RESUMO
Gut epithelial barrier disruption is commonly observed in Western diseases like diabetes and inflammatory bowel disease (IBD). Enhanced epithelial permeability triggers inflammatory responses and gut microbiota dysbiosis. Reduced bacterial diversity in IBD affects gut microbiota metabolism, altering microbial products such as secondary bile acids (BAs), which potentially play a role in gut barrier regulation and immunity. Dietary fibers such as pectin may substitute effects of these BAs. The study examines transepithelial electrical resistance of gut epithelial T84 cells and the gene expression of tight junctions after exposure to (un)sulfated secondary BAs. This is compared to the impact of the dietary fiber pectin with different degrees of methylation (DM) and blockiness (DB), with disruption induced by calcium ionophore A23187 under both normal and hyperglycemic conditions. Unsulfated lithocholic acid (LCA) and deoxycholic acid (DCA) show a stronger rescuing effect, particularly evident under 20 mM glucose levels. DM19 with high DB (HB) and DM43HB pectin exhibit rescuing effects under both glucose conditions. Notably, DM19HB and DM43HB display higher rescue effects under 20 mM glucose compared to 5 mM glucose. The study demonstrates that specific pectins such as DM19HB and DM43HB may serve as alternatives for preventing barrier disruption in the case of disturbed DCA metabolism.
Assuntos
Ácidos e Sais Biliares , Hiperglicemia , Pectinas , Pectinas/farmacologia , Humanos , Ácidos e Sais Biliares/metabolismo , Ácido Desoxicólico/farmacologia , Mucosa Intestinal/metabolismo , Mucosa Intestinal/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Linhagem Celular , Junções Íntimas/efeitos dos fármacos , Junções Íntimas/metabolismo , Ácido Litocólico/farmacologia , Fibras na Dieta/farmacologia , Glucose/metabolismo , Microbioma Gastrointestinal/efeitos dos fármacos , Permeabilidade/efeitos dos fármacosRESUMO
We evaluated modulation of the immunosuppressive tumor microenvironment in both local and liver metastatic colorectal cancer (LMCC), focusing on tumor-associated macrophages, which are the predominant immunosuppressive cells in LMCC. We developed an orally administered metronomic chemotherapy regimen, oral CAPOX. This regimen combines capecitabine and a nano-micelle encapsulated, lysine-linked deoxycholate and oxaliplatin complex (OPt/LDC-NM). The treatment effectively modulated immune cells within the tumor microenvironment by activating the cGAS-STING pathway and inducing immunogenic cell death. This therapy modulated immune cells more effectively than did capecitabine monotherapy, the current standard maintenance chemotherapy for colorectal cancer. The macrophage-modifying effect of oral CAPOX was mediated via the cGAS-STING pathway. This is a newly identified mode of immune cell activation induced by metronomic chemotherapy. Moreover, oral CAPOX synergized with anti-PD-1 antibody (αPD-1) to enhance the T-cell-mediated antitumor immune response. In the CT26. CL25 subcutaneous model, combination therapy achieved a 91 % complete response rate with a confirmed memory effect against the tumor. This combination also altered the immunosuppressive tumor microenvironment in LMCC, which αPD-1 monotherapy could not achieve. Oral CAPOX and αPD-1 combination therapy outperformed the maximum tolerated dose for treating LMCC, suggesting metronomic therapy as a promising strategy.
Assuntos
Neoplasias Colorretais , Neoplasias Hepáticas , Proteínas de Membrana , Nucleotidiltransferases , Oxaliplatina , Microambiente Tumoral , Microambiente Tumoral/efeitos dos fármacos , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Neoplasias Colorretais/imunologia , Animais , Proteínas de Membrana/metabolismo , Oxaliplatina/farmacologia , Oxaliplatina/uso terapêutico , Oxaliplatina/administração & dosagem , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/imunologia , Administração Oral , Linhagem Celular Tumoral , Nucleotidiltransferases/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Capecitabina/farmacologia , Capecitabina/uso terapêutico , Capecitabina/administração & dosagem , Humanos , Transdução de Sinais/efeitos dos fármacos , Feminino , Ácido Desoxicólico/química , Ácido Desoxicólico/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Macrófagos Associados a Tumor/efeitos dos fármacos , Macrófagos Associados a Tumor/imunologia , Macrófagos Associados a Tumor/metabolismoRESUMO
ABCC3 (also known as MRP3) is an ATP binding cassette transporter for bile acids, whose expression is downregulated in colorectal cancer through the Wnt/ß-catenin signaling pathway. However, it remained unclear how downregulation of ABCC3 expression contributes to colorectal carcinogenesis. We explored the role of ABCC3 in the progression of colorectal cancer-in particular, focusing on the regulation of bile acid export. Gene expression analysis of colorectal adenoma isolated from familial adenomatous polyposis patients revealed that genes related to bile acid secretion including ABCC3 were downregulated as early as at the stage of adenoma formation. Knockdown or overexpression of ABCC3 increased or decreased intracellular concentration of deoxycholic acid, a secondary bile acid, respectively, in colorectal cancer cells. Forced expression of ABCC3 suppressed deoxycholic acid-induced activation of MAPK signaling. Finally, we found that nonsteroidal anti-inflammatory drugs increased ABCC3 expression in colorectal cancer cells, suggesting that ABCC3 could be one of the targets for therapeutic intervention of familial adenomatous polyposis. Our data thus suggest that downregulation of ABCC3 expression contributes to colorectal carcinogenesis through the regulation of intracellular accumulation of bile acids and activity of MAPK signaling.
