RESUMO
In this study, we explored the role and mechanism of repulsive guidance molecule B (RGMb, also known as Dragon) in the protective effects of curcumin against renal fibrosis and verified Dragon's effect on renal tubular epithelial cell apoptosis and cell programmability. Unilateral ureteral obstruction (UUO) was surgically induced in rats to establish a model of renal interstitial fibrosis (RIF). The rats were then treated with curcumin. Curcumin prominently decreased the serum creatinine (SCr) and blood urea nitrogen (BUN) levels, and also improved the tubular injury in the UUO-induced rats. Curcumin significantly downregulated the TGF-ß1, P-Smad2/3, cleaved caspase-3, cleaved caspase-8 and Dragon levels. Dragon knockdown also markedly reduced the TGF-ß1, P-Smad2/3, Smad2/3, cleaved caspase-3, cleaved caspase-8, fibronectin, collagen I, collagen IV, vimentin, and α-SMA expression levels. Conversely, Dragon overexpression caused higher expression levels of these proteins, and curcumin reversed this effect. Furthermore, Dragon knockdown increased the E-cadherin levels, whereas Dragon overexpression decreased these levels. Overexpressing Dragon significantly decreased the cell viability, and curcumin reversed this effect. In conclusion, curcumin acted on Dragon and attenuated RIF in UUO rat models. Curcumin downregulated the TGF-ß1/Smad signaling pathway and inhibited Dragon and fibrogenic molecules in both rats and HK-2 cells.
Assuntos
Curcumina/farmacologia , Fibrose/tratamento farmacológico , Proteínas Ligadas por GPI/biossíntese , Rim/efeitos dos fármacos , Proteínas do Tecido Nervoso/biossíntese , Receptores de Superfície Celular/biossíntese , Obstrução Ureteral/tratamento farmacológico , Animais , Nitrogênio da Ureia Sanguínea , Caspase 3/metabolismo , Creatinina/metabolismo , Fibrose/metabolismo , Fibrose/patologia , Proteínas Ligadas por GPI/efeitos dos fármacos , Humanos , Rim/metabolismo , Rim/patologia , Masculino , Proteínas do Tecido Nervoso/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Receptores de Superfície Celular/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Fator de Crescimento Transformador beta1/metabolismo , Obstrução Ureteral/metabolismoRESUMO
In this chapter, we will describe a method we set up to synthesize two profluorescent strigolactone (SL) mimic probes (GC240 and GC242) and the optimized protocols developed to study the enzymatic properties of various strigolactone receptors. The Arabidopsis AtD14 SL receptor is used here as a model for this purpose.
Assuntos
Proteínas de Arabidopsis/metabolismo , Arabidopsis/metabolismo , Bioensaio , Corantes Fluorescentes/síntese química , Compostos Heterocíclicos com 3 Anéis/metabolismo , Lactonas/metabolismo , Receptores de Superfície Celular/metabolismo , Arabidopsis/efeitos dos fármacos , Arabidopsis/genética , Proteínas de Arabidopsis/efeitos dos fármacos , Proteínas de Arabidopsis/genética , Ensaios de Triagem em Larga Escala , Medições Luminescentes , Reguladores de Crescimento de Plantas/farmacologia , Receptores de Superfície Celular/efeitos dos fármacos , Receptores de Superfície Celular/genética , Transdução de SinaisRESUMO
Many foods and drinks contain histamine; however, the mechanisms that drive histamine taste perception have not yet been investigated. Here, we use a simple model organism, Drosophila melanogaster, to dissect the molecular sensors required to taste histamine. We first investigated histidine and histamine taste perception by performing a binary food choice assay and electrophysiology to identify essential sensilla for histamine sensing in the labellum. Histamine was found to activate S-type sensilla, which harbor bitter-sensing gustatory receptor neurons. Moreover, unbiased genetic screening for chemoreceptors revealed that a gustatory receptor, GR22e and an ionotropic receptor, IR76b are required for histamine sensing. Ectopic expression of GR22e was sufficient to induce a response in I-type sensilla, which normally do not respond to histamine. Taken together, our findings provide new insights into the mechanisms by which insects discriminate between the toxic histamine and beneficial histidine via their taste receptors.
