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1.
Phytother Res ; 38(3): 1610-1622, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38296262

RESUMO

Gastroesophageal reflux disease (GERD) is the most common foregut disease, affecting about 20% of the adult population. Esophageal epithelial barrier plays a fundamental role in the pathophysiology of GERD; however, pharmacological therapies mainly aim to reduce the acidity of the gastroesophageal environment rather than to protect esophageal tissue integrity. This study aims to evaluate the efficacy of an oral solution containing xyloglucan and pea proteins (XP) in reestablishing gastroesophageal tissue integrity and biochemical markers. To induce GERD, C57BL/6 mice were alternatively overfed and fasted for 56 days and then treated with XP, sodium alginate, omeprazole, or omeprazole+XP twice daily for 7 days. Gastric pain and inflammatory markers were evaluated after 3 and 7 days of treatment. After sacrifice, the esophagi and stomachs were surgically removed for macroscopic and histological examination. Gastric pain was significantly reduced at days 3 and 7 by XP, omeprazole, and omeprazole+XP, while alginates were ineffective at day 3. XP was able to diminish gastric macroscopic damage and demonstrated the same efficacy as omeprazole in reducing esophageal damage. XP significantly reduced histological damage, with an efficacy comparable to that of omeprazole, but superior to alginates. Inflammatory markers were significantly reduced by XP, with superior efficacy compared with alginates at day 7. Interestingly, XP was also able to significantly increase gastric pH. This study demonstrated that XP restored gastric homeostasis, improved esophageal integrity, and decreased inflammation and pain with a similar efficacy to omeprazole and greater than alginates.


Assuntos
Refluxo Gastroesofágico , Glucanos , Proteínas de Ervilha , Xilanos , Animais , Camundongos , Proteínas de Ervilha/uso terapêutico , Modelos Animais de Doenças , Camundongos Endogâmicos C57BL , Refluxo Gastroesofágico/tratamento farmacológico , Omeprazol/farmacologia , Omeprazol/uso terapêutico , Dor/tratamento farmacológico
2.
J Neuroinflammation ; 20(1): 155, 2023 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-37391829

RESUMO

Parkinson's disease (PD) is characterized by the degeneration of dopaminergic nigrostriatal neurons, which causes disabling motor disorders. Scientific findings support the role of epigenetics mechanism in the development and progression of many neurodegenerative diseases, including PD. In this field, some studies highlighted an upregulation of Enhancer of zeste homolog 2 (EZH2) in the brains of PD patients, indicating the possible pathogenic role of this methyltransferase in PD. The aim of this study was to evaluate the neuroprotective effects of GSK-343, an EZH2 inhibitor, in an in vivo model of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic degeneration. Specifically, nigrostriatal degeneration was induced by MPTP intraperitoneal injection. GSK-343 was administered intraperitoneally daily at doses of 1 mg/kg, 5 mg/kg and 10 mg/kg, mice were killed 7 days after MPTP injection. Our results demonstrated that GSK-343 treatment significantly improved behavioral deficits and reduced the alteration of PD hallmarks. Furthermore, GSK-343 administration significantly attenuated the neuroinflammatory state through the modulation of canonical and non-canonical NF-κB/IκBα pathway as well as the cytokines expression and glia activation, also reducing the apoptosis process. In conclusion, the obtained results provide further evidence that epigenetic mechanisms play a pathogenic role in PD demonstrating that the inhibition of EZH2, mediated by GSK-343, could be considered a valuable pharmacological strategy for PD.


Assuntos
Fármacos Neuroprotetores , Animais , Camundongos , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Apoptose , Cegueira , Encéfalo , Citocinas
3.
Cell Mol Neurobiol ; 43(4): 1637-1659, 2023 May.
Artigo em Inglês | MEDLINE | ID: mdl-36121569

