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1.
Front Immunol ; 15: 1403764, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38915411

RESUMO

Immune system recognizes invading microbes at both pathogen and antigen levels. Toll-like receptors (TLRs) play a key role in the first-line defense against pathogens. Major functions of TLRs include cytokine and chemokine production. TLRs share common downstream signaling pathways with other receptors. The crosstalk revolving around TLRs is rather significant and complex, underscoring the intricate nature of immune system. The profiles of produced cytokines and chemokines via TLRs can be affected by other receptors. Integrins are critical heterodimeric adhesion molecules expressed on many different cells. There are studies describing synergetic or inhibitory interplay between TLRs and integrins. Thus, we reviewed the crosstalk between TLRs and integrins. Understanding the nature of the crosstalk could allow us to modulate TLR functions via integrins.


Assuntos
Integrinas , Receptor Cross-Talk , Transdução de Sinais , Receptores Toll-Like , Humanos , Receptores Toll-Like/metabolismo , Integrinas/metabolismo , Integrinas/imunologia , Animais , Citocinas/metabolismo , Imunidade Inata
3.
Biomed Pharmacother ; 175: 116615, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38663101

RESUMO

Estrogens play a critical role in the initiation and progression of breast cancer. Estrogen receptor (ER)α, ERß, and G protein-coupled estrogen receptor are the primary receptors for estrogen in breast cancer. These receptors are mainly activated by binding with estrogens. The crosstalk between ERs and membrane growth factor receptors creates additional pathways that amplify the effects of their ligands and promote tumor growth. This crosstalk may cause endocrine therapy resistance in ERα-positive breast cancer. Furthermore, this may explain the resistance to anti-human epidermal growth factor receptor-2 (HER2) treatment in ERα-/HER2-positive breast cancer and chemotherapy resistance in triple-negative breast cancer. Accordingly, it is necessary to understand the complex crosstalk between ERs and growth factor receptors. In this review, we delineate the crosstalk between ERs and membrane growth factor receptors in breast cancer. Moreover, this review highlights the current progress in clinical treatment and discusses how pharmaceuticals target the crosstalk. Lastly, we discuss the current challenges and propose potential solutions regarding the implications of targeting crosstalk via pharmacological inhibition. Overall, the present review provides a landscape of the crosstalk between ERs and membrane growth factor receptors in breast cancer, along with valuable insights for future studies and clinical treatments using a chemotherapy-sparing regimen to improve patient quality of life.


Assuntos
Neoplasias da Mama , Receptores de Estrogênio , Humanos , Receptores de Estrogênio/metabolismo , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Feminino , Animais , Receptor Cross-Talk/efeitos dos fármacos , Receptores de Fatores de Crescimento/metabolismo , Receptores de Fatores de Crescimento/antagonistas & inibidores , Terapia de Alvo Molecular , Transdução de Sinais/efeitos dos fármacos , Antineoplásicos/uso terapêutico , Antineoplásicos/farmacologia
4.
Acta Physiol (Oxf) ; 240(5): e14134, 2024 05.
Artigo em Inglês | MEDLINE | ID: mdl-38488216

RESUMO

The renin-angiotensin system (RAS) plays a key role in blood pressure regulation. The RAS is a complex interconnected system composed of two axes with opposite effects. The pressor arm, represented by angiotensin (Ang) II and the AT1 receptor (AT1R), mediates the vasoconstrictor, proliferative, hypertensive, oxidative, and pro-inflammatory effects of the RAS, while the depressor/protective arm, represented by Ang-(1-7), its Mas receptor (MasR) and the AT2 receptor (AT2R), opposes the actions elicited by the pressor arm. The AT1R, AT2R, and MasR belong to the G-protein-coupled receptor (GPCR) family. GPCRs operate not only as monomers, but they can also function in dimeric (homo and hetero) or higher-order oligomeric states. Due to the interaction with other receptors, GPCR properties may change: receptor affinity, trafficking, signaling, and its biological function may be altered. Thus, heteromerization provides a newly recognized means of modulation of receptor function, as well as crosstalk between GPCRs. This review is focused on angiotensin receptors, and how their properties are influenced by crosstalk with other receptors, adding more complexity to an already complex system and potentially opening up new therapeutic approaches.


