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1.
Biomed Pharmacother ; 156: 113952, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36411662

RESUMO

BACKGROUND AND PURPOSE: Although the prevalence of nonalcoholic steatohepatitis (NASH) is rapidly increasing, effective therapy is lacking. Tenofovir alafenamide (TAF) is a widely used antiviral drug for hepatitis B. In this study, we investigated the potential pharmacological effects of TAF on NASH. EXPERIMENTAL APPROACH: Two different NASH mouse models were established: 1) by subcutaneous injection of streptozotocin (0.2 mg) and feeding the mice a high-fat, high-cholesterol (HFHC) diet, and 2) feeding the mice a choline-deficient, L-amino acid-defined, high-fat (CDAHF) diet. KEY RESULTS: Serum alanine aminotransferase and triglyceride levels in TAF-treated NASH mice were significantly lower than those in the mock-treated ones. The livers from the TAF-treated NASH mice showed attenuated mononuclear phagocyte (MP) infiltration compared to those from the mock-treated ones. TAF-treated NASH mice exhibited decreased liver infiltration of activated MPs (IAIE+/PD-L1+/MerTK+). In ex vivo experiments using sorted human CD14+ monocytes treated with lipopolysaccharide (LPS) and/or TAF, we confirmed the decreased level of phosphorylated AKT in TAF-treated LPS-stimulated monocytes compared to that in the mock-treated ones. Mouse liver immunoblotting showed that phosphorylation levels of AKT were significantly lower in the TAF-treated NASH group than in the mock-treated group. CONCLUSION AND IMPLICATIONS: TAF exerts anti-inflammatory effects in NASH livers by attenuating AKT phosphorylation in intrahepatic activated MPs. Therefore, TAF may serve as a new therapeutic option for NASH.


Assuntos
Hepatopatia Gordurosa não Alcoólica , Camundongos , Humanos , Animais , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Proteínas Proto-Oncogênicas c-akt , Fosforilação , Lipopolissacarídeos/farmacologia , Adenina/farmacologia , Dieta Hiperlipídica , Monócitos
2.
Oxid Med Cell Longev ; 2022: 1652244, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36299604

RESUMO

Corilagin, a gallotannin, shows excellent antioxidant and anti-inflammatory effects. The NLRP3 inflammasome dysfunction has been implicated in a variety of inflammation diseases. However, it remains unclear how corilagin regulates the NLRP3 inflammasome to relieve gouty arthritis. In this study, bone marrow-derived macrophages (BMDMs) were pretreated with lipopolysaccharide (LPS) and then incubated with NLRP3 inflammasome agonists, such as adenine nucleoside triphosphate (ATP), nigericin, and monosodium urate (MSU) crystals. The MSU crystals were intra-articular injected to induce acute gouty arthritis. Here we showed that corilagin reduced lactate dehydrogenase (LDH) secretion and the proportion of propidium iodide- (PI-)stained cells. Corilagin suppressed the expression of N-terminal of the pyroptosis executive protein gasdermin D (GSDMD-NT). Corilagin restricted caspase-1 p20 and interleukin (IL)-1ß release. Meanwhile, corilagin attenuated ASC oligomerization and speck formation. Our findings confirmed that corilagin diminished NLRP3 inflammasome activation and macrophage pyroptosis. We further discovered that corilagin limited the mitochondrial reactive oxygen species (ROS) production and prevented the interaction between TXNIP and NLRP3, but ROS activator imiquimod could antagonize the inhibitory function of corilagin on NLRP3 inflammasome and macrophage pyroptosis. Additionally, corilagin ameliorated MSU crystals induced joint swelling, inhibited IL-1ß production, and abated macrophage and neutrophil migration into the joint capsule. Collectively, these results demonstrated that corilagin suppressed the ROS/TXNIP/NLRP3 pathway to repress inflammasome activation and pyroptosis and suggest its potential antioxidative role in alleviating NLRP3-dependent gouty arthritis.


Assuntos
Artrite Gotosa , Piroptose , Humanos , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Taninos Hidrolisáveis/farmacologia , Taninos Hidrolisáveis/uso terapêutico , Lipopolissacarídeos/farmacologia , Artrite Gotosa/tratamento farmacológico , Artrite Gotosa/metabolismo , Ácido Úrico/uso terapêutico , Antioxidantes/farmacologia , Nigericina/farmacologia , Nigericina/uso terapêutico , Imiquimode/farmacologia , Imiquimode/uso terapêutico , Propídio/farmacologia , Propídio/uso terapêutico , Nucleosídeos/farmacologia , Caspase 1/metabolismo , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Interleucina-1beta/metabolismo , Anti-Inflamatórios/farmacologia , Trifosfato de Adenosina/farmacologia , Adenina/farmacologia , Lactato Desidrogenases
3.
Vox Sang ; 117(10): 1163-1170, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36102116