Assuntos
Proteínas de Drosophila , Histamina , Histidina , Receptores de Superfície Celular , Receptores Ionotrópicos de Glutamato , Animais , Células Quimiorreceptoras/efeitos dos fármacos , Proteínas de Drosophila/efeitos dos fármacos , Proteínas de Drosophila/genética , Proteínas de Drosophila/fisiologia , Drosophila melanogaster/genética , Drosophila melanogaster/fisiologia , Eletrofisiologia , Histamina/farmacologia , Histidina/farmacologia , Receptores de Superfície Celular/efeitos dos fármacos , Receptores de Superfície Celular/genética , Receptores de Superfície Celular/fisiologia , Receptores Ionotrópicos de Glutamato/efeitos dos fármacos , Receptores Ionotrópicos de Glutamato/genética , Receptores Ionotrópicos de Glutamato/fisiologia , Sensilas/efeitos dos fármacos , Sensilas/metabolismo , Canais de Sódio/efeitos dos fármacos , Canais de Sódio/genética , Canais de Sódio/fisiologia , Paladar/genética , Paladar/fisiologiaRESUMO
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes the coronavirus disease 2019 (COVID-19). The World Health Organization (WHO) has announced that COVID-19 is a pandemic having a higher spread rate rather than the mortality. Identification of a potential approach or therapy against COVID-19 is still under consideration. Therefore, it is essential to have an insight into SARS-CoV-2, its interacting partner, and domains for an effective treatment. The present study is divided into three main categories, including SARS-CoV-2 prominent receptor and its expression levels, other interacting partners, and their binding domains. The first section focuses primarily on coronaviruses' general aspects (SARS-CoV-2, SARS-CoV, and the Middle East Respiratory Syndrome Coronaviruses (MERS-CoV)) their structures, similarities, and mode of infections. The second section discusses the host receptors which includes the human targets of coronaviruses like dipeptidyl peptidase 4 (DPP4), CD147, CD209L, Angiotensin-Converting Enzyme 2 (ACE2), and other miscellaneous targets (type-II transmembrane serine proteases (TTSPs), furin, trypsin, cathepsins, thermolysin, elastase, phosphatidylinositol 3-phosphate 5-kinase, two-pore segment channel, and epithelium sodium channel C-α subunit). The human cell receptor, ACE2 plays an essential role in the Renin-Angiotensin system (RAS) pathway and COVID-19. Thus, this section also discusses the ACE2 expression and risk of COVID-19 infectivity in various organs and tissues such as the liver, lungs, intestine, heart, and reproductive system in the human body. Absence of ACE2 protein expression in immune cells could be used for limiting the SARS-CoV-2 infection. The third section covers the current available approaches for COVID-19 treatment. Overall, this review focuses on the critical role of human cell receptors involved in coronavirus pathogenesis, which would likely be used in designing target-specific drugs to combat COVID-19.
Assuntos
Antivirais/farmacologia , Tratamento Farmacológico da COVID-19 , Receptores de Superfície Celular/efeitos dos fármacos , Receptores Virais/efeitos dos fármacos , Antivirais/uso terapêutico , COVID-19/virologia , Humanos , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/isolamento & purificaçãoRESUMO
Most lepidopteran insect larvae exhibit stepwise feeding behaviors, such as palpation using the maxillary palps (MPs) followed by test biting and persistent biting. However, the purpose of palpation has been unclear. In particular, nothing is known about the neurons in the MP and their mode of recognition of undesired plants, although such neurons have been suggested to exist. In this study, we used larvae of the stenophagous insect Bombyx mori and compared the roles of palpation and test biting in the selection of feeding behavior. When the larvae were given non-host plant leaves, they did not initiate test biting, indicating that non-host plant leaves were recognized via palpation without biting, and that this behavior resulted in a lack of persistent biting, as the leaves were judged non-suitable for consumption. Surface extracts of inedible leaves significantly suppressed test biting of mulberry leaves, a host plant of B. mori, suggesting that secondary metabolites on the leaf surface of inedible leaves function as test biting suppressors, even when another conditions are suitable for test biting. The allelochemical coumarin, which is found in the inedible leaves of cherry, Cerasus speciosa, significantly suppressed test biting of mulberry leaves, suggesting that coumarin is a possible deterrent to the eating of cherry leaves. Using the electrophysiological method of tip recording and a leaf-surface extract as the test material, leaf-surface compound-responsive neurons were identified in the MP. In addition, several neurons that respond to coumarin in the attomolar range were identified, suggesting that the larvae use ultrasensitive neurons in the MP to recognize inedible leaves. In the HEK293T cell heterologous expression system, the B. mori gustatory receptors BmGr53 and BmGr19, which were previously found to be expressed in the MP and to respond to coumarin in the attomolar range, responded to a leaf-surface extract of C. speciosa, suggesting that these receptors may be present on the inedible-leaf-recognizing neurons of the MP. These findings suggest that ultrasensitive plant secondary metabolite-recognizing neurons in the MP allow for the recognition of non-host plants via palpation without risking damage caused by ingesting harmful allelochemicals.
