RESUMO
Recent data indicate that extracellular ATP affects wound healing efficacy via P2Y2-dependent signaling pathway. In the current work, we propose double-modified ATP analogue-alpha-thio-beta,gamma-methylene-ATP as a potential therapeutic agent for a skin regeneration. For the better understanding of structure-activity relationship, beside tested ATP analogues, the appropriate single-modified derivatives of target compound, such as alpha-thio-ATP and beta,gamma-methylene-ATP, were also tested in the context of their involvement in the activation of ATP-dependent purinergic signaling pathway via the P2Y2 receptor. The diastereomerically pure alpha-thio-modified-ATP derivatives were obtained using the oxathiaphospholane method as separate SP and RP diastereomers. Both the single- and double- modified ATP analogues were then tested for their impact on the viability and migration of human keratinocytes. The involvement of P2Y2-dependent purinergic signaling was analyzed in silico by molecular docking of the tested compounds to the P2Y2 receptor and experimentally by studying intracellular calcium mobilization in the human keratinocytes HaCaT. The effects obtained for ATP analogues were compared with the results for ATP as a natural P2Y2 agonist. To confirm the contribution of the P2Y2 receptor to the observed effects, the tests were also performed in the presence of the selective P2Y2 antagonist-AR-C118925XX. The ability of the alpha-thio-beta,gamma-methylene-ATP to influence cell migration was analyzed in vitro on the model HaCaT and MDA-MB-231 cells by wound healing assay and transwell migration test as well as in vivo using zebrafish system. The impact on tissue regeneration was estimated based on the regrowth rate of cut zebrafish tails. The in vitro and in vivo studies have shown that the SP-alpha-thio-beta,gamma-methylene-ATP analogue promotes regeneration-related processes, making it a suitable agent for enhance wound healing. Performed studies indicated its impact on the cell migration, induction of epithelial-mesenchymal transition and intracellular calcium mobilization. The enhanced regeneration of cut zebrafish tails confirmed the pro-regenerative activity of this ATP analogue. Based on the performed studies, the SP-alpha-thio-beta,gamma-methylene-ATP is proposed as a potential therapeutic agent for wound healing and skin regeneration treatment.
Assuntos
Trifosfato de Adenosina , Queratinócitos , Cicatrização , Peixe-Zebra , Cicatrização/efeitos dos fármacos , Humanos , Trifosfato de Adenosina/metabolismo , Animais , Queratinócitos/efeitos dos fármacos , Queratinócitos/metabolismo , Simulação de Acoplamento Molecular , Movimento Celular/efeitos dos fármacos , Receptores Purinérgicos P2Y2/metabolismo , Transdução de Sinais/efeitos dos fármacos , Cálcio/metabolismo , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
An injectable hydrogel formulation is developed utilizing low- and high-molecular-weight chitosan (LCH and HCH) incorporated with curcumin and α-tocopherol-loaded liposomes (Lip/Cur+Toc). Cur and Toc releases are delayed within the hydrogels. The injectability of hydrogels is proved via rheological analyses. In vitro studies are conducted using human dental pulp stem cells (hDPSCs) and human gingival fibroblasts (hGFs) to examine the biological performance of the hydrogels toward endodontics and periodontics, respectively. The viability of hDPSCs treated with the hydrogels with Lip/Cur+Toc is the highest till day 14, compared to the neat hydrogels. During odontogenic differentiation tests, alkaline phosphatase (ALP) enzyme activity of hDPSCs is induced in the Cur-containing groups. Biomineralization is enhanced mostly with Lip/Cur+Toc incorporation. The viability of hGFs is the highest in HCH combined with Lip/Cur+Toc while wound healing occurs almost 100% in both (Lip/Cur+Toc@LCH and Lip/Cur+Toc@HCH) after 2 days. Antioxidant activity of Lip/Cur+Toc@LCH on hGFs is significantly the highest among the groups. Antimicrobial tests demonstrate that Lip/Cur+Toc@LCH is more effective against Escherichia coli whereas so is Lip/Cur+Toc@HCH against Staphylococcus aureus. The antimicrobial mechanism of the hydrogels is investigated for the first time through various computational models. LCH and HCH loaded with Lip/Cur+Toc are promising candidates with multi-functional features for endodontics and periodontics.