RESUMO

BACKGROUND AND OBJECTIVES: Di-ethyl-hexyl-phthalate (DEHP) is currently the main plasticizer used for whole blood collection systems. However, in Europe, after May 2025, DEHP may no longer be used above 0.1% (w/w) in medical devices. DEHP stabilizes red cell membranes, thereby suppressing haemolysis during storage. Here we compared in vitro quality parameters of red cell concentrates (RCCs) collected and stored in DEHP-, DINCH- or DINCH/BTHC-PVC hybrid blood bags with saline-adenine-glucose-mannitol (SAGM) or phosphate-adenine-glucose-guanosine-saline-mannitol (PAGGSM) storage solution. Last, we performed haemovigilance surveillance for RCC collected in DINCH-PVC and stored in PAGGSM/BTHC-PVC. MATERIALS AND METHODS: In vitro quality parameters of RCC were determined during 42 days of storage. Haemovigilance surveillance was conducted to compare the frequency and type of transfusion reaction. RESULTS: Haemolysis levels were increased in SAGM/BTHC-PVC as compared to SAGM/DEHP-PVC (0.66% ± 0.18% vs. 0.36% ± 0.17%). PAGGSM storage solution was able to adequately suppress haemolysis to levels observed during storage in SAGM/DEHP-PVC, both in BTHC-PVC (0.38% ± 0.12%), and to a slightly lesser extent in DINCH-PVC (0.48% ± 0.17%). A total of 1650 PAGGSM/BTHC-PVC and 5662 SAGM/DEHP-PVC RCC were transfused yielding a transfusion reaction frequency of 0.24% (95% CI 0.0000-0.0048) and 0.44% (95% CI 0.0027-0.0061) respectively. CONCLUSION: The in vitro quality of RCC stored in PAGGSM/BTHC-PVC and SAGM/DEHP-PVC is comparable. There is no indication that transfusion of erythrocytes stored in PAGGSM/BTHC-PVC results in increased transfusion reaction frequency. These initial results provide a basis for further clinical evaluation to narrow down the confidence interval of transfusion reaction frequency.


Assuntos
Carcinoma de Células Renais , Dietilexilftalato , Neoplasias Renais , Reação Transfusional , Adenina/farmacologia , Preservação de Sangue/métodos , Butiratos , Carcinoma de Células Renais/metabolismo , Eritrócitos/metabolismo , Glucose/metabolismo , Guanosina , Hemólise , Humanos , Neoplasias Renais/metabolismo , Manitol/farmacologia , Fosfatos/metabolismo , Plastificantes , Cloreto de Polivinila , Cloreto de Sódio
4.
Mol Nutr Food Res ; 66(22): e2101105, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36059191

RESUMO

SCOPE: Intestinal dysbiosis has been reported to play an important role in the pathogenesis of various diseases, including chronic kidney disease (CKD). Here, to evaluate whether probiotic supplements can have protective effects against kidney injury in an animal model of CKD is aimed. METHODS AND RESULTS: An animal model of CKD is established by feeding C57BL/6 mice a diet containing 0.2% adenine. These model mice are administered Lactobacillus acidophilus KBL409 daily for 4 weeks. Features of adenine-induce CKD (Ade-CKD) mice, such as prominent kidney fibrosis and higher levels of serum creatinine and albuminuria are improved by administration of KBL409. Ade-CKD mice also exhibit a disrupted intestinal barrier and elevate levels of TNF-α, IL-6, and 8-hydroxy-2'-deoxyguanosine. These changes are attenuated by KBL409. Administration of KBL409 significantly reduces macrophage infiltration and promotes a switch to the M2 macrophage phenotype and increasing regulatory T cells. Notably, the NLRP3 inflammasome pathway is activated in the kidneys of Ade-CKD and decreases by KBL409. In primary kidney tubular epithelial cells treated with p-cresyl sulfate, short-chain fatty acids significantly increase M2 macrophage polarization factors and decrease profibrotic markers. CONCLUSIONS: These results demonstrate that supplementation with the probiotic KBL409 has beneficial immunomodulating effects and protects against kidney injury.


Assuntos
Probióticos , Insuficiência Renal Crônica , Camundongos , Animais , Lactobacillus acidophilus , Camundongos Endogâmicos C57BL , Fibrose , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/patologia , Probióticos/farmacologia , Rim/metabolismo , Modelos Animais de Doenças , Adenina/farmacologia , Adenina/metabolismo
5.
Cytokine ; 158: 155977, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-35933851

RESUMO

Adenosine (ADO) generation in the tumor microenvironment (TME) plays important roles in the promotion of tumor growth, invasion, and metastasis and in suppression of the antitumor immune response. Recently, adenosine deaminase (ADA) activity in the TME has been proposed to be a compensatory mechanism against toxic accumulation of ADO in cancerous tissues. In the present study, the expression and functional activity of ADA in cervical cancer (CeCa) tumor cells were analyzed: C33A (HPV-), CaSki (HPV + ), and HeLa (HPV + ) cells. CeCa tumor cells, as well as activated T lymphocytes (ATLs), which were used as a positive control, showed different ADA contents in the membrane and intracellularly and a strong ability to convert ADO into inosine (INO). Treatment of tumor cells with EHNA, a specific ADA inhibitor, decreased the viability of CeCa tumor cells in a dose-dependent manner. In C33A (EHNA half maximal inhibitory concentration (IC50) = 374 µM), CaSki (EHNA IC50 = 273.6 µM), and HeLa (EHNA IC50 = 252.2 µM) cells, EHNA strongly reversed the resistance of tumor cells to the cytotoxic effect of high concentrations of ADO; 38.82 ± 3.1%, 47.18 ± 4.7%, and 71.63 ± 6.9% of the cells were apoptotic, and 40 ± 4.8%, 52 ± 5.3% and 70 ± 6.8% of the cells had mitochondrial membrane damage, respectively. In ATLs (EHNA IC50 = 391.8 µM) treated with EHNA, 32.4 ± 4.4% were apoptotic, and 32 ± 4.3% had mitochondrial membrane damage. These results suggest that the presence and activity of ADA in CeCa tumor cells can provide protection against the cytotoxic effect of high ADO contents in the TME. Therefore, the inhibition of ADA could be a strategy for the treatment of CeCa.


