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1.
Eur J Med Chem ; 245(Pt 1): 114917, 2023 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-36395646

RESUMO

JNK3 is a key factor driving the pathophysiology of neuronal apoptosis. Since demonstrating the therapeutic potential of JNK3 inhibitors in Alzheimer's disease, we aimed to broaden their chemical diversity for drug development. In continuation with our previous research, a series of compounds with the tetrahydrocyclopenta[d]imidazole scaffold as a core moiety was developed as JNK3 inhibitors based on in silico modeling analysis. The biochemical kinase assay results revealed that the JNK3 inhibitory effects and isoform selectivity of the compounds developed in this study were significantly higher than that of previously developed inhibitors. In particular, the IC50 values of compounds 18c, 19c, 22b, and 26c, which exhibited excelled isoform selectivity, against JNK3 were 0.716, 0.564, 0.379, and 0.779 nM, respectively, which were more potent than those of any known JNK3 inhibitors. Additionally, compounds 18c, 18c, 22b, and 22c effectively protected the neuronal cells against amyloid beta-induced apoptosis. Docking studies indicated that the tetrahydrocyclopenta[d]imidazole scaffold retained all the optimal interactions. Meanwhile, BBB PAMPA and ADME prediction suggested that the tested compounds had a favorable BBB permeability and pharmacokinetic profile. Therefore, the tetrahydrocyclopenta[d]imidazole scaffold is a promising candidate for developing JNK3 inhibitors. In particular, compound 22b is a potential starting point for the preclinical optimization of novel JNK3 inhibitors.


Assuntos
Doença de Alzheimer , Doenças Neurodegenerativas , Humanos , Simulação de Acoplamento Molecular , Peptídeos beta-Amiloides , Imidazóis/farmacologia , Doença de Alzheimer/tratamento farmacológico
2.
Eur J Med Chem ; 245(Pt 1): 114893, 2023 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-36395649

RESUMO

Diabetic neuropathic pain (DNP) is a common, complex, and severe complication of diabetes. It can lead to increased mortality, lower-limb amputations, and distressing neuropathic symptoms. Available therapies for DNP are broad-spectrum analgesics, related to various side effects. Transient receptor potential vanilloid-1 (TRPV1) is widely expressed within the peripheral and central nervous systems and plays an essential role in pain perception and regulation. Both TRPV1 agonists and antagonists could reduce the sensitivity to nociception. Some exhibit blood glucose homeostasis regulates function by influencing insulin secretion and receptor sensitivity. Since TRPV1 has exhibited the unique advantages of simultaneously managing blood sugar and pain, developing new TRPV1 channel modulators for diabetes-related pain syndrome is a promising alternative to conventional therapy. In this review, the role of TRPV1 in the pathogenesis of DNP has been described and challenges of TRPV1 modulators have been explored to be a new therapy for DNP.


Assuntos
Antineoplásicos , Diabetes Mellitus , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Neuralgia , Canais de Potencial de Receptor Transitório , Humanos , Glicemia , Neuralgia/tratamento farmacológico , Canais de Cátion TRPV
3.
Eur J Med Chem ; 245(Pt 2): 114920, 2023 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-36399875

RESUMO

Bone marrow transplantation is regarded as the most effective immunotherapy for hematologic cancer, but it generally faces difficulties in matching. Aberrant expression of histone deacetylases (HDACs) is closely related to the occurrence and development of hematological cancer. Recent studies suggested that HDACs might play a critical role in initiating anti-cancer immune response or enhancing anti-cancer immunotherapy. Besides, combining HDAC inhibition and immunotherapy could prevent immunotherapy resistance in some degree and reach an extended treatment window. This review summarized the relationship between HDACs and immune and described the current understanding of HDACs in immunotherapy for hematologic cancer.