Assuntos
Receptores Acoplados a Proteínas G , Sistema Renina-Angiotensina , Humanos , Sistema Renina-Angiotensina/fisiologia , Animais , Receptores Acoplados a Proteínas G/metabolismo , Transdução de Sinais/fisiologia , Receptor Cross-Talk/fisiologia , Receptores de Angiotensina/metabolismo , Receptor Tipo 1 de Angiotensina/metabolismo , Pressão Sanguínea/fisiologia , Receptor Tipo 2 de Angiotensina/metabolismo
5.
Methods Mol Biol ; 2740: 141-154, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38393474

RESUMO

Cell division requires a massive rewiring of cellular pathways, including molecular routes involved in providing energy for cell survival and functionality. The energetic requirements and the metabolic opportunities for generating energy change during the different phases of the cell cycle and how these processes are connected is still poorly understood. This chapter discusses basic concepts for a coordinated analysis of cell cycle progression and metabolism and provides specific protocols for studying these two connected processes in mammalian cells.


Assuntos
Divisão Celular , Receptor Cross-Talk , Animais , Ciclo Celular , Mamíferos
6.
J Steroid Biochem Mol Biol ; 232: 106352, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37330071

RESUMO

The vitamin D receptor with its ligand 1,25 dihydroxy vitamin D3 (1,25D3) regulates epidermal stem cell fate, such that VDR removal from Krt14 expressing keratinocytes delays re-epithelialization of epidermis after wound injury in mice. In this study we deleted Vdr from Lrig1 expressing stem cells in the isthmus of the hair follicle then used lineage tracing to evaluate the impact on re-epithelialization following injury. We showed that Vdr deletion from these cells prevents their migration to and regeneration of the interfollicular epidermis without impairing their ability to repopulate the sebaceous gland. To pursue the molecular basis for these effects of VDR, we performed genome wide transcriptional analysis of keratinocytes from Vdr cKO and control littermate mice. Ingenuity Pathway analysis (IPA) pointed us to the TP53 family including p63 as a partner with VDR, a transcriptional factor that is essential for proliferation and differentiation of epidermal keratinocytes. Epigenetic studies on epidermal keratinocytes derived from interfollicular epidermis showed that VDR is colocalized with p63 within the specific regulatory region of MED1 containing super-enhancers of epidermal fate driven transcription factor genes such as Fos and Jun. Gene ontology analysis further implicated that Vdr and p63 associated genomic regions regulate genes involving stem cell fate and epidermal differentiation. To demonstrate the functional interaction between VDR and p63, we evaluated the response to 1,25(OH)2D3 of keratinocytes lacking p63 and noted a reduction in epidermal cell fate determining transcription factors such as Fos, Jun. We conclude that VDR is required for the epidermal stem cell fate orientation towards interfollicular epidermis. We propose that this role of VDR involves cross-talk with the epidermal master regulator p63 through super-enhancer mediated epigenetic dynamics.


Assuntos
Receptor Cross-Talk , Receptores de Calcitriol , Animais , Camundongos , Receptores de Calcitriol/genética , Receptores de Calcitriol/metabolismo , Epiderme/metabolismo , Queratinócitos/metabolismo , Células Epidérmicas/metabolismo , Diferenciação Celular/genética , Fatores de Transcrição/metabolismo , Vitamina D/metabolismo
7.
Int J Mol Sci ; 24(11)2023 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-37298230

RESUMO

Ovarian cancer (OC) is one of the deadliest gynecological cancers, largely due to the fast development of metastasis and drug resistance. The immune system is a critical component of the OC tumor microenvironment (TME) and immune cells such as T cells, NK cells, and dendritic cells (DC) play a key role in anti-tumor immunity. However, OC tumor cells are well known for evading immune surveillance by modulating the immune response through various mechanisms. Recruiting immune-suppressive cells such as regulatory T cells (Treg cells), macrophages, or myeloid-derived suppressor cells (MDSC) inhibit the anti-tumor immune response and promote the development and progression of OC. Platelets are also involved in immune evasion by interaction with tumor cells or through the secretion of a variety of growth factors and cytokines to promote tumor growth and angiogenesis. In this review, we discuss the role and contribution of immune cells and platelets in TME. Furthermore, we discuss their potential prognostic significance to help in the early detection of OC and to predict disease outcome.


