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1.
Cells ; 10(6)2021 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-34201214

RESUMO

In late 2019, the betacoronavirus SARS-CoV-2 was identified as the viral agent responsible for the coronavirus disease 2019 (COVID-19) pandemic. Coronaviruses Spike proteins are responsible for their ability to interact with host membrane receptors and different proteins have been identified as SARS-CoV-2 interactors, among which Angiotensin-converting enzyme 2 (ACE2), and Basigin2/EMMPRIN/CD147 (CD147). CD147 plays an important role in human immunodeficiency virus type 1, hepatitis C virus, hepatitis B virus, Kaposi's sarcoma-associated herpesvirus, and severe acute respiratory syndrome coronavirus infections. In particular, SARS-CoV recognizes the CD147 receptor expressed on the surface of host cells by its nucleocapsid protein binding to cyclophilin A (CyPA), a ligand for CD147. However, the involvement of CD147 in SARS-CoV-2 infection is still debated. Interference with both the function (blocking antibody) and the expression (knock down) of CD147 showed that this receptor partakes in SARS-CoV-2 infection and provided additional clues on the underlying mechanism: CD147 binding to CyPA does not play a role; CD147 regulates ACE2 levels and both receptors are affected by virus infection. Altogether, these findings suggest that CD147 is involved in SARS-CoV-2 tropism and represents a possible therapeutic target to challenge COVID-19.


Assuntos
Enzima de Conversão de Angiotensina 2/fisiologia , Basigina/fisiologia , SARS-CoV-2/fisiologia , Internalização do Vírus , Células A549 , Enzima de Conversão de Angiotensina 2/metabolismo , Animais , Basigina/antagonistas & inibidores , Basigina/genética , COVID-19/patologia , COVID-19/prevenção & controle , COVID-19/virologia , Células CACO-2 , Linhagem Celular , Chlorocebus aethiops , Células Hep G2 , Interações Hospedeiro-Patógeno , Humanos , Terapia de Alvo Molecular , Interferência de RNA/fisiologia , RNA Interferente Pequeno/farmacologia , RNA Interferente Pequeno/uso terapêutico , Receptores Virais/metabolismo , Receptores Virais/fisiologia , SARS-CoV-2/metabolismo , Células Vero , Tropismo Viral/fisiologia
2.
Int J Mol Sci ; 22(12)2021 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-34198685

RESUMO

Hearing loss affects many people worldwide and occurs often as a result of age, ototoxic drugs and/or excessive noise exposure. With a growing number of elderly people, the number of people suffering from hearing loss will also increase in the future. Despite the high number of affected people, for most patients there is no curative therapy for hearing loss and hearing aids or cochlea implants remain the only option. Important treatment approaches for hearing loss include the development of regenerative therapies or the inhibition of cell death/promotion of cell survival pathways. The mammalian target of rapamycin (mTOR) pathway is a central regulator of cell growth, is involved in cell survival, and has been shown to be implicated in many age-related diseases. In the inner ear, mTOR signaling has also started to gain attention recently. In this review, we will emphasize recent discoveries of mTOR signaling in the inner ear and discuss implications for possible treatments for hearing restoration.


Assuntos
Orelha Interna/patologia , Perda Auditiva/tratamento farmacológico , Terapia de Alvo Molecular , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo , Animais , Humanos , Regeneração
3.
Int J Mol Sci ; 22(12)2021 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-34203854