Assuntos
Neoplasias Colorretais , Ácido Desoxicólico , Regulação Neoplásica da Expressão Gênica , Sistema de Sinalização das MAP Quinases , Proteínas Associadas à Resistência a Múltiplos Medicamentos , Humanos , Polipose Adenomatosa do Colo/metabolismo , Polipose Adenomatosa do Colo/genética , Polipose Adenomatosa do Colo/patologia , Linhagem Celular Tumoral , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Neoplasias Colorretais/genética , Ácido Desoxicólico/farmacologia , Ácido Desoxicólico/metabolismo , Regulação para Baixo , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genéticaRESUMO
Concentrations of the secondary bile acid, deoxycholic acid (DCA), are aberrantly elevated in colorectal cancer (CRC) patients, but the consequences remain poorly understood. Here, we screened a library of gut microbiota-derived metabolites and identified DCA as a negative regulator for CD8+ T cell effector function. Mechanistically, DCA suppressed CD8+ T cell responses by targeting plasma membrane Ca2+ ATPase (PMCA) to inhibit Ca2+-nuclear factor of activated T cells (NFAT)2 signaling. In CRC patients, CD8+ T cell effector function negatively correlated with both DCA concentration and expression of a bacterial DCA biosynthetic gene. Bacteria harboring DCA biosynthetic genes suppressed CD8+ T cells effector function and promoted tumor growth in mice. This effect was abolished by disrupting bile acid metabolism via bile acid chelation, genetic ablation of bacterial DCA biosynthetic pathway, or specific bacteriophage. Our study demonstrated causation between microbial DCA metabolism and anti-tumor CD8+ T cell response in CRC, suggesting potential directions for anti-tumor therapy.
Assuntos
Neoplasias Colorretais , Microbioma Gastrointestinal , Humanos , Camundongos , Animais , Ácidos e Sais Biliares , Ácido Desoxicólico/farmacologia , Linfócitos T CD8-PositivosRESUMO
Deoxycholic acid derivatives containing various heterocyclic functional groups at C-3 on the steroid scaffold were designed and synthesized as promising dual tyrosyl-DNA phosphodiesterase 1 and 2 (TDP1 and TDP2) inhibitors, which are potential targets to potentiate topoisomerase poison antitumor therapy. The methyl esters of DCA derivatives with benzothiazole or benzimidazole moieties at C-3 demonstrated promising inhibitory activity in vitro against TDP1 with IC50 values in the submicromolar range. Furthermore, methyl esters 4d-e, as well as their acid counterparts 3d-e, inhibited the phosphodiesterase activity of both TDP1 and TDP2. The combinations of compounds 3d-e and 4d-e with low-toxic concentrations of antitumor drugs topotecan and etoposide showed significantly greater cytotoxicity than the compounds alone. The docking of the derivatives into the binding sites of TDP1 and TDP2 predicted plausible binding modes of the DCA derivatives.
Assuntos
Inibidores de Fosfodiesterase , Diester Fosfórico Hidrolases , Inibidores de Fosfodiesterase/química , Diester Fosfórico Hidrolases/metabolismo , Modelos Moleculares , Ácido Desoxicólico/farmacologia , Relação Estrutura-AtividadeRESUMO
RESULT: The review delves into the realm of reducing submental fat, presenting a comprehensive analysis of various lipolytic agents used in plastic surgery and dermatology. The introduction establishes the context by defining the key indicators of a youthful neck and emphasizing the significant influence of fat in the aging process, particularly in the submental area. The usage of aminophylline involves subcutaneous injections, facilitating fat breakdown by increasing cyclic adenosine monophosphate and inhibiting adenosine receptors. Hypotonic pharmacologic lipo-dissolution induces fat dissolution via injected compounds under pressure, while lipolytic lymphatic drainage employs hyaluronidase to reduce tissue viscosity, aiding fat circulation. Glycerophosphorylcholine containing choline alfoscerate claims to activate fat metabolism, whereas the utilization of phosphatidylcholine combined with deoxycholate lacks cosmetic approval due to safety concerns. Deoxycholic acid has FDA approval for submental fat reduction, yet its mechanisms remain incompletely understood. Understanding the complex anatomy and mechanisms of lipolytic agents is essential for safe and effective submental fat reduction, despite evolving practices and off-label utilization. Clinical guidelines and references support this discussion, offering insights for safer applications.