RESUMO

Spinal cord injury (SCI) leads to long-term and permanent motor dysfunctions, and nervous system abnormalities. Injury to the spinal cord triggers a signaling cascade that results in activation of the inflammatory cascade, apoptosis, and Zn(II) ion homeostasis. Trehalose (Tre), a nonreducing disaccharide, and L-carnosine (Car), (ß-alanyl-L-histidine), one of the endogenous histidine dipeptides have been recognized to suppress early inflammatory effects, oxidative stress and to possess neuroprotective effects. We report on the effects of the conjugation of Tre with Car (Tre-car) in reducing inflammation in in vitro and in vivo models. The in vitro study was performed using rat pheochromocytoma cells (PC12 cell line). After 24 h, Tre-car, Car, Tre, and Tre + Car mixture treatments, cells were collected and used to investigate Zn2+ homeostasis. The in vivo model of SCI was induced by extradural compression of the spinal cord at the T6-T8 levels. After treatments with Tre, Car and Tre-Car conjugate 1 and 6 h after SCI, spinal cord tissue was collected for analysis. In vitro results demonstrated the ionophore effect and chelating features of L-carnosine and its conjugate. In vivo, the Tre-car conjugate treatment counteracted the activation of the early inflammatory cascade, oxidative stress and apoptosis after SCI. The Tre-car conjugate stimulated neurotrophic factors release, and influenced Zn2+ homeostasis. We demonstrated that Tre-car, Tre and Car treatments improved tissue recovery after SCI. Tre-car decreased proinflammatory, oxidative stress mediators release, upregulated neurotrophic factors and restored Zn2+ homeostasis, suggesting that Tre-car may represent a promising therapeutic agent for counteracting the consequences of SCI.


Assuntos
Carnosina , Traumatismos da Medula Espinal , Ratos , Animais , Carnosina/farmacologia , Carnosina/uso terapêutico , Trealose/farmacologia , Trealose/uso terapêutico , Zinco/farmacologia , Traumatismos da Medula Espinal/metabolismo , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Medula Espinal/metabolismo , Apoptose , Fatores de Crescimento Neural/farmacologia , Homeostase
4.
Mar Drugs ; 21(5)2023 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-37233492

RESUMO

Inflammatory bowel diseases (IBDs) involving Crohn's disease (CD) and ulcerative colitis (UC) are gastrointestinal (GI) disorders in which abdominal pain, discomfort, and diarrhea are the major symptoms. The immune system plays an important role in the pathogenesis of IBD and, as indicated by several clinical studies, both innate and adaptative immune response has the faculty to induce gut inflammation in UC patients. An inappropriate mucosal immune response to normal intestinal constituents is a main feature of UC, thus leading to an imbalance in local pro- and anti-inflammatory species. Ulva pertusa, a marine green alga, is known for its important biological properties, which could represent a source of beneficial effects in various human pathologies. We have already demonstrated the anti-inflammatory, antioxidant, and antiapoptotic effects of an Ulva pertusa extract in a murine model of colitis. In this study, we aimed to examine thoroughly Ulva pertusa immunomodulatory and pain-relieving properties. Colitis was induced by using the DNBS model (4 mg in 100 µL of 50% ethanol), whereas Ulva pertusa was administered daily at the dosage of 50 and 100 mg/kg by oral gavage. Ulva pertusa treatments have been shown to relieve abdominal pain while modulating innate and adaptative immune-inflammatory responses. This powerful immunomodulatory activity was specifically linked with TLR4 and NLRP3 inflammasome modulation. In conclusion, our data suggest Ulva pertusa as a valid approach to counteract immune dysregulation and abdominal discomfort in IBD.


Assuntos
Colite Ulcerativa , Colite , Doenças Inflamatórias Intestinais , Ulva , Humanos , Animais , Camundongos , Colite/induzido quimicamente , Colite/tratamento farmacológico , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/tratamento farmacológico , Dor Abdominal , Sistema Imunitário
5.
Int J Mol Sci ; 24(19)2023 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-37834102