RESUMO

This review highlights potential molecular targets for treating neuropathic orofacial pain based on current findings in animal models. Preclinical research is currently elucidating the pathophysiology of the disease and identifying the molecular targets for better therapies using animal models that mimic this category of orofacial pain, especially post-traumatic trigeminal neuropathic pain (PTNP) and primary trigeminal neuralgia (PTN). Animal models of PTNP and PTN simulate their etiologies, that is, trauma to the trigeminal nerve branch and compression of the trigeminal root entry zone, respectively. Investigations in these animal models have suggested that biological processes, including inflammation, enhanced neuropeptide-mediated pain signal transmission, axonal ectopic discharges, and enhancement of interactions between neurons and glial cells in the trigeminal pathway, are underlying orofacial pain phenotypes. The molecules associated with biological processes, whose expressions are substantially altered following trigeminal nerve damage or compression of the trigeminal nerve root, are potentially involved in the generation and/or exacerbation of neuropathic orofacial pain and can be potential molecular targets for the discovery of better therapies. Application of therapeutic candidates, which act on the molecular targets and modulate biological processes, attenuates pain-associated behaviors in animal models. Such therapeutic candidates including calcitonin gene-related peptide receptor antagonists that have a reasonable mechanism for ameliorating neuropathic orofacial pain and meet the requirements for safe administration to humans seem worth to be evaluated in clinical trials. Such prospective translation of the efficacy of therapeutic candidates from animal models to human patients would help develop better therapies for neuropathic orofacial pain.


Assuntos
Dor Facial/tratamento farmacológico , Terapia de Alvo Molecular , Neuralgia/tratamento farmacológico , Animais , Modelos Animais de Doenças , Dor Facial/complicações , Dor Facial/patologia , Humanos , Neuralgia/complicações , Neuralgia/patologia , Gânglio Trigeminal/patologia
4.
Int J Mol Sci ; 22(12)2021 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-34203974

RESUMO

In the two decades since the discovery of TNNI3K it has been implicated in multiple cardiac phenotypes and physiological processes. TNNI3K is an understudied kinase, which is mainly expressed in the heart. Human genetic variants in TNNI3K are associated with supraventricular arrhythmias, conduction disease, and cardiomyopathy. Furthermore, studies in mice implicate the gene in cardiac hypertrophy, cardiac regeneration, and recovery after ischemia/reperfusion injury. Several new papers on TNNI3K have been published since the last overview, broadening the clinical perspective of TNNI3K variants and our understanding of the underlying molecular biology. We here provide an overview of the role of TNNI3K in cardiomyopathy and arrhythmia covering both a clinical perspective and basic science advancements. In addition, we review the potential of TNNI3K as a target for clinical treatments in different cardiac diseases.


Assuntos
Cardiopatias/enzimologia , Proteínas Serina-Treonina Quinases/metabolismo , Animais , Modelos Animais de Doenças , Cardiopatias/genética , Cardiopatias/patologia , Cardiopatias/fisiopatologia , Humanos , Terapia de Alvo Molecular , Proteínas Serina-Treonina Quinases/genética , Regeneração
5.
Cells ; 10(6)2021 06 08.
Artigo em Inglês | MEDLINE | ID: covidwho-1264419

RESUMO

In late 2019, the betacoronavirus SARS-CoV-2 was identified as the viral agent responsible for the coronavirus disease 2019 (COVID-19) pandemic. Coronaviruses Spike proteins are responsible for their ability to interact with host membrane receptors and different proteins have been identified as SARS-CoV-2 interactors, among which Angiotensin-converting enzyme 2 (ACE2), and Basigin2/EMMPRIN/CD147 (CD147). CD147 plays an important role in human immunodeficiency virus type 1, hepatitis C virus, hepatitis B virus, Kaposi's sarcoma-associated herpesvirus, and severe acute respiratory syndrome coronavirus infections. In particular, SARS-CoV recognizes the CD147 receptor expressed on the surface of host cells by its nucleocapsid protein binding to cyclophilin A (CyPA), a ligand for CD147. However, the involvement of CD147 in SARS-CoV-2 infection is still debated. Interference with both the function (blocking antibody) and the expression (knock down) of CD147 showed that this receptor partakes in SARS-CoV-2 infection and provided additional clues on the underlying mechanism: CD147 binding to CyPA does not play a role; CD147 regulates ACE2 levels and both receptors are affected by virus infection. Altogether, these findings suggest that CD147 is involved in SARS-CoV-2 tropism and represents a possible therapeutic target to challenge COVID-19.