Assuntos
Tecido Adiposo , Técnicas Cosméticas , Humanos , Ácido Desoxicólico/farmacologia , Injeções Subcutâneas , Aminofilina/farmacologia , Gordura SubcutâneaRESUMO
OBJECTIVE: Radiogenic skin injury (RSI) is a common complication during cancer radiotherapy or accidental exposure to radiation. The aim of this study is to investigate the metabolism of bile acids (BAs) and their derivatives during RSI. METHODS: Rat skin tissues were irradiated by an X-ray linear accelerator. The quantification of BAs and their derivatives were performed by liquid chromatography-mass spectrometry (LC-MS)-based quantitative analysis. Key enzymes in BA biosynthesis were analyzed from single-cell RNA sequencing (scRNA-Seq) data of RSI in the human patient and animal models. The in vivo radioprotective effect of deoxycholic acid (DCA) was detected in irradiated SD rats. RESULTS: Twelve BA metabolites showed significant differences during the progression of RSI. Among them, the levels of cholic acid (CA), DCA, muricholic acid (MCA), chenodeoxycholic acid (CDCA), glycocholic acid (GCA), glycohyodeoxycholic acid (GHCA), 12-ketolithocholic acid (12-ketoLCA) and ursodeoxycholic acid (UDCA) were significantly elevated in irradiated skin, whereas lithocholic acid (LCA), tauro-ß-muricholic acid (Tß-MCA) and taurocholic acid (TCA) were significantly decreased. Additionally, the results of scRNA-Seq indicated that genes involved in 7a-hydroxylation process, the first step in BA synthesis, showed pronounced alterations in skin fibroblasts or keratinocytes. The alternative pathway of BA synthesis is more actively altered than the classical pathway after ionizing radiation. In the model of rat radiogenic skin damage, DCA promoted wound healing and attenuated epidermal hyperplasia. CONCLUSIONS: Ionizing radiation modulates the metabolism of BAs. DCA is a prospective therapeutic agent for the treatment of RSI.
Assuntos
Ácidos e Sais Biliares , Metabolismo dos Lipídeos , Humanos , Ratos , Animais , Ratos Sprague-Dawley , Ácido Desoxicólico/farmacologia , Radiação IonizanteRESUMO
Deoxycholate (deoxycholic acid) and collagenase are naturally occurring substances whose ability to degrade adipose tissue and collagen respectively has given rise to a variety of therapeutic applications. This article will discuss the indications for the use of deoxycholic acid, primarily its well-established role in the non-surgical reduction of submental fat, with a focus on patient assessment, procedural technique, risks, pitfalls, and key clinical tips. It will also review the indications for collagenase as a degradation therapy, its mechanism of action, and benefits in the management of wound healing, scarring, and adipose tissue modification.
Assuntos
Técnicas Cosméticas , Ácido Desoxicólico , Humanos , Ácido Desoxicólico/farmacologia , Ácido Desoxicólico/uso terapêutico , Injeções Subcutâneas , Tecido Adiposo , Colagenases/uso terapêutico , Gordura SubcutâneaRESUMO
Deoxycholic acid (DCA), lithocholic acid (LCA), and ursodeoxycholic acid (UDCA) are bile acids that may serve as permeation enhancers when incorporated within the nanogel matrix for drug delivery in the inner ear. In this study, thermoresponsive nanogels were formulated with DCA, LCA and UDCA and their rheological properties and biocompatibility were assessed. The impact of nanogel on cellular viability was evaluated via cell viability assay, the impact of nanogels on cellular bioenergetic parameters was estimated by Seahorse mito-stress test and glycolysis-stress test, while the presence of intracellular free radicals was assessed by reactive oxygen species assay. Nanogels showed a high level of biocompatibility after 24-hour exposure to auditory and macrophage cell lines, with minimal cytotoxicity compared to untreated control. Incubation with nanogels did not alter cellular respiration and glycolysis of the auditory cell line but showed possible mitochondrial dysfunction in macrophages, suggesting tissue-dependent effects of bile acids. Bile acid-nanogels had minimal impact on intracellular reactive oxygen species, with LCA demonstrating the most pro-oxidative behaviour. This study suggests that thermoresponsive nanogels with bile acid, particularly DCA and UDCA, may be promising candidates for inner ear drug delivery.