Assuntos
Plaquetas , Neoplasias , Neoplasias Ovarianas , Feminino , Humanos , Plaquetas/imunologia , Plaquetas/patologia , Células Mieloides/metabolismo , Neoplasias/metabolismo , Neoplasias Ovarianas/metabolismo , Prognóstico , Microambiente Tumoral , Sistema Imunitário/citologia , Sistema Imunitário/imunologia , Receptor Cross-Talk/imunologia
8.
Cancer Res ; 83(9): 1383-1385, 2023 05 02.
Artigo em Inglês | MEDLINE | ID: mdl-37128849

RESUMO

High-grade serous ovarian cancer (HGSOC) is the deadliest subtype of ovarian cancer, and most patients do not survive more than 5 years after diagnosis. Yet, for reasons that are often elusive, approximately 15% of women with advanced-stage HGSOC will survive longer than 10 years. An understanding of the biological basis of long-term survival with HGSOC may elucidate novel prognostic factors and targets for treatment. Past analyses of the clinicopathologic features of these women and genetic profiles of their tumors have not revealed a unifying explanation for their increased longevity. In this issue of Cancer Research, Ferri-Borgogno and colleagues investigate the tumor microenvironment (TME) in samples from both long- and short-term survivors using spatial transcriptomics and single-cell RNA sequencing. They found that, in metastatic tumors, various populations of cancer-associated fibroblasts (CAF) in the TME play different roles in supporting the malignant phenotype of ovarian cancer cells. Higher density of CAFs, particularly αSMA+VIM+PDGFRß+ CAFs, was associated with lower tumor immune infiltration and short-term survival. There was also marked expression of periostin and CD36 in spatially resolved CAFs, as well as a prevalence of the APOE-LRP5 ligand-receptor pair at the tumor-stromal interface in tissue from short-term survivors. These findings suggest that, in short-term survivors, CAFs are able to more effectively promote tumorigenicity, stemness, and chemoresistance in the nearby tumor. See related article by Ferri-Borgogno et al., p. 1503.


Assuntos
Sobreviventes de Câncer , Fibroblastos Associados a Câncer , Neoplasias Ovarianas , Humanos , Feminino , Receptor Cross-Talk , Microambiente Tumoral , Ligantes , Transcriptoma , Neoplasias Ovarianas/patologia , Fibroblastos Associados a Câncer/metabolismo
9.
Cancer Res ; 83(9): 1503-1516, 2023 05 02.
Artigo em Inglês | MEDLINE | ID: mdl-36787106

RESUMO

Advanced high-grade serous ovarian cancer (HGSC) is an aggressive disease that accounts for 70% of all ovarian cancer deaths. Nevertheless, 15% of patients diagnosed with advanced HGSC survive more than 10 years. The elucidation of predictive markers of these long-term survivors (LTS) could help identify therapeutic targets for the disease, and thus improve patient survival rates. To investigate the stromal heterogeneity of the tumor microenvironment (TME) in ovarian cancer, we used spatial transcriptomics to generate spatially resolved transcript profiles in treatment-naïve advanced HGSC from LTS and short-term survivors (STS) and determined the association between cancer-associated fibroblasts (CAF) heterogeneity and survival in patients with advanced HGSC. Spatial transcriptomics and single-cell RNA-sequencing data were integrated to distinguish tumor and stroma regions, and a computational method was developed to investigate spatially resolved ligand-receptor interactions between various tumor and CAF subtypes in the TME. A specific subtype of CAFs and its spatial location relative to a particular ovarian cancer cell subtype in the TME correlated with long-term survival in patients with advanced HGSC. Also, increased APOE-LRP5 cross-talk occurred at the stroma-tumor interface in tumor tissues from STS compared with LTS. These findings were validated using multiplex IHC. Overall, this spatial transcriptomics analysis revealed spatially resolved CAF-tumor cross-talk signaling networks in the ovarian TME that are associated with long-term survival of patients with HGSC. Further studies to confirm whether such cross-talk plays a role in modulating the malignant phenotype of HGSC and could serve as a predictive biomarker of patient survival are warranted. SIGNIFICANCE: Generation of spatially resolved gene expression patterns in tumors from patients with ovarian cancer surviving more than 10 years allows the identification of novel predictive biomarkers and therapeutic targets for better patient management. See related commentary by Kelliher and Lengyel, p. 1383.