Assuntos
Bombyx , Comportamento Alimentar/fisiologia , Feromônios , Percepção Gustatória/fisiologia , Animais , Bombyx/metabolismo , Bombyx/fisiologia , Células Quimiorreceptoras/metabolismo , Cumarínicos/farmacologia , Células HEK293 , Humanos , Larva/metabolismo , Larva/fisiologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Feromônios/farmacologia , Extratos Vegetais/farmacologia , Folhas de Planta/metabolismo , Receptores de Superfície Celular/efeitos dos fármacos , Paladar/fisiologiaRESUMO
Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disorder that primarily affects the joints. One hypothesis for the pathogenesis of RA is that disease begins at mucosal sites as a consequence of interactions between the mucosal immune system and an aberrant local microbiota, and then transitions to involve the synovial joints. Alterations in the composition of the microbial flora in the lungs, mouth and gut in individuals with preclinical and established RA suggest a role for mucosal dysbiosis in the development and perpetuation of RA, although establishing whether these alterations are the specific consequence of intestinal involvement in the setting of a systemic inflammatory process, or whether they represent a specific localization of disease, is an ongoing challenge. Data from mouse models of RA and investigations into the preclinical stages of disease also support the hypothesis that these alterations to the microbiota predate the onset of disease. In addition, several therapeutic options widely used for the treatment of RA are associated with alterations in intestinal microbiota, suggesting that modulation of intestinal microbiota and/or intestinal barrier function might be useful in preventing or treating RA.
Assuntos
Artrite Reumatoide/imunologia , Artrite Reumatoide/microbiologia , Articulações/patologia , Microbiota/imunologia , Mucosa/imunologia , Animais , Antirreumáticos/efeitos adversos , Artrite Reumatoide/metabolismo , Artrite Reumatoide/patologia , Modelos Animais de Doenças , Disbiose/complicações , Disbiose/imunologia , Feminino , Microbioma Gastrointestinal/efeitos dos fármacos , Microbioma Gastrointestinal/imunologia , Humanos , Articulações/imunologia , Masculino , Camundongos , Microbiota/efeitos dos fármacos , Mucosa/microbiologia , Receptores de Superfície Celular/efeitos dos fármacos , Receptores de Superfície Celular/imunologia , Receptores de Superfície Celular/metabolismo , Líquido Sinovial/imunologiaRESUMO
Predictions for target engagement are often used to guide drug development. In particular, when selecting the recommended phase 2 dose of a drug that is very safe, and where good biomarkers for response may not exist (e.g. in immuno-oncology), a receptor occupancy prediction could even be the main determinant in justifying the approved dose, as was the case for atezolizumab. The underlying assumption in these models is that when the drug binds its target, it disrupts the interaction between the target and its endogenous ligand, thereby disrupting downstream signaling. However, the interaction between the target and its endogenous binding partner is almost never included in the model. In this work, we take a deeper look at the in vivo system where a drug binds to its target and disrupts the target's interaction with an endogenous ligand. We derive two simple steady state inhibition metrics (SSIMs) for the system, which provides intuition for when the competition between drug and endogenous ligand should be taken into account for guiding drug development.
Assuntos
Ligação Competitiva , Desenvolvimento de Medicamentos/métodos , Farmacocinética , Farmacologia/métodos , Receptores de Superfície Celular/metabolismo , Receptores de Droga/metabolismo , Humanos , Ligantes , Modelos Estatísticos , Receptores de Superfície Celular/efeitos dos fármacosRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Usnic acid (UA) is one of the well-known lichen metabolites that induces liver injury. It is mainly extracted from Usnea longissima and U. diffracta in China or from other lichens in other countries. U. longissima has been used as traditional Chinese medicine for treatment of cough, pain, indigestion, wound healing and infection. More than 20 incidences with hepatitis and liver failure have been reported by the US Food and Drug Administration since 2000. UA is an uncoupler of oxidative phosphorylation causing glutathione and ATP depletion. Previous histological studies observed extensive cell and organelle swellings accompanied with hydrotropic vacuolization of hepatocytes. AIM OF THE STUDY: This study was to investigate the mechanism of UA-induced liver toxicity in normal human L02 liver cells and ICR mice using various techniques, such as immunoblotting and siRNA transfection. MATERIALS AND METHODS: Assays were performed to evaluate the oxidative stress and levels of GSH, MDA and SOD. Double flouresencence staining was used for the detection of apoptotic cell death. The protein expressions, such as glutathione S transferase, glutathione reductase, glutathione peroxidase 4, catalase, c-Jun N-terminal protein kinase, caspases, gastamin-D and porimin were detected by Western blotting. Comparisons between transfected and non-transfected cells were applied for the elucidation of the role of porimin in UA-induced hepatotoxicity. Histopathological examination of mice liver tissue, serum total bilirubin and hepatic enzymes of alanine aminotransferase and aspatate aminotransferase were also studied. RESULTS: The protein expressions of glutathione reductase, glutathione S transferase and glutathione peroxidase-4 were increased significantly in normal human L02 liver cells. Catalase expression was diminished in dose-dependent manner. Moreover, (+)-UA did not induce the activation of caspase-3, caspase-1 or gasdermin-D. No evidence showed the occurrence of pyroptosis. However, the porimin expressions were increased significantly. In addition, (+)-UA caused no cytotoxicity in the porimin silencing L02 cells. CONCLUSIONS: In conclusion, (+)-UA induces oncotic L02 cell death via increasing protein porimin and the formation of irreversible membrane pores. This may be the potential research area for future investigation in different aspects especially bioactivity and toxicology.