RESUMO

A spinal cord injury (SCI) is a well-defined debilitating traumatic event to the spinal cord that usually triggers permanent changes in motor, sensory, and autonomic functions. Injured tissue becomes susceptible to secondary mechanisms caused by SCIs, which include pro-inflammatory cytokine release, the activation of astrocytes and microglia, and increased neuronal sensibility. As a consequence, the production of factors such as GFAP, IBA-1, TNF-α, IL-1ß, IFN-γ, and S100-ß slow down or inhibit central nervous system (CNS) regeneration. In this regard, a thorough understanding of the mechanisms regulating the CNS, and specifically SCI, is essential for the development of new therapeutic strategies. It has been demonstrated that basic fibroblast growth factor (bFGF) was successful in the modulation of neurotrophic activity, also promoting neurite survival and tissue repair, thus resulting in the valuable care of CNS disorders. However, bFGF therapeutic use is limited due to the undesirable effects developed following its administration. Therefore, the synthetic compound mimetic of bFGF, SUN11602 (with chemical name 4-[[4-[[2-[(4-Amino-2,3,5,6-tetramethylphenyl)amino]acetyl]methylamino]-1-piperidinyl]methyl]benzamide), has been reported to show neuroprotective activities similar to those of bFGF, also demonstrating a good pharmacokinetic profile. Here, we aimed to investigate the neuroprotective activity of this bFGF-like compound in modulating tissue regeneration, neuroinflammation, and Ca2+ overload by using a subacute mouse model of SCI. SUN11602 (1, 2.5, and 5 mg/kg) was administered orally to mice for 72 h daily following the in vivo model of SCI, which was generated by the extradural compression of the spinal cord. The data obtained demonstrated that SUN11602 treatment considerably decreased motor alteration and diminished the neuroinflammatory state through the regulation of glial activation, the NF-κB pathway, and kinases. Additionally, by controlling Ca2+-binding proteins and restoring neurotrophin expression, we showed that SUN11602 therapy restored the equilibrium of the neuronal circuit. Because of these findings, bFGF-like compounds may be an effective tool for reducing inflammation in SCI patients while enhancing their quality of life.


Assuntos
Fator 2 de Crescimento de Fibroblastos , Traumatismos da Medula Espinal , Humanos , Camundongos , Animais , Doenças Neuroinflamatórias , Qualidade de Vida , Traumatismos da Medula Espinal/metabolismo , Medula Espinal/metabolismo , Homeostase
6.
Int J Mol Sci ; 24(4)2023 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-36834534

RESUMO

Psoriasis is a chronic inflammatory skin disease characterized by epidermal gene abnormalities, epidermal barrier defects and inflammation. Corticosteroids are considered to be standard treatments, but often come with side effects and lose efficacy with long-term use. Alternative treatments targeting the epidermal barrier defect are needed to manage the disease. Film-forming substances such as xyloglucan, pea protein and Opuntia ficus-indica extract (XPO) have generated interest for their ability to restore skin barrier integrity and may pose an alternative approach to disease management. Thus, the aim of this two-part study was to evaluate the barrier-protective properties of a topical cream containing XPO on the membrane permeability of keratinocytes exposed to inflammatory conditions and compare its efficacy to dexamethasone (DXM) in an in vivo model of psoriasis-like dermatitis. XPO treatment significantly reduced S. aureus adhesion, subsequent skin invasion and restored epithelial barrier function in keratinocytes. Furthermore, the treatment restored the integrity of keratinocytes, reducing tissue damage. In mice with psoriasis-like dermatitis, XPO significantly reduced erythema, inflammatory markers and epidermal thickening with a superior efficacy to dexamethasone. Given the promising results, XPO may represent a novel steroid-sparing therapeutic for epidermal-related diseases such as psoriasis, thanks to its ability to preserve skin barrier function and integrity.


Assuntos
Dermatite , Opuntia , Proteínas de Ervilha , Psoríase , Dermatopatias , Camundongos , Animais , Staphylococcus aureus , Dexametasona
7.
Int J Mol Sci ; 24(11)2023 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-37298200

RESUMO

Parkinson's disease (PD) is a disorder that is characterized by progressive and selective neuronal injury and cell death. Recent studies have provided accumulating evidence for a significant role of the immune system and neuroinflammation in PD pathogenesis. On this basis, many scientific articles have highlighted the anti-inflammatory and neuroprotective properties of Antrodia camphorata (AC), an edible fungus containing various bioactive compounds. This study aimed to evaluate the inhibitory effect of AC administration on neuroinflammation and oxidative stress in a murine model of MPTP-induced dopaminergic degeneration. AC (10, 30, 100 mg/kg) was administered daily by oral gavage starting 24 h after the first administration of MPTP, and mice were sacrificed 7 days after MPTP induction. In this study, treatment with AC significantly reduced the alteration of PD hallmarks, increasing tyrosine hydroxylase expression and reducing the number of alpha-synuclein-positive neurons. In addition, AC treatment restored the myelination process of neurons associated with PD and attenuated the neuroinflammatory state. Furthermore, our study demonstrated that AC was able to reduce the oxidative stress induced by MPTP injection. In conclusion, this study highlighted that AC could be a potential therapeutic agent for the treatment of neurodegenerative disorders such as PD.