Assuntos
Antineoplásicos , Infecções por Papillomavirus , Neoplasias do Colo do Útero , Adenina/farmacologia , Adenosina/metabolismo , Adenosina/farmacologia , Adenosina Desaminase/metabolismo , Feminino , Humanos , Microambiente Tumoral , Neoplasias do Colo do Útero/tratamento farmacológico
6.
Adv Sci (Weinh) ; 9(30): e2200717, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-36045417

RESUMO

Selective inhibition of targeted protein kinases is an effective therapeutic approach for treatment of human malignancies, which interferes phosphorylation of cellular substrates. However, a drug-imposed selection creates pressures for tumor cells to acquire chemoresistance-conferring mutations or activating alternative pathways, which can bypass the inhibitory effects of kinase inhibitors. Thus, identifying downstream phospho-substrates conferring drug resistance is of great importance for developing poly-pharmacological and targeted therapies. To identify functional phosphorylation sites involved in 5-fluorouracil (5-FU) resistance during its treatment of colorectal cancer cells, CRISPR-mediated cytosine base editor (CBE) and adenine base editor (ABE) are utilized for functional screens by mutating phosphorylated amino acids with two libraries specifically targeting 7779 and 10 149 phosphorylation sites. Among the top enriched gRNAs-induced gain-of-function mutants, the target genes are involved in cell cycle and post-translational covalent modifications. Moreover, several substrates of RSK2 and PAK4 kinases are discovered as main effectors in responding to 5-FU chemotherapy, and combinational treatment of colorectal cancer cells with 5-FU and RSK2 inhibitor or PAK4 inhibitor can largely inhibit cell growth and enhance cell apoptosis through a RSK2/TP53BP1/γ-H2AX phosphorylation signaling axis. It is proposed that this screen approach can be used for functional phosphoproteomics in chemotherapy of various human diseases.


Assuntos
Neoplasias Colorretais , Resistencia a Medicamentos Antineoplásicos , Humanos , Resistencia a Medicamentos Antineoplásicos/genética , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas , Fluoruracila/farmacologia , Fluoruracila/uso terapêutico , Proteínas Quinases/genética , Proteínas Quinases/metabolismo , Proteínas Quinases/farmacologia , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Adenina/farmacologia , Adenina/uso terapêutico , Aminoácidos/genética , Aminoácidos/farmacologia , Aminoácidos/uso terapêutico , Citosina/farmacologia , Citosina/uso terapêutico , Quinases Ativadas por p21/genética , Quinases Ativadas por p21/metabolismo , Quinases Ativadas por p21/farmacologia
7.
Biomater Sci ; 10(15): 4356-4366, 2022 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-35786722

RESUMO

Hepatitis B represents a major global public health burden, which is caused by the hepatitis B virus (HBV) with a high infection rate. Although several anti-HBV drugs have been developed for clinical treatment of hepatitis B, the current therapeutic strategies still suffer from undeniable adverse effects, insufficient efficacy after systemic administration and chronic inflammation. Here, we develop a carrier-free metal-organic hybrid nanoassembly that is co-loaded with tenofovir (TFV), an anti-viral agent and phosphorylated glycyrrhetinic acid (GAP), an anti-inflammatory compound (TFV/GAP/NA) to enhance the anti-HBV effect and alleviate the inflammatory response for hepatitis B treatment. The nanoassembly is easily prepared through the ionic interactions between the anionic phosphonate/phosphate groups from TFV/GAP and the zirconium cation, which has a stable nanostructure and a high drug-loading capacity. The nanoassembly prolongs the circulation time with reduced drug leakage in the blood and elevates drug accumulation in the liver after intravascular administration. After internalization mediated by the GAP ligand-GA receptor interaction, TFV/GAP/NA disassembles by the phosphatase-triggered degradation of the phosphate ester bonds in GAP and releases TFV, GAP and GA within the HBV-positive hepatocytes. The released TFV interferes with the HBV polymerase to inhibit the viral DNA replication, while the released GAP and GA suppress the pro-inflammatory protein expression. In mouse models, treatment with TFV/GAP/NA inhibits HBV production and alleviates inflammation-mediated liver injury.


Assuntos
Antivirais , Hepatite B , Adenina/farmacologia , Animais , Antivirais/farmacologia , Replicação do DNA , DNA Viral/farmacologia , DNA Viral/uso terapêutico , Hepatite B/tratamento farmacológico , Vírus da Hepatite B/metabolismo , Inflamação/tratamento farmacológico , Camundongos , Organofosfatos , Fosfatos , Tenofovir/farmacologia , Tenofovir/uso terapêutico , Replicação Viral
8.
Inflammation ; 45(5): 1895-1910, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35727396