Assuntos
Ácidos e Sais Biliares , Ácido Desoxicólico , Nanogéis , Ácido Desoxicólico/farmacologia , Espécies Reativas de Oxigênio , Ácido Ursodesoxicólico/farmacologia , Ácido Litocólico , Linhagem Celular , MacrófagosRESUMO
BACKGROUND: Commensal bacteria secrete metabolites that reach distant cancer cells through the circulation and influence cancer behavior. Deoxycholic acid (DCA), a hormone-like metabolite, is a secondary bile acid specifically synthesized by intestinal microbes. DCA may have both pro- and antineoplastic effects in cancers. METHODS AND RESULTS: The pancreatic adenocarcinoma cell lines, Capan-2 and BxPC-3, were treated with 0.7 µM DCA, which corresponds to the reference concentration of DCA in human serum. DCA influenced the expression of epithelial to mesenchymal transition (EMT)-related genes, significantly decreased the expression level of the mesenchymal markers, transcription factor 7- like 2 (TCF7L2), snail family transcriptional repressor 2 (SLUG), CLAUDIN-1, and increased the expression of the epithelial genes, zona occludens 1 (ZO-1) and E-CADHERIN, as shown by real-time PCR and Western blotting. Consequently, DCA reduced the invasion capacity of pancreatic adenocarcinoma cells in Boyden chamber experiments. DCA induced the protein expression of oxidative/nitrosative stress markers. Moreover, DCA reduced aldehyde dehydrogenase 1 (ALDH1) activity in an Aldefluor assay and ALDH1 protein level, suggesting that DCA reduced stemness in pancreatic adenocarcinoma. In Seahorse experiments, DCA induced all fractions of mitochondrial respiration and glycolytic flux. The ratio of mitochondrial oxidation and glycolysis did not change after DCA treatment, suggesting that cells became hypermetabolic. CONCLUSION: DCA induced antineoplastic effects in pancreatic adenocarcinoma cells by inhibiting EMT, reducing cancer stemness, and inducing oxidative/nitrosative stress and procarcinogenic effects such as hypermetabolic bioenergetics.
Assuntos
Adenocarcinoma , Antineoplásicos , Neoplasias Pancreáticas , Humanos , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/genética , Transição Epitelial-Mesenquimal , Antineoplásicos/farmacologia , Ácido Desoxicólico/farmacologia , Linhagem Celular Tumoral , Neoplasias PancreáticasRESUMO
In cancer therapy, a drug delivery system (DDS) has been widely studied to achieve selective drug accumulation at the tumor site. However, DDS still has a major drawback in that it requires multistep processes for intracellular delivery, resulting in low efficiency of drug delivery. To overcome this problem, we recently reported a molecular block (MB) that disrupts cancer cell membranes in the cancer microenvironment using deoxycholic acid (DCA). However, the MB showed considerable cytotoxicity even at neutral pH, possibly due to the structural hydrophobic property of DCA. Herein, we focused on selecting the most suitable bile acid for an MB that possessed high responsiveness to the cancer microenvironment without cytotoxicity at neutral pH. Cell viabilities of the free bile acids such as DCA, chenodeoxycholic acid (CDCA), cholic acid (CA), and ursodeoxycholic acid (UDCA) were evaluated at neutral pH (pH = 7.4) and a cancer acidic environment (pH = 6.3-6.5). The half-maximal inhibition concentration (IC50) value of UDCA at pH = 7.4 showed an approximately 7.5-fold higher IC50 value than that at pH = 6.3, whereas the other bile acids yielded less than a 4-fold IC50 value difference between the same pHs. Biocompatible poly(vinyl alcohol) (PVA) was functionalized with UDCA (PVA-UDCA) for the synthesis of higher responsiveness to the cancer microenvironment without cytotoxicity at neutral pH. Importantly, 56% pancreatic cancer cell death was observed at pH = 6.5, whereas only 10% was detected at neutral pH by the PVA-UDCA treatment. However, PVA-DCA indicated almost the same cancer cell death property, independent of pH conditions. These results suggest PVA-UDCA shows great potential for a new class of MB.
