinylated Up284 to RPN13. RA475 shows improved solubility and distinct pharmacodynamic properties compared to Up284. Specifically, tetraubiquitin firefly luciferase expressed in leg muscle was stabilized in mice more effectively upon IP treatment with RA475 than with Up284. However, pharmacologic analysis showed that RA475 was more rapidly cleared from the circulation, and less orally available than Up284. RA475 shows reduced ability to cross the blood-brain barrier and in vitro inhibition of HERG. Treatment of mice with RA475 profoundly inhibited the intraperitoneal growth of the ID8-luciferase ovarian tumor model. Likewise, RA475 treatment of immunocompetent mice inhibited the growth of spontaneous genetically-engineered peritoneal tumor, as did weekly cisplatin dosing. The combination of RA475 and cisplatin significantly extended survival compared to individual treatments, consistent with synergistic cytotoxicity in vitro. In sum, RA475 is a promising candidate covalent RPN13i with potential utility for treatment of patients with advanced EOC in combination with cisplatin.


Subject(s)
Ovarian Neoplasms , Female , Animals , Humans , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/pathology , Ovarian Neoplasms/metabolism , Mice , Cell Line, Tumor , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Antineoplastic Agents/chemistry , Spiro Compounds/pharmacology , Spiro Compounds/therapeutic use , Spiro Compounds/chemistry , Xenograft Model Antitumor Assays , Carcinoma, Ovarian Epithelial/drug therapy , Guanidines/pharmacology , Guanidines/therapeutic use , Guanidines/chemistry , Intracellular Signaling Peptides and Proteins
7.
Chem Biol Interact ; 399: 111134, 2024 Aug 25.
Article in English | MEDLINE | ID: mdl-38969276

ABSTRACT

Polyhexamethyleneguanidine phosphate (PHMG-P) is a biocide of guanidine family that can cause a fatal lung damage if exposed directly to the lungs. No reports exist regarding the toxicity of PHMG-P in neonatal animals. Therefore, this study aimed to determine PHMG-P toxicity in neonatal and 8-week-old mice after they were intranasally instilled with 1.5 mg/kg, 3 mg/kg, and 4.5 mg/kg PHMG-P. PHMG-P lung exposure resulted in more severe pulmonary toxicity in adult mice than in newborn mice. In the high-dose group of newborn mice, a minimal degree of inflammatory cell infiltration and fibrosis in the lung were detected, whereas more severe pathological lesions including granulomatous inflammation, fibrosis, and degeneration of the bronchiolar epithelium were observed in adult mice. At day 4, C-C motif chemokine ligand 2 (CCL2), a potent chemokine for monocytes, was upregulated but recovered to normal levels at day 15 in newborn mice. However, increased CCL2 and IL-6 levels were sustained at day 15 in adult mice. When comparing the differentially expressed genes of newborn and adult mice through RNA-seq analysis, there were expression changes in several genes associated with inflammation in neonates that were similar or different from those in adults. Although no significant lung damage occurred in newborns, growth inhibition was observed which was not reversed until the end of the experiment. Further research is needed to determine how growth inhibition from neonatal exposure to PHMG-P affects adolescent and young adult health.


Subject(s)
Animals, Newborn , Chemokine CCL2 , Guanidines , Lung , Animals , Mice , Guanidines/toxicity , Lung/drug effects , Lung/pathology , Lung/metabolism , Chemokine CCL2/metabolism , Chemokine CCL2/genetics , Interleukin-6/metabolism , Interleukin-6/genetics , Mice, Inbred C57BL , Female , Male , Lung Injury/chemically induced , Lung Injury/pathology
8.
Ecotoxicol Environ Saf ; 281: 116680, 2024 Aug.
Article in English | MEDLINE | ID: mdl-38964057