Assuntos
Intoxicação por MPTP , Fármacos Neuroprotetores , Doença de Parkinson , Camundongos , Animais , Doença de Parkinson/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Modelos Animais de Doenças , Doenças Neuroinflamatórias , Camundongos Endogâmicos C57BL , Neurônios Dopaminérgicos/metabolismo , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Fármacos Neuroprotetores/metabolismo , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina/farmacologia , Intoxicação por MPTP/metabolismo
8.
Int J Mol Sci ; 24(3)2023 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-36769105

RESUMO

Oral squamous cell carcinoma (OSCC) is a common human tumor, that originates from buccal mucosa and the tongue, associated with a high mortality rate. Currently, the treatment for OSCC involves surgery, chemotherapy and radiotherapy; however, survival outcomes for OSCC patients remain poor. For this reason, it is necessary to investigate new therapeutic strategies to counteract the progression of OSCC. In this study, we aimed to evaluate the role of dimethyl fumarate (DMF) in modulation of OSCC progression, both in vitro and in an in vivo orthotopic xenograft model. In vitro results revealed that DMF was able to reduce the expression of anti-apoptotic factors as BCL-2 and increased the expression of pro-apoptotic factors as Bax, Caspase-3 and BID. DMF appears to be involved in the modulation of oxidative stress mediators, such as MnSOD and HO-1. Furthermore, DMF showed to reduce the migratory ability of tumor cells and to modulate the expression of markers of epithelial-mesenchymal transition (EMT), as N-cadherin and E-cadherin. The in vivo study confirmed the data obtained in vitro significantly decreasing tumor mass and also reducing oxidative stress and apoptosis. Therefore, based on these results, the use of DMF could be considered a promising strategy to counteract oral cancer progression.


Assuntos
Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , Neoplasias Bucais , Humanos , Carcinoma de Células Escamosas de Cabeça e Pescoço , Carcinoma de Células Escamosas/patologia , Neoplasias Bucais/patologia , Fumarato de Dimetilo/farmacologia , Fumarato de Dimetilo/uso terapêutico , Transição Epitelial-Mesenquimal , Apoptose , Estresse Oxidativo , Linhagem Celular Tumoral , Proliferação de Células
9.
J Neuroinflammation ; 19(1): 107, 2022 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-35526035

RESUMO

BACKGROUND: Parkinson's disease (PD) is the second most frequent neurodegenerative disease. PD etiopathogenesis is multifactorial and not yet fully known, however, the scientific world advised the establishment of neuroinflammation among the possible risk factors. In this field, basic fibroblast growth factor/fibroblast growth factor receptor-1 (bFGF/FGFR1) could be a promising way to treat CNS-mediated inflammation; unfortunately, the use of bFGF as therapeutic agent is limited by its side effects. The novel synthetic compound SUN11602 exhibited neuroprotective activities like bFGF. With this perspective, this study aimed to evaluate the effect of SUN11602 administration in a murine model of MPTP-induced dopaminergic degeneration. METHODS: Specifically, nigrostriatal degeneration was induced by intraperitoneal injection of MPTP (80 mg/kg). SUN11602 (1 mg/kg, 2.5 mg/kg, and 5 mg/kg) was administered daily by oral gavage starting from 24 h after the first administration of MPTP. Mice were killed 7 days after MPTP induction. RESULTS: The results obtained showed that SUN11602 administration significantly reduced the alteration of PD hallmarks, attenuating the neuroinflammatory state via modulation of glial activation, NF-κB pathway, and cytokine overexpression. Furthermore, we demonstrated that SUN11602 treatment rebalanced Ca2+ overload in neurons by regulating Ca2+-binding proteins while inhibiting the apoptotic cascade. CONCLUSION: Therefore, in the light of these findings, SUN11602 could be considered a valuable pharmacological strategy for PD.