Assuntos
Sobreviventes de Câncer , Cistadenocarcinoma Seroso , Neoplasias Ovarianas , Feminino , Humanos , Transcriptoma , Receptor Cross-Talk , Ligantes , Neoplasias Ovarianas/patologia , Cistadenocarcinoma Seroso/patologia , Biomarcadores Tumorais/genética , Microambiente Tumoral
10.
Prog Mol Biol Transl Sci ; 195: 101-120, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36707150

RESUMO

G protein-coupled receptors (GPCRs) are expressed by most tissues in the body and are exploited pharmacologically in a variety of pathological conditions including diabetes, cardiovascular disease, neurological diseases, and cancers. Numerous cell signaling pathways can be regulated by GPCR activation, depending on the specific GPCR, ligand and cell type. Ion channels are among the many effector proteins downstream of these signaling pathways. Saliently, ion channels are also recognized as druggable targets, and there is evidence that their activity may regulate GPCR function via membrane potential and cytoplasmic ion concentration. Overall, there appears to be a large potential for crosstalk between ion channels and GPCRs. This might have implications not only for targeting GPCRs for drug development, but also opens the possibility of co-targeting them with ion channels to achieve improved therapeutic outcomes. In this review, we highlight the large variety of possible GPCR-ion channel crosstalk modes.


Assuntos
Canais Iônicos , Receptor Cross-Talk , Receptores Acoplados a Proteínas G , Transdução de Sinais , Humanos , Doenças Cardiovasculares/metabolismo , Canais Iônicos/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Receptor Cross-Talk/fisiologia
11.
J Microbiol ; 61(1): 1-11, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36719618

RESUMO

The skin's epidermis is an essential barrier as the first guard against invading pathogens, and physical protector from external injury. The skin microbiome, which consists of numerous bacteria, fungi, viruses, and archaea on the epidermis, play a key role in skin homeostasis. Antibiotics are a fast-acting and effective treatment method, however, antibiotic use is a nuisance that can disrupt skin homeostasis by eradicating beneficial bacteria along with the intended pathogens and cause antibiotic-resistant bacteria spread. Increased numbers of antimicrobial peptides (AMPs) derived from humans and bacteria have been reported, and their roles have been well defined. Recently, modulation of the skin microbiome with AMPs rather than artificially synthesized antibiotics has attracted the attention of researchers as many antibiotic-resistant strains make treatment mediation difficult in the context of ecological problems. Herein, we discuss the overall insights into the skin microbiome, including its regulation by different AMPs, as well as their composition and role in health and disease.


Assuntos
Peptídeos Catiônicos Antimicrobianos , Peptídeos Antimicrobianos , Bactérias , Microbiota , Pele , Humanos , Antibacterianos/química , Peptídeos Catiônicos Antimicrobianos/farmacologia , Peptídeos Catiônicos Antimicrobianos/uso terapêutico , Peptídeos Catiônicos Antimicrobianos/química , Pele/microbiologia , Microbiota/fisiologia , Receptor Cross-Talk
13.
J Transl Med ; 20(1): 407, 2022 09 05.
Artigo em Inglês | MEDLINE | ID: mdl-36064558