Assuntos
Enzima de Conversão de Angiotensina 2/fisiologia , Basigina/fisiologia , SARS-CoV-2/fisiologia , Internalização do Vírus , Células A549 , Enzima de Conversão de Angiotensina 2/metabolismo , Animais , Basigina/antagonistas & inibidores , Basigina/genética , COVID-19/patologia , COVID-19/prevenção & controle , COVID-19/virologia , Células CACO-2 , Linhagem Celular , Chlorocebus aethiops , Células Hep G2 , Interações Hospedeiro-Patógeno , Humanos , Terapia de Alvo Molecular , Interferência de RNA/fisiologia , RNA Interferente Pequeno/farmacologia , RNA Interferente Pequeno/uso terapêutico , Receptores Virais/metabolismo , Receptores Virais/fisiologia , SARS-CoV-2/metabolismo , Células Vero , Tropismo Viral/fisiologia
6.
Molecules ; 26(11)2021 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-34199418

RESUMO

Since neurodevelopmental disorders (NDDs) influence more than 3% of children worldwide, there has been intense investigation to understand the etiology of disorders and develop treatments. Although there are drugs such as aripiprazole, risperidone, and lurasidone, these medications are not cures for the disorders and can only help people feel better or alleviate their symptoms. Thus, it is required to discover therapeutic targets in order to find the ultimate treatments of neurodevelopmental disorders. It is suggested that abnormal neuronal morphology in the neurodevelopment process is a main cause of NDDs, in which the serotonergic system is emerging as playing a crucial role. From this point of view, we noticed the correlation between serotonin receptor subtype 7 (5-HT7R) and NDDs including autism spectrum disorder (ASD), fragile X syndrome (FXS), and Rett syndrome (RTT). 5-HT7R modulators improved altered behaviors in animal models and also affected neuronal morphology via the 5-HT7R/G12 signaling pathway. Through the investigation of recent studies, it is suggested that 5-HT7R could be a potential therapeutic target for the treatment of NDDs.


Assuntos
Terapia de Alvo Molecular/métodos , Transtornos do Neurodesenvolvimento/metabolismo , Receptores de Serotonina/metabolismo , Animais , Humanos , Transtornos do Neurodesenvolvimento/tratamento farmacológico , Antagonistas da Serotonina/farmacologia , Antagonistas da Serotonina/uso terapêutico , Agonistas do Receptor de Serotonina/farmacologia , Agonistas do Receptor de Serotonina/uso terapêutico , Transdução de Sinais/efeitos dos fármacos
7.
Int J Mol Sci ; 22(12)2021 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-34204445

RESUMO

Choriocarcinoma (CC), a subtype of trophoblastic disease, is a rare and highly aggressive neoplasm. There are two main CC subtypes: gestational and non-gestational, (so called when it develops as a component of a germ cell tumor or is related to a somatic mutation of a poorly differentiated carcinoma), each with very diverse biological activity. A therapeutic approach is highly effective in patients with early-stage CC. The advanced stage of the disease also has a good prognosis with around 95% of patients cured following chemotherapy. However, advancements in diagnosis and treatment are always needed to improve outcomes for patients with CC. Long non-coding (lnc) RNAs are non-coding transcripts that are longer than 200 nucleotides. LncRNAs can act as oncogenes or tumor suppressor genes. Deregulation of their expression has a key role in tumor development, angiogenesis, differentiation, migration, apoptosis, and proliferation. Furthermore, detection of cancer-associated lncRNAs in body fluids, such as blood, saliva, and urine of cancer patients, is emerging as a novel method for cancer diagnosis. Although there is evidence for the potential role of lncRNAs in a number of cancers of the female genital tract, their role in CC is poorly understood. This review summarizes the current knowledge of lncRNAs in gestational CC and how this may be applied to future therapeutic strategies in the treatment of this rare cancer.