ABSTRACT

Inhaling polyhexamethylene guanidine (PHMG) aerosol, a broad-spectrum disinfectant, can lead to severe pulmonary fibrosis. Ferroptosis, a form of programmed cell death triggered by iron-dependent lipid peroxidation, is believed to play a role in the chemical-induced pulmonary injury. This study aimed to investigate the mechanism of ferroptosis in the progression of PHMG-induced pulmonary fibrosis. C57BL/6 J mice and the alveolar type II cell line MLE-12 were used to evaluate the toxicity of PHMG in vivo and in vitro, respectively. The findings indicated that iron deposition was observed in PHMG induced pulmonary fibrosis mouse model and ferroptosis related genes have changed after 8 weeks PHMG exposure. Additionally, there were disturbances in the antioxidant system and mitochondrial damage in MLE-12 cells following a 12-hour treatment with PHMG. Furthermore, the study observed an increase in lipid peroxidation and a decrease in GPX4 activity in MLE-12 cells after exposure to PHMG. Moreover, pretreatment with the ferroptosis inhibitors Ferrostatin-1 (Fer-1) and Liproxstatin-1 (Lip-1) not only restored the antioxidant system and GPX4 activity but also mitigated lipid peroxidation. Current data exhibit the role of ferroptosis pathway in PHMG-induced pulmonary fibrosis and provide a potential target for future treatment.


Subject(s)
Ferroptosis , Guanidines , Lipid Peroxidation , Mice, Inbred C57BL , Phospholipid Hydroperoxide Glutathione Peroxidase , Pulmonary Fibrosis , Animals , Ferroptosis/drug effects , Pulmonary Fibrosis/chemically induced , Pulmonary Fibrosis/pathology , Mice , Lipid Peroxidation/drug effects , Cell Line , Guanidines/toxicity , Guanidines/pharmacology , Male , Alveolar Epithelial Cells/drug effects , Alveolar Epithelial Cells/pathology , Cyclohexylamines/pharmacology , Phenylenediamines , Quinoxalines , Spiro Compounds
9.
Chem Biol Interact ; 399: 111154, 2024 Aug 25.
Article in English | MEDLINE | ID: mdl-39025286

ABSTRACT

Clothianidin, classified as a second-generation neonicotinoid, has achieved extensive application due to its high efficacy against insect pests. This broad-spectrum usage has resulted in its frequent detection in environmental surveys. CYP2C19 and CYP3A4 are crucial for converting clothianidin to desmethyl-clothianidin (dm-clothianidin). The expression of these CYP450s can be significantly influenced by genetic polymorphisms. The objective of our research was to examine the catalytic effects of 27 CYP3A4 variants and 31 CYP2C19 variants on the metabolism of clothianidin within recombinant insect microsomes. These variants were assessed through a well-established incubation procedure. In addition, the concentration of its metabolite dm-clothianidin was quantified by employing an ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). Lastly, the kinetic parameters of these CYP3A4 and CYP2C19 variants were calculated by applying Michaelis-Menten kinetic analysis to fit the data. The observed changes in enzyme activity were related to the metabolic transformation of clothianidin to dm-clothianidin. In the CYP2C19 metabolic pathway, one variant (CYP2C19.23) showed no notable change in intrinsic clearance (CLint), four variants (CYP2C19.29, .30, .31 and L16F) demonstrated a marked increase in CLint (110.86-183.46 %), and the remaining 25 variants exhibited a considerable decrease in CLint (26.38-89.79 %), with a maximum decrease of 73.62 % (CYP2C19.6). In the CYP3A4 metabolic pathway, 26 variants demonstrated significantly reduced CLint (10.54-52.52 %), with a maximum decrease of 89.46 % (CYP3A4.20). Our results suggested that most variants of CYP3A4 and CYP2C19 significantly altered the enzymatic activities associated with clothianidin metabolism to various degrees. This study provides new insights into assessing the metabolic behavior of pesticides and delivers crucial data that can guide clinical detoxification strategies.