Assuntos
Intoxicação por MPTP , Doenças Neurodegenerativas , Fármacos Neuroprotetores , Doença de Parkinson , Animais , Apoptose , Benzamidas , Proteínas de Ligação ao Cálcio/metabolismo , Modelos Animais de Doenças , Neurônios Dopaminérgicos , Fator 2 de Crescimento de Fibroblastos , Intoxicação por MPTP/tratamento farmacológico , Camundongos , Camundongos Endogâmicos C57BL , Doenças Neurodegenerativas/tratamento farmacológico , Doenças Neuroinflamatórias , Fármacos Neuroprotetores/farmacologia , Doença de Parkinson/metabolismo , Fenilenodiaminas
10.
Ann Neurol ; 90(1): 4-14, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33547827

RESUMO

Intracellular protein trafficking via the endosomes plays a key role in the maintenance of normal neuronal function. Although many diseases of the central nervous system exhibit specific pathological hallmarks, abnormalities of the endosome system are common traits for several of them, including Alzheimer disease (AD). Three main routes originate from the endosomes: the recycling, degradation, and retrograde pathways. Studies have shown that the majority of Down syndrome subjects develop AD pathology and manifest altered morphology and number of endosomes, and abnormalities in lysosome acidification and exosome secretion, suggesting that dysfunction of one of these pathways could play a functional role in the AD-like phenotype of the syndrome. Two of the major endosomal routes are mediated by the retromer complex, a multimeric system responsible for transport of cargo from the endosome to the trans-Golgi network or to the cell membrane. Recently, a new endosome system structurally related to the retromer, called "retriever," has been reported. Whereas we know a great deal about the neuropathophysiology of the retromer complex, no precise pathogenic role for the retriever has yet been identified. Here, we will review the neurobiology of the endosome system and its role as key player in the development of AD-like pathology in Down syndrome. Additionally, we will discuss current knowledge on these two main endosome systems, retromer and retriever, and their potential as novel therapeutic targets. ANN NEUROL 2021;90:4-14.


Assuntos
Doença de Alzheimer/metabolismo , Encéfalo/metabolismo , Síndrome de Down/metabolismo , Endossomos/metabolismo , Doença de Alzheimer/patologia , Animais , Encéfalo/patologia , Síndrome de Down/patologia , Endossomos/patologia , Humanos , Rede trans-Golgi/metabolismo
11.
Int J Mol Sci ; 23(9)2022 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-35563235

RESUMO

Migraine is a common brain-disorder that affects 15% of the population. Converging evidence shows that migraine is associated with gastrointestinal disorders. However, the mechanisms underlying the interaction between the gut and brain in patients with migraine are not clear. In this study, we evaluated the role of the short-chain fatty acids (SCFAs) as sodium propionate (SP) and sodium butyrate (SB) on microbiota profile and intestinal permeability in a mouse model of migraine induced by nitroglycerine (NTG). The mice were orally administered SB and SP at the dose of 10, 30 and 100 mg/kg, 5 min after NTG intraperitoneal injections. Behavioral tests were used to evaluate migraine-like pain. Histological and molecular analyses were performed on the intestine. The composition of the intestinal microbiota was extracted from frozen fecal samples and sequenced with an Illumina MiSeq System. Our results demonstrated that the SP and SB treatments attenuated hyperalgesia and pain following NTG injection. Moreover, SP and SB reduced histological damage in the intestine and restored intestinal permeability and the intestinal microbiota profile. These results provide corroborating evidence that SB and SP exert a protective effect on central sensitization induced by NTG through a modulation of intestinal microbiota, suggesting the potential application of SCFAs as novel supportive therapies for intestinal disfunction associated with migraine.