Assuntos
Anti-Infecciosos/toxicidade , Benzofuranos/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Isquemia/metabolismo , Receptores de Superfície Celular/metabolismo , Animais , Inibidores de Caspase/farmacologia , Caspases/metabolismo , Morte Celular/efeitos dos fármacos , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Doença Hepática Induzida por Substâncias e Drogas/patologia , Técnicas de Silenciamento de Genes , Glutationa/metabolismo , Glutationa/farmacologia , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/efeitos dos fármacos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Isquemia/induzido quimicamente , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Fígado/efeitos dos fármacos , Fígado/patologia , Camundongos Endogâmicos ICR , Necrose/induzido quimicamente , Estresse Oxidativo/efeitos dos fármacos , Proteínas de Ligação a Fosfato/metabolismo , Receptores de Superfície Celular/efeitos dos fármacos , Receptores de Superfície Celular/genéticaAssuntos
Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/metabolismo , Inflamação/metabolismo , Sinoviócitos/metabolismo , Animais , Antígenos CD/efeitos dos fármacos , Antígenos CD/metabolismo , Antígenos de Diferenciação Mielomonocítica/efeitos dos fármacos , Antígenos de Diferenciação Mielomonocítica/metabolismo , Artrite Reumatoide/patologia , Variação Biológica da População , Progressão da Doença , Fosfatase 1 de Especificidade Dupla/efeitos dos fármacos , Fosfatase 1 de Especificidade Dupla/metabolismo , Fibroblastos/metabolismo , Glucocorticoides/farmacologia , Humanos , Inflamação/fisiopatologia , Macrófagos/metabolismo , Camundongos , Modelos Animais , Receptor Tipo 1 de Melanocortina/agonistas , Receptor Notch3/metabolismo , Receptores de Superfície Celular/efeitos dos fármacos , Receptores de Superfície Celular/metabolismoRESUMO
Enhanced cancer treatment remains as one of the focused areas for researchers around the world. Hence, the progress in this direction will be a challenge and an opportunity in, inter-disciplinary field to mitigate the suffering of millions in the upcoming decades. As we see, cancer death rate has also progressively increased despite the current impressive treatment regimens but also due to the non-availability of vaccines and the re-occurring of cancer in substantially recovered patients. Currently, numerous treatment strategies like surgical removal of solid tumors followed by radiation with a combination of immunotherapy/chemotherapy by the researchers and clinicians are routinely being followed. However, recurrence and distant metastasis often occur following radiation therapy, commonly due to the generation of radio-resistance through deregulation of the cell cycle, cell death, and inhibition of DNA damage repair mechanisms. Thus, chemotherapeutic/immunotherapeutic treatment systems have progressed remarkably in the latest years owing to destroying tumors, noninvasive, and affordable charge of therapy. But, traditional chemotherapeutic approaches target the DNA of mutated and normal healthy cells, resulting in a significantly increased risk of toxicity and drug resistance. Thus, many receptors targeted therapies are in the developmental phase of discovery. Cancer cells have a specialized set of surface receptors that provide potential targets for cancer therapeutics. Cell surface receptor-dependent endocytosis is well a known major mechanism for the internalization of macromolecular drugs. This review emphasizes the recent development of several surface receptors mediated cancer-targeting approaches for the effective delivery of various therapeutic formulations.
Assuntos
Antineoplásicos/química , Antineoplásicos/uso terapêutico , Sistemas de Liberação de Medicamentos , Neoplasias/tratamento farmacológico , Receptores de Superfície Celular/efeitos dos fármacos , Antineoplásicos/administração & dosagem , Humanos , NanotecnologiaRESUMO
BACKGROUND: Therapies for metabolic diseases are numerous, yet improving insulin sensitivity beyond that induced by weight loss remains challenging. Therefore, search continues for novel treatment candidates that can stimulate insulin sensitivity and increase weight loss efficacy in combination with current treatment options. Calcitonin gene-related peptide (CGRP) and amylin belong to the same peptide family and have been explored as treatments for metabolic diseases. However, their full potential remains controversial. SCOPE OF REVIEW: In this article, we introduce this rather complex peptide family and its corresponding receptors. We discuss the physiology of the peptides with a focus on metabolism and insulin sensitivity. We also thoroughly review the pharmacological potential of amylin, calcitonin, CGRP, and peptide derivatives as treatments for metabolic diseases, emphasizing their ability to increase insulin sensitivity based on preclinical and clinical studies. MAJOR CONCLUSIONS: Amylin receptor agonists and dual amylin and calcitonin receptor agonists are relevant treatment candidates, especially because they increase insulin sensitivity while also assisting weight loss, and their unique mode of action complements incretin-based therapies. However, CGRP and its derivatives seem to have only modest if any metabolic effects and are no longer of interest as therapies for metabolic diseases.