Subject(s)
Cytochrome P-450 CYP2C19 , Cytochrome P-450 CYP3A , Guanidines , Neonicotinoids , Polymorphism, Genetic , Thiazoles , Cytochrome P-450 CYP2C19/genetics , Cytochrome P-450 CYP2C19/metabolism , Cytochrome P-450 CYP3A/genetics , Cytochrome P-450 CYP3A/metabolism , Thiazoles/metabolism , Guanidines/metabolism , Neonicotinoids/metabolism , Humans , Animals , Kinetics , Tandem Mass Spectrometry , Insecticides/metabolism , Microsomes/metabolism
10.
Environ Toxicol Chem ; 43(9): 2039-2044, 2024 Sep.
Article in English | MEDLINE | ID: mdl-38967272

ABSTRACT

Data from prior research indicate the prepupal stage of the monarch butterfly life cycle is more sensitive to clothianidin exposure than the larval stage. A set of experiments was conducted to determine if the dietary clothianidin exposures that cause prepupal mortality are environmentally relevant. Monarch larvae were raised from egg to pupae on clothianidin-contaminated swamp milkweed plants (Asclepias incarnata). Larval growth as well as larval and prepupal survival were monitored throughout the experiments, in which the exposures ranged from 1.4 to 2793.1 ng/g leaf. Exposures of 5.4 to 46.9 ng/g leaf resulted primarily in prepupal mortality, whereas higher exposures of 1042.4 to 2793.1 ng/g leaf resulted exclusively in larval mortality, indicating the prepupal stage is more sensitive to clothianidin exposure than the larval stage. A median lethal concentration and a 10% lethal concentration of 37 and 6 ng/g leaf, respectively, were estimated for prepupal mortality. Both effect concentrations are within the range of clothianidin concentrations reported in leaves collected from wild milkweed plants, indicating prepupal mortality is an environmentally relevant effect. Environ Toxicol Chem 2024;43:2039-2044. © 2024 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.


Subject(s)
Butterflies , Guanidines , Insecticides , Larva , Neonicotinoids , Thiazoles , Animals , Butterflies/drug effects , Butterflies/growth & development , Thiazoles/toxicity , Neonicotinoids/toxicity , Guanidines/toxicity , Larva/drug effects , Larva/growth & development , Insecticides/toxicity , Asclepias , Plant Leaves/chemistry , Pupa/drug effects , Pupa/growth & development , Dietary Exposure
11.
Open Biol ; 14(7): 240057, 2024 Jul.
Article in English | MEDLINE | ID: mdl-39043224

ABSTRACT

With the spread of resistance to long-established insecticides targeting Anopheles malaria vectors, understanding the actions of compounds newly identified for vector control is essential. With new commercial vector-control products containing neonicotinoids under development, we investigate the actions of 6 neonicotinoids (imidacloprid, thiacloprid, clothianidin, dinotefuran, nitenpyram and acetamiprid) on 13 Anopheles gambiae nicotinic acetylcholine receptor (nAChR) subtypes produced by expression of combinations of the Agα1, Agα2, Agα3, Agα8 and Agß1 subunits in Xenopus laevis oocytes, the Drosophila melanogaster orthologues of which we have previously shown to be important in neonicotinoid actions. The presence of the Agα2 subunit reduces neonicotinoid affinity for the mosquito nAChRs, whereas the Agα3 subunit increases it. Crystal structures of the acetylcholine binding protein (AChBP), an established surrogate for the ligand-binding domain, with dinotefuran bound, shows a unique target site interaction through hydrogen bond formation and CH-N interaction at the tetrahydrofuran ring. This is of interest as dinotefuran is also under trial as the toxic element in baited traps. Multiple regression analyses show a correlation between the efficacy of neonicotinoids for the Agα1/Agα2/Agα8/Agß1 nAChR, their hydrophobicity and their rate of knockdown of adult female An. gambiae, providing new insights into neonicotinoid features important for malaria vector control.


Subject(s)
Anopheles , Guanidines , Insecticides , Mosquito Vectors , Neonicotinoids , Nitro Compounds , Receptors, Nicotinic , Animals , Anopheles/metabolism , Anopheles/genetics , Anopheles/drug effects , Neonicotinoids/pharmacology , Receptors, Nicotinic/metabolism , Receptors, Nicotinic/genetics , Receptors, Nicotinic/chemistry , Insecticides/pharmacology , Insecticides/chemistry , Nitro Compounds/pharmacology , Nitro Compounds/chemistry , Guanidines/pharmacology , Mosquito Vectors/drug effects , Mosquito Vectors/genetics , Xenopus laevis , Ligands , Pyridines/pharmacology , Malaria/transmission , Malaria/parasitology , Thiazoles/pharmacology , Thiazoles/chemistry , Thiazoles/metabolism , Thiazines/pharmacology , Thiazines/chemistry , Oocytes/metabolism , Oocytes/drug effects , Female , Insect Proteins/metabolism , Insect Proteins/genetics , Insect Proteins/chemistry , Imidazoles/pharmacology , Imidazoles/chemistry
12.
BMC Infect Dis ; 24(1): 733, 2024 Jul 25.
Article in English | MEDLINE | ID: mdl-39054424