RESUMO

BACKGROUND: Atrial fibrosis plays a critical role in the development of atrial fibrillation (AF). Exosomes are a promising cell-free therapeutic approach for the treatment of AF. The purposes of this study were to explore the mechanisms by which exosomes derived from atrial myocytes regulate atrial remodeling and to determine whether their manipulation facilitates the therapeutic modulation of potential fibrotic abnormalities during AF. METHODS: We isolated exosomes from atrial myocytes and patient serum, and microRNA (miRNA) sequencing was used to analyze exosomal miRNAs in exosomes derived from atrial myocytes and patient serum. mRNA sequencing and bioinformatics analyses corroborated the key genes that were direct targets of miR-210-3p. RESULTS: The miRNA sequencing analysis identified that miR-210-3p expression was significantly increased in exosomes from tachypacing atrial myocytes and serum from patients with AF. In vitro, the miR-210-3p inhibitor reversed tachypacing-induced proliferation and collagen synthesis in atrial fibroblasts. Accordingly, miR-210-3p knock out (KO) reduced the incidence of AF and ameliorated atrial fibrosis induced by Ang II. The mRNA sequencing analysis and dual-luciferase reporter assay showed that glycerol-3-phosphate dehydrogenase 1-like (GPD1L) is a potential target gene of miR-210-3p. The functional analysis suggested that GPD1L regulated atrial fibrosis via the PI3K/AKT signaling pathway. In addition, silencing GPD1L in atrial fibroblasts induced cell proliferation, and these effects were reversed by a PI3K inhibitor (LY294002). CONCLUSIONS: Atrial myocyte-derived exosomal miR-210-3p promoted cell proliferation and collagen synthesis by inhibiting GPD1L in atrial fibroblasts. Preventing pathological crosstalk between atrial myocytes and fibroblasts may be a novel target to ameliorate atrial fibrosis in patients with AF.


Assuntos
Fibrilação Atrial , Exossomos , Glicerolfosfato Desidrogenase , Átrios do Coração , MicroRNAs , Miócitos Cardíacos , Fibrilação Atrial/complicações , Fibrilação Atrial/genética , Fibrilação Atrial/metabolismo , Fibrilação Atrial/patologia , Colágeno/metabolismo , Exossomos/genética , Exossomos/metabolismo , Exossomos/patologia , Fibrose/genética , Fibrose/metabolismo , Fibrose/patologia , Glicerolfosfato Desidrogenase/genética , Glicerolfosfato Desidrogenase/metabolismo , Átrios do Coração/metabolismo , Átrios do Coração/patologia , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Fosfatidilinositol 3-Quinases/metabolismo , RNA Mensageiro/metabolismo , Receptor Cross-Talk
14.
Front Immunol ; 13: 907636, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35967419

RESUMO

Tumor-associated macrophages (TAMs) are involved in the growth of prostate cancer (PrC), while the molecular mechanisms underlying the interactive crosstalk between TAM and PrC cells remain largely unknown. Platelet-derived growth factor (PDGF) is known to promote mesenchymal stromal cell chemotaxis to the tumor microenvironment. Recently, activation of spindle pole body component 25 (SPC25) has been shown to promote PrC cell proliferation and is associated with PrC stemness. Here, the relationship between SPC25 and PDGF in the crosstalk between TAM and PrC was investigated. Significant increases in both PDGF and SPC25 levels were detected in PrC specimens compared to paired adjacent normal prostate tissues. A significant correlation was detected between PDGF and SPC25 levels in PrC specimens and cell lines. SPC25 increased PDGF production and tumor cell growth in cultured PrC cells and in xenotransplantation. Mechanistically, SPC25 appeared to activate PDGF in PrC likely through Early Growth Response 1 (Egr1), while the secreted PDGF signaled to TAM through PDGFR on macrophages and polarized macrophages, which, in turn, induced the growth of PrC cells likely through their production and secretion of transforming growth factor ß1 (TGFß1). Thus, our data suggest that SPC25 triggers the crosstalk between TAM and PrC cells via SPC25/PDGF/PDGFR/TGFß1 receptor signaling to enhance PrC growth.