Assuntos
Neoplasias Hematológicas , Histona Desacetilases , Humanos , Neoplasias Hematológicas/tratamento farmacológico , Imunoterapia
4.
Eur J Med Chem ; 245(Pt 2): 114919, 2023 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-36399877

RESUMO

Abnormal activation of the NLR family pyrin domain containing 3 (NLRP3) inflammasome is closely associated with a variety of inflammatory diseases. Herein, we describe the discovery and optimization of a series of NLRP3 inflammasome inhibitors based on the oridonin skeleton. These inhibitors exhibited moderate to potent inhibitory activity against interleukin 1ß (IL-1ß) release. Compound E6 showed the strongest inhibitory activity and better safety range against IL-1ß (IC50 = 0.45 ± 0.02 µM, selectivity index = 36.49). Compared with oridonin, the activity and selectivity index of compound E6 increased 11.5 and 7.2 times, respectively. Compound E6 also exhibited broad-spectrum activity and specificity. Compound E6 mainly reduced the release of IL-1ß by targeting the NLRP3 protein, thereby inhibiting the NLRP3-caspase 1-gasdermin D (GSDMD), as well as inhibiting the caspase 4-GSDMD signaling pathway. Further studies revealed an important therapeutic effect of E6 on dextran sulfate sodium-induced colitis. Compound E6 may be promising for the treatment of NLRP3-related diseases including inflammatory bowel disease.


Assuntos
Colite , Inflamassomos , Humanos , Proteína 3 que Contém Domínio de Pirina da Família NLR , Sulfato de Dextrana , Colite/induzido quimicamente , Colite/tratamento farmacológico
5.
Eur J Med Chem ; 245(Pt 1): 114913, 2023 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-36399923

RESUMO

Computer-aided drug design and structure-based drug design techniques were used to find 18 novel hydrazidoarylaminopyrimidine-based BTK/FLT3 dual inhibitors. At 1 µM and 0.05 µM, the majority of the target compounds inhibited BTK and FLT3 by more than 80%, respectively. Among these, compound RSH-7 inhibited BTK and FLT3 most effectively, with IC50 values of 47 and 12 nM, respectively, which were superior to spebrutinib (BTK IC50 = 54 nM) and sorafenib (FLT3 IC50 = 33 nM). RSH-7 effectively inhibited the proliferation of multiple hematological malignancy cells with IC50 values ranging from 3 to 17 nM, which were 81-133 folds lower than spebrutinib. Furthermore, RSH-7 strongly inhibited BTK and FLT3 signaling and induced apoptosis in jeko-1 cells by upregulating pro-apoptotic proteins and downregulating Bcl-2 levels. RSH-7 showed moderate in vitro ADME properties. Importantly, RSH-7 demonstrated highly efficacious and well-tolerated in jeko-1 (50 mg/kg, TGI = 79.78%) and MV4-11 (20 mg/kg, TGI = 94.84%) xenograft models. These findings indicated that RSH-7 may be a promising lead compound for the treatment of hematological malignancies.


Assuntos
Neoplasias Hematológicas , Humanos , Animais , Neoplasias Hematológicas/tratamento farmacológico , Acrilamidas , Apoptose , Modelos Animais de Doenças , Tirosina Quinase 3 Semelhante a fms
6.
Eur J Med Chem ; 245(Pt 2): 114918, 2023 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-36401884

RESUMO

Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease characterized with high mortality, unknown etiology, and lack of effective treatment. Many evidences validate that inhibiting the activation of STAT3 is an attractive therapeutic strategy for IPF. Herein, based on our previous findings that nifuroxazide (NIF) could effectively attenuate pulmonary fibrosis by inhibiting STAT3 activation, a series of diarylacylhydrazones derivatives have been designed and synthesized. Among them, compounds 44 and 52 could inhibit TGF-ß1-induced abnormal activation of NIH-3T3 and A549 cells, as well as migration and EMT of A549 cells. In a bleomycin-induced mouse pulmonary fibrosis model, the oral administration of 44 and 52 (bioavailability F = 31.75% and 42.08%) improved mouse lung function and slowed the progression of IPF. Moreover, 52 could reverse the pulmonary fibrosis in treatment model. Collectively, this work shows 44 and 52 could be a potential lead compound for the treatment of IPF, and it is worthy of further study.