ABSTRACT

Elevated resistance to pyrethroids in major malaria vectors has led to the introduction of novel insecticides including neonicotinoids. There is a fear that efficacy of these new insecticides could be impacted by cross-resistance mechanisms from metabolic resistance to pyrethroids. In this study, after evaluating the resistance to deltamethrin, clothianidin and mixture of clothianidin + deltamethrin in the lab using CDC bottle assays, the efficacy of the new IRS formulation Fludora® Fusion was tested in comparison to clothianidin and deltamethrin applied alone using experimental hut trials against wild free-flying pyrethroid-resistant Anopheles funestus from Elende and field An. gambiae collected from Nkolondom reared in the lab and released in the huts. Additionally, cone tests on the treated walls were performed each month for a period of twelve months to evaluate the residual efficacy of the sprayed products. Furthermore, the L1014F-kdr target-site mutation and the L119F-GSTe2 mediated metabolic resistance to pyrethroids were genotyped on a subset of mosquitoes from the EHT to assess the potential cross-resistance. All Anopheles species tested were fully susceptible to clothianidin and clothianidin + deltamethrin mixture in CDC bottle assay while resistance was noted to deltamethrin. Accordingly, Fludora® Fusion (62.83% vs 42.42%) and clothianidin (64.42% vs 42.42%) induced significantly higher mortality rates in EHT than deltamethrin (42.42%) against free flying An. funestus from Elende in month 1 (M1) and no significant difference in mortality was observed between the first (M1) and sixth (M6) months of the evaluation (P > 0.05). However, lower mortality rates were recorded against An. gambiae s.s from Nkolondom (mortality rates 50%, 45.56% and 26.68%). In-situ cone test on the wall showed a high residual efficacy of Fludora® Fusion and clothianidin on the susceptible strain KISUMU (> 12 months) and moderately on the highly pyrethroid-resistant An. gambiae strain from Nkolondom (6 months). Interestingly, no association was observed between the L119F-GSTe2 mutation and the ability of mosquitoes to survive exposure to Fludora® Fusion, whereas a trend was observed with the L1014F-kdr mutation. This study highlights that Fludora® Fusion, through its clothianidin component, has good potential of controlling pyrethroid-resistant mosquitoes with prolonged residual efficacy. This could be therefore an appropriate tool for vector control in several malaria endemic regions.


Subject(s)
Anopheles , Insecticide Resistance , Insecticides , Malaria , Mosquito Control , Mosquito Vectors , Pyrethrins , Animals , Pyrethrins/pharmacology , Anopheles/drug effects , Anopheles/genetics , Insecticide Resistance/genetics , Insecticides/pharmacology , Mosquito Control/methods , Cameroon , Mosquito Vectors/drug effects , Mosquito Vectors/genetics , Malaria/transmission , Malaria/prevention & control , Guanidines/pharmacology , Nitriles/pharmacology , Female , Thiazoles/pharmacology , Neonicotinoids/pharmacology , Housing
13.
BMC Infect Dis ; 24(1): 709, 2024 Jul 19.
Article in English | MEDLINE | ID: mdl-39030491