Assuntos
Proteínas Associadas aos Microtúbulos , Fator de Crescimento Derivado de Plaquetas , Próstata , Neoplasias da Próstata , Corpos Polares do Fuso , Macrófagos Associados a Tumor , Linhagem Celular Tumoral , Humanos , Masculino , Proteínas Associadas aos Microtúbulos/metabolismo , Fator de Crescimento Derivado de Plaquetas/metabolismo , Próstata/metabolismo , Neoplasias da Próstata/metabolismo , Receptor Cross-Talk/fisiologia , Receptores do Fator de Crescimento Derivado de Plaquetas/metabolismo , Transdução de Sinais , Corpos Polares do Fuso/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Microambiente Tumoral , Macrófagos Associados a Tumor/metabolismo
15.
Int J Mol Sci ; 23(14)2022 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-35887027

RESUMO

There are fundamental sex differences in the regulation of energy homeostasis. Better understanding of the underlying mechanisms of energy balance that account for this asymmetry will assist in developing sex-specific therapies for sexually dimorphic diseases such as obesity. Multiple organs, including the hypothalamus and adipose tissue, play vital roles in the regulation of energy homeostasis, which are regulated differently in males and females. Various neuronal populations, particularly within the hypothalamus, such as arcuate nucleus (ARC), can sense nutrient content of the body by the help of peripheral hormones such leptin, derived from adipocytes, to regulate energy homeostasis. This review summarizes how adipose tissue crosstalk with homeostatic network control systems in the brain, which includes energy regulatory regions and the hypothalamic-pituitary axis, contribute to energy regulation in a sex-specific manner. Moreover, development of obesity is contingent upon diet and environmental factors. Substances from diet and environmental contaminants can exert insidious effects on energy metabolism, acting peripherally through the aryl hydrocarbon receptor (AhR). Developmental AhR activation can impart permanent alterations of neuronal development that can manifest a number of sex-specific physiological changes, which sometimes become evident only in adulthood. AhR is currently being investigated as a potential target for treating obesity. The consensus is that impaired function of the receptor protects from obesity in mice. AhR also modulates sex steroid receptors, and hence, one of the objectives of this review is to explain why investigating sex differences while examining this receptor is crucial. Overall, this review summarizes sex differences in the regulation of energy homeostasis imparted by the adipose-hypothalamic axis and examines how this axis can be affected by xenobiotics that signal through AhR.


Assuntos
Tecido Adiposo , Metabolismo Energético , Hipotálamo , Receptor Cross-Talk , Receptores de Hidrocarboneto Arílico , Caracteres Sexuais , Tecido Adiposo/metabolismo , Animais , Metabolismo Energético/fisiologia , Feminino , Homeostase , Hipotálamo/metabolismo , Masculino , Camundongos , Obesidade/metabolismo , Receptor Cross-Talk/fisiologia , Receptores de Hidrocarboneto Arílico/metabolismo
16.
Inflammopharmacology ; 30(2): 549-563, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35243557

RESUMO

Chronic pain is among the most burdensome and devastating disorders affecting millions of people worldwide. Recent studies suggest the role of kinesin nanomotors in development and maintenance of chronic pain. KIF17 is a member of kinesin superfamily that binds to NR2B cargo system via mLin10 scaffolding protein and makes the NMDARs functional at cell surface. NMDA receptor activation is known to induce the central sensitization and excitotoxicity which can be recognized by the glial cells followed by the release of cytokine storm at spinal and supraspinal level leading to chronic pain. In this study, we have investigated the role of aurora kinase in the regulation of KIF17 and NR2B trafficking in the animal model of chronic inflammatory pain. Tozasertib (10, 20, and 40 mg/kg i.p.), a pan aurora kinase inhibitor, significantly attenuates acute inflammatory pain and suppresses enhanced pain hypersensitivity to heat, cold, and mechanical stimuli in CFA-injected rats. Molecular investigations suggest enhanced expression of KIF17/mLin10/NR2B in L4-L5 dorsal root ganglion (DRG) and spinal cord of CFA-injected rats which was significantly attenuated on treatment with tozasertib. Moreover, tozasertib treatment significantly attenuated CFA-induced oxido-nitrosative stress and macrophage activation in DRG and microglia activation in spinal cord of rats. Findings from the current study suggest that tozasertib mediates anti-nociceptive activity by inhibiting aurora kinase-mediated KIF17/mLin10/NR2B signaling.