Assuntos
Fibrose Pulmonar Idiopática , Animais , Camundongos , Humanos , Fibrose Pulmonar Idiopática/induzido quimicamente , Fibrose Pulmonar Idiopática/tratamento farmacológico , Células A549 , Bleomicina/farmacologia , Disponibilidade Biológica , Administração Oral , Modelos Animais de Doenças
7.
Biosens Bioelectron ; 220: 114840, 2023 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-36402101

RESUMO

Heart disease is the leading cause of death worldwide and imposes a significant burden on healthcare systems globally. A major hurdle to the development of more effective therapeutics is the reliance on animal models that fail to faithfully recapitulate human pathophysiology. The predictivity of in vitro models that lack the complexity of in vivo tissue remain poor as well. To combat these issues, researchers are developing organ-on-a-chip models of the heart that leverage the use of human induced pluripotent stem cell-derived cardiomyocytes in combination with novel platforms engineered to better recapitulate tissue- and organ-level physiology. The integration of novel biosensors into these platforms is also a critical step in the development of these models, as they allow for increased throughput, real-time and longitudinal phenotypic assessment, and improved efficiency during preclinical disease modeling and drug screening studies. These platforms hold great promise for both improving our understanding of heart disease as well as for screening potential therapeutics based on clinically relevant endpoints with better predictivity of clinical outcomes. In this review, we describe state-of-the-art heart-on-a-chip platforms, the integration of novel biosensors into these models for real-time and continual monitoring of tissue-level physiology, as well as their use for modeling heart disease and drug screening applications. We also discuss future perspectives and further advances required to enable clinical trials-on-a-chip and next-generation precision medicine platforms.


Assuntos
Técnicas Biossensoriais , Cardiopatias , Células-Tronco Pluripotentes Induzidas , Animais , Humanos , Avaliação Pré-Clínica de Medicamentos , Dispositivos Lab-On-A-Chip , Cardiopatias/diagnóstico , Cardiopatias/tratamento farmacológico , Miócitos Cardíacos
8.
Drug Deliv ; 30(1): 28-39, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36457288

RESUMO

Sorafenib (SRF) presents undesirable effects in clinical treatment, due to the lack of targeting, poor water solubility, and obvious side effects. In this study, we constructed a novel nanodrug carrier system for accurate and efficient delivery of SRF, improving its therapeutic effects and achieving tumor-specific imaging. The hollow mesoporous MnO2 (H-MnO2) nanoparticles equipped with target substance aptamers (APT) on the surface were used to load SRF for the first time. The resulting H-MnO2-SRF-APT could specifically bound to glypican-3 (GPC3) receptors on the surface of hepatocellular carcinoma (HCC), rapidly undergoing subsequent degradation under decreased pH conditions in the tumor microenvironment (TME) and releasing the loaded SRF. In this process, Mn2+ ions were used for T1-weighted magnetic resonance imaging simultaneously. The in vitro cell experiments indicated that H-MnO2-SRF-APT showed much more effects on the inhibition in the proliferation of Huh7 and HepG2 HCC cells than that of the non-targeted H-MnO2-SRF and free SRF. Besides, the in vivo results further confirmed that H-MnO2-SRF-APT could effectively inhibit the growth of xenograft tumors Huh7 in the naked mouse with good biosafety. In conclusion, H-MnO2-SRF-APT could significantly enhance the therapeutic effect of SRF and is expected to be a new way of diagnosis and treatment of HCC.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Animais , Camundongos , Sorafenibe , Carcinoma Hepatocelular/tratamento farmacológico , Compostos de Manganês , Neoplasias Hepáticas/tratamento farmacológico , Óxidos , Oligonucleotídeos , Microambiente Tumoral , Glipicanas
9.
Exp Neurol ; 359: 114240, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36216124