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Proteolysis targeting chimera (PROTACs) provide a novel therapeutic approach that is revolutionizing drug discovery. The success of PROTACs largely depends on the combination of their three fragments: E3 ligase ligand, linker and protein of interest (POI)-targeting ligand. We summarize the pivotal significance of the precise combination of the E3 ligase ligand with the POI-recruiting warhead, which is crucial for the successful execution of cellular processes and achieving the desired outcomes. Therefore, the key to our selection was the use of at least two ligands recruiting two different ligases. This approach enables a direct comparison of the impacts of the specific ligases on target degradation.
Assuntos
Proteólise , Ubiquitina-Proteína Ligases , Ubiquitina-Proteína Ligases/metabolismo , Humanos , Proteólise/efeitos dos fármacos , Ligantes , Proteínas Quinases/metabolismo , Descoberta de Drogas/métodos , AnimaisRESUMO
Among lipids, lysophosphatidylcholines (LPCs) with various fatty acyl chains have been identified as potential agonists of G protein-coupled receptors (GPCRs). Recently, targeting GPCRs has been switched to diabetes and obesity. Concomitantly, our last findings indicate the insulin secretagogue properties of cis and trans palmitoleic acid (16:1, n-7) resulting from GPCR activation, however, associated with different signaling pathways. We here report the synthesis of LPCs bearing two geometrical isomers of palmitoleic acids and investigation of their impact on human pancreatic ß cells viability, insulin secretion, and activation of four GPCRs previously demonstrated to be targeted by free fatty acids and LPCs. Moreover, molecular modeling was exploited to investigate the probable binding sites of tested ligands and calculate their affinity toward GPR40, GPR55, GPR119, and GPR120 receptors.
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Lipase inhibition is one of the directions to control obesity. In vitro assays have confirmed the inhibitory effect of selected xanthophylls, including astaxanthin, fucoxanthinol, fucoxanthin, and neoxanthin. Similarly, an in-silico study also demonstrated the successful inhibition of pancreatic lipase by astaxanthin. Unfortunately, the efficacy of these protocols in the emulsion state typical of lipid digestion remains untested. To address this issue, the current study employed the pH-stat test, which mimics lipid digestion in the gastrointestinal tract, to evaluate native and prepared sea buckthorn and rapeseed oils with varying xanthophyll contents from 0 to 1400 mg/kg oil. Furthermore, a molecular docking of zeaxanthin and violaxanthin (commonly found in plant-based foods), astaxanthin (widely distributed in foods of marine origin) and orlistat (approved as a drug) was performed. The in-silico studies revealed comparable inhibitory potential of all tested xanthophylls (variation from - 8.0 to - 9.3 kcal/mol), surpassing that of orlistat (- 6.5 kcal/mol). Nonetheless, when tested in an emulsified state, the results of pH-stat digestion failed to establish the inhibitory effect of xanthophylls in the digested oils. In fact, lipolysis of native xanthophyll-rich sea buckthorn oil was approximately 22% higher than that of the xanthophyll-low preparation. The key insight derived from this study is that the amphiphilic properties of xanthophylls during the digestion of xanthophyll-rich lipids/meals facilitate emulsion formation, which leads to enhanced fat lipolysis.