ABSTRACT

BACKGROUND: Camostat mesylate, an oral serine protease inhibitor, is a powerful TMPRSS2 inhibitor and has been reported as a possible antiviral treatment against COVID-19. Therefore, we aim to assess the safety and efficacy of camostat mesylate for COVID-19 treatment. METHODS: A systematic review and meta-analysis synthesizing randomized controlled trials from PubMed, Scopus, Embase, Cochrane, Web of Science, clinical trials.gov, and medrxiv until June 2023. The outcomes were pooled using Mean difference (MD) for continuous outcomes and risk ratio (RR) for dichotomous outcomes. The protocol is registered in PROSPERO with ID CRD42023439633. RESULTS: Nine RCTs, including 1,623 patients, were included in this analysis. There was no difference between camostat mesylate and placebo in producing negative PCR test results at 1-7 days (RR: 0.76, 95% CI: [0.54, 1.06] P = 0.1), 8-14 days (RR: 1.02, 95% CI: [0.84, 1.23] P = 0.87), or 15-21 days (RR: 0.99, 95% CI: [0.82, 1.19] P = 0.90); clinical resolution of symptoms at 1-7 days (RR: 0.94 (95% CI: 0.58, 1.53) P = 0.81), 8-14 days (RR: 0.91, 95% CI: [0.74, 1.11] P = 0.33, ), or 15-21 days (RR: 0.77, 95% CI: [0.40, 1.51] P = 0.45); and time to symptom improvement (MD:-0.38 weeks (95% CI: [-1.42, 0.66] P = 0.47, I2 = 85%). CONCLUSION: Camostat mesylate did not improve clinical outcomes in patients with COVID-19, compared to placebo.


Subject(s)
Antiviral Agents , COVID-19 Drug Treatment , Guanidines , Randomized Controlled Trials as Topic , SARS-CoV-2 , Humans , SARS-CoV-2/drug effects , Antiviral Agents/therapeutic use , Antiviral Agents/adverse effects , Guanidines/therapeutic use , Guanidines/adverse effects , Treatment Outcome , COVID-19 , Gabexate/therapeutic use , Serine Proteinase Inhibitors/therapeutic use , Serine Proteinase Inhibitors/adverse effects , Esters
14.
Methods Mol Biol ; 2833: 145-152, 2024.
Article in English | MEDLINE | ID: mdl-38949708

ABSTRACT

Mycobacterium tuberculosis is an infectious pathogen that requires biosafety level-3 laboratory for handling. The risk of transmission is high to laboratory staff, and to manage the organism safely, it is necessary to construct high containment laboratory facilities at great expense. This limits the application of tuberculosis diagnostics to areas where there is insufficient capital to invest in laboratory infrastructure. In this method, we describe a process of inactivating sputum samples by either heat or guanidine thiocyanate (GTC) that renders them safe without affecting the quantification of viable bacteria. This method eliminates the need for level 3 containment laboratory for the tuberculosis molecular bacterial load assay (TB-MBLA) and is applicable in low- and middle-income countries.


Subject(s)
Containment of Biohazards , Mycobacterium tuberculosis , Sputum , Thiocyanates , Mycobacterium tuberculosis/isolation & purification , Humans , Containment of Biohazards/methods , Sputum/microbiology , Bacterial Load/methods , Tuberculosis/diagnosis , Tuberculosis/microbiology , Tuberculosis/prevention & control , Guanidines , Hot Temperature , Microbial Viability
15.
J Nucl Med ; 65(8): 1286-1292, 2024 Aug 01.
Article in English | MEDLINE | ID: mdl-38960713