Assuntos
Coriocarcinoma/genética , Suscetibilidade a Doenças , Regulação Neoplásica da Expressão Gênica , RNA Longo não Codificante/genética , Neoplasias Uterinas/genética , Biomarcadores Tumorais , Coriocarcinoma/diagnóstico , Coriocarcinoma/metabolismo , Feminino , Humanos , Técnicas de Diagnóstico Molecular , Terapia de Alvo Molecular , Gradação de Tumores , Estadiamento de Neoplasias , Gravidez , Neoplasias Uterinas/diagnóstico , Neoplasias Uterinas/metabolismo
8.
Int J Mol Sci ; 22(12)2021 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-34207975

RESUMO

Molecular studies have provided increasing evidence that Parkinson's disease (PD) is a protein conformational disease, where the spread of alpha-synuclein (ASN) pathology along the neuraxis correlates with clinical disease outcome. Pathogenic forms of ASN evoke oxidative stress (OS), neuroinflammation, and protein alterations in neighboring cells, thereby intensifying ASN toxicity, neurodegeneration, and neuronal death. A number of evidence suggest that homeostasis between bioactive sphingolipids with opposing function-e.g., sphingosine-1-phosphate (S1P) and ceramide-is essential in pro-survival signaling and cell defense against OS. In contrast, imbalance of the "sphingolipid biostat" favoring pro-oxidative/pro-apoptotic ceramide-mediated changes have been indicated in PD and other neurodegenerative disorders. Therefore, we focused on the role of sphingolipid alterations in ASN burden, as well as in a vast range of its neurotoxic effects. Sphingolipid homeostasis is principally directed by sphingosine kinases (SphKs), which synthesize S1P-a potent lipid mediator regulating cell fate and inflammatory response-making SphK/S1P signaling an essential pharmacological target. A growing number of studies have shown that S1P receptor modulators, and agonists are promising protectants in several neurological diseases. This review demonstrates the relationship between ASN toxicity and alteration of SphK-dependent S1P signaling in OS, neuroinflammation, and neuronal death. Moreover, we discuss the S1P receptor-mediated pathways as a novel promising therapeutic approach in PD.


Assuntos
Doença de Parkinson/metabolismo , Transdução de Sinais , alfa-Sinucleína/metabolismo , Animais , Humanos , Lisofosfolipídeos/metabolismo , Terapia de Alvo Molecular , Neuroproteção , Doença de Parkinson/etiologia , Esfingosina/análogos & derivados , Esfingosina/metabolismo , alfa-Sinucleína/toxicidade
9.
Int J Mol Sci ; 22(12)2021 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-34208390

RESUMO

APE1 (DNA (apurinic/apyrimidinic site) endonuclease 1) is a key enzyme of one of the major DNA repair routes, the BER (base excision repair) pathway. APE1 fulfils additional functions, acting as a redox regulator of transcription factors and taking part in RNA metabolism. The mechanisms regulating APE1 are still being deciphered. Structurally, human APE1 consists of a well-characterized globular catalytic domain responsible for its endonuclease activity, preceded by a conformationally flexible N-terminal extension, acquired along evolution. This N-terminal tail appears to play a prominent role in the modulation of APE1 and probably in BER coordination. Thus, it is primarily involved in mediating APE1 localization, post-translational modifications, and protein-protein interactions, with all three factors jointly contributing to regulate the enzyme. In this review, recent insights on the regulatory role of the N-terminal region in several aspects of APE1 function are covered. In particular, interaction of this region with nucleophosmin (NPM1) might modulate certain APE1 activities, representing a paradigmatic example of the interconnection between various regulatory factors.


Assuntos
Reparo do DNA , DNA Liase (Sítios Apurínicos ou Apirimidínicos)/química , DNA Liase (Sítios Apurínicos ou Apirimidínicos)/genética , Sequência de Aminoácidos , Humanos , Modelos Biológicos , Terapia de Alvo Molecular , Domínios Proteicos , Processamento de Proteína Pós-Traducional
10.
Rinsho Ketsueki ; 62(6): 562-571, 2021.
Artigo em Japonês | MEDLINE | ID: mdl-34219082

RESUMO

Acute myeloid leukemia (AML) is a heterogeneous disease, and recent advances in sequencing technology have revealed that the accumulation of various genetic abnormalities is deeply involved in the pathogenesis of AML and its clonal evolutions during disease progression. Prognostic classifications and therapeutic strategies based on the cytogenetic and genetic abnormalities have been proposed, and several new therapeutic agents targeting the molecular abnormalities have been energetically investigated to eliminate AML cells. In the last few years, several new agents, including FLT3, IDH, BCL-2, and Hedgehog inhibitors, have been approved for the treatment of newly diagnosed AML, and their clinical applications have begun in the United States. Although there has been a delay of several years, the clinical development of these new agents is also underway in Japan, and it is expected that a new era of AML treatment will begin in the near future. It is necessary to establish novel risk-adopted treatment strategies incorporating these agents in monotherapies and/or effectively designed combination therapies.