Assuntos
Dor Crônica , Cinesinas , Piperazinas , Receptores de N-Metil-D-Aspartato , Animais , Dor Crônica/tratamento farmacológico , Dor Crônica/metabolismo , Humanos , Hiperalgesia/tratamento farmacológico , Piperazinas/farmacologia , Ratos , Receptor Cross-Talk , Receptores de N-Metil-D-Aspartato/metabolismo
17.
Biomed Pharmacother ; 146: 112588, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-35062062

RESUMO

Tumor-associated macrophages (TAMs) are among the abundant cell populations of the tumor microenvironment (TME), which have pivotal roles in tumor development, chemoresistance, immune evasion, and metastasis. Growing evidence indicates that TAMs and the cross-talk between TAMs and tumoral endothelial cells can substantially contribute to tumor angiogenesis, which is considered a vital process for cancer development. Besides, tumoral endothelial cells can regulate the leukocyte infiltration to the TME in solid cancers and contribute to immune evasion. Therefore, targeting the immunosuppressive TAMs and the cross-talk between them can be a promising strategy for improving anti-tumoral immune responses. This review aims to summarize the biology of TAMs, their recently identified roles in tumor development/angiogenesis, and recent advances in macrophage-based cancer immunotherapy approaches for treating cancers.


Assuntos
Imunoterapia/métodos , Neoplasias/imunologia , Microambiente Tumoral , Macrófagos Associados a Tumor/metabolismo , Antineoplásicos Imunológicos/uso terapêutico , Células Endoteliais , Humanos , Neoplasias/tratamento farmacológico , Receptor Cross-Talk , Macrófagos Associados a Tumor/patologia
18.
Int J Med Sci ; 19(1): 175-185, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34975311

RESUMO

Our previous study found that the combination of halofuginone (HF) and artemisinin (ATS) synergistically arrest colorectal cancer (CRC) cells at the G1/G0 phase of the cell cycle; however, it remains unclear whether HF-ATS induces cell death. Here we report that HF-ATS synergistically induced caspase-dependent apoptosis in CRC cells. Specifically, both in vitro and in vivo experiments showed that HF or HF-ATS induces apoptosis via activation of caspase-9 and caspase-8 while only caspase-9 is involved in ATS-induced apoptosis. Furthermore, we found HF or HF-ATS induces autophagy; ATS can't induce autophagy until caspase-9 is blocked. Further analyzing the crosstalk between autophagic and caspase activation in CRC cells, we found autophagy is essential for activation of caspase-8, and ATS switches to activate capase-8 via induction of autophagy when caspase-9 is inhibited. When apoptosis is totally blocked, HF-ATS switches to induce autophagic cell death. This scenario was then confirmed in studies of chemoresistance CRC cells with defective apoptosis. Our results indicate that HF-ATS induces cell death via interaction between apoptosis and autophagy in CRC cells. These results highlight the value of continued investigation into the potential use of this combination in cancer therapy.


Assuntos
Apoptose/efeitos dos fármacos , Artemisininas/farmacologia , Neoplasias Colorretais/patologia , Piperidinas/farmacologia , Quinazolinonas/farmacologia , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Artemisininas/uso terapêutico , Autofagia/efeitos dos fármacos , Caspase 8/metabolismo , Caspase 9/metabolismo , Linhagem Celular Tumoral , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/metabolismo , Sinergismo Farmacológico , Ativação Enzimática , Humanos , Piperidinas/uso terapêutico , Quinazolinonas/uso terapêutico , Receptor Cross-Talk
19.
Endocrinology ; 163(2)2022 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-34977930