RESUMO

Presently there is no drug therapy for curing epilepsy. Despite many advancements in epilepsy research, nearly 30% of people with epilepsy remain refractory to current antiseizure medications (ASM). Cannabidiol (CBD) has recently been approved as an ASM for pediatric refractory seizures, but it has not been widely tested for adult epileptogenesis and focal onset seizures. In this study, we investigated the efficacy of the FDA-approved CBD in controlling epileptogenesis and complex focal onset seizures using the mouse kindling model of human temporal lobe epilepsy. We also tested combination regimens of CBD with other ASMs. The two primary outcome measures were disease modification and suppression of generalized seizures. In the epileptogenesis study, CBD had a striking effect in attenuating kindling development, with a dose-dependent decrease in behavioral and electrographic seizure activity. In the retention study, mice previously treated with CBD had significantly reduced overall seizure burden, suggesting disease modification. In a fully-kindled seizure study, CBD produced rapid and atypical U-shaped dose-dependent protection against generalized seizures (ED50, 52 mg/kg, i.p.). In a time-course study, CBD showed a maximal protective effect within 1 h of injection, and it declined within 4 h with a biphasic response. In the combination study, CBD produced synergistic/ additive protection when given with midazolam and ganaxolone but not with tiagabine, indicating its strong potential as an adjunct ASM. Finally, the protective effects of CBD were not associated with motor and functional impairments. These preclinical findings demonstrate the potential of adjunct CBD for controlling adult complex focal onset seizure conditions.


Assuntos
Canabidiol , Epilepsia do Lobo Temporal , Epilepsia , Humanos , Criança , Camundongos , Animais , Canabidiol/farmacologia , Canabidiol/uso terapêutico , Epilepsia do Lobo Temporal/tratamento farmacológico , Anticonvulsivantes/farmacologia , Anticonvulsivantes/uso terapêutico , Convulsões/tratamento farmacológico , Epilepsia/tratamento farmacológico , Modelos Animais de Doenças
11.
Cell Signal ; 101: 110492, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36241056

RESUMO

In recent decades, there has been a significant amount of research into breast cancer, with some important breakthroughs in the treatment of both primary and metastatic breast cancers. It's a well-known fact that treating breast cancer is still a challenging endeavour even though physicians have a fantastic toolset of the latest treatment options at their disposal. Due to limitations of current clinical treatment options, traditional chemotherapeutic drugs, and surgical options are still required to address this condition. In recent years, there have been several developments resulting in a wide range of treatment options. This review article discusses the cellular and molecular foundation of chemotherapeutic drugs, endocrine system-based treatments, biological therapies, gene therapy, and innovative techniques for treating breast cancer.


Assuntos
Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/terapia , Neoplasias da Mama/tratamento farmacológico
12.
Artigo em Inglês | MEDLINE | ID: mdl-36414428

RESUMO

Many challenges exist in the precise diagnosis and clinical management of secondary progressive multiple sclerosis (SPMS) because of the lack of definitive clinical, imaging, immunologic, or pathologic criteria that demarcate the transition from relapsing-remitting MS to SPMS. This review provides an overview of the diagnostic criteria/definition and the heterogeneity associated with different SPMS patient populations; it also emphasizes the importance of available prospective/retrospective tools to identify patients with SPMS earlier in the disease course so that approved disease-modifying therapies and nonpharmacological strategies will translate into better outcomes. Delivery of such interventions necessitates an evolving patient-clinician dialog within the context of a multidisciplinary team.


