RESUMO
Influenza viruses remain a major threat to human health. Four classes of drugs have been approved for the prevention and treatment of influenza infections. Oseltamivir, a neuraminidase inhibitor, is a first-line anti-influenza drug, and baloxavir is part of the newest generation of anti-influenza drugs that targets the viral polymerase. The emergence of drug resistance has reduced the efficacy of established antiviral drugs. Combination therapy is one of the options for controlling drug resistance and enhancing therapeutical efficacies. Here, we evaluate the antiviral effects of baloxavir combined with neuraminidase inhibitors (NAIs) against wild-type influenza viruses, as well as influenza viruses with drug-resistance mutations. The combination of baloxavir with NAIs led to significant synergistic effects; however, the combination of baloxavir with laninamivir failed to result in a synergistic effect on influenza B viruses. Considering the rapid emergence of drug resistance to baloxavir, we believe that these results will be beneficial for combined drug use against influenza.
Assuntos
Antivirais , Dibenzotiepinas , Farmacorresistência Viral , Sinergismo Farmacológico , Inibidores Enzimáticos , Morfolinas , Neuraminidase , Piridonas , Triazinas , Dibenzotiepinas/farmacologia , Antivirais/farmacologia , Triazinas/farmacologia , Morfolinas/farmacologia , Piridonas/farmacologia , Neuraminidase/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Humanos , Vírus da Influenza B/efeitos dos fármacos , Animais , Piridinas/farmacologia , Tiazóis/farmacologia , Guanidinas/farmacologia , Orthomyxoviridae/efeitos dos fármacos , Cães , Células Madin Darby de Rim Canino , Influenza Humana/tratamento farmacológico , Influenza Humana/virologia , Ácidos Siálicos , Vírus da Influenza A/efeitos dos fármacos , Tiepinas/farmacologia , Triazóis/farmacologia , Benzimidazóis/farmacologia , PiranosRESUMO
The use of nitrification inhibitors has been suggested as a strategy to decrease cadmium (Cd) accumulation in crops. However, the most efficient nitrification inhibitor for mitigating crop Cd accumulation remains to be elucidated, and whether and how changes in soil microbial structure are involved in this process also remains unclear. To address these questions, this study applied three commercial nitrification inhibitors, namely, dicyandiamide (DCD), 3,4-dimethylpyrazole phosphate (DMPP), and nitrapyrin (NP), to pakchoi. The results showed that both DCD and DMPP (but not NP) could efficiently decrease Cd concentrations in pakchoi in urea- and ammonium-fertilized soils. In addition, among the three tested nitrification inhibitors, DMPP was the most efficient in decreasing the Cd concentration in pakchoi. The nitrification inhibitors decreased pakchoi Cd concentrations by suppressing acidification-induced Cd availability and reshaping the soil microbial structure; the most effective nitrification inhibitor was DMPP. Ammonia oxidation generates the most protons during nitrification and is inhibited by nitrification inhibitors. Changes in environmental factors and predatory bacterial abundance caused by the nitrification inhibitors changed the soil microbial structure and increased the potential participants in plant Cd accumulation. In summary, our study identified DMPP as the most efficient nitrification inhibitor for mitigating crop Cd contamination and observed that the soil microbial structural changes caused by the nitrification inhibitors contributed to decreasing Cd concentration in pakchoi.
Assuntos
Cádmio , Guanidinas , Nitrificação , Microbiologia do Solo , Cádmio/metabolismo , Nitrificação/efeitos dos fármacos , Guanidinas/metabolismo , Guanidinas/farmacologia , Poluentes do Solo/metabolismo , Pirazóis/farmacologia , Solo/química , Fertilizantes , Amônia/metabolismoRESUMO
The widespread production and utilization of graphene oxide (GO) raise concerns about its environmental release and potential ecological impacts, particularly in agricultural soil. Effective nitrogen (N) management, especially through nitrification inhibitors like dicyandiamide (DCD), might mitigate the negative effects of GO exposure on soil microbes via N biostimulation. This study quantified changes in soil physicochemical properties, nitrous oxide (N2O) emissions, microbial activity, biomass, and community after treatments with GO and DCD. The GO exposure significantly reduced bacterial 16S rRNA gene abundance and the biomass of major bacterial phyla. It also stimulated pathways linked to human diseases. However, DCD application alleviated the negative effects of GO exposure on soil bacterial biomass. While DCD application significantly reduced soil N2O emission, the GO application tended to hinder the inhibiting performance of DCD. Our findings highlight the hazards of GO exposure to soil microbes and the potential mitigation strategy with soil N management.