Assuntos
Antineoplásicos , Leucemia Mieloide Aguda , Antineoplásicos/uso terapêutico , Proteínas Hedgehog , Humanos , Japão , Leucemia Mieloide Aguda/tratamento farmacológico , Terapia de Alvo Molecular , Estados Unidos
11.
Int J Mol Sci ; 22(12)2021 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-34207103

RESUMO

Ovarian cancer response to immunotherapy is limited; however, the evaluation of sensitive/resistant target treatment subpopulations based on stratification by tumor biomarkers may improve the predictiveness of response to immunotherapy. These markers include tumor mutation burden, PD-L1, tumor-infiltrating lymphocytes, homologous recombination deficiency, and neoantigen intratumoral heterogeneity. Future directions in the treatment of ovarian cancer include the utilization of these biomarkers to select ideal candidates. This paper reviews the role of immunotherapy in ovarian cancer as well as novel therapeutics and study designs involving tumor biomarkers that increase the likelihood of success with immunotherapy in ovarian cancer.


Assuntos
Imunoterapia , Neoplasias Ovarianas/terapia , Medicina de Precisão , Antígenos de Neoplasias/imunologia , Biomarcadores Tumorais , Ensaios Clínicos como Assunto , Gerenciamento Clínico , Suscetibilidade a Doenças , Feminino , Humanos , Imunoterapia/efeitos adversos , Imunoterapia/métodos , Terapia de Alvo Molecular , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/etiologia , Neoplasias Ovarianas/mortalidade , Medicina de Precisão/efeitos adversos , Medicina de Precisão/métodos , Resultado do Tratamento
12.
Int J Mol Sci ; 22(12)2021 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-34207126

RESUMO

Although immune checkpoint inhibitors have changed the treatment paradigm of a variety of cancers, including non-small-cell lung cancer, not all patients respond to immunotherapy in the same way. Predictive biomarkers for patient selection are thus needed. Tumor mutation burden (TMB), defined as the total number of somatic/acquired mutations per coding area of a tumor genome (Mut/Mb), has emerged as a potential predictive biomarker of response to immune checkpoint inhibitors. We found that the limited use of TMB in clinical practice is due to the difficulty in its detection and compounded by several different biological, methodological and economic issues. The incorporation of both TMB and PD-L1 expression or other biomarkers into multivariable predictive models could result in greater predictive power.


Assuntos
Biomarcadores Tumorais , Carcinoma Pulmonar de Células não Pequenas/genética , Predisposição Genética para Doença , Neoplasias Pulmonares/genética , Mutação , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/terapia , Ensaios Clínicos como Assunto , Gerenciamento Clínico , Estudos de Associação Genética , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/terapia , Terapia de Alvo Molecular , Avaliação de Resultados da Assistência ao Paciente
13.
Int J Mol Sci ; 22(12)2021 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-34207360

RESUMO

Discoidin domain receptor (DDR) is a collagen-activated receptor tyrosine kinase that plays critical roles in regulating essential cellular processes such as morphogenesis, differentiation, proliferation, adhesion, migration, invasion, and matrix remodeling. As a result, DDR dysregulation has been attributed to a variety of human cancer disorders, for instance, non-small-cell lung carcinoma (NSCLC), ovarian cancer, glioblastoma, and breast cancer, in addition to some inflammatory and neurodegenerative disorders. Since the target identification in the early 1990s to date, a lot of efforts have been devoted to the development of DDR inhibitors. From a medicinal chemistry perspective, we attempted to reveal the progress in the development of the most promising DDR1 and DDR2 small molecule inhibitors covering their design approaches, structure-activity relationship (SAR), biological activity, and selectivity.