Assuntos
Microbioma Gastrointestinal , Transtornos de Enxaqueca , Animais , Ácido Butírico/farmacologia , Ácido Butírico/uso terapêutico , Suplementos Nutricionais , Modelos Animais de Doenças , Ácidos Graxos Voláteis/efeitos adversos , Humanos , Hiperalgesia/induzido quimicamente , Hiperalgesia/tratamento farmacológico , Camundongos , Transtornos de Enxaqueca/induzido quimicamente , Transtornos de Enxaqueca/tratamento farmacológico , Nitroglicerina/efeitos adversos , Dor/tratamento farmacológico
12.
Int J Mol Sci ; 23(22)2022 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-36430394

RESUMO

Glioblastoma (GB) is a tumor of the central nervous system characterized by high proliferation and invasiveness. The standard treatment for GB includes radiotherapy and chemotherapy; however, new therapies are needed. Particular attention was given to the role of histone methyltransferase enhancer of zeste-homolog-2 (EZH2) in GB. Recently, several EZH2-inhibitors have been developed, particularly GSK343 is well-known to regulate apoptosis and autophagy processes; however, its abilities to modulate canonical/non-canonical NF-κB/IκBα pathways or an immune response in GB have not yet been investigated. Therefore, this study investigated for the first time the effect of GSK343 on canonical/non-canonical NF-κB/IκBα pathways and the immune response, by an in vitro, in vivo and ex vivo model of GB. In vitro results demonstrated that GSK343 treatments 1, 10 and 25 µM significantly reduced GB cell viability, showing the modulation of canonical/non-canonical NF-κB/IκBα pathway activation. In vivo GSK343 reduced subcutaneous tumor mass, regulating canonical/non-canonical NF-κB/IκBα pathway activation and the levels of reactive oxygen species (ROS), malondialdehyde (MDA), and superoxide dismutase (SOD). Ex vivo results confirmed the anti-proliferative effect of GSK343 and also demonstrated its ability to regulate immune response through CXCL9, CXCL10 and CXCL11 expression in GB. Thus, GSK343 could represent a therapeutic strategy to counteract GB progression, thanks to its ability to modulate canonical/non-canonical NF-κB/IκBα pathways and immune response.


Assuntos
Proteína Potenciadora do Homólogo 2 de Zeste , Glioblastoma , Humanos , Glioblastoma/tratamento farmacológico , NF-kappa B/metabolismo , Inibidor de NF-kappaB alfa
13.
Int J Mol Sci ; 23(24)2022 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-36555334

RESUMO

High-grade brain tumors are malignant tumors with poor survival and remain the most difficult tumors to treat. An important contributing factor to the development and progression of brain tumors is their ability to evade the immune system. Several immunotherapeutic strategies including vaccines and checkpoint inhibitors have been studied to improve the effectiveness of the immune system in destroying cancer cells. Recent studies have shown that kinase inhibitors, capable of inhibiting signal transduction cascades that affect cell proliferation, migration, and angiogenesis, have additional immunological effects. In this review, we explain the beneficial therapeutic effects of novel small-molecule kinase inhibitors and explore how, through different mechanisms, they increase the protective antitumor immune response in high-grade brain tumors.


Assuntos
Neoplasias Encefálicas , Inibidores de Proteínas Quinases , Humanos , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Transdução de Sinais , Imunidade , Sistema Imunitário , Microambiente Tumoral , Imunoterapia
14.
Int J Mol Sci ; 23(24)2022 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-36555359

RESUMO

Protein phosphatase 2A (PP2A) is a highly complex heterotrimeric Ser/Thr phosphatase that regulates many cellular processes. PP2A is dysregulated in several human diseases, including oncological pathology; interestingly, PP2A appears to be essential for controlling cell growth and may be involved in cancer development. The role of PP2A as a tumor suppressor has been extensively studied and reviewed. To leverage the potential clinical utility of combination PP2A inhibition and radiotherapy treatment, it is vital that novel highly specific PP2A inhibitors be developed. In this review, the existing literature on the role of PP2A in brain tumors, especially in gliomas and glioblastoma (GBM), was analyzed. Interestingly, the review focused on the role of PP2A inhibitors, focusing on CIP2A inhibition, as CIP2A participated in tumor cell growth by stimulating cell-renewal survival, cellular proliferation, evasion of senescence and inhibition of apoptosis. This review suggested CIP2A inhibition as a promising strategy in oncology target therapy.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Proteína Fosfatase 2 , Humanos , Autoantígenos/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Proteína Fosfatase 2/metabolismo
15.
J Cell Mol Med ; 25(16): 7855-7866, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34245104