Assuntos
Bactérias , Grafite , Guanidinas , Óxido Nitroso , Microbiologia do Solo , Solo , Grafite/química , Bactérias/genética , Bactérias/classificação , Bactérias/efeitos dos fármacos , Bactérias/isolamento & purificação , Solo/química , Guanidinas/farmacologia , Guanidinas/química , Fertilizantes/análise , Agricultura/métodosRESUMO
Dodine is an important surfactant-based chemical fungicide used widely to kill fungi associated with black spot and foliar diseases on several fruit plants, such as apples, pears, peaches, and strawberries. However, the extensive use of dodine depicts the genotoxic effect, which may cause gene-associated diseases. Dodine can destabilize G-quadruplex (G4) DNA, which is one of the key targets for cancer therapy. Hence, finding an eco-friendly medium that can reduce or reverse the destabilization effect of dodine on G4 is important. This study investigates the efficacy of ionic liquids (ILs) containing a 1,1,3,3-tetramethyl guanidinium (TMG) cation with various anions (chloride, acetate, trifluoroacetate, octanoate, and perfluorooctanoate) in restoring the structure and stability of G4 induced by dodine. Our findings demonstrate that all ILs effectively reverse dodine-induced destabilization of G4, with the required concentration varying based on the lipophilicity of IL's anions. Specifically, higher concentrations of TMG-chloride and TMG-acetate are needed compared to TMG-perfluorooctanoate for the same effect. The IL anions remove dodine from G4 binding sites, while the TMG cation's interaction with G4 mitigates the destabilizing effect of dodine. This study indicates that ILs can be an eco-friendly medium for the storage of dodine to reverse the effect of dodine on G4.
Assuntos
Fungicidas Industriais , Quadruplex G , Líquidos Iônicos , Líquidos Iônicos/química , Líquidos Iônicos/farmacologia , Quadruplex G/efeitos dos fármacos , Fungicidas Industriais/química , Fungicidas Industriais/farmacologia , DNA/química , Guanidinas/química , Guanidinas/farmacologiaRESUMO
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.
Assuntos
Envelhecimento , Produtos Finais de Glicação Avançada , Guanidinas , Rim , Camundongos Endogâmicos C57BL , Estresse Oxidativo , Animais , Produtos Finais de Glicação Avançada/metabolismo , Masculino , Envelhecimento/metabolismo , Camundongos , Rim/metabolismo , Rim/patologia , Estresse Oxidativo/efeitos dos fármacos , Guanidinas/farmacologia , Nefropatias/metabolismo , Nefropatias/patologia , Fibrose/metabolismoRESUMO
Diaphorina citri is a serious citrus pest. Dinotefuran is highly insecticidal against D. citri. To analyze the sublethal effects of dinotefuran on D. citri adults, an indoor toxicity test was performed, which revealed that the lethal concentration 50 (LC50) values were 4.23 and 0.50 µg/mL for 24 and 48 h treatments, respectively. RNA-Seq led to the identification of 71 and 231 differentially expressed genes (DEGs) after dinotefuran treatments with LC20 and LC50 doses, respectively. Many of the DEGs are significantly enriched in the apoptosis pathway. Dinotefuran-induced apoptosis in the gut cells was confirmed through independent assays of 4',6-diamidino-2-phenylindole (DAPI) and TdT-mediated dUTP nick end labeling (TUNEL) staining. Increased levels of reactive oxygen species (ROS) and a loss of mitochondrial membrane potential were observed. Four caspase genes were identified, and dinotefuran treatments resulted in increased mRNA levels of DcCasp1 and DcCasp3a. These findings shed light on the sublethal effects of dinotefuran on D. citri.