RESUMO

The association between chronic kidney disease (CKD) and pulmonary pathophysiological changes is well stablished. Nevertheless, the effects of aerobic exercise (AE) on lungs of CKD need further clarification. Thus, Swiss mice were divided in control, AE, CKD, and CKD + AE groups. CKD was induced by 0.2% adenine intake during 8 weeks (4 weeks of CKD induction and 4 weeks of AE). AE consisted in running on treadmill, at moderate intensity, 30 min/day, 5 days/week, during 4 weeks. Twenty-four hours after the last training day, functional capacity test was performed, and 48 h after the test, mice were euthanized. CKD mice showed a significant increase in urine output, serum urea, and creatinine concentrations, and decreased body weight and urine density, besides oxidative damage (p = 0.044), edema area (p < 0.001), leukocyte infiltration (p = 0.040), and collagen area in lung tissue (p = 0.004). AE resulted in an increase of distance traveled (p = 0.049) and maximum speed (p = 0.046), increased activity of catalase (p = 0.031) and glutathione peroxidase (p = 0.048) in lungs, increased levels of nitric oxide (NOx) in serum (p = 0.001) and bronchoalveolar lavage fluid (p = 0.047), and decreased kidney histological injury (p = 0.018) of CKD mice. However, AE also increased oxidative damage (p = 0.003) and did not change collagen content or perivascular edema in lungs (p > 0.05) of CKD mice. Therefore, AE attenuated kidney injury and improved antioxidants defenses in lungs. Despite no significant changes in pulmonary damage, AE significantly improved physical performance in CKD mice.


Assuntos
Antioxidantes , Insuficiência Renal Crônica , Adenina/farmacologia , Animais , Antioxidantes/farmacologia , Catalase/metabolismo , Creatinina , Glutationa Peroxidase , Rim/patologia , Pulmão/metabolismo , Camundongos , Óxido Nítrico , Estresse Oxidativo , Desempenho Físico Funcional , Insuficiência Renal Crônica/induzido quimicamente , Insuficiência Renal Crônica/patologia , Ureia/farmacologia
9.
Acta Cir Bras ; 37(3): e370304, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35674582

RESUMO

PURPOSE: To investigate the protective effects of Shenkang injection (SKI) on adenine-induced chronic renal failure (CRF) in rat. METHODS: Sprague Dawley rats were randomly divided into five groups: control, model, and SKI groups (5, 10, 20 mL/kg). Rats in model and SKI groups were treated with adenine i.g. at a dose of 150 mg/kg every day for 12 weeks to induce CRF. Twelve weeks later, SKI was administered to the rat i.p. for four weeks. The effects of SKI on kidney injury and fibrosis were detected. RESULTS: SKI inhibited the elevation of the urine level of N-acetyl-b-D-glucosaminidase, kidney injury molecule-1, beta-2-microglobulin, urea protein in CRF rats. The serum levels of uric acid and serum creatinine increased and albumin decreased in the model group, which was prevented by SKI. SKI inhibited the release of inflammatory cytokines and increasing the activities of antioxidant enzymes in serum. SKI inhibited the expression of transforming growth factor-ß1, vascular cell adhesion molecule 1, intercellular adhesion molecule 1, collagen I, collagen III, endothelin-1, laminin in kidney of CRF rats. CONCLUSIONS: SKI protected against adenine-induced kidney injury and fibrosis and exerted anti-inflammatory, and antioxidant effects in CRF rats.


Assuntos
Falência Renal Crônica , Insuficiência Renal Crônica , Adenina/metabolismo , Adenina/farmacologia , Adenina/uso terapêutico , Animais , Medicamentos de Ervas Chinesas , Fibrose , Rim , Falência Renal Crônica/induzido quimicamente , Falência Renal Crônica/tratamento farmacológico , Falência Renal Crônica/prevenção & controle , Ratos , Ratos Sprague-Dawley , Insuficiência Renal Crônica/tratamento farmacológico
10.
Br J Pharmacol ; 179(16): 4136-4156, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35393682

RESUMO

BACKGROUND AND PURPOSE: Although no effective therapy is available to stop or reverse CKD progression targeting its key feature, the loss of peritubular capillaries (PTCs) leading to interstitial fibrosis, myeloid-derived growth factor (MYDGF) with tissue-repairing activities enlightens its therapeutic potential for CKD. However, the extremely short circulatory lifetime (15 min) restricts its application. EXPERIMENTAL APPROACH: We selected a tandem repeated (TR) region of human CD164 as a carrier to fuse with MYDGF and then investigated for biophysical and pharmacokinetic changes. The MYDGF164 bioactivities were validated in HUVECs and then assessed in HK-2 cells. We also investigated its efficacy in unilateral ureteral obstruction (UUO)-treated mice and in adenine-induced CKD rats. KEY RESULTS: MYDGF164 was modified with sialoglycans, improving its resistance to serum proteases and increasing its hydrodynamic radius. The half-life of MYDGF164 was significantly prolonged but retained its original cell proliferation, anti-apoptosis, and tubulogenesis activities. It selectively stimulated the proliferation in endothelial and epithelial cells through phosphorylating MAPK1/3. MYDGF164 alleviated capillary rarefaction, hypoxia, renal fibrosis, and tubular atrophy in UUO mice and in adenine-induced CKD rats. MYDGF164 restored renal function, with normalized creatinine and urea levels in adenine-induced CKD rats. Histopathology and immunohistochemistry revealed that MYDGF164 protection was related to its cell-proliferative, anti-apoptosis, and angiogenesis activities. CONCLUSIONS AND IMPLICATIONS: This study is the first successful example of using a tandem repeated region of hCD164 as a cargo protein for the pharmacokinetic improvement of therapeutic proteins. Our findings highlight the potential of MYDGF164 in alleviating renal fibrosis in CKD.