Assuntos
Lipase , Xantofilas , Hidrólise , Orlistate , Emulsões , Simulação de Acoplamento Molecular , Xantofilas/farmacologia , Luteína , Lipídeos , Óleos , DigestãoRESUMO
PROTACs represent an emerging field in medicinal chemistry, which has already led to the development of compounds that reached clinical studies. Posttranslational modifications contribute to the complexity of proteomes, with 2846 disease-associated sites. PROTAC field is very advanced in targeting kinases, while its use for enzymes mediating posttranslational modifications of the basic amino acid residues, started to be developed recently. Therefore, we bring together this less popular class of PROTACs, targeting lysine acetyltransferases/deacetylases, lysine and arginine methyltransferases, ADP-ribosyltransferases, E3 ligases, and ubiquitin-specific proteases. We put special emphasis on structural aspects of PROTAC elements to facilitate the lengthy experimental endeavours directed towards developing PROTACs. We will cover the period from the inception of the field, 2017, to April 2023.
Assuntos
Lisina , Quimera de Direcionamento de Proteólise , Arginina , Ubiquitina-Proteína Ligases , Processamento de Proteína Pós-TraducionalRESUMO
Dietary trans-palmitoleic acid (trans 16:1n-7, tPOA), a biomarker for high-fat dairy product intake, has been associated with a lower risk of type 2 diabetes mellitus (T2DM) in some cross-sectional and prospective epidemiological studies. Here, we investigated the insulin secretion-promoting activity of tPOA and compared them with the effects evoked by the cis-POA isomer (cPOA), an endogenous lipokine biosynthesized in the liver and adipose tissue, and found in some natural food sources. The debate about the positive and negative relationships of those two POA isomers with metabolic risk factors and the underlying mechanisms is still going on. Therefore, we examined the potency of both POA isomers to potentiate insulin secretion in murine and human pancreatic ß cell lines. We also investigated whether POA isomers activate G protein-coupled receptors proposed as potential targets for T2DM treatment. We show that tPOA and cPOA augment glucose-stimulated insulin secretion (GSIS) to a similar extent; however, their insulin secretagogue activity is associated with different signaling pathways. We also performed ligand docking and molecular dynamics simulations to predict the preferred orientation of POA isomers and the strength of association between those two fatty acids and GPR40, GPR55, GPR119, and GPR120 receptors. Overall, this study provides insight into the bioactivity of tPOA and cPOA toward selected GPCR functions, indicating them as targets responsible for the insulin secretagogue action of POA isomers. It reveals that both tPOA and cPOA may promote insulin secretion and subsequently regulate glucose homeostasis.
Assuntos
Diabetes Mellitus Tipo 2 , Humanos , Camundongos , Animais , Secreção de Insulina , Diabetes Mellitus Tipo 2/metabolismo , Estudos Prospectivos , Estudos Transversais , Secretagogos de Insulina , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Glucose/metabolismo , Biomarcadores/metabolismo , Insulina/metabolismo , Receptores de Canabinoides/metabolismoRESUMO
Protein prenylation is a post-translational modification controlling the localization, activity, and protein-protein interactions of small GTPases, including the Ras superfamily. This covalent attachment of either a farnesyl (15 carbon) or a geranylgeranyl (20 carbon) isoprenoid group is catalyzed by four prenyltransferases, namely farnesyltransferase (FTase), geranylgeranyltransferase type I (GGTase-I), Rab geranylgeranyltransferase (GGTase-II), and recently discovered geranylgeranyltransferase type III (GGTase-III). Blocking small GTPase activity, namely inhibiting prenyltransferases, has been proposed as a potential disease treatment method. Inhibitors of prenyltransferase have resulted in substantial therapeutic benefits in various diseases, such as cancer, neurological disorders, and viral and parasitic infections. In this review, we overview the structure of FTase, GGTase-I, GGTase-II, and GGTase-III and summarize the current status of research on their inhibitors.