Assuntos
Esclerose Múltipla Crônica Progressiva , Esclerose Múltipla , Humanos , Esclerose Múltipla Crônica Progressiva/diagnóstico , Esclerose Múltipla Crônica Progressiva/tratamento farmacológico , Prognóstico , Estudos Retrospectivos , Estudos Prospectivos
13.
Bioorg Chem ; 130: 106252, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36379149

RESUMO

We investigated synthetic amino acid-based approach to design short peptide-based antibiotics. Tautomerically restricted, amphiphilic 1-aryl-l-histidines along with hydrophobic tryptophan were utilized to synthesize the designed peptides. l-Trp-l-His(1-biphenyl)-NHBzl (12e, IC50 = 1.91 µg/mL; MIC = 3.46 µg/mL) and l-His[1-(4-n-butylphenyl)]-l-Trp-l-His[1-(4-n-butylphenyl)]-NHBzl (16d, IC50 = 1.36 µg/mL; MIC = 2.46 µg/mL) produced potency against Cryptococcus neoformans. Peptides with moderate antibacterial activities (IC50s = 4.40-8.80 µg/mL) were also identified. The mechanism of action and cellular changes revealed that membrane disruption due to interactions of the positively charged peptides with the negatively charged membrane of the cryptococcal cells result in permeabilization, leading to pore formation. The internal localization of the peptides instigated the interactions with DNA causing fragmentation of the genetic material, which together with membrane disruption led to cell death. Flow cytometric analysis points to cells death by apoptotic pathway. Time kill kinetics and synergistic study confirmed the fungicidal nature and synergism with amphotericin B.


Assuntos
Criptococose , Cryptococcus neoformans , Aminoácidos/metabolismo , Antifúngicos/farmacologia , Antifúngicos/metabolismo , Testes de Sensibilidade Microbiana , Criptococose/tratamento farmacológico , Peptídeos/farmacologia , Peptídeos/metabolismo , Membrana Celular
14.
Bioorg Chem ; 130: 106215, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36384067

RESUMO

Discoidin domain receptors (DDRs) are one of the less explored targets for the treatment of cancer which belong to receptor tyrosine kinases family. Discoidin domain receptors (DDRs) are a collagen-activated receptor tyrosine kinase and essential for controlling cellular functions like proliferation, morphogenesis, adhesion, differentiation, invasion, matrix remodeling, and migration. Although there are many targets and their inhibitors are reported which treat cancer. But most of drugs were amalgamated with moderate to severe side effects. This results in untreated cancerous cells. One of the reasons that cancer is considered challenging to treat because the targets were mutating rapidly and the inhibitor become less potent. The target identification is a tedious task for the researchers from the early 1990 s till date. When it comes to cancer, there has not been any magical stick to treat it undisputedly. Therefore, need for discovery of new receptor may helpful to overcome these difficulties. The development of DDR inhibitors has received a lot of attention ever since the target was discovered. In this review we have reported the development of most promising DDR1 and DDR2 small molecule inhibitors from the perspective of medicinal chemistry. We have also discussed about the clinical trials, recent patents, selectivity biological activity, and structure-activity relationship (SAR) of DDR1 and DDR2 inhibitors.


Assuntos
Antineoplásicos , Neoplasias , Humanos , Receptores com Domínio Discoidina , Receptores Mitogênicos/química , Receptores Proteína Tirosina Quinases/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Neoplasias/tratamento farmacológico , Relação Estrutura-Atividade
15.
Bioorg Chem ; 130: 106261, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36399866

RESUMO

In this work, we have investigated the one pot strategy for the Cu(I)-mediated synthesis of new triazoles bearing nitroindazole moieties using different copper catalysts. The biological activity of newly synthesized nitroindazolyltriazoles towards Alzheimer's disease-related targets, namely cholinesterases, monoamine oxidases, and amyloid aggregation, were investigated. Predictions of target affinity, physicochemical parameters, gastrointestinal absorption and brain penetration were achieved by means of in silico tools.