Assuntos
Nefropatias , Insuficiência Renal Crônica , Obstrução Ureteral , Adenina/farmacologia , Animais , Modelos Animais de Doenças , Fibrose , Meia-Vida , Humanos , Peptídeos e Proteínas de Sinalização Intercelular , Rim/patologia , Nefropatias/metabolismo , Camundongos , Mucinas/uso terapêutico , Ratos , Insuficiência Renal Crônica/tratamento farmacológico , Obstrução Ureteral/metabolismo
11.
Curr Pharm Des ; 28(8): 661-670, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35366767

RESUMO

BACKGROUND: S-Allylcysteine (SAC), an organosulfur phytochemical sourced from aged garlic extract, is well known for its varied biomedical applications, such as anti-oxidant, anti-inflammatory, and detoxification mechanisms. Despite this, the scientific findings on the defensive impact of SAC against kidney failure (KF) are still unclear. Therefore, in the current investigation, the animal model of KF was induced by adenine in Wistar rats, and the animals were divided into four groups as control, KF induction using adenine, SAC treated KF rats for an experimental duration of 8 weeks. METHODS: KF progression was assessed by various serum and tissue markers, and the results demonstrated that the renal functions' markers, KIM-1 (kidney injury molecule-1), cystatin, NGAL (neutrophil gelatinase-associated lipocalin), were found increased in adenine-treated rats compared to control. In addition, the inflammatory markers, matrix proteins, and fibrosis signatures explicated by RT-PCR, ELISA demonstrated a profound increase. On the other hand, rats received SAC mitigated KF considerably (p < 0.001) with restored cellular functions. Besides, SAC pre-treatment abrogated the cytokines and pro-inflammatory signals (COX-2 and PGE2) in a dose-dependent manner. CONCLUSION: Furthermore, the fibrosis signaling markers mediators, such as SMAD-2,-3 were increased with associated matrix proteins. Thus, the present study substantiated that SAC possesses a significant renoprotective effect that might have been demonstrated by the inhibition of the TGF-ß1/Smad3 signaling pathway.


Assuntos
Falência Renal Crônica , Insuficiência Renal Crônica , Adenina/farmacologia , Idoso , Animais , Cisteína/análogos & derivados , Fibrose , Humanos , Ratos , Ratos Wistar , Proteínas Smad/metabolismo , Proteína Smad3/metabolismo , Fator de Crescimento Transformador beta1/metabolismo
12.
Cells ; 11(8)2022 04 14.
Artigo em Inglês | MEDLINE | ID: mdl-35456016

RESUMO

Bruton's Tyrosine Kinase (BTK) is considered crucial in the activation and survival of both physiological and malignant B-cells. In recent years, ibrutinib, an oral BTK inhibitor, became a breakthrough therapy for hematological malignancies, such as chronic lymphocytic. However, ibrutinib's feasibility might not end there. Several other kinases with established involvement with solid malignancies (i.e., EGFR, HER2) have been found to be inhibited by this agent. Recent discoveries indicate that BTK is a potential anti-solid tumor therapy target. Consequently, ibrutinib, a BTK-inhibitor, has been studied as a therapeutic option in solid malignancies. While most preclinical studies indicate ibrutinib to be an effective therapeutic option in some specific indications, such as NSCLC and breast cancer, clinical trials contradict these observations. Nevertheless, while ibrutinib failed as a monotherapy, it might become an interesting part of a multidrug regime: not only has a synergism between ibrutinib and other compounds, such as trametinib or dactolisib, been observed in vitro, but this BTK inhibitor has also been established as a radio- and chemosensitizer. This review aims to describe the milestones in translating BTK inhibitors to solid tumors in order to understand the future potential of this agent better.


Assuntos
Neoplasias da Mama , Piperidinas , Adenina/análogos & derivados , Adenina/farmacologia , Tirosina Quinase da Agamaglobulinemia , Neoplasias da Mama/patologia , Feminino , Humanos , Piperidinas/farmacologia
13.
Thromb Res ; 212: 72-80, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35247800

RESUMO

BACKGROUND: Bruton's kinase (Btk) is critical for collagen-triggered platelet signal transduction. The Btk inhibitor ibrutinib has been shown to selectively block platelet adhesion to atherosclerotic plaque material under laminar arterial flow. However, this has not been studied under a shear gradient, which is characteristic for atherothrombosis. OBJECTIVE: To determine the effect of ibrutinib treatment on in vitro thrombus formation on collagen and atherosclerotic plaque material in the absence or presence of a shear gradient. METHODS: Blood was obtained from patients with chronic lymphocytic leukemia, mantle-cell lymphoma and Waldenström macroglobulinemia with and without ibrutinib treatment and perfused through a microfluidic channel with(out) 60% stenosis over Horm type I collagen or human atherosclerotic plaque homogenate. RESULTS: At a constant shear rate of 1500 s-1, platelet deposition was significantly decreased in blood from haematological malignancy patients treated with ibrutinib as compared to untreated patients, on atherosclerotic plaque material but not on collagen. However, thrombus size, stability, and height, were reduced on both plaque material and collagen. An increase in shear rate up to 3900 s-1, as induced by 60% stenosis, resulted in decreased platelet deposition and thrombus parameters on plaque material but not on collagen when compared to a laminar shear of 1500 s-1. Ibrutinib treatment decreased platelet deposition and thrombus parameters even further around the stenosis. CONCLUSION: Treatment of patients with haematological disorders with the Btk inhibitor ibrutinib reduces in vitro platelet deposition, thrombus size and contraction on human atherosclerotic plaque around a stenosis when compared to patients not receiving ibrutinib.