Assuntos
Calcitonina/agonistas , Polipeptídeo Amiloide das Ilhotas Pancreáticas/agonistas , Doenças Metabólicas/tratamento farmacológico , Receptores de Peptídeo Relacionado com o Gene de Calcitonina/agonistas , Animais , Peptídeo Relacionado com Gene de Calcitonina/farmacologia , Humanos , Resistência à Insulina , Obesidade/tratamento farmacológico , Receptores da Calcitonina/agonistas , Receptores de Superfície Celular/efeitos dos fármacos , Redução de PesoRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: The combination of Astragalus membranaceus and Salvia miltiorrhiza (AS) is an effective prescription that is widely used to treat chronic kidney disease (CKD) clinically in traditional Chinese medicine. Our previous studies have shown that AS can alleviate early CKD through the "gut-kidney axis", but the regulatory role of AS in the "gut-kidney axis" in the middle and late stages of CKD caused by cyclosporin A-induced chronic nephrotoxicity (CICN) has remained unclear. AIM OF THE STUDY: To explore the protective effect of AS by regulating the intestinal flora to further control the miRNA-mRNA interaction profiles in CICN. MATERIALS AND METHODS: Thirty-two mice were divided into four groups: Normal (N) (olive oil), Model (M) (CsA, 30 mg kg-1 d-1), AS (CsA + AS, 30 + 8.4 g kg-1 d-1) and FMT-AS (CsA + Faeces of AS group, 30 mg + 10 mL kg-1 d-1). The mice were treated for 6 weeks. Changes in renal function related metabolites were detected, pathological changes in the colon and kidney were observed, and 16S rDNA sequencing was performed on mouse faeces. In addition, miRNA and mRNA sequencing were performed on the kidney to construct differential expression (DE) profiles of the other 3 groups compared with group M. The target mRNAs among the DE miRNAs were then predicted, and an integrated analysis was performed with the DE mRNAs to annotate gene function by KEGG. DE miRNAs and DE mRNAs related to CICN in the overlapping top 20 KEGG pathways were screened and verified. RESULTS: Eight metabolites that could worsen renal function were increased in group M, accompanied by thickening of the glomerular basement membrane, vacuolar degeneration of renal tubules, and proliferation of collagen fibres, while AS and FMT-AS intervention amended these changes to varying degrees. Simultaneously, intestinal permeability increased, the abundance and diversity of the flora decreased, and the ratio of Firmicum to Bacteroides (F/B) increased in group M. The AS and FMT-AS treatments reversed the flora disorder and increased probiotics producing butyric acid and lactic acid, especially Akkermansia and Lactobacillus, which might regulate the 12 overlapping top 20 KEGG pathways, such as Butanoate metabolism, Tryptophan metabolism and several RF-related pathways, leading to the remission of renal metabolism. Finally, 15 DE miRNAs and 45 DE mRNAs were screened as the therapeutic targets, and the results coincided with the sequencing results. CONCLUSION: AS could alleviate renal fibrosis and metabolism caused by CICN through the "gut-kidney axis". Probiotics such as Akkermansia and Lactobacillus were the primary driving factors, and the miRNA-mRNA interaction profiles, especially Butanoate metabolism and Tryptophan metabolism, may be an important subsequent response and regulatory mechanism.
Assuntos
Astragalus propinquus/química , Medicamentos de Ervas Chinesas/farmacologia , Microbioma Gastrointestinal/efeitos dos fármacos , Insuficiência Renal Crônica/tratamento farmacológico , Salvia miltiorrhiza/química , Animais , Ácido Butírico , Colo/efeitos dos fármacos , Colo/metabolismo , Colo/microbiologia , Colo/patologia , Ciclosporina/toxicidade , Medicamentos de Ervas Chinesas/uso terapêutico , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Ácidos Graxos/metabolismo , Transplante de Microbiota Fecal , Perfilação da Expressão Gênica , Regulação da Expressão Gênica/efeitos dos fármacos , Ácido Láctico , Masculino , Medicina Tradicional Chinesa , Camundongos Endogâmicos C57BL , MicroRNAs/efeitos dos fármacos , MicroRNAs/metabolismo , Estresse Oxidativo/efeitos dos fármacos , RNA Mensageiro/efeitos dos fármacos , RNA Mensageiro/metabolismo , Receptores de Superfície Celular/efeitos dos fármacos , Insuficiência Renal Crônica/induzido quimicamente , Insuficiência Renal Crônica/microbiologia , Insuficiência Renal Crônica/patologiaRESUMO
White-backed planthopper (Sogatella furcifera, Hemiptera: Delphacidae) is an important migratory pest of rice. It causes severe economic losses by reducing crop production. Vg and VgR are important proteins that help in the successful reproduction of insects and have been studied in many insects. To understand the molecular mechanisms underlying the effects of insecticides on white-backed planthopper reproduction, we studied the expression profiles of SfVg, SfVg-like, and SfVgR in white-backed planthopper exposed to insecticides. SfVg and SfVgR silencing inhibited the ovarian development, number of eggs laid by, and hatching rate of white-backed planthopper. Thiamethoxam LC10 significantly inhibited SfVg-like and SfVgR expression. In contrast, triazophos LC25 significantly promoted SfVg, SfVg-like, and SfVgR expression and increased vitellogenin content in white-backed planthopper. These results demonstrate that insecticides can regulate the reproduction of white-backed planthopper by altering the expression of SfVg and SfVgR, thereby affecting the population density of white-backed planthopper. These findings build a foundation for improving our understanding of the molecular mechanisms underlying the effects of insecticides on the reproduction and resurgence of pests.