Assuntos
Apoptose , Guanidinas , Proteínas de Insetos , Inseticidas , Mitocôndrias , Neonicotinoides , Nitrocompostos , Apoptose/efeitos dos fármacos , Animais , Neonicotinoides/toxicidade , Nitrocompostos/toxicidade , Nitrocompostos/farmacologia , Inseticidas/toxicidade , Inseticidas/farmacologia , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Mitocôndrias/genética , Proteínas de Insetos/genética , Proteínas de Insetos/metabolismo , Guanidinas/toxicidade , Guanidinas/farmacologia , Hemípteros/efeitos dos fármacos , Hemípteros/genética , Espécies Reativas de Oxigênio/metabolismo , Trato Gastrointestinal/efeitos dos fármacos , Trato Gastrointestinal/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacosRESUMO
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.
Assuntos
Anopheles , Sistema Enzimático do Citocromo P-450 , Guanidinas , Resistência a Inseticidas , Inseticidas , Malária , Neonicotinoides , Piretrinas , Tiazóis , Animais , Tiazóis/farmacologia , Guanidinas/farmacologia , Resistência a Inseticidas/genética , Anopheles/efeitos dos fármacos , Anopheles/genética , Piretrinas/farmacologia , Piretrinas/metabolismo , Neonicotinoides/farmacologia , Inseticidas/farmacologia , Sistema Enzimático do Citocromo P-450/metabolismo , Sistema Enzimático do Citocromo P-450/genética , Especificidade por Substrato , Mosquitos Vetores/efeitos dos fármacos , Mosquitos Vetores/genética , Proteínas de Insetos/metabolismo , Proteínas de Insetos/genéticaRESUMO
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 â¼1.5 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.
Assuntos
Neoplasias da Mama , Proliferação de Células , Guanidinas , Receptor ErbB-2 , Trocador 1 de Sódio-Hidrogênio , Sulfonas , Guanidinas/farmacologia , Feminino , Animais , Receptor ErbB-2/metabolismo , Receptor ErbB-2/genética , Receptor ErbB-2/antagonistas & inibidores , Trocador 1 de Sódio-Hidrogênio/metabolismo , Trocador 1 de Sódio-Hidrogênio/antagonistas & inibidores , Trocador 1 de Sódio-Hidrogênio/genética , Camundongos , Humanos , Sulfonas/farmacologia , Proliferação de Células/efeitos dos fármacos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/genética , Simportadores de Sódio-Bicarbonato/metabolismo , Simportadores de Sódio-Bicarbonato/genética , Simportadores de Sódio-Bicarbonato/antagonistas & inibidores , Linhagem Celular Tumoral , Concentração de Íons de HidrogênioRESUMO
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.
Assuntos
Apoptose , Guanidinas , Fenóis , Espécies Reativas de Oxigênio , Neoplasias de Mama Triplo Negativas , Humanos , Apoptose/efeitos dos fármacos , Neoplasias de Mama Triplo Negativas/patologia , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Linhagem Celular Tumoral , Feminino , Fenóis/farmacologia , Guanidinas/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Sobrevivência Celular/efeitos dos fármacosRESUMO
Patients with diabetes often experience fragile fractures despite normal or higher bone mineral density (BMD), a phenomenon termed the diabetic bone paradox (DBP). The pathogenesis and therapeutics opinions for diabetic bone disease (DBD) are not fully explored. In this study, we utilize two preclinical diabetic models, the leptin receptor-deficient db/db mice (DB) mouse model and the streptozotocin-induced diabetes (STZ) mouse model. These models demonstrate higher BMD and lower mechanical strength, mirroring clinical observations in diabetic patients. Advanced glycation end products (AGEs) accumulate in diabetic bones, causing higher non-enzymatic crosslinking within collagen fibrils. This inhibits intrafibrillar mineralization and leads to disordered mineral deposition on collagen fibrils, ultimately reducing bone strength. Guanidines, inhibiting AGE formation, significantly improve the microstructure and biomechanical strength of diabetic bone and enhance bone fracture healing. Therefore, targeting AGEs may offer a strategy to regulate bone mineralization and microstructure, potentially preventing the onset of DBD.