Assuntos
Leucemia Linfocítica Crônica de Células B , Piperidinas , Adenina/análogos & derivados , Adenina/farmacologia , Adulto , Constrição Patológica , Humanos , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Piperidinas/farmacologia , Piperidinas/uso terapêutico , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico
14.
Future Med Chem ; 14(8): 557-570, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35332778

RESUMO

Background: Post-translational modifications of histones constitute a dynamic process impacting gene expression. A well-studied modification is lysine methylation. Among the lysine histone methyltransferases, DOT1L is implicated in various diseases, making it a very interesting target for drug discovery. DOT1L has two substrates, the SAM cofactor that gives the methyl group and the lysine H3K79 substrate. Results: Using molecular docking, the authors explored new bisubstrate analogs to enlarge the chemical landscape of DOT1L inhibitors. The authors showed that quinazoline can successfully replace the adenine in the design of bisubstrate inhibitors of DOT1L, showing similar activity compared with the adenine derivative but with diminished cytotoxicity. Conclusion: The docking model is validated together with the use of quinazoline in the design of bisubstrate inhibitors.


Assuntos
Histona-Lisina N-Metiltransferase , Leucemia , Adenina/farmacologia , Antídotos , Histona-Lisina N-Metiltransferase/metabolismo , Humanos , Leucemia/metabolismo , Simulação de Acoplamento Molecular , Quinazolinas/farmacologia
15.
Acta Pharmacol Sin ; 43(10): 2609-2623, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35347248

RESUMO

Renal fibrosis is an unavoidable end result of all forms of progressive chronic kidney diseases (CKD). Discovery of efficacious drugs against renal fibrosis is in crucial need. In a preliminary study we found that a derivative of artemisinin, dihydroartemisinin (DHA), exerted strong renoprotection, and reversed renal fibrosis in adenine-induced CKD mouse model. In this study we investigated the anti-fibrotic mechanisms of DHA, particularly its specific target in renal cells. Renal fibrosis was induced in mice by unilateral ureteral obstruction (UUO) or oral administration of adenine (80 mg · kg-1), the mice received DHA (30 mg · kg-1 · d-1, i.g.) for 14 or 21 days, respectively. We showed that DHA administration markedly attenuated the inflammation and fibrotic responses in the kidneys and significantly improved the renal function in both the renal fibrosis mouse models. In adenine-treated mice, DHA was more effective than 5-azacytidine against renal fibrosis. The anti-fibrotic effects of DHA were also observed in TGF-ß1-treated HK-2 cells. In order to determine the target protein of DHA, we conducted pull-down technology coupled with shotgun proteomics using a small-molecule probe based on the structure of DHA (biotin-DHA). As a results, DNA methyltransferase 1 (DNMT1) was identified as the anti-fibrotic target of DHA in 3 different types of renal cell lines (HK-2, HEK293 and 3T3). We demonstrated that DHA directly bound to Asn 1529 and Thr 1528 of DNMT1 with a Kd value of 8.18 µM. In primary mouse renal tubular cells, we showed that DHA (10 µM) promoted DNMT1 degradation via the ubiquitin-proteasome pathway. DHA-reduced DNMT1 expression effectively reversed Klotho promoter hypermethylation, which led to the reversal of Klotho protein loss in the kidney of UUO mice. This subsequently resulted in inhibition of the Wnt/ß-catenin and TGF-ß/Smad signaling pathways and consequently conferred renoprotection in the animals. Knockdown of Klotho abolished the renoprotective effect of DHA in UUO mice. Our study reveals a novel pharmacological activity for DHA, i.e., renoprotection. DHA exhibits this effect by targeting DNMT1 to reverse Klotho repression. This study provides an evidence for the possible clinical application of DHA in the treatment of renal fibrosis.


Assuntos
Artemisininas , Rim , Insuficiência Renal Crônica , Obstrução Ureteral , Adenina/farmacologia , Animais , Artemisininas/farmacologia , Artemisininas/uso terapêutico , Azacitidina/metabolismo , Azacitidina/farmacologia , Azacitidina/uso terapêutico , Biotina/metabolismo , Biotina/farmacologia , Biotina/uso terapêutico , DNA/metabolismo , Metilases de Modificação do DNA/antagonistas & inibidores , Metilases de Modificação do DNA/metabolismo , Fibrose , Glucuronidase/genética , Células HEK293 , Humanos , Rim/patologia , Proteínas Klotho/efeitos dos fármacos , Proteínas Klotho/metabolismo , Camundongos , Complexo de Endopeptidases do Proteassoma/metabolismo , Insuficiência Renal Crônica/induzido quimicamente , Insuficiência Renal Crônica/tratamento farmacológico , Fator de Crescimento Transformador beta/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Ubiquitinas/metabolismo , Ubiquitinas/farmacologia , Ubiquitinas/uso terapêutico , Obstrução Ureteral/tratamento farmacológico , beta Catenina/metabolismo
16.
N Engl J Med ; 386(8): 735-743, 2022 02 24.
Artigo em Inglês | MEDLINE | ID: mdl-35196427