Assuntos
Proteínas do Ovo/efeitos dos fármacos , Hemípteros/efeitos dos fármacos , Inseticidas/farmacologia , Receptores de Superfície Celular/efeitos dos fármacos , Vitelogeninas/efeitos dos fármacos , Animais , Produtos Agrícolas , Proteínas do Ovo/genética , Proteínas do Ovo/metabolismo , Fertilidade/efeitos dos fármacos , Expressão Gênica , Genes de Insetos , Hemípteros/fisiologia , Organotiofosfatos/farmacologia , Oryza , Controle de Pragas , Receptores de Superfície Celular/genética , Receptores de Superfície Celular/metabolismo , Reprodução/efeitos dos fármacos , Tiametoxam/farmacologia , Triazóis/farmacologia , Vitelogeninas/genética , Vitelogeninas/metabolismoRESUMO
This study aims to investigate the global profiling of genes and miRNAs expression to explore the regulatory effects of eicosapentaenoic acid (EPA) in visceral adipose tissue (VAT) of obese mice. We used male mice, fed either a high-fat diet (HF) or HF supplemented with EPA (HF-EPA), for 11 weeks. RNA, and small RNA profiling, were performed by RNAseq analysis. We conducted analyses using Ingenuity Pathway Analysis software (IPA®) and validated candidate genes and miRNAs related to lipid mediators and inflammatory pathways using qRT-PCR. We identified 153 genes differentially downregulated, and 62 microRNAs differentially expressed in VAT from HF-EPA compared to HF. Genes with a positive association with inflammation, chemotaxis, insulin resistance, and inflammatory cell death, such as Irf5, Alox5ap, Tlrs, Cd84, Ccr5, Ccl9, and Casp1, were downregulated by EPA. Moreover, EPA significantly reduced LTB4 levels, a lipid mediator with a central role in inflammation and insulin resistance in obesity. The pathways and mRNA/microRNA interactions identified in our study corroborated with data validated for inflammatory genes and miRNAs. Together, our results identified key VAT inflammatory targets and pathways, which are regulated by EPA. These targets merit further investigation to better understand the protective mechanisms of EPA in obesity-associated inflammation.
Assuntos
Anti-Inflamatórios/farmacologia , Ácido Eicosapentaenoico/farmacologia , Gordura Intra-Abdominal/metabolismo , Animais , Anti-Inflamatórios/uso terapêutico , Dieta Hiperlipídica/efeitos adversos , Ácido Eicosapentaenoico/uso terapêutico , Perfilação da Expressão Gênica , Regulação da Expressão Gênica/efeitos dos fármacos , Redes Reguladoras de Genes/efeitos dos fármacos , Inflamação/metabolismo , Gordura Intra-Abdominal/efeitos dos fármacos , Leucotrieno B4/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Obesos , MicroRNAs/metabolismo , Obesidade/induzido quimicamente , Obesidade/genética , Obesidade/metabolismo , Receptores de Superfície Celular/efeitos dos fármacos , Receptores de Superfície Celular/genética , Transdução de Sinais/efeitos dos fármacos , Transcrição Gênica/efeitos dos fármacos , TranscriptomaRESUMO
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal human malignancies. Gemcitabine and doxorubicin are commonly used as the chemotherapy agents, but most of PDAC tumors eventually acquired resistance to chemotherapy. Accumulating evidence indicates that Insulin-like growth factor binding protein 3 (IGFBP-3) plays a key role against tumor growth but its expression has commonly suppressed. The present study was designed to evaluate IGFBP-3 effects in chemotherapy sensitization of PDAC cells. Here, we report that the re-sensitization of chemoresistant PDAC cells was occurred by IGFBP-3 through recruitment of its death receptor (IGFBP-3R). Using gemcitabine, doxorubicin-resistant PDAC cell lines, we found that IGFBP-3 sensitized chemoresistant cells by activating apoptosis (as evaluated by Bax up-regulation, Bcl-2 down-regulation as well as Caspase-3 and Caspase 8 activation). IGFBP-3R was also found to have higher expression level in resistant AsPc-1 and MIA PaCa-2 cells in comparison to parental cells. IGFBP-3R was also highly expressed in PDAC tumor which exposed to chemotherapy in comparison to un-treated PDAC tumors. In addition, we confirmed our finding by using specific siRNA to knocking down of IGFBP-3R which prevents IGFBP-3 Chemosensitization. Taken together, the present study for the first time indicates the clinical relevance for combining IGFBP-3 with chemotherapy to reduce chemoresistance in PDAC.