Assuntos
Receptor com Domínio Discoidina 1/antagonistas & inibidores , Receptor com Domínio Discoidina 2/antagonistas & inibidores , Neoplasias/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Animais , Sítios de Ligação , Biomarcadores Tumorais , Receptor com Domínio Discoidina 1/química , Receptor com Domínio Discoidina 1/metabolismo , Receptor com Domínio Discoidina 2/química , Receptor com Domínio Discoidina 2/metabolismo , Gerenciamento Clínico , Suscetibilidade a Doenças , Desenho de Fármacos , Humanos , Inflamação/tratamento farmacológico , Inflamação/etiologia , Inflamação/metabolismo , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Estrutura Molecular , Terapia de Alvo Molecular , Neoplasias/tratamento farmacológico , Neoplasias/etiologia , Neoplasias/patologia , Doenças Neurodegenerativas/tratamento farmacológico , Doenças Neurodegenerativas/etiologia , Doenças Neurodegenerativas/metabolismo , Ligação Proteica , Conformação Proteica , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/uso terapêutico , Relação Estrutura-Atividade
14.
Nat Commun ; 12(1): 4228, 2021 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-34244484

RESUMO

Homozygous deletion of methylthioadenosine phosphorylase (MTAP) in cancers such as glioblastoma represents a potentially targetable vulnerability. Homozygous MTAP-deleted cell lines in culture show elevation of MTAP's substrate metabolite, methylthioadenosine (MTA). High levels of MTA inhibit protein arginine methyltransferase 5 (PRMT5), which sensitizes MTAP-deleted cells to PRMT5 and methionine adenosyltransferase 2A (MAT2A) inhibition. While this concept has been extensively corroborated in vitro, the clinical relevance relies on exhibiting significant MTA accumulation in human glioblastoma. In this work, using comprehensive metabolomic profiling, we show that MTA secreted by MTAP-deleted cells in vitro results in high levels of extracellular MTA. We further demonstrate that homozygous MTAP-deleted primary glioblastoma tumors do not significantly accumulate MTA in vivo due to metabolism of MTA by MTAP-expressing stroma. These findings highlight metabolic discrepancies between in vitro models and primary human tumors that must be considered when developing strategies for precision therapies targeting glioblastoma with homozygous MTAP deletion.


Assuntos
Neoplasias Encefálicas/genética , Encéfalo/patologia , Desoxiadenosinas/metabolismo , Glioblastoma/genética , Purina-Núcleosídeo Fosforilase/deficiência , Tionucleosídeos/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Encéfalo/efeitos dos fármacos , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Meios de Cultivo Condicionados/metabolismo , Desoxiadenosinas/análise , Feminino , Secções Congeladas , Glioblastoma/tratamento farmacológico , Glioblastoma/patologia , Homozigoto , Humanos , Metabolômica , Metionina Adenosiltransferase/metabolismo , Terapia de Alvo Molecular/métodos , Medicina de Precisão/métodos , Proteína-Arginina N-Metiltransferases/metabolismo , Purina-Núcleosídeo Fosforilase/genética , Deleção de Sequência , Tionucleosídeos/análise , Ensaios Antitumorais Modelo de Xenoenxerto
15.
Hematol Oncol ; 39 Suppl 1: 31-38, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34105823

RESUMO

Mantle cell lymphoma (MCL) is clinically characterized by its heterogenous behavior with courses ranging from indolent cases that do not require therapy for years to highly aggressive MCL with very limited prognosis. A better understanding of the complex biology of MCL has already led to the approval of several innovative agents, expanding the landscape of MCL therapies and improving therapeutic options especially for refractory or relapsed disease. Nevertheless, to further optimize MCL treatment, early identification of individual risk profile and risk-adapted, patient-tailored choice of therapeutic strategy needs to be prospectively incorporated in clinical patient management. This review highlights recent advances in deciphering the molecular background of MCL, the definition of prognostically relevant factors and the identification of potential druggable targets and summarizes current treatment recommendations for primary and relapsed/refractory MCL including novel targeted therapies.