Assuntos
Dimetilaliltranstransferase , Carbono/metabolismo , Dimetilaliltranstransferase/metabolismo , Farnesiltranstransferase , Prenilação de Proteína , TerpenosRESUMO
Rab geranylgeranyltransferase (GGTase-II, RGGT) catalyses the post-translational modification of eukaryotic Rab GTPases, proteins implicated in several pathologies, including cancer, diabetes, neurodegenerative, and infectious diseases. Thus, RGGT inhibitors are believed to be a potential platform for the development of drugs and tools for studying processes related to the abnormal activity of Rab GTPases. Here, a series of new α-phosphonocarboxylates have been prepared in the first attempt of rational design of covalent inhibitors of RGGT derived from non-covalent inhibitors. These compounds were equipped with electrophilic groups capable of binding cysteines, which are present in the catalytic cavity of RGGT. A few of these analogues have shown micromolar activity against RGGT, which correlated with their ability to inhibit the proliferation of the HeLa cancer cell line. The proposed mechanism of this inhibitory activity was rationalised by molecular docking and mass spectrometric measurements, supported by stability and reactivity studies.
Assuntos
Alquil e Aril Transferases , Alquil e Aril Transferases/metabolismo , Células HeLa , Humanos , Simulação de Acoplamento Molecular , Proteínas rab de Ligação ao GTP/metabolismoRESUMO
Sea buckthorn berries contain lipids rich in palmitoleic acid, carotenoids, tocols and sterols, but their composition varies greatly depending on the cultivar and region of cultivation. Therefore, the current study presents the chemical composition of fruit flesh oils of cultivars grown in Poland and compares them with plants grown worldwide. Among tested cultivars, the highest shares of palmitoleic acid were determined in Golden Rain and Luczystaja cvs. Ten grams of sea buckthorn flesh oil provides at least 28% of vitamin A, 50% of vitamin E and 5% of sterols of the recommended dietary allowance (RDA) values for adults. The final part of this study is dedicated to a preliminary study of the optimization of the oleosome yield by the centrifugation method. The maximum oleosome yield can be obtained at a relatively low centrifugal force (below 8000×g), while optimal temperature and time should be laboratory determined for each cultivar.
Assuntos
Hippophae , Carotenoides/análise , Frutas/química , Gotículas Lipídicas/química , PolôniaRESUMO
Nanocellulose deserves special attention among the large group of biocompatible biomaterials. It exhibits good mechanical properties, which qualifies it for potential use as a scaffold imitating cartilage. However, the reconstruction of cartilage is a big challenge due to this tissue's limited regenerative capacity resulting from its lack of vascularization, innervations, and sparsely distributed chondrocytes. This feature restricts the infiltration of progenitor cells into damaged sites. Unfortunately, differentiated chondrocytes are challenging to obtain, and mesenchymal stem cells have become an alternative approach to promote chondrogenesis. Importantly, nanocellulose scaffolds induce the differentiation of stem cells into chondrocyte phenotypes. In this review, we present the recent progress of nanocellulose-based scaffolds promoting the development of cartilage tissue, especially within the emphasis on chondrogenic differentiation and expansion.
RESUMO
A fundamental role of pancreatic ß-cells to maintain proper blood glucose level is controlled by the Ras superfamily of small GTPases that undergo post-translational modifications, including prenylation. This covalent attachment with either a farnesyl or a geranylgeranyl group controls their localization, activity, and protein-protein interactions. Small GTPases are critical in maintaining glucose homeostasis acting in the pancreas and metabolically active tissues such as skeletal muscles, liver, or adipocytes. Hyperglycemia-induced upregulation of small GTPases suggests that inhibition of these pathways deserves to be considered as a potential therapeutic approach in treating T2D. This Perspective presents how inhibition of various points in the mevalonate pathway might affect protein prenylation and functioning of diabetes-affected tissues and contribute to chronic inflammation involved in diabetes mellitus (T2D) development. We also demonstrate the currently available molecular tools to decipher the mechanisms linking the mevalonate pathway's enzymes and GTPases with diabetes.