Assuntos
Carcinoma Ductal Pancreático/tratamento farmacológico , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/uso terapêutico , Neoplasias Pancreáticas/tratamento farmacológico , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Carcinoma Ductal Pancreático/metabolismo , Caspases/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacologia , Doxorrubicina/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Neoplasias Pancreáticas/metabolismo , RNA Interferente Pequeno/farmacologia , Receptores de Superfície Celular/efeitos dos fármacos , Receptores de Superfície Celular/metabolismo , Receptores de Morte Celular , GencitabinaRESUMO
Osteoarthritis (OA), primarily characterized by articular cartilage destruction, is the most common form of age-related degenerative whole-joint disease. No disease-modifying treatments for OA are currently available. Although OA is primarily characterized by cartilage destruction, our understanding of the processes controlling OA progression is poor. Here, we report the association of OA with increased levels of osteoclast-associated receptor (OSCAR), an immunoglobulin-like collagen-recognition receptor. In mice, OSCAR deletion abrogates OA manifestations, such as articular cartilage destruction, subchondral bone sclerosis, and hyaline cartilage loss. These effects are a result of decreased chondrocyte apoptosis, which is caused by the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in induced OA. Treatments with human OSCAR-Fc fusion protein attenuates OA pathogenesis caused by experimental OA. Thus, this work highlights the function of OSCAR as a catabolic regulator of OA pathogenesis, indicating that OSCAR blockade is a potential therapy for OA.
Assuntos
Apoptose/efeitos dos fármacos , Cartilagem Articular/metabolismo , Condrócitos/metabolismo , Osteoartrite/metabolismo , Osteoclastos/metabolismo , Receptores de Superfície Celular/metabolismo , Idoso , Animais , Cartilagem Articular/patologia , Condrócitos/patologia , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Osteoartrite/tratamento farmacológico , Osteoartrite/patologia , Receptores de Superfície Celular/efeitos dos fármacos , Receptores de Superfície Celular/genética , Ligante Indutor de Apoptose Relacionado a TNF/metabolismoRESUMO
Aseptic loosening induced by osteolysis is recognized as a late complication of joint replacement. Osteoclasts stimulated by Titanium (Ti) nanoparticles play a critical role in periprosthetic osteolysis. Emerging evidence indicates that melatonin, a hormone primarily synthesized by the pineal gland, has been shown an inhibitory effect on osteoclast formation. However, it is unclear whether melatonin could suppress Ti-particle-induced osteoclastogenesis and what the underlying mechanisms were involved in. Herein, we aimed to investigate the effect of melatonin on osteoclast differentiation and osteolysis stimulated by Ti particles. Our results showed that the in vitro osteoclastogenesis of mouse bone marrow monocytes (BMMs) stimulated by Ti particles was suppressed by melatonin treatments in a dose-dependent manner. Further experiments revealed that melatonin up-regulated the expression of the nuclear factor erythroid 2-related factor 2 (Nrf2) and catalase (CAT) at both the mRNA and protein levels. The role of the Nrf2/CAT signaling pathway was confirmed by the fact that silencing the expression of NRF2 by small interfering RNA (siRNA) counteracted the anti-osteolysis effects of melatonin. Furthermore, in vivo intraperitoneal injection of melatonin successfully attenuated periprosthetic osteolysis induced by Ti particles in a murine calvarial model. Our findings demonstrate that melatonin is a promising therapeutic agent for treating periprosthetic osteolysis by inhibiting the Ti-particle-stimulated osteoclastogenesis via activation of the Nrf2/Catalase signaling pathway.
Assuntos
Catalase/metabolismo , Inflamação/tratamento farmacológico , Melatonina/farmacologia , Fator 2 Relacionado a NF-E2/metabolismo , Osteólise/tratamento farmacológico , Actinas/efeitos dos fármacos , Animais , Células da Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/metabolismo , Catalase/genética , Catepsina K/efeitos dos fármacos , Catepsina K/genética , Diferenciação Celular/efeitos dos fármacos , Células Cultivadas , Inflamação/induzido quimicamente , Inflamação/metabolismo , Masculino , Melatonina/uso terapêutico , Camundongos Endogâmicos C57BL , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Fator 2 Relacionado a NF-E2/genética , Osteoclastos/efeitos dos fármacos , Osteogênese/efeitos dos fármacos , Osteólise/induzido quimicamente , Receptores de Superfície Celular/efeitos dos fármacos , Receptores de Superfície Celular/genética , Transdução de Sinais/efeitos dos fármacos , Crânio/efeitos dos fármacos , Crânio/metabolismo , Crânio/patologia , Fosfatase Ácida Resistente a Tartarato/efeitos dos fármacos , Fosfatase Ácida Resistente a Tartarato/genética , Titânio/efeitos adversosRESUMO
Industry screens of large chemical libraries have traditionally relied on rich media to ensure rapid bacterial growth in high-throughput testing. We used eukaryotic, nutrient-limited growth media in a compound screen that unmasked a previously unknown hyperactivity of the old antibiotic, rifabutin (RBT), against highly resistant Acinetobacter baumannii. In nutrient-limited, but not rich, media, RBT was 200-fold more potent than rifampin. RBT was also substantially more effective in vivo. The mechanism of enhanced efficacy was a Trojan horse-like import of RBT, but not rifampin, through fhuE, only in nutrient-limited conditions. These results are of fundamental importance to efforts to discover antibacterial agents.