Assuntos
Antineoplásicos/uso terapêutico , Linfoma de Célula do Manto , Terapia de Alvo Molecular , Humanos , Linfoma de Célula do Manto/tratamento farmacológico , Linfoma de Célula do Manto/genética , Linfoma de Célula do Manto/metabolismo
16.
Int J Mol Sci ; 22(11)2021 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-34072574

RESUMO

Neurofibromatosis (NF) is a neurocutaneous syndrome characterized by the development of tumors of the central or peripheral nervous system including the brain, spinal cord, organs, skin, and bones. There are three types of NF: NF1 accounting for 96% of all cases, NF2 in 3%, and schwannomatosis (SWN) in <1%. The NF1 gene is located on chromosome 17q11.2, which encodes for a tumor suppressor protein, neurofibromin, that functions as a negative regulator of Ras/MAPK and PI3K/mTOR signaling pathways. The NF2 gene is identified on chromosome 22q12, which encodes for merlin, a tumor suppressor protein related to ezrin-radixin-moesin that modulates the activity of PI3K/AKT, Raf/MEK/ERK, and mTOR signaling pathways. In contrast, molecular insights on the different forms of SWN remain unclear. Inactivating mutations in the tumor suppressor genes SMARCB1 and LZTR1 are considered responsible for a majority of cases. Recently, treatment strategies to target specific genetic or molecular events involved in their tumorigenesis are developed. This study discusses molecular pathways and related targeted therapies for NF1, NF2, and SWN and reviews recent clinical trials which involve NF patients.


Assuntos
Suscetibilidade a Doenças , Neurilemoma/etiologia , Neurofibromatoses/etiologia , Neurofibromatose 1/etiologia , Neurofibromatose 2/etiologia , Neoplasias Cutâneas/etiologia , Animais , Biomarcadores Tumorais , Ensaios Clínicos como Assunto , Modelos Animais de Doenças , Genes da Neurofibromatose 1 , Genes da Neurofibromatose 2 , Predisposição Genética para Doença , Humanos , Modelos Biológicos , Terapia de Alvo Molecular , Mutação , Neurilemoma/diagnóstico , Neurilemoma/terapia , Neurofibromatoses/diagnóstico , Neurofibromatoses/terapia , Neurofibromatose 1/diagnóstico , Neurofibromatose 1/terapia , Neurofibromatose 2/diagnóstico , Neurofibromatose 2/terapia , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/terapia , Resultado do Tratamento
17.
Int J Mol Sci ; 22(9)2021 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-34062987

RESUMO

Cannabidiol (CBD), the major nonpsychoactive Cannabis constituent, has been proposed for the treatment of a wide panel of neurological and neuropsychiatric disorders, including anxiety, schizophrenia, epilepsy and drug addiction due to the ability of its versatile scaffold to interact with diverse molecular targets that are not restricted to the endocannabinoid system. Albeit the molecular mechanisms responsible for the therapeutic effects of CBD have yet to be fully elucidated, many efforts have been devoted in the last decades to shed light on its complex pharmacological profile. In particular, an ever-increasing number of molecular targets linked to those disorders have been identified for this phytocannabinoid, along with the modulatory effects of CBD on their cascade signaling. In this view, here we will try to provide a comprehensive and up-to-date overview of the molecular basis underlying the therapeutic effects of CBD involved in the treatment of neurological and neuropsychiatric disorders.