RESUMO

Traumatic brain injury (TBI) provokes primary and secondary damage on endothelium and brain parenchyma, leading neurons die rapidly by necrosis. The mammalian target of rapamycin signalling pathway (mTOR) manages numerous aspects of cellular growth, and it is up-regulated after moderate to severe traumatic brain injury (TBI). Currently, the significance of this increased signalling event for the recovery of brain function is unclear; therefore, we used two different selective inhibitors of mTOR activity to discover the functional role of mTOR inhibition in a mouse model of TBI performed by a controlled cortical impact injury (CCI). Treatment with KU0063794, a dual mTORC1 and mTORC2 inhibitor, and with rapamycin as well-known inhibitor of mTOR, was performed 1 and 4 hours subsequent to TBI. Results proved that mTOR inhibitors, especially KU0063794, significantly improved cognitive and motor recovery after TBI, reducing lesion volumes. Also, treatment with mTOR inhibitors ameliorated the neuroinflammation associated with TBI, showing a diminished neuronal death and astrogliosis after trauma. Our findings propose that the involvement of selective mTORC1/2 inhibitor may represent a therapeutic strategy to improve recovery after brain trauma.


Assuntos
Lesões Encefálicas Traumáticas/complicações , Inibidores de MTOR/farmacologia , Morfolinas/farmacologia , Doenças Neuroinflamatórias/tratamento farmacológico , Neurônios/efeitos dos fármacos , Pirimidinas/farmacologia , Sirolimo/farmacologia , Serina-Treonina Quinases TOR/antagonistas & inibidores , Animais , Morte Celular , Proliferação de Células , Modelos Animais de Doenças , Inibidores Enzimáticos/farmacologia , Imunossupressores/farmacologia , Masculino , Camundongos , Doenças Neuroinflamatórias/etiologia , Doenças Neuroinflamatórias/metabolismo , Doenças Neuroinflamatórias/patologia , Neurônios/metabolismo , Neurônios/patologia , Transdução de Sinais
16.
Int J Mol Sci ; 22(19)2021 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-34638811

RESUMO

A breached nasal epithelial barrier plays an important role in driving allergic rhinitis (AR). Corticosteroids remain the standard of care (SoC) but come with side effects, thus alternative safe and effective treatments able to avoid inflammation and restore barrier integrity are needed. The aim of the present study is to evaluate the barrier-forming capacity of a xyloglucan-based nasal spray (XG) and compare its efficacy to several SoC treatments (corticosteroid spray, oral mast-cell stabilizer and oral antihistamine) in reducing allergic responses in addition to its effect when concomitantly administered with an antihistamine. An ovalbumin (OVA)-induced mouse AR model was used. XG shows a significant efficacy in reducing histological damage in AR mice; improves nasal rubbing and histamine-induced hyper-responsiveness. Total and OVA-specific IgE as well as pro-inflammatory cytokines are significantly reduced compared to OVA challenged-mice, with im-proved efficacy when used as an add-on treatment. However, XG reduces mucous secreting cells (PAS-positive) and mucin mRNA expression similar to the corticosteroid-treated mice. XG-spray maintains tight junction protein expression (ZO-1) and conversely decreases HDAC1 significantly; the latter being highly expressed in AR patients. Moreover, the concomitant treatment showed in all of the endpoints a similar efficacy to the corticosteroids. This innovative approach may represent a novel therapeutic strategy for nasal respiratory diseases like AR, reducing undesirable side effects and improving the quality of life in patients.


Assuntos
Glucanos/farmacologia , Mucosa Nasal/imunologia , Sprays Nasais , Rinite Alérgica/prevenção & controle , Xilanos/farmacologia , Animais , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/imunologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Rinite Alérgica/induzido quimicamente , Rinite Alérgica/imunologia , Proteína da Zônula de Oclusão-1/imunologia
17.
Int J Mol Sci ; 22(21)2021 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-34769337