ABSTRACT

Meta-[123I]iodobenzylguanidine ([123I]MIBG) scintigraphy with SPECT/CT is the standard of care for diagnosing and monitoring neuroblastoma. Replacing [123I]MIBG with the new PET tracer meta-[18F]fluorobenzylguanidine ([18F]MFBG) and further improving sensitivity and reducing noise in a new long-axial-field-of-view (LAFOV) PET/CT scanner enable increased image quality and a faster acquisition time, allowing examinations to be performed without sedation or general anesthesia (GA). Focusing on feasibility, we present our first experience with [18F]MFBG LAFOV PET/CT and compare it with [123I]MIBG scintigraphy plus SPECT/CT for imaging in neuroblastoma in children. Methods: A pilot of our prospective, single-center study recruited children with neuroblastoma who were referred for [123I]MIBG scintigraphy with SPECT/CT. Within 1 wk of [123I]MIBG scintigraphy and SPECT/low-dose CT, [18F]MFBG LAFOV PET/ultra-low-dose CT was performed 1 h after injection (1.5-3 MBq/kg) without sedation or GA, in contrast to the 24-h postinjection interval needed for scanning with [123I]MIBG, the 2- to 2.5-h acquisition time, and the GA often needed in children less than 6 y old. Based on the spirocyclic iodonium-ylide precursor, [18F]MFBG was produced in a fully automated good manufacturing practice-compliant procedure. We present the feasibility of the study. Results: In the first paired scans of the first 10 children included (5 at diagnosis, 2 during treatment, 2 during surveillance, and 1 at relapse), [18F]MFBG PET/CT scan showed a higher number of radiotracer-avid lesions in 80% of the cases and an equal number of lesions in 20% of the cases. The SIOPEN score was higher in 50% of the cases, and the Curie score was higher in 70% of the cases. In particular, intraspinal, retroperitoneal lymph node, and bone marrow involvement was diagnosed with much higher precision. None of the children (median age, 1.6 y; range, 0.1-7.9 y) had sedation or GA during the PET procedure, whereas 80% had GA during [123I]MIBG scintigraphy with SPECT/CT. A PET acquisition time of only 2 min without motion artifacts was the data requirement of the 10-min acquisition time for reconstruction to provide a clinically useful image. Conclusion: This pilot study demonstrates the feasibility of performing [18F]MFBG LAFOV PET/CT for imaging of neuroblastoma. Further, an increased number of radiotracer-avid lesions, an increased SIOPEN score, and an increased Curie score were seen on [18F]MFBG LAFOV PET/CT compared with [123I]MIBG scintigraphy with SPECT/CT, and GA and sedation was avoided in all patients. Thus, with a 1-d protocol, a significantly shorter scan time, a higher sensitivity, and the avoidance of GA and sedation, [18F]MFBG LAFOV PET/CT shows promise for future staging and response assessment and may also have a clinical impact on therapeutic decision-making for children with neuroblastoma.


Subject(s)
Anesthesia, General , Neuroblastoma , Positron Emission Tomography Computed Tomography , Neuroblastoma/diagnostic imaging , Humans , Child, Preschool , Female , Male , Child , Positron Emission Tomography Computed Tomography/methods , Infant , 3-Iodobenzylguanidine , Guanidines , Prospective Studies , Pilot Projects , Radiopharmaceuticals
16.
Bone ; 187: 117211, 2024 Oct.
Article in English | MEDLINE | ID: mdl-39053792

ABSTRACT

Osteonecrosis of the jaw (ONJ) is a relatively rare side effect after prolonged use of bisphosphonates, which are drugs used to treat bone resorption in osteoporosis and certain cancers. This study introduces a novel ONJ model in rats by combining exposure to bisphosphonates, oral surgery, and bacterial inoculation. Potential ONJ preventive effects of polyguanidine (GuaDex) or antibiotics were evaluated. The study consisted of twenty-four male Wistar rats were divided into four groups. Groups 1 to 3 were given weekly doses of i.v. Zoledronic acid (ZA), four weeks before and two weeks after an osteotomy procedure on their left mandibular first molar. Group 4 was a negative control. Streptococcus gordonii bacteria were introduced into the osteotomy pulp chamber and via the food for seven days. On day eight, the rats were given different treatments. Group 1 was given a GuaDex injection into the osteotomy socket, Group 2 was given an intramuscular (i.m.) injection of clindamycin, Group 3 (positive control) was given an i.m. injection of saline, and Group 4 was given an i.m. injection of saline. Blood samples were taken two weeks after the osteotomy procedure, after which the rats were euthanized. Bone healing, bone mineral density, histology, and blood status were analyzed. The results showed that Group 1 (GuaDex) had no ONJ, extensive ongoing bone regeneration, active healing activity, vascularization, and no presence of bacteria. Group 2 (clindamycin) showed early stages of ONJ, avascular areas, and bacteria. Group 3 showed stages of ONJ, inflammatory infiltrates, defective healing, and bacterial presence, and Group 4 had normal healing activity and no bacterial presence. Conclusion: ZA treatment and bacterial inoculation after tooth extraction inhibited bone remodeling/healing and induced ONJ characteristic lesions in the rats. Only GuaDex apparently prevented ONJ development, stimulated bone remodeling, and provided an antimicrobial effect.