Assuntos
Canabidiol/uso terapêutico , Transtornos Mentais/tratamento farmacológico , Transtornos Mentais/genética , Terapia de Alvo Molecular , Animais , Canabidiol/química , Canabidiol/farmacologia , Humanos , Canais Iônicos/metabolismo , Modelos Moleculares
18.
Int J Mol Sci ; 22(9)2021 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-34063168

RESUMO

Gliomas are the most common and challenging malignancies of the central nervous system (CNS), due to their infiltrative nature, tendency to recurrence, and poor response to treatments. Indeed, despite the advances in neurosurgical techniques and in radiation therapy, the modest effects of therapy are still challenging. Moreover, tumor recurrence is associated with the onset of therapy resistance; it is therefore critical to identify effective and well-tolerated pharmacological approaches capable of inducing durable responses in the appropriate patient groups. Molecular alterations of the RTK/PI3K/Akt/mTOR signaling pathway are typical hallmarks of glioma, and several clinical trials targeting one or more players of this axis have been launched, showing disappointing results so far, due to the scarce BBB permeability of certain compounds or to the occurrence of resistance/tolerance mechanisms. However, as RTK/PI3K/mTOR is one of the pivotal pathways regulating cell growth and survival in cancer biology, targeting still remains a strong rationale for developing strategies against gliomas. Future rigorous clinical studies, aimed at addressing the tumor heterogeneity, the interaction with the microenvironment, as well as diverse posology adjustments, are needed-which might unravel the therapeutic efficacy and response prediction of an RTK/PI3K/mTOR-based approach.


Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/enzimologia , Glioma/tratamento farmacológico , Glioma/enzimologia , Terapia de Alvo Molecular , Fosfatidilinositol 3-Quinases/metabolismo , Receptores Proteína Tirosina Quinases/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Animais , Humanos , Transdução de Sinais
19.
Int J Mol Sci ; 22(9)2021 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-34066677

RESUMO

Muscarinic acetylcholine receptors (mAChRs) belong to the superfamily of G-protein-coupled receptors (GPCRs). The family of mAChRs is composed of five subtypes, M1, M2, M3, M4 and M5, which have distinct expression patterns and functions. In the eye and its adnexa, mAChRs are widely expressed and exert multiple functions, such as modulation of tear secretion, regulation of pupil size, modulation of intraocular pressure, participation in cell-to-cell signaling and modula-tion of vascular diameter in the retina. Due to this variety of functions, it is reasonable to assume that abnormalities in mAChR signaling may contribute to the development of various ocular diseases. On the other hand, mAChRs may offer an attractive therapeutic target to treat ocular diseases. Thus far, non-subtype-selective mAChR ligands have been used in ophthalmology to treat dry eye disease, myopia and glaucoma. However, these drugs were shown to cause various side-effects. Thus, the use of subtype-selective ligands would be useful to circumvent this problem. In this review, we give an overview on the localization and on the functional role of mAChR subtypes in the eye and its adnexa with a special focus on the retina. Moreover, we describe the pathophysiological role of mAChRs in retinal diseases and discuss potential therapeutic approaches.


Assuntos
Terapia de Alvo Molecular , Receptores Muscarínicos/metabolismo , Retina/metabolismo , Animais , Humanos , Modelos Biológicos , Transdução de Sinais
20.
Int J Mol Sci ; 22(9)2021 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-34066780

RESUMO

Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and the second most common cause of cancer-related death globally. This type of liver cancer is frequently detected at a late stage by current biomarkers because of the high clinical and biological heterogeneity of HCC tumours. From a plethora of molecules and cellular compounds, small nanoparticles with an endosomal origin are valuable cancer biomarkers or cargos for novel treatments. Despite their small sizes, in the range of 40-150 nm, these particles are delimited by a lipid bilayer membrane with a specific lipid composition and carry functional information-RNA, proteins, miRNAs, long non-coding RNAs (lncRNAs), or DNA fragments. This review summarizes the role of exosomal microRNA (miRNA) species as biomarkers in HCC therapy. After we briefly introduce the exosome biogenesis and the methods of isolation and characterization, we discuss miRNA's correlation with the diagnosis and prognosis of HCC, either as single miRNA species, or as specific panels with greater clinical impact. We also review the role of exosomal miRNAs in the tumourigenic process and in the cell communication pathways through the delivery of cargos, including proteins or specific drugs.


Assuntos
Biomarcadores Tumorais/genética , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/genética , Exossomos/genética , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , MicroRNAs/genética , Terapia de Alvo Molecular , Animais , Biomarcadores Tumorais/metabolismo , Progressão da Doença , Humanos , MicroRNAs/metabolismo
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