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores Enzimáticos/farmacologia , Hipoglicemiantes/farmacologia , Proteínas Monoméricas de Ligação ao GTP/antagonistas & inibidores , Animais , Diabetes Mellitus Tipo 2/metabolismo , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/química , Humanos , Hipoglicemiantes/química , Estrutura Molecular , Proteínas Monoméricas de Ligação ao GTP/metabolismo , Relação Estrutura-AtividadeRESUMO
Insulin plays a significant role in carbohydrate homeostasis as the blood glucose lowering hormone. Glucose-induced insulin secretion (GSIS) is augmented by glucagon-like peptide (GLP-1), a gastrointestinal peptide released in response to ingesting nutriments. The secretion of insulin and GLP-1 is mediated by the binding of nutrients to G protein-coupled receptors (GPCRs) expressed by pancreatic ß-cells and enteroendocrine cells, respectively. Therefore, insulin secretagogues and incretin mimetics currently serve as antidiabetic treatments. This study demonstrates the potency of synthetic isoprenoid derivatives of lysophosphatidylcholines (LPCs) to stimulate GSIS and GLP-1 release. Murine insulinoma cell line (MIN6) and enteroendocrinal L cells (GLUTag) were incubated with LPCs bearing geranic acid (1-GA-LPC), citronellic acid (1-CA-LPC), 3,7-dimethyl-3-vinyloct-6-enoic acid (GERA-LPC), and (E)-3,7,11-trimethyl- 3-vinyldodeca-6,10-dienoic acid (1-FARA-LPC). Respective free terpene acids were also tested for comparison. Besides their insulin- and GLP-1-secreting capabilities, we also investigated the cytotoxicity of tested compounds, the ability to intracellular calcium ion mobilization, and targeted GPCRs involved in maintaining lipid and carbohydrate homeostasis. We observed the high cytotoxicity of 1-GERA-LPC and 1-FARA-LPC in contrast 1-CA-LPC and 1-GA-LPC. Moreover, 1-CA-LPC and 1-GA-LPC demonstrated the stimulatory effect on GSIS and 1-CA-LPC augmented GLP-1 secretion. Insulin and GLP-1 release appeared to be GPR40-, GPR55-, GPR119- and GPR120-dependent.
Assuntos
Peptídeo 1 Semelhante ao Glucagon/biossíntese , Secreção de Insulina/efeitos dos fármacos , Insulina/biossíntese , Metabolismo dos Lipídeos/efeitos dos fármacos , Lisofosfatidilcolinas/farmacologia , Receptores Acoplados a Proteínas G/metabolismo , Terpenos/farmacologia , Cálcio/metabolismo , Humanos , Espaço Intracelular/metabolismo , Lisofosfatidilcolinas/química , Estrutura Molecular , Terpenos/químicaRESUMO
Chronic wound healing is currently a severe problem due to its incidence and associated complications. Intensive research is underway on substances that retain their biological activity in the wound microenvironment and stimulate the formation of new blood vessels critical for tissue regeneration. This group includes synthetic compounds with proangiogenic activity. Previously, we identified phosphorothioate analogs of nucleoside 5'-O-monophosphates as multifunctional ligands of P2Y6 and P2Y14 receptors. The effects of a series of unmodified and phosphorothioate nucleotide analogs on the secretion of VEGF from keratinocytes and fibroblasts, as well as their influence on the viability and proliferation of keratinocytes, fibroblasts, and endothelial cells were analyzed. In addition, the expression profiles of genes encoding nucleotide receptors in tested cell models were also investigated. In this study, we defined thymidine 5'-O-monophosphorothioate (TMPS) as a positive regulator of angiogenesis. Preliminary analyses confirmed the proangiogenic potency of TMPS in vivo.