Subject(s)
Bisphosphonate-Associated Osteonecrosis of the Jaw , Rats, Wistar , Animals , Male , Bisphosphonate-Associated Osteonecrosis of the Jaw/prevention & control , Bisphosphonate-Associated Osteonecrosis of the Jaw/pathology , Rats , Diphosphonates/pharmacology , Diphosphonates/adverse effects , Guanidines/pharmacology , Guanidines/therapeutic use
17.
Pol Merkur Lekarski ; 52(3): 332-336, 2024.
Article in English | MEDLINE | ID: mdl-39007472

ABSTRACT

OBJECTIVE: Aim: The aim of the research is to study the cytokine prof i le (IL-1ß, IL 6, TNF-α, IL-4, IL-10) in bronchoalveolar lavage of lungs in experimental APS and its correction with L-arginine and aminoguanidine. PATIENTS AND METHODS: Materials and Methods: Antiphospholipid syndrome was modeled on white female BALB/c mice. L-arginine (25 mg/kg) and aminoguanidine (10 mg/kg) were used for its correction. The concentration of cytokines in bronchoalveolar lavage from the lungs was assessed using the ELISA test. RESULTS: Results: It was established that in cases of APS the concentration of proinf l ammatory cytokines IL-1ß, IL-6 and TNF-a increased in 1.9, 2.3 and 6.6 times, respectively, compare to the control. At the same time a decrease of the IL-4 in 1.7 and IL-10 in 1.8 times was found in the APS group compare to the control. L-arginine reduced the level of proinf l ammatory cytokines IL-1ß by 22%, IL-6 - by 36%, and TNF-α - by 23% compare to the animals with APS. At the same time, the level of anti-inf l ammatory cytokines increased: IL-4 - by 46%, IL-10 - by 57% compare to the APS animal group. Aminoguanidine, a selective iNOS inhibitor, did not cause any signif i cant decrease in pro-inf l ammatory cytokines but the level of anti-inf l ammatory cytokines IL-4 increased by 44% and IL-10 - by 49%. CONCLUSION: Conclusions: The precursor of the NO synthesis L-arginine leads to a decrease in the concentrations of IL-1ß, IL-6, TNF-a and an increase of IL-4 and IL-10 compare to the group of BALB/c mice with APS.


Subject(s)
Antiphospholipid Syndrome , Arginine , Cytokines , Guanidines , Mice, Inbred BALB C , Animals , Antiphospholipid Syndrome/drug therapy , Antiphospholipid Syndrome/metabolism , Arginine/pharmacology , Mice , Female , Cytokines/metabolism , Guanidines/pharmacology , Nitric Oxide/metabolism , Bronchoalveolar Lavage Fluid/chemistry , Disease Models, Animal , Humans , Interleukin-10/metabolism , Tumor Necrosis Factor-alpha/metabolism
18.
J Econ Entomol ; 117(4): 1518-1525, 2024 Aug 12.
Article in English | MEDLINE | ID: mdl-38936424

ABSTRACT

Most field corn in the United States receives a neonicotinoid seed treatment for the management of early-season, soil-dwelling insect pests. Grubs of Maladera formosae (Brenske) (Coleoptera: Scarabaeidae) have been reported feeding on young field corn with both low and high rates of clothianidin seed treatments in Indiana, Michigan, and Ohio. Anecdotally, these infestations are restricted to sandy soils in the region. The purpose of this study was to (1) evaluate whether grub populations in corn are restricted to sandy soils, (2) assess whether soil type influences M. formosae survival, and (3) determine whether soil type affects clothianidin uptake by the plant, possibly explaining the observed differences in M. formosae abundance by soil type. We observed nearly 10-times more grubs in sand (>80% sand content) than loam (<80% sand content) soil within a single corn field. Grub survival to adult was not influenced by soil type. We then compared the concentrations of clothianidin seed treatment in the roots and shoots of corn seedlings grown in either sand or loam soil over time. Similar amounts of the active ingredient were found in the roots and shoots of corn grown in both soil types. Within 2 week, the clothianidin concentrations in both soil types had significantly declined in roots and shoots and were no different from the no-insecticide control. These findings suggest that factors other than insecticide exposure contribute to the higher abundance of M. formosae larvae in sand relative to loam soils, even within the same field.