RESUMO

BACKGROUND: Covalent (irreversible) Bruton's tyrosine kinase (BTK) inhibitors have transformed the treatment of multiple B-cell cancers, especially chronic lymphocytic leukemia (CLL). However, resistance can arise through multiple mechanisms, including acquired mutations in BTK at residue C481, the binding site of covalent BTK inhibitors. Noncovalent (reversible) BTK inhibitors overcome this mechanism and other sources of resistance, but the mechanisms of resistance to these therapies are currently not well understood. METHODS: We performed genomic analyses of pretreatment specimens as well as specimens obtained at the time of disease progression from patients with CLL who had been treated with the noncovalent BTK inhibitor pirtobrutinib. Structural modeling, BTK-binding assays, and cell-based assays were conducted to study mutations that confer resistance to noncovalent BTK inhibitors. RESULTS: Among 55 treated patients, we identified 9 patients with relapsed or refractory CLL and acquired mechanisms of genetic resistance to pirtobrutinib. We found mutations (V416L, A428D, M437R, T474I, and L528W) that were clustered in the kinase domain of BTK and that conferred resistance to both noncovalent BTK inhibitors and certain covalent BTK inhibitors. Mutations in BTK or phospholipase C gamma 2 (PLCγ2), a signaling molecule and downstream substrate of BTK, were found in all 9 patients. Transcriptional activation reflecting B-cell-receptor signaling persisted despite continued therapy with noncovalent BTK inhibitors. CONCLUSIONS: Resistance to noncovalent BTK inhibitors arose through on-target BTK mutations and downstream PLCγ2 mutations that allowed escape from BTK inhibition. A proportion of these mutations also conferred resistance across clinically approved covalent BTK inhibitors. These data suggested new mechanisms of genomic escape from established covalent and novel noncovalent BTK inhibitors. (Funded by the American Society of Hematology and others.).


Assuntos
Tirosina Quinase da Agamaglobulinemia/genética , Resistencia a Medicamentos Antineoplásicos/genética , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Mutação , Fosfolipase C gama/genética , Inibidores de Proteínas Quinases/uso terapêutico , Adenina/análogos & derivados , Adenina/farmacologia , Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Tirosina Quinase da Agamaglobulinemia/ultraestrutura , Humanos , Pessoa de Meia-Idade , Piperidinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Receptores de Antígenos de Linfócitos B/metabolismo , Análise de Sequência de RNA , Transdução de Sinais/efeitos dos fármacos
17.
Sci Rep ; 12(1): 2711, 2022 02 17.
Artigo em Inglês | MEDLINE | ID: mdl-35177646

RESUMO

Cancer stem cells (CSCs) are suggested to be responsible for drug resistance and aggressive phenotypes of tumors. Mechanisms of CSC induction are still under investigation. Our lab has established a novel method to generate CSCs from iPSCs under a cancerous microenvironment mimicked by the conditioned medium (CM) of cancer-derived cells. Here, we analyzed the transcriptome of CSCs, which were converted from iPSCs with CM from pancreatic ductal adenocarcinoma cells. The differentially expressed genes were identified and used to explore pathway enrichment. From the comparison of the CSCs with iPSCs, genes with elevated expression were related to the ErbB2/3 signaling pathway. Inhibition of either ErbB2 with lapatinib as a tyrosine kinase inhibitor or ErbB3 with TX1-85-1 or siRNAs arrested cell proliferation, inhibited the in vitro tumorigenicity, and lead to loss of stemness in the converting cells. The self-renewal and tube formation abilities of cells were also abolished while CD24 and Oct3/4 levels were reduced, and the MAPK pathway was overactivated. This study shows a potential involvement of the ErbB2/ErbB3 pathway in CSC generation and could lead to new insight into the mechanism of tumorigenesis and the way of cancer prevention.


Assuntos
Células-Tronco Pluripotentes Induzidas/metabolismo , Células-Tronco Neoplásicas/metabolismo , Receptor ErbB-2/metabolismo , Receptor ErbB-3/metabolismo , Acrilamidas/farmacologia , Adenina/análogos & derivados , Adenina/farmacologia , Carcinoma Ductal Pancreático/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Autorrenovação Celular/efeitos dos fármacos , Meios de Cultivo Condicionados , Regulação Neoplásica da Expressão Gênica , Humanos , Lapatinib/farmacologia , Sistema de Sinalização das MAP Quinases , Neoplasias Pancreáticas/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Receptor ErbB-2/antagonistas & inibidores , Receptor ErbB-3/antagonistas & inibidores , Receptor ErbB-3/genética , Transdução de Sinais
18.
Mol Med Rep ; 25(2)2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-35014689