Assuntos
Densidade Óssea , Diabetes Mellitus Experimental , Produtos Finais de Glicação Avançada , Animais , Produtos Finais de Glicação Avançada/metabolismo , Camundongos , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Experimental/complicações , Biomineralização , Masculino , Camundongos Endogâmicos C57BL , Receptores para Leptina/metabolismo , Receptores para Leptina/genética , Osso e Ossos/metabolismo , Osso e Ossos/patologia , Doenças Ósseas/patologia , Doenças Ósseas/metabolismo , Modelos Animais de Doenças , Colágeno/metabolismo , Complicações do Diabetes/metabolismo , Complicações do Diabetes/patologia , Guanidinas/farmacologiaRESUMO
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.
Assuntos
Osteonecrose da Arcada Osseodentária Associada a Difosfonatos , Ratos Wistar , Animais , Masculino , Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/prevenção & controle , Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/patologia , Ratos , Difosfonatos/farmacologia , Difosfonatos/efeitos adversos , Guanidinas/farmacologia , Guanidinas/uso terapêuticoRESUMO
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/6â¯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.
Assuntos
Ferroptose , Guanidinas , Peroxidação de Lipídeos , Camundongos Endogâmicos C57BL , Fosfolipídeo Hidroperóxido Glutationa Peroxidase , Fibrose Pulmonar , Animais , Ferroptose/efeitos dos fármacos , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/patologia , Camundongos , Peroxidação de Lipídeos/efeitos dos fármacos , Linhagem Celular , Guanidinas/toxicidade , Guanidinas/farmacologia , Masculino , Células Epiteliais Alveolares/efeitos dos fármacos , Células Epiteliais Alveolares/patologia , Cicloexilaminas/farmacologia , Fenilenodiaminas , Quinoxalinas , Compostos de EspiroRESUMO
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.
Assuntos
Anopheles , Resistência a Inseticidas , Inseticidas , Malária , Controle de Mosquitos , Mosquitos Vetores , Piretrinas , Animais , Piretrinas/farmacologia , Anopheles/efeitos dos fármacos , Anopheles/genética , Resistência a Inseticidas/genética , Inseticidas/farmacologia , Controle de Mosquitos/métodos , Camarões , Mosquitos Vetores/efeitos dos fármacos , Mosquitos Vetores/genética , Malária/transmissão , Malária/prevenção & controle , Guanidinas/farmacologia , Nitrilas/farmacologia , Feminino , Tiazóis/farmacologia , Neonicotinoides/farmacologia , HabitaçãoRESUMO
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.
Assuntos
Neoplasias Ovarianas , Feminino , Animais , Humanos , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/metabolismo , Camundongos , Linhagem Celular Tumoral , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Antineoplásicos/química , Compostos de Espiro/farmacologia , Compostos de Espiro/uso terapêutico , Compostos de Espiro/química , Ensaios Antitumorais Modelo de Xenoenxerto , Carcinoma Epitelial do Ovário/tratamento farmacológico , Guanidinas/farmacologia , Guanidinas/uso terapêutico , Guanidinas/química , Peptídeos e Proteínas de Sinalização IntracelularRESUMO
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.
Assuntos
Síndrome Antifosfolipídica , Arginina , Citocinas , Guanidinas , Camundongos Endogâmicos BALB C , Animais , Síndrome Antifosfolipídica/tratamento farmacológico , Síndrome Antifosfolipídica/metabolismo , Arginina/farmacologia , Camundongos , Feminino , Citocinas/metabolismo , Guanidinas/farmacologia , Óxido Nítrico/metabolismo , Líquido da Lavagem Broncoalveolar/química , Modelos Animais de Doenças , Humanos , Interleucina-10/metabolismo , Fator de Necrose Tumoral alfa/metabolismoRESUMO
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.