Assuntos
Neoplasias , Ácido Ursodesoxicólico , Ácido Ursodesoxicólico/farmacologia , Ácido Ursodesoxicólico/uso terapêutico , Ácido Desoxicólico/farmacologia , Ácido Desoxicólico/metabolismo , Microambiente Tumoral , Ácidos e Sais Biliares/farmacologia , Ácido Cólico/farmacologia , Neoplasias/tratamento farmacológicoRESUMO
Cholic acid (1, CD), deoxycholic (3, DCA), chenodeoxycholic acid (5, CDCA), ursodeoxycholic acid (7, UDCA), and lithocholic acid (9, LCA) were acetylated and converted into their piperazinyl spacered rhodamine B conjugates 16-20. While the parent bile acids showed almost no cytotoxic effects for several human tumor cell lines, the piperazinyl amides were cytostatic but an even superior effect was observed for the rhodamine B conjugates. Extra staining experiments showed these compounds as mitocans; they led to a cell arrest in the G1 phase.
Assuntos
Ácidos e Sais Biliares , Ácido Ursodesoxicólico , Humanos , Ácidos e Sais Biliares/farmacologia , Ácido Cólico/farmacologia , Ácido Ursodesoxicólico/farmacologia , Ácido Quenodesoxicólico , Linhagem Celular Tumoral , Ácido Desoxicólico/farmacologia , Ácidos Cólicos/farmacologiaRESUMO
Introduction: A growing body of evidence indicates that the dysbiosis of both mammary and intestinal microbiota is associated with the initiation and progression of breast tumors. However, the microbial characteristics of patients with breast tumors vary widely across studies, and replicable biomarkers for early-stage breast tumor diagnosis remain elusive. Methods: We demonstrate a machine learning-based method for the analysis of breast tissue and gut microbial differences among patients with benign breast disease, patients with breast cancer (BC), and healthy individuals using 16S rRNA sequence data retrieved from eight studies. QIIME 2.0 and R software (version 3.6.1) were used for consistent processing. A naive Bayes classifier was trained on the RDP v16 reference database to assign taxonomy using the Vsearch software. Results: After re-analyzing with a total of 768 breast tissue samples and 1,311 fecal samples, we confirmed that Halomonas and Shewanella were the most representative genera of BC tissue. Bacteroides are frequently and significantly enriched in the intestines of patients with breast tumor. The areas under the curve (AUCs) of random forest models were 74.27% and 68.08% for breast carcinoma tissues and stool samples, respectively. The model was validated for effectiveness via cohort-to-cohort transfer (average AUC =0.65) and leave-one-cohort-out (average AUC = 0.66). The same BC-associated biomarker Clostridium_XlVa exists in the tissues and the gut. The results of the in-vitro experiments showed that the Clostridium-specific-related metabolite deoxycholic acid (DCA) promotes the proliferation of HER2-positive BC cells and stimulates G0/G1 phase cells to enter the S phase, which may be related to the activation of peptide-O-fucosyltransferase activity functions and the neuroactive ligand-receptor interaction pathway. Discussion: The results of this study will improve our understanding of the microbial profile of breast tumors. Changes in the microbial population may be present in both the tissues and the gut of patients with BC, and specific markers could aid in the early diagnosis of BC. The findings from in-vitro experiments confirmed that Clostridium-specific metabolite DCA promotes the proliferation of BC cells. We propose the use of stool-based biomarkers in clinical application as a non-invasive and convenient diagnostic method.
Assuntos
Neoplasias da Mama , Microbioma Gastrointestinal , Humanos , Feminino , RNA Ribossômico 16S/genética , Teorema de Bayes , Microbioma Gastrointestinal/fisiologia , Clostridium/genética , Fezes , Biomarcadores Tumorais , Ácido Desoxicólico/farmacologiaRESUMO
BACKGROUND: Recent studies have demonstrated that dysfunction of the intestinal barrier is a significant contributing factor to the development of severe acute pancreatitis (SAP). A stable intestinal mucosa barrier functions as a major anatomic and functional barrier, owing to the balance between intestinal epithelial cell (IEC) proliferation and apoptosis. There is some evidence that calcium overload may trigger IEC apoptosis and that calcineurin (CaN)/nuclear factor of activated T-cells (NFAT) signaling might play an important role in calcium-mediated apoptosis. AIM: To investigate the potential mechanisms underlying the therapeutic effect of Qingyi decoction (QYD) in SAP. METHODS: A rat model of SAP was created via retrograde infusion of sodium deoxycholate. Serum levels of amylase, tumor necrosis factor (TNF-α), interleukin (IL)-6, D-lactic acid, and diamine oxidase (DAO); histological changes; and apoptosis of IECs were examined in rats with or without QYD treatment. The expression of the two subunits of CaN and NFAT in intestinal tissue was measured via quantitative real-time polymerase chain reaction and western blotting. For in vitro studies, Caco-2 cells were treated with lipopolysaccharide (LPS) and QYD serum, and then cell viability and intracellular calcium levels were detected. RESULTS: Retrograde infusion of sodium deoxycholate increased the severity of pancreatic and intestinal pathology and the levels of serum amylase, TNF-α, and IL-6. Both the indicators of intestinal mucosa damage (D-lactic acid and DAO) and the levels of IEC apoptosis were elevated in the SAP group. QYD treatment reduced the serum levels of amylase, TNF-α, IL-6, D-lactic acid, and DAO and attenuated the histological findings. IEC apoptosis associated with SAP was ameliorated under QYD treatment. In addition, the protein expression levels of the two subunits of CaN were remarkably elevated in the SAP group, and the NFATc3 gene was significantly upregulated at both the transcript and protein levels in the SAP group compared with the control group. QYD significantly restrained CaN and NFATc3 gene expression in the intestine, which was upregulated in the SAP group. Furthermore, QYD serum significantly decreased the LPS-induced elevation in intracellular free Ca2+ levels and inhibited cell death. CONCLUSION: QYD can exert protective effects against intestinal mucosa damage caused by SAP and the protective effects are mediated, at least partially, by restraining IEC apoptosis via the CaN/NFATc3 pathway.