Assuntos
Acinetobacter baumannii/efeitos dos fármacos , Antibacterianos/farmacologia , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Nutrientes/metabolismo , Rifabutina/farmacologia , Infecções por Acinetobacter/tratamento farmacológico , Infecções por Acinetobacter/microbiologia , Acinetobacter baumannii/genética , Animais , Proteínas de Bactérias/efeitos dos fármacos , Proteínas de Bactérias/genética , Colistina/farmacologia , Modelos Animais de Doenças , Farmacorresistência Bacteriana Múltipla/genética , Deleção de Genes , Regulação Bacteriana da Expressão Gênica , Ensaios de Triagem em Larga Escala , Masculino , Camundongos , Camundongos Endogâmicos C3H , Testes de Sensibilidade Microbiana , Receptores de Superfície Celular/efeitos dos fármacos , Receptores de Superfície Celular/genética , Rifampina/farmacologiaRESUMO
Discriminatory drug delivery into target cells is essential to effectively elicit the drug activity and to avoid off-target side effects; however, transporting drugs across the cell membrane is difficult due to factors such as molecular size, hydrophilicity, intercellular adhesiveness, and efflux transporters, particularly, in the brain capillary endothelial cells. Drug delivery into the brain is blocked by the blood-brain barrier (BBB). Thus, developing drugs for the central nervous system (CNS) diseases remains a challenge. The approach based on receptor-mediated transcytosis (RMT) can overcome this impassable problem at the BBB. Well-designed molecules for RMT form conjugates with the ligand and drugs via linkers or nanoparticles. Cell penetrating peptides (CPPs), receptor-targeting peptides, and monoclonal antibodies (mAbs) are often used as ligands. The binding of ligand to the receptor on the endothelial cell surface induces endocytosis. Existing exosomes comprising the conjugates move in the cytoplasm and fuse with the opposite plasma membrane to release them. Subsequently, the transcytosed conjugate-loaded drugs or released drugs from the conjugates elicit activity in the brain. As receptors, transferrin receptor (TfR), low-density lipoprotein receptor (LDLR), and insulin receptor (InsR) have been used to intendedly induce transcytosis. Presently, several clinical trials on CNS drugs for Alzheimer's and Parkinson disease are hindered due to poor drug distribution into the brain. Therefore, this strategy based on RMT is a promising method for CNS drugs to be transported into the brain. In this review, I introduce the practicality and possibility of drug delivery into brain across the BBB using RMT.
Assuntos
Barreira Hematoencefálica/efeitos dos fármacos , Fármacos do Sistema Nervoso Central/farmacologia , Sistemas de Liberação de Medicamentos , Receptores de Superfície Celular/metabolismo , Transcitose/efeitos dos fármacos , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Animais , Barreira Hematoencefálica/metabolismo , Fármacos do Sistema Nervoso Central/química , Humanos , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/metabolismo , Receptores de Superfície Celular/efeitos dos fármacosRESUMO
The cell surface level of apolipoprotein E receptor 2 (ApoER2) increases by cyclic transport of ApoER2 and then activates Reelin signaling pathway to exert neuroprotective function in AD. ApoER2 ligand Apolipoprotein E4 (ApoE4) inhibits the recycling of ApoER2 to the cell surface rendering neurons unresponsive to Reelin. Carnosic acid (CA) is proven to possess neuroprotective and neurotrophic functions in Alzheimer's disease (AD) mouse model. However, there are few reports about how ApoE4 impairs the recycling of ApoER2 and if CA can affect the cyclic transport of ApoER2. In this study, we demonstrated that ApoE4 attenuates the binding of sorting nexin 17 (SNX17) to ApoER2 and inhibits the recycling of ApoER2, resulting in decreased cell surface level of ApoER2. Further, we found that CA enhances the binding of SNX17 to ApoER2, counteracts the negative effects of ApoE4 on the cell surface level of ApoER2 to reverse the ApoE4-induced reduction in Reelin signaling activation by increasing the phosphorylation of the N-methyl-D-aspartate receptor (NMDAR) and cAMP-response element-binding protein (CREB) and the expression of Gria2. Thus, CA promotes neurite growth inhibited by ApoE4. Our work suggests that CA may be a potential approach to attenuate the risk of ApoE4-associated AD.