Assuntos
Anopheles , Guanidinas , Inseticidas , Mosquitos Vetores , Neonicotinoides , Nitrocompostos , Receptores Nicotínicos , Animais , Anopheles/metabolismo , Anopheles/genética , Anopheles/efeitos dos fármacos , Neonicotinoides/farmacologia , Receptores Nicotínicos/metabolismo , Receptores Nicotínicos/genética , Receptores Nicotínicos/química , Inseticidas/farmacologia , Inseticidas/química , Nitrocompostos/farmacologia , Nitrocompostos/química , Guanidinas/farmacologia , Mosquitos Vetores/efeitos dos fármacos , Mosquitos Vetores/genética , Xenopus laevis , Ligantes , Piridinas/farmacologia , Malária/transmissão , Malária/parasitologia , Tiazóis/farmacologia , Tiazóis/química , Tiazóis/metabolismo , Tiazinas/farmacologia , Tiazinas/química , Oócitos/metabolismo , Oócitos/efeitos dos fármacos , Feminino , Proteínas de Insetos/metabolismo , Proteínas de Insetos/genética , Proteínas de Insetos/química , Imidazóis/farmacologia , Imidazóis/químicaRESUMO
A series of thirteen cyclic sulfonyl guanidines were prepared and evaluated against tumor-associated human (h) carbonic anhydrase (CA, EC 4.2.1.1) isoforms hCA IX and hCA XII, as well as against off-target cytosolic isoforms hCA I and hCA II. The compounds reported here were generally inactive against both off-target isoforms (KI>100â µM), while all of them moderately inhibited both target isoforms hCA IX and XII in the submicromolar to micromolar ranges in which KI values spanned from 0.57 to 8.4â µM against hCA IX and from 0.34 to 9.7 against hCA XII. Due to the notable selectivity of the title compounds toward isoforms hCA IX and XII, they can be considered as useful scaffolds for further chemical optimization to develop new highly selective antitumor agents.
Assuntos
Inibidores da Anidrase Carbônica , Anidrases Carbônicas , Guanidinas , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/farmacologia , Inibidores da Anidrase Carbônica/química , Humanos , Anidrases Carbônicas/metabolismo , Relação Estrutura-Atividade , Guanidinas/farmacologia , Guanidinas/síntese química , Guanidinas/química , Estrutura Molecular , Anidrase Carbônica II/antagonistas & inibidores , Anidrase Carbônica II/metabolismo , Anidrase Carbônica IX/antagonistas & inibidores , Anidrase Carbônica IX/metabolismo , Anidrase Carbônica I/antagonistas & inibidores , Anidrase Carbônica I/metabolismo , Relação Dose-Resposta a Droga , Isoenzimas/antagonistas & inibidores , Isoenzimas/metabolismo , Antígenos de Neoplasias/metabolismoRESUMO
Dynamic covalent polymers (DCPs) that strike a balance between high performance and rapid reconfiguration have been a challenging task. For this purpose, a solution is proposed in the form of a new dynamic covalent supramolecular motif-guanidine urea structure (GUAs). GUAs contain complex and diverse chemical structures as well as unique bonding characteristics, allowing guanidine urea supramolecular polymers to demonstrate advanced physical properties. Noncovalent interaction aggregates (NIAs) have been confirmed to form in GUA-DCPs through multistage H-bonding and π-π stacking, resulting in an extremely high Young's modulus of 14 GPa, suggesting remarkable mechanical strength. Additionally, guanamine urea linkages in GUAs, a new type of dynamic covalent bond, provide resins with excellent malleability and reprocessability. Guanamine urea metathesis is validated using small molecule model compounds, and the temperature dependent infrared and rheological behavior of GUA-DCPs following the dissociative exchange mechanism. Moreover, the inherent photodynamic antibacterial properties are extensively verified by antibacterial experiments. Even after undergoing three reprocessing cycles, the antibacterial rate of GUA-DCPs remains above 99% after 24 h, highlighting their long-lasting antibacterial effectiveness. GUA-DCPs with dynamic nature, tuneable composition, and unique combination of properties make them promising candidates for various technological advancements.