Assuntos
Amina Oxidase (contendo Cobre) , Pancreatite , Doença Aguda , Amina Oxidase (contendo Cobre)/metabolismo , Amina Oxidase (contendo Cobre)/farmacologia , Amilases , Animais , Células CACO-2 , Calcineurina/efeitos adversos , Calcineurina/metabolismo , Cálcio/metabolismo , Ácido Desoxicólico/metabolismo , Ácido Desoxicólico/farmacologia , Ácido Desoxicólico/uso terapêutico , Medicamentos de Ervas Chinesas , Células Epiteliais/patologia , Humanos , Interleucina-6/metabolismo , Mucosa Intestinal/patologia , Ácido Láctico/metabolismo , Lipopolissacarídeos/farmacologia , Pancreatite/patologia , Ratos , Ratos Sprague-Dawley , Linfócitos T/metabolismo , Fator de Necrose Tumoral alfa/metabolismoRESUMO
A series of deoxycholic acid-chalcone amides were synthesised and tested against the human lung cancer cell line, A549 and the cervical cancer cell line, SiHa. Among the synthesised deoxycholic acid-chalcone conjugates, some conjugates showed encouraging results as anticancer agents with good in vitro activity. More precisely, deoxycholic acid-chalcone conjugates 4b (IC50: 0.51 µM) and 4e (IC50: 0.84 µM) having 2nitrophenyl and 3,4,5trimethoxyphenyl groups exhibited a good activity against human cancer cell-line SiHa and while 4d (IC50: 0.25 µM) and 4b (IC50: 1.71 µM) showed better activity against A549 lung cancer cell line with respect to deoxycholic acid and chalcones. The anticancer activity of the bile acid conjugated chalcones was more than the activity of chalcone and deoxycholic acid alone. The results indicate that a bile acid conjugate strategy may be beneficial in improving the biological activity of chalcone derivatives. The enhanced activity of certain compounds may be due to their increased bioavailability.
Assuntos
Antineoplásicos , Chalcona , Chalconas , Neoplasias Pulmonares , Ácidos e Sais Biliares/farmacologia , Linhagem Celular Tumoral , Proliferação de Células , Chalcona/farmacologia , Chalconas/farmacologia , Ácido Desoxicólico/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Relação Estrutura-AtividadeRESUMO
PURPOSE: Cholecystectomy (XGB) is widely recognized as a risk factor for colon cancer (CC). Continuous exposure of the colonic epithelium to deoxycholic acid (DCA) post-XGB may exert cytotoxic effects and be involved in the progression of CC. However, the functions of the XGB-induced DCA increase and the underlying mechanism remain unclear. METHODS: Colitis-associated CC (CAC) mouse models constructed by AOM-DSS inducement were used to confirm the effect of XGB on the CC progression. Hematoxylin & eosin staining was performed to assess the tumor morphology of CAC mouse models tissues. Various cell biological assays including EdU, live-cell imaging, wound-healing assays, and flow cytometry for cell cycle and apoptosis were used to evaluate the effect of DCA on CC progression. The correlation among XGB, DCA, and CC and their underlying mechanisms were detected with immunohistochemistry, mass spectrometry, transcriptome sequencing, qRT-PCR, and western blotting. RESULTS: Here we proved that XGB increased the plasma DCA level and promoted colon carcinogenesis in a colitis-associated CC mouse model. Additionally, we revealed that DCA promoted the proliferation and migration of CC cells. Further RNA sequencing showed that 120 mRNAs were upregulated, and 118 downregulated in DCA-treated CC cells versus control cells. The upregulated mRNAs were positively correlated with Wnt signaling and cell cycle-associated pathways. Moreover, DCA treatment could reduced the expression of the farnesoid X receptor (FXR) and subsequently increased the levels of ß-Catenin and c-Myc in vitro and in vivo. Moreover, the FXR agonist GW4064 decreased the proliferation of CC cells by repressing the expression of ß-catenin. CONCLUSION: We concluded that XGB-induced DCA exposure could promote the progression of CC by inhibiting FXR expression and enhancing the Wnt-ß-catenin pathway. Video Abstract.