Subject(s)
Coleoptera , Guanidines , Insecticides , Neonicotinoids , Soil , Thiazoles , Zea mays , Animals , Zea mays/growth & development , Soil/chemistry , Guanidines/analysis , Michigan , Larva/growth & development
19.
Environ Entomol ; 53(4): 716-722, 2024 Aug 17.
Article in English | MEDLINE | ID: mdl-38907530

ABSTRACT

Neonicotinoid insecticide seed treatments are commonly used in rice (Oryza sativa) production to control rice water weevil (Lisorhoptrus oryzophilus). With the use of neonicotinoid seed treatments, there is potential that honey bees (Apis mellifera) could be exposed to neonicotinoids through translocation to the pollen. Studies were conducted in 2015 and 2016 to determine the level of neonicotinoids present in flag leaves, pollen, and grain of rice. Thiamethoxam was applied as a seed treatment and foliar prior to flooding. Clothianidin was applied as a seed treatment and as a foliar at a preflood and postflood timing. Subsamples of flag leaves, pollen, and grain were analyzed for positive neonicotinoid detections and abundance. Thiamethoxam was detected in 8.9% of samples and clothianidin was detected in 1.4% of samples. For both thiamethoxam and clothianidin, more positive samples were observed in flag leaf samples than in pollen or grain. An average of 4.30 ng/g of thiamethoxam was detected in flag leaves from seed-applied thiamethoxam. An average of 1.25 ng/g of clothianidin was found in flag leaves from a preflood application of clothianidin. A survey of honey bees present in rice fields was conducted in Mississippi and Arkansas to determine the abundance of honey bees present in rice fields based on the time of day. Honey bee densities were low in rice, with less than 5% and 3% positive detections observed in Mississippi and Arkansas, respectively. More positive detections and higher densities of honey bees were observed for mid-day sampling than for morning or evening sampling.


Subject(s)
Guanidines , Insecticides , Neonicotinoids , Oryza , Thiamethoxam , Thiazoles , Animals , Bees/drug effects , Insecticides/analysis , Neonicotinoids/analysis , Guanidines/analysis , Guanidines/toxicity , Thiamethoxam/analysis , Thiazoles/analysis , Seeds , Pollen , Plant Leaves/chemistry
20.
Environ Pollut ; 357: 124453, 2024 Sep 15.
Article in English | MEDLINE | ID: mdl-38936038

ABSTRACT

The environmental transmission of antibiotic resistance genes (ARGs) and metal resistance genes (MRGs) exerted devastating threats to global public health, and their interactions with other emerging contaminants (ECs) have raised increasing concern. This study investigated that the abundances of ARGs and MRGs with the predominant type of efflux pump were simultaneously increased (8.4-59.1%) by disinfectant polyhexamethylene guanidine (PHMG) during waste activated sludge (WAS) anaerobic digestion. The aggregation of the same microorganisms (i.e., Hymenobacter and Comamonas) and different host bacteria (i.e., Azoarcus and Thauera) were occurred upon exposure to PHMG, thereby increasing the co-selection and propagation of MRGs and ARGs by vertical gene transfer. Moreover, PHMG enhanced the process of horizontal gene transfer (HGT), facilitating their co-transmission by the same mobile genetic elements (20.2-223.7%). Additionally, PHMG up-regulated the expression of critical genes (i.e., glnB, trpG and gspM) associated with the HGT of ARGs and MRGs (i.e., two-component regulatory system and quorum sensing) and exocytosis system (i.e., bacterial secretion system). Structural equation model analysis further verified that the key driver for the simultaneous enrichment of ARGs and MRGs under PHMG stress was microbial community structure. The study gives new insights into the aggravated environmental risks and mechanisms of ECs in sludge digestion system, providing guidance for subsequent regulation and control of ECs.


Subject(s)
Disinfectants , Guanidines , Sewage , Sewage/microbiology , Disinfectants/toxicity , Disinfectants/pharmacology , Guanidines/toxicity , Gene Transfer, Horizontal , Metals/toxicity , Anaerobiosis , Drug Resistance, Microbial/genetics , Bacteria/genetics , Bacteria/drug effects , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/toxicity , Waste Disposal, Fluid , Drug Resistance, Bacterial/genetics
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