RESUMO

Triple­negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, and it often becomes resistant to paclitaxel (PTX) therapy. Autophagy plays an important cytoprotective role in PTX­induced tumor cell death, and targeting autophagy has been promising for improving the efficacy of tumor chemotherapy in recent years. The aim of the present study was to clarify the mechanism of PTX inducing autophagy in TNBC cells to provide a potential clinical chemotherapy strategy of PTX for TNBC. The present study reported that PTX induced both apoptosis and autophagy in MDA­MB­231 cells and that inhibition of autophagy promoted apoptotic cell death. Furthermore, it was found that forkhead box transcription factor O1 (FOXO1) enhanced PTX­induced autophagy through a transcriptional activation pattern in MDA­MB­231 cells, which was associated with the downstream target genes autophagy related 5, class III phosphoinositide 3­kinase vacuolar protein sorting 34, autophagy related 4B cysteine peptidase, beclin 1 and microtubule associated protein 1 light chain 3ß. Knocking down FOXO1 attenuated the survival of MDA­MB­231 cells in response to PTX treatment. These findings may be beneficial for improving the treatment efficacy of PTX and to develop autophagic targeted therapy for TNBC.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Proteína Forkhead Box O1/metabolismo , Paclitaxel/farmacologia , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/metabolismo , Adenina/análogos & derivados , Adenina/farmacologia , Proteína 5 Relacionada à Autofagia/metabolismo , Proteína Beclina-1/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Classe III de Fosfatidilinositol 3-Quinases/metabolismo , Cisteína Endopeptidases/metabolismo , Resistencia a Medicamentos Antineoplásicos/fisiologia , Proteína Forkhead Box O1/genética , Humanos , Proteínas Associadas aos Microtúbulos/metabolismo
19.
Int J Biol Sci ; 18(1): 166-179, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34975325

RESUMO

The use of large molecules for immunotherapy has led to exciting developments in cancer treatment, such as the development of PD-1/PD-L1 antibodies. However, small molecule targeted therapies still lack effective immune-functional classes. Ideal anticancer drugs should simultaneously generate immune memory when killing cancer cells to prevent tumor relapse and metastasis. To this end, we carried out a rationally designed strategy to develop novel classes of small molecule compounds with bifunctional targeting and immunostimulatory abilities by conjugating targeting compounds with TLR7 agonists, generating immune-targeting conjugates (ImmunTacs). GY161, as a representative ImmunTac, was synthesized via chemical conjugation of ibrutinib with a TLR7 agonist. In vitro, GY161 stimulated the production of cytokines by mouse spleen lymphocytes, promoted the maturation of dendritic cells (DCs), and inhibited the growth and induced the apoptosis of B16 melanoma cells by regulating the c-Met/ß-catenin pathway. In vivo, GY161 enhanced the frequency of CD8+ T cells in spleens and tumors, suppressed the growth of B16 melanoma cell-derived tumors and prolonged the survival time of mice. In summary, GY161 could prevent melanoma progression through direct tumor killing and by triggering specific immunity. These results strongly suggest that ImmunTacs are a reliable and promising strategy for developing small molecule immunogenic anticancer drugs.


Assuntos
Adenina/análogos & derivados , Linfócitos T CD8-Positivos/imunologia , Imunoterapia/métodos , Melanoma/tratamento farmacológico , Melanoma/imunologia , Piperidinas/farmacologia , Receptor 7 Toll-Like/agonistas , Adenina/química , Adenina/farmacologia , Animais , Apoptose , Ciclo Celular , Linhagem Celular Tumoral , Progressão da Doença , Feminino , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Estrutura Molecular , Piperidinas/química , Ensaios Antitumorais Modelo de Xenoenxerto
20.
Mol Med Rep ; 25(3)2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35059738

RESUMO

The present study explored the protective effect of exogenous hydrogen sulfide (H2S) on lipopolysaccharide (LPS)­induced acute kidney injury (AKI) and the underlying mechanisms. To establish an AKI injury mouse model, LPS (10 mg/kg) was intraperitoneally injected into mice pretreated with 0.8 mg/kg sodium hydrosulfide hydrate (NaHS), an H2S donor. The mouse survival rate and the degree of kidney injury were examined. To construct a cell damage model, HK­2 cells were pretreated with different concentrations (0.1, 0.3 and 0.5 mM) of NaHS, and then the cells were stimulated with LPS (1 µg/ml). The cell viability, autophagy, apoptosis levels and the release of inflammatory factors were examined in mouse kidney tissue and HK­2 renal tubular epithelial cells. It was found that pretreatment with NaHS significantly improved the survival rate of septic AKI mice, and reduced the renal damage, release of inflammatory factors and apoptosis. In HK­2 cells, NaHS protected cells from LPS caused damage via promoting autophagy and inhibiting apoptosis and the release of inflammatory factors. In order to clarify the relationship between autophagy and apoptosis and inflammatory factors, this study used 3­methyladenine (3­MA) to inhibit autophagy. The results revealed that 3­MA eliminated the protective effect of NaHS in HK­2 cells and AKI mice. Overall, NaHS can protect from LPS­induced AKI by promoting autophagy and inhibiting apoptosis and the release of inflammatory factors.


Assuntos
Injúria Renal Aguda/prevenção & controle , Autofagia/efeitos dos fármacos , Sulfeto de Hidrogênio/farmacologia , Rim/efeitos dos fármacos , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/metabolismo , Adenina/análogos & derivados , Adenina/farmacologia , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Humanos , Sulfeto de Hidrogênio/metabolismo , Rim/patologia , Rim/ultraestrutura , Lipopolissacarídeos , Masculino , Camundongos Endogâmicos C57BL , Microscopia Eletrônica de Transmissão , Substâncias Protetoras/metabolismo , Substâncias Protetoras/farmacologia , Sulfetos/metabolismo , Sulfetos/farmacologia
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