Assuntos
Colecistectomia , Neoplasias do Colo , Ácido Desoxicólico , Via de Sinalização Wnt , Animais , Carcinogênese/genética , Linhagem Celular Tumoral , Proliferação de Células , Colecistectomia/efeitos adversos , Colite/genética , Neoplasias do Colo/etiologia , Neoplasias do Colo/patologia , Ácido Desoxicólico/metabolismo , Ácido Desoxicólico/farmacologia , Regulação Neoplásica da Expressão Gênica , Camundongos , beta Catenina/metabolismoRESUMO
Deoxycholic Acid (DCA), which is an FDA-approved compound for the reduction of submental fat, has evolved through an unanticipated and surprising sequence of events. Initially, it was used as a solvent for Phosphatidylcholine (PDC), which was thought to promote lipolysis, but it was later proven to be the bioactive component of the formula and is currently widely used as Kybella. It has also been used off-label to treat other types of fat deposits like lipomas, HIV lipodystrophy, and excess orbital fat. Despite widespread clinical use, there has been no consensus clarifying the mechanisms of DCA and PDC alone or in combination. Furthermore, despite PDC's removal from the FDA-approved formula, some studies do suggest it plays an important role in fat reduction. To provide some clarity, we conducted a PubMed search and reviewed 41 articles using a comprehensive list of terms in three main categories, using the AND operator: 1) Phosphatidylcholines 2) Deoxycholic Acid, and 3) Lipoma. We isolated articles that studied PDC, DCA, and a PDC/DCA compound using cell biology, molecular and genetic techniques. We divided relevant articles into those that studied these components using histologic techniques and those that utilized specific cell death and lipolysis measurement techniques. Most morphologic studies indicated that PDC/DCA, DCA, and PDC, all induce some type of cell death with accompanying inflammation and fibrosis. Most morphologic studies also suggest that PDC/DCA and DCA alone are non-selective for adipocytes. Biochemical studies describing PDC and DCA alone indicate that DCA acts as a detergent and rapidly induces necrosis while PDC induces TNF-α release, apoptosis, and subsequent enzymatic lipolysis after at least 24 hours. Additional papers have suggested a synergistic effect between the two compounds. Our review integrates the findings of this growing body of literature into a proposed mechanism of fat reduction and provides direction for further studies.
Assuntos
Tecido Adiposo , Substâncias Redutoras , Adipócitos , Ácido Desoxicólico/farmacologia , Humanos , Inflamação/tratamento farmacológico , Substâncias Redutoras/farmacologiaRESUMO
BACKGROUND: Hyodeoxycholic acid (HDCA) is a natural secondary bile acid with enormous pharmacological effects, such as modulating inflammation in neuron. However, whether HDCA could suppress microglial inflammation has not been elucidated yet. AIMS: To determine the anti-microglial inflammatory effect of HDCA in lipopolysaccharide (LPS) models and its mechanisms. METHODS: The effect of HDCA was evaluated in LPS-stimulated BV2 microglial cells in vitro and the cortex of LPS-treated mice in vivo. Immunohistochemistry and immunofluorescence were used to visualize the localization of nuclear factor kappa light-chain enhancer of activated B cells (NF-κB) and ionized calcium-binding adaptor protein-1 (Iba-1), respectively. The mRNA expression of inflammatory cytokines was measured by RT-qPCR. The protein expression of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), takeda G-coupled protein receptor 5 (TGR5), and the phosphorylation of protein kinase B (AKT), NF-κB, and inhibitor of NF-κB protein α (IκBα) was examined by Western blot. RESULTS: HDCA inhibited the inflammatory responses in LPS-treated BV2 cells and in the cortex of LPS-treated mice, evidenced by decreased production of inflammatory mediators such as iNOS, COX-2, tumor necrosis factor (TNF-α), interleukin (IL)-6, and IL-1ß. Further study demonstrated that HDCA repressed the phosphorylation, nuclear translocation, and transcriptional activity of NF-κB and inhibited the activation of AKT in BV-2 cells induced by LPS. Meanwhile, addition of TGR5 inhibitor, triamterene, abolished the effects of HDCA on TGR5, AKT, and NF-κB. CONCLUSION: The present study demonstrated that HDCA prevents LPS-induced microglial inflammation in vitro and in vivo, the action of which is via regulating TGR5/AKT/NF-κB signaling pathway.