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Espaço Extracelular/química , Fibroblastos/fisiologia , Células Endoteliais da Veia Umbilical Humana/fisiologia , Queratinócitos/fisiologia , Neovascularização Fisiológica , Nucleotídeos/farmacologia , Adulto , Proliferação de Células/efeitos dos fármacos , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Células HaCaT , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Queratinócitos/efeitos dos fármacos , Queratinócitos/metabolismo , Neovascularização Fisiológica/efeitos dos fármacos , Neovascularização Fisiológica/genética , Oligonucleotídeos Fosforotioatos/farmacologia , Receptores Purinérgicos P2Y/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
The impaired spatial arrangement and connections between cells creating islets of Langerhans as well as altered expression of G protein-coupled receptors (GPCRs) often lead to dysfunction of insulin-secreting pancreatic ß cells and can significantly contribute to the development of diabetes. Differences in glucose-stimulated insulin secretion (GSIS) are noticeable not only in diabetic individuals but also in model pancreatic ß cells, e.g., ßTC3 and MIN6 ß cell lines with impaired and normal insulin secretion, respectively. Now, we compare the ability of GPCR agonists (lysophosphatidylcholines bearing fatty acid chains of different lengths) to potentiate GSIS in ßTC3 and MIN6 ß cell models, cultured as adherent monolayers and in a form of pseudoislets (PIs) with pancreatic MS1 endothelial cells. Our aim was also to investigate differences in expression of the GPCRs responsive to LPCs in these experimental systems. Aggregation of ß cells into islet-like structures greatly enhanced the expression of Gpr40, Gpr55, and Gpr119 receptors. In contrast, the co-culture of ßTC3 cells with endothelial cells converted the GPCR expression pattern closer to the pattern observed in MIN6 cells. Additionally, the efficiencies of various LPC species in ßTC3-MS1 PIs also shifted toward the MIN6 cell model.
Assuntos
Betacelulina/metabolismo , Glucose/metabolismo , Secreção de Insulina/fisiologia , Células Secretoras de Insulina/metabolismo , Insulina/metabolismo , Lisofosfatidilcolinas/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , HumanosRESUMO
The migration of chondrocytes from healthy to injured tissues is one of the most important challenges during cartilage repair. Additionally, maintenance of the chondrogenic phenotype remains another limitation, especially during monolayer culture in vitro. Using both the differentiated and undifferentiated chondrogenic ATDC5 cell line, we showed that extracellular nucleotides are able to increase the migration rate of chondrocytes without affecting their chondrogenic phenotype. We checked the potency of natural nucleotides (ATP, ADP, UTP, and UDP) as well as their stable phosphorothioate analogs, containing a sulfur atom in the place of one nonbridging oxygen atom in a phosphate group. We also detected P2y1, P2y2, P2y4, P2y6, P2y12, P2y13, and P2y14 mRNA transcripts for nucleotide receptors, demonstrating that P2y1 and P2y13 are highly upregulated in differentiated ATDC5 cells. We showed that ADPßS, UDPßS, and ADP are the best stimulators of migration of differentiated chondrocytes. Additionally, ADP and ADPßS positively affected the expression of type II collagen, a structural component of the cartilage matrix.
Assuntos
Movimento Celular/efeitos dos fármacos , Condrócitos/metabolismo , Colágeno Tipo II/biossíntese , Regulação da Expressão Gênica/efeitos dos fármacos , Nucleotídeos/farmacologia , Animais , Cartilagem/metabolismo , Linhagem Celular , Matriz Extracelular/metabolismo , Camundongos , Receptores Purinérgicos P2Y/metabolismoRESUMO
Diabetes mellitus is a worldwide health problem with high rates of mortality and morbidity. Management of diabetes mellitus by dietary components is achievable especially at the initial stage of the disease. Several studies confirmed the antidiabetic activities of simple phenolic acids and lysophosphatidylcholine (LPC). The main goal of this study was to identify new potential insulin secretion modulators obtained by combining the structures of two natural compounds, namely O-methyl derivatives of phenolic acids and phospholipids. LPC and phosphatidylcholine bearing methoxylated aromatic carboxylic acids were tested as potential agents able to improve glucose-stimulated insulin secretion (GSIS) and intracellular calcium mobilization in MIN6 ß pancreatic cell line. Our results show that LPC with covalently bonded molecule of p-anisic acid at the sn-1 position was able to induce GSIS and intracellular calcium flux. Notably, 1-anisoyl-2-hydroxy-sn-glycero-3-phosphocholine did not affect the viability of MIN6 cells, suggesting its potential safe use. Furthermore, we have shown that three G protein coupled receptors, namely GPR40, GPR55, and GPR119, are targeted by this LPC derivative.