Assuntos
Doença de Alzheimer , Humanos , Doença de Alzheimer/tratamento farmacológico , Proteínas Amiloidogênicas , Colinesterases , Encéfalo , Monoaminoxidase
16.
Int J Cancer ; 152(1): 15-23, 2023 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-35579989

RESUMO

Global phase 3 trials have demonstrated the priority of several next-generation anaplastic lymphoma kinase-tyrosine kinase inhibitors (ALK-TKIs). However, clinical studies are conducted with specific populations that differ from the real world. The study aimed to evaluate the clinical outcomes of alectinib in real-world settings. Patients with advanced nonsmall-cell lung cancer (NSCLC) and EML4-ALK fusion were enrolled from two medical centers between June 2018 and June 2020. The primary endpoints were objective response rate (ORR) and progression-free survival (PFS) to alectinib. The secondary endpoint was response of brain metastases. The risk factors for disease progression were also investigated. In total, 127 patients with advanced NSCLC were enrolled into this study. Of them, 54.3% received first-line alectinib. The 1- and 2-year PFS rates were 77.4% and 68.3%, respectively. ORR and disease control rate (DCR) were 53.5% and 91.3%, respectively. Among patients with brain metastases, intracranial ORR and DCR were 63.6% and 88.6%, respectively. In addition, we found that "crizotinib pretreatment", "liver metastasis" and "TP53 co-mutation" were individually associated with shorter PFS in alectinib treatment. In conclusion, this study confirms the salient clinical outcomes of alectinib for ALK-fusion-driven NSCLC patients with or without brain metastases, adding real-world evidence to the priority of alectinib in clinical practice.


Assuntos
Neoplasias Encefálicas , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Quinase do Linfoma Anaplásico/genética , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Inibidores de Proteínas Quinases/farmacologia
17.
Int J Cancer ; 152(1): 66-78, 2023 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-35579992

RESUMO

In clear cell renal cell carcinoma (ccRCC), glycolysis is enhanced mainly because of the increased expression of key enzymes in glycolysis. Hence, the discovery of new molecular biomarkers for glycolysis may help guide and establish a precise system of diagnosis and treatment for ccRCC. Expression profiles of 1079 tumor samples of ccRCC patients (including 311 patients treated with everolimus or nivolumab) were downloaded from public databases. Proteomic profiles of 232 ccRCC samples were obtained from Fudan University Shanghai Cancer Center (FUSCC). Biological changes, tumor microenvironment and prognostic differences were explored between samples with various glycolysis characteristics. There were significant differences in CD8+ effector T cells, epithelial-to-mesenchymal transition and pan-fibroblast TGFb between the Low and High glyScore groups. The tumor mutation burden of the Low glyScore group was lower than that of the High glyScore group. And higher glyScore was significantly associated with worse overall survival (OS) in 768 ccRCC patients (P < .0001). External validation in FUSCC cohort also indicated that glyScore was of strong ability for predicting OS (P < .05). GlyScore may serve as a biomarker for predicting everolimus response in ccRCC patients due to its significant associations with progression-free survival (PFS). And glyScore may also predict overall survival in patients treated with nivolumab. We calculated the glyScore in ccRCC and the defined glyScore was of strong ability for predicting OS. In addition, glyScore may also serve as a biomarker for predicting PFS in patients treated with everolimus and could predict OS in patients treated with nivolumab.


Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Humanos , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/metabolismo , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/genética , Neoplasias Renais/diagnóstico , Nivolumabe , Everolimo/uso terapêutico , Proteômica , China , Prognóstico , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Glicólise , Microambiente Tumoral
18.
Int J Cancer ; 152(2): 110-122, 2023 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-35765844

RESUMO

Pancreatic cancer (PC) is a cancer of the digestive system, and pancreatic ductal adenocarcinoma (PDAC) accounts for approximately 90% of all PC cases. Exosomes derived from PDAC (PDAC-exosomes) promote PDAC development and metastasis. Exosomes are nanoscale vesicles secreted by most cells, which can carry biologically active molecules and mediate communication and cargo transportation among cells. Recent studies have focused on transforming exosomes into good drug delivery systems (DDSs) to improve the clinical treatment of PDAC. This review considers PDAC as the main research object to introduce the role of PDAC-exosomes in PDAC development and metastasis. This review focuses on the following two themes: (a) the great potential of PDAC-exosomes as new diagnostic markers for PDAC, and (b) the transformation of exosomes into potential DDSs.