Assuntos
Ácido Desoxicólico , NF-kappa B , Proteínas Proto-Oncogênicas c-akt , Receptores Acoplados a Proteínas G , Transdução de Sinais , Animais , Ciclo-Oxigenase 2/metabolismo , Ácido Desoxicólico/farmacologia , Inflamação/metabolismo , Lipopolissacarídeos , Camundongos , Microglia , NF-kappa B/metabolismo , Óxido Nítrico/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Chenodeoxycholic acid and ursodeoxycholic acid (CDCA and UDCA, respectively) have been conjugated with paclitaxel (PTX) anticancer drugs through a high-yield condensation reaction. Bile acid-PTX hybrids (BA-PTX) have been investigated for their pro-apoptotic activity towards a selection of cancer cell lines as well as healthy fibroblast cells. Chenodeoxycholic-PTX hybrid (CDC-PTX) displayed cytotoxicity and cytoselectivity similar to PTX, whereas ursodeoxycholic-PTX hybrid (UDC-PTX) displayed some anticancer activity only towards HCT116 colon carcinoma cells. Pacific Blue (PB) conjugated derivatives of CDC-PTX and UDC-PTX (CDC-PTX-PB and UDC-PTX-PB, respectively) were also prepared via a multistep synthesis for evaluating their ability to enter tumor cells. CDC-PTX-PB and UDC-PTX-PB flow cytometry clearly showed that both CDCA and UDCA conjugation to PTX improved its incoming into HCT116 cells, allowing the derivatives to enter the cells up to 99.9%, respect to 35% in the case of PTX. Mean fluorescence intensity analysis of cell populations treated with CDC-PTX-PB and UDC-PTX-PB also suggested that CDC-PTX-PB could have a greater ability to pass the plasmatic membrane than UDC-PTX-PB. Both hybrids showed significant lower toxicity with respect to PTX on the NIH-3T3 cell line.
Assuntos
Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Ácidos e Sais Biliares/química , Ácidos e Sais Biliares/farmacologia , Paclitaxel/química , Paclitaxel/farmacologia , Animais , Antineoplásicos Fitogênicos/síntese química , Apoptose/efeitos dos fármacos , Ácidos e Sais Biliares/síntese química , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Neoplasias do Colo/tratamento farmacológico , Ácido Desoxicólico/análogos & derivados , Ácido Desoxicólico/síntese química , Ácido Desoxicólico/química , Ácido Desoxicólico/farmacologia , Humanos , Leucemia/tratamento farmacológico , Camundongos , Paclitaxel/análogos & derivados , Paclitaxel/síntese químicaRESUMO
BACKGROUND: Autologous vessels graft (Inner diameter < 6 mm) harvesting always challenged during bypass grafting surgery and its complication shows poor outcome. Tissue engineered vascular graft allow to generate biological graft without any immunogenic complication. The approach presented in this study is to induce graft remodeling through heparin coating in luminal surface of small diameter (Inner diameter < 1 mm) decellularized arterial graft. METHODS: Decellularization of graft was done using SDS, combination of 0.5% sodium dodecyl sulfate and 0.5% sodium deoxycholate and only sodium deoxycholate. Decellularization was confirmed on basis of histology, and DAPI. Characterization of extracellular matrix was analyzed using histology and scanning electron microscopy. Surface modification of decellularized vascular graft was done with heparin coating. Heparin immobilization was evaluated by toluidine blue stain. Heparin-coated graft was transplanted end to end anastomosis in femoral artery in rat. RESULTS: Combination of 0.5% sodium dodecyl sulfate and 0.5% Sodium deoxycholate showed complete removal of xenogeneic cells. The heparin coating on luminal surface showed anti-thrombogenicity and endothelialization. Mechanical testing revealed no significant differences in strain characteristics and modulus between native tissues, decellularized scaffolds and transplanted scaffold. Collectively, this study proposed a heparin-immobilized ECM coating to surface modification offering functionalize biomaterials for developing small-diameter vascular grafts. CONCLUSION: We conclude that xenogeneic decellularized arterial scaffold with heparin surface modification can be fabricated and successfully transplanted small diameter (inner diameter < 1 mm) decellularized arterial graft.