Assuntos
Ácido Benzoico/farmacologia , Ácidos Carboxílicos/farmacologia , Secreção de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/metabolismo , Lisofosfatidilcolinas/farmacologia , Fosfatidilcolinas/farmacologia , Receptores Acoplados a Proteínas G/metabolismo , Animais , Cálcio/metabolismo , Células Cultivadas , Glucose/farmacologia , Camundongos , Estimulação QuímicaRESUMO
Twelve phosphonopropionates derived from 2-hydroxy-3-imidazo[1,2-a]pyridin-3-yl-2-phosphonopropionic acid (3-IPEHPC) were synthesized and evaluated for their activity as inhibitors of protein geranylgeranylation. The nature of the substituent in the C6 position of imidazo[1,2-a]pyridine ring was responsible for the compound's activity against Rab geranylgeranyl transferase (RGGT). The most active inhibitors disrupted Rab11A prenylation in the human cervical carcinoma HeLa cell line. The esterification of carboxylic acid in the phosphonopropionate moiety turned the inhibitor into an inactive analog.
RESUMO
G protein-coupled receptors (GPCRs) are the most intensively studied drug targets, because of their diversity, cell-specific expression, and druggable sites accessible at the cell surface. Preclinical and clinical studies suggest that targeting GPCRs activated by fatty acid-derived lipids may have potential to improve glucose homeostasis and reduce complications in patients with type 2 diabetes (T2D). Despite the discontinued development of fasiglifam (TAK-875), the first FFA1 agonist to reach late-stage clinical trials, lipid-sensing receptors remain a viable target, albeit with a need for further characterization of their binding mode, intracellular signaling, and toxicity. Herein, we analyze general discovery trends, various signaling pathways, as well as possible challenges following activation of GPCRs that have been validated clinically to control blood glucose levels.
Assuntos
Diabetes Mellitus Tipo 2/metabolismo , Ácidos Graxos/metabolismo , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Animais , Benzofuranos/administração & dosagem , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/genética , Humanos , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Sulfonas/administração & dosagemRESUMO
The article presents the method of preparation of new, stable bacterial cellulose composites with perforated solid materials for biomedical applications, comprising reconstructive surgery of soft and hard tissues. The composites were obtained in specially designed bioreactors equipped with a set of perforated mesh stripes threaded vertically to the culture medium, ensuring perpendicular growth of bacterial nanocellulose synthesized by Komagataeibacter xylinus E25 in stationary culture. The developed biocomposites have been tested for stability and mechanical strength, as well as for their in vitro inflammatory responses shown as mast cell degranulation with N-acetyl-ß-d-hexosaminidase release and mast cell adhesion. The obtained results indicate that the composites components are well integrated after the process of cultivation and purification. Bacterial nanocellulose does not negatively influence mechanical properties of the polypropylene porous mesh, preserving its tensile strength, elasticity, and load. Moreover, application of bacterial cellulose makes the composites less immunogenic as compared to polypropylene itself. Therefore, the composites have the great potential of application in medicine, and depending on the applied porous material, might be used either in hernioplasty (if porous hernia mesh is used), cranioplasty (if perforated metal or polymeric cranial implant is applied), or as a protective barrier in any application that requires biocompatibility or antiadhesive properties improvement. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 107B: 978-987, 2019.