Assuntos
Carcinoma Ductal Pancreático , Exossomos , Neoplasias Pancreáticas , Humanos , Exossomos/patologia , Linhagem Celular Tumoral , Carcinoma Ductal Pancreático/diagnóstico , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/patologia , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/patologia , Sistemas de Liberação de Medicamentos
19.
Int J Cancer ; 152(2): 259-266, 2023 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-35913764

RESUMO

Anti-GD2 monoclonal antibodies (mAb) improve the prognosis of high-risk neuroblastoma (HR-NB). Worldwide experience almost exclusively involves toddlers and older patients treated after multimodality or second-line therapies, that is, many months postdiagnosis. In contrast, at our center, infants received anti-GD2 mAbs because this immunotherapy started during or immediately after induction chemotherapy. We now report on the feasibility, safety, and long-term survival in this vulnerable age group. Thirty-three HR-NB patients were <19 months old when started on 3F8 (murine mAb; n = 21) or naxitamab (humanized-3F8; n = 12), with 30″ to 90″ intravenous infusions. Patients received analgesics and antihistamines. Common toxicities (pain, urticaria, cough) were manageable, allowing outpatient treatment. Capillary leak, posterior reversible encephalopathy syndrome, and mAb-related long-term toxicities did not occur. Two 3F8 cycles were aborted due to bradycardia (a preexisting condition) and asthmatic symptoms, respectively. One patient received ½ dose of Day 1 naxitamab because of hypotension; full doses were subsequently administered. Post-mAb treatments included chemotherapy, radiotherapy, and anti-NB vaccine. Among 3F8 patients, 17/21 are in complete remission off all treatment at 5.6+ to 24.1+ (median 13.4+) years from diagnosis. Among naxitamab patients, 10/12 remain relapse-free post-mAb at 1.7+ to 4.3+ (median 3.1+) years from diagnosis. Toxicity was similar with short outpatient infusions and matched that observed with these and other anti-GD2 mAbs in older patients. These findings were reassuring given that naxitamab is dosed >2.5× higher (~270 mg/m2 /cycle) than 3F8, dinutuximab, and dinutuximab beta (70-100 mg/m2 /cycle). HR-NB in infants proved to be highly curable.


Assuntos
Antineoplásicos , Neuroblastoma , Síndrome da Leucoencefalopatia Posterior , Humanos , Lactente , Camundongos , Animais , Idoso , Síndrome da Leucoencefalopatia Posterior/induzido quimicamente , Síndrome da Leucoencefalopatia Posterior/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Anticorpos Monoclonais/efeitos adversos , Neuroblastoma/tratamento farmacológico , Imunoterapia , Fatores Imunológicos/uso terapêutico , Antineoplásicos/uso terapêutico
20.
Methods Mol Biol ; 2598: 375-379, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36355306

RESUMO

The collagenase-induced experimental osteoarthritis model is in general applied in mice but can also be used in other small species. The model is mainly based on the induction of joint laxity but has also a major inflammatory component. In this chapter, the induction is described by two injections of collagenase at the start of the model. Investigators who will use this model have to have ample experience in intra-articular injection in mice.


Assuntos
Cartilagem Articular , Osteoartrite , Camundongos , Animais , Modelos Animais de Doenças , Osteoartrite/induzido quimicamente , Osteoartrite/tratamento farmacológico , Colagenases/efeitos adversos , Injeções Intra-Articulares
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