RESUMO

Luminal breast cancer (BrCa) has a favorable prognosis compared with other tumor subtypes. However, with time, tumors may evolve and lead to disease progression; thus, there is a great interest in unraveling the mechanisms that drive tumor metastasis and endocrine resistance. In this review, we focus on one of the many pathways that have been involved in tumor progression, the fibroblast growth factor/fibroblast growth factor receptor (FGFR) axis. We emphasize in data obtained from in vivo experimental models that we believe that in luminal BrCa, tumor growth relies in a crosstalk with the stromal tissue. We revisited the studies that illustrate the interaction between hormone receptors and FGFR. We also highlight the most frequent alterations found in BrCa cell lines and provide a short review on the trials that use FGFR inhibitors in combination with endocrine therapies. Analysis of these data suggests there are many players involved in this pathway that might be also targeted to decrease FGF signaling, in addition to specific FGFR inhibitors that may be exploited to increase their efficacy.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Fatores de Crescimento de Fibroblastos/fisiologia , Receptores de Fatores de Crescimento de Fibroblastos/fisiologia , Receptores de Esteroides/fisiologia , Transdução de Sinais/fisiologia , Animais , Inibidores da Aromatase/uso terapêutico , Neoplasias da Mama/química , Neoplasias da Mama/terapia , Linhagem Celular Tumoral , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Receptor alfa de Estrogênio/análise , Feminino , Fatores de Crescimento de Fibroblastos/genética , Amplificação de Genes , Humanos , Camundongos , Mutação , Receptor Cross-Talk/fisiologia , Receptores de Fatores de Crescimento de Fibroblastos/antagonistas & inibidores , Receptores de Fatores de Crescimento de Fibroblastos/genética
20.
J Neurosci ; 42(7): 1173-1183, 2022 02 16.
Artigo em Inglês | MEDLINE | ID: mdl-34965978

RESUMO

The physical interaction and functional cross talk among the different subtypes of neuronal nicotinic acetylcholine receptors (nAChRs) expressed in the various tissues is unknown. Here, we have investigated this issue between the only two nAChRs subtypes expressed, the α7 and α3ß4 subtypes, in a human native neuroendocrine cell (the chromaffin cell) using electrophysiological patch-clamp, fluorescence, and Förster resonance energy transfer (FRET) techniques. Our data show that α7 and α3ß4 receptor subtypes require their mutual and maximal efficacy of activation to increase their expression, to avoid their desensitization, and therefore, to increase their activity. In this way, after repetitive stimulation with acetylcholine (ACh), α7 and α3ß4 receptor subtypes do not desensitize, but they do with choline. The nicotinic current increase associated with the α3ß4 subtype is dependent on Ca2+ In addition, both receptor subtypes physically interact. Interaction and expression of both subtypes are reversibly reduced by tyrosine and serine/threonine phosphatases inhibition, not by Ca2+ In addition, expression is greater in human chromaffin cells from men compared to women, but FRET efficiency is not affected. Together, our findings indicate that human α7 and α3ß4 subtypes mutually modulate their expression and activity, providing a promising line of research to pharmacologically regulate their activity.SIGNIFICANCE STATEMENT Desensitization of nicotinic receptors is accepted to occur with repetitive agonist stimulation. However, here we show that human native α3ß4 and α7 nicotinic acetylcholine receptor (nAChR) subtypes do not desensitize, and instead, increase their activity when they are activated by the physiological agonist acetylcholine (ACh). An indispensable requirement is the activation of the other receptor subtype with maximal efficacy, and the presence of Ca2+ to cooperate in the case of the α3ß4 current increase. Because choline is an α3ß4 partial agonist, it will act as a limiting factor of nicotinic currents enhancement in the absence of ACh, but in its presence, it will further potentiate α7 currents.


Assuntos
Células Cromafins/metabolismo , Receptor Cross-Talk/fisiologia , Receptores Nicotínicos/metabolismo , Receptor Nicotínico de Acetilcolina alfa7/metabolismo , Animais , Humanos , Camundongos , Camundongos Endogâmicos C57BL
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