Assuntos
Antibacterianos , Guanidina , Ureia , Antibacterianos/farmacologia , Antibacterianos/química , Ureia/química , Ureia/farmacologia , Guanidina/química , Guanidina/farmacologia , Polímeros/química , Polímeros/farmacologia , Guanidinas/química , Guanidinas/farmacologiaRESUMO
Targeting delivery to the infection site and good affinity of vehicle to the bacterial are two main concerns in therapy of bacterial infection, and on-demand release of drug is another important issue. In this work, a liposome drug delivery system (HA/P/BAI-lip) incorporated with baicalein and modified by PHMG and HA was prepared. Several characterizations were conducted to examine the physical properties of liposome. Then it was applied to treatments of MRSA induced dorsal subcutaneous abscess model and the thigh muscle infected model. The presence of guanidine group in HA/P/BAI-lip rendered the liposome satisfactory bacterial target ability and good pH sensitive properties. The lipase secreted by bacterial could promote the hydrolysis of soybean phosphatidylcholine (SPC) in liposome. The modification of HA in HA/P/BAI-lip could lead the drug system to the exact infected site where CD44 was abundant because of inflammation. The low pH microenvironment characteristic of bacterial infection could induce the swelling of liposome following by degradation. Taken together, baicalein could be released selectively at the infected site to exert antibacterial capacity. HA/P/BAI-lip showed impressive antibacterial ability and dramatically decrease the bacterial burden of infection site and alleviate the infiltration of inflammatory cells, facilitating the recovery of infection.
Assuntos
Antibacterianos , Flavanonas , Ácido Hialurônico , Lipossomos , Staphylococcus aureus Resistente à Meticilina , Infecções Estafilocócicas , Lipossomos/química , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Animais , Antibacterianos/farmacologia , Antibacterianos/química , Infecções Estafilocócicas/tratamento farmacológico , Ácido Hialurônico/química , Ácido Hialurônico/farmacologia , Flavanonas/farmacologia , Flavanonas/química , Flavanonas/administração & dosagem , Camundongos , Guanidinas/farmacologia , Guanidinas/química , Concentração de Íons de HidrogênioRESUMO
Spinal cord injury (SCI) is a devastating condition for which effective clinical treatment is currently lacking. During the acute phase of SCI, myriad pathological changes give rise to subsequent secondary injury. The results of our previous studies indicated that treating rats post-SCI with nafamostat mesilate (NM) protected the blood-spinal cord barrier (BSCB) and exerted an antiapoptotic effect. However, the optimal dosage for mice with SCI and the underlying mechanisms potentially contributing to recovery, especially during the acute phase of SCI, have not been determined. In this study, we first determined the optimal dosage of NM for mice post-SCI (5 mg/kg/day). Subsequently, our RNA-seq findings revealed that NM has the potential to inhibit pyroptosis after SCI. These findings were further substantiated by subsequent Western blot (WB) and Immunofluorescence (IF) analyses in vivo. These results indicate that NM can alleviate NLRP3 (NOD-like receptor thermal protein domain associated protein 3)-mediated pyroptosis by modulating the NF-κB signaling pathway and reducing the protein expression levels of NIMA-related kinase 7 (NEK7) and cathepsin B (CTSB). In vitro experimental results supported our in vivo findings, revealing the effectiveness of NM in suppressing pyroptosis induced by adenosine triphosphate (ATP) and lipopolysaccharide (LPS) in BV2 cells. These results underscore the potential of NM to regulate NLRP3-mediated pyroptosis following SCI. Notably, compared with other synthetic compounds, NM exhibits greater versatility, suggesting that it is a promising clinical treatment option for SCI.