RESUMO

Ischemia/reperfusion injury (IRI) is a complex pathophysiological process characterized by blood circulation disorder caused by various factors, such as traumatic shock, surgery, organ transplantation, and thrombus. Severe metabolic dysregulation and tissue structure destruction are observed upon restoration of blood flow to the ischemic tissue. The kidney is a highly perfused organ, sensitive to ischemia and reperfusion injury, and the incidence of renal IRI has high morbidity and mortality. Several studies showed that infiltration of inflammatory cells, apoptosis, and angiogenesis are important mechanisms involved in renal IRI. Despite advances in research, effective therapies for renal IRI are lacking. Recently it has been demonstrated the role of KYP2047, a selective inhibitor of prolyl oligopeptidase (POP), in the regulation of inflammation, apoptosis, and angiogenesis. Thus, this research focused on the role of POP in kidney ischemia/reperfusion (KI/R). An in vivo model of KI/R was performed and mice were subjected to KYP2047 treatment (intraperitoneal, 0.5, 1 and 5 mg/kg). Histological analysis, Masson's trichrome and periodic acid shift (PAS) staining, immunohistochemical and Western blots analysis, real-time PCR (RT-PCR) and ELISA were performed on kidney samples. Moreover, serum creatinine and blood urea nitrogen (BUN) were quantified. POP-inhibition by KYP2047 treatment, only at the doses of 1 and 5 mg/kg, significantly reduced renal injury and collagen amount, regulated inflammation through canonical and non-canonical NF-κB pathway, and restored renal function. Moreover, KYP2047 modulated angiogenesis markers, such as TGF-ß and VEGF, also slowing down apoptosis. Interestingly, treatment with KYP2047 modulated PP2A activity. Thus, these findings clarified the role of POP inhibition in AKI, also offering novel therapeutic target for renal injury after KI/R.


Assuntos
Injúria Renal Aguda/prevenção & controle , Isquemia/complicações , Prolina/análogos & derivados , Prolil Oligopeptidases/antagonistas & inibidores , Traumatismo por Reperfusão/complicações , Injúria Renal Aguda/enzimologia , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/patologia , Animais , Apoptose , Creatinina/metabolismo , Masculino , Camundongos , Prolina/farmacologia , Transdução de Sinais
18.
Int J Mol Sci ; 22(20)2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34681768

RESUMO

Oral cancer is one of the most common human malignancies, and its incidence is increasing worldwide. In particular, oral squamous cell carcinoma (OSCC) is characterized by high rates of proliferation, invasiveness, and metastasis. Currently, standard treatment for OSCC includes surgical removal, chemotherapy, and radiotherapy; however, the survival rate of patients with OSCC remains low, thus new therapies are needed. It has been proven that excessive NLRP3 inflammasome activation and apoptosis alteration may contribute to oral cancer progression. This study aimed to investigate the effect of BAY-117082, an NLRP3 inflammasome inhibitor, in an in vitro and in vivo xenograft model of oral cancer. In vitro results revealed that BAY-117082 at concentrations of 5, 10, and 30 µM was able to reduce OSCC cell viability. BAY-117082 at higher concentrations significantly reduced NLRP3, ASC, caspase-1, IL-1ß, and IL-18 expression. Moreover, Bax, Bad, and p53 expression were increased, whereas Bcl-2 expression was reduced. Furthermore, the in vivo study demonstrated that BAY-117082 at doses of 2.5 and 5 mg/kg significantly decreased subcutaneous tumor mass, and also reduced NLRP3 inflammasome pathway activation. Therefore, based on these results, the use of BAY-117082 could be considered a promising strategy to counteract oral cancer progression, thanks its ability to modulate the NLRP3 inflammasome and apoptosis pathways.


Assuntos
Carcinoma de Células Escamosas/patologia , Proliferação de Células/efeitos dos fármacos , Neoplasias Bucais/patologia , Nitrilas/farmacologia , Sulfonas/farmacologia , Animais , Carcinoma de Células Escamosas/tratamento farmacológico , Progressão da Doença , Humanos , Inflamassomos/antagonistas & inibidores , Inflamassomos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias Bucais/tratamento farmacológico , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Nitrilas/uso terapêutico , Sulfonas/uso terapêutico , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
19.
Int J Mol Sci ; 22(9)2021 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-33946718

RESUMO

Cancer is a multifactorial disease that affects millions of people every year and is one of the most common causes of death in the world. The high mortality rate is very often linked to late diagnosis; in fact, nowadays there are a lack of efficient and specific markers for the early diagnosis and prognosis of cancer. In recent years, the discovery of new diagnostic markers, including microRNAs (miRNAs), has been an important turning point for cancer research. miRNAs are small, endogenous, non-coding RNAs that regulate gene expression. Compelling evidence has showed that many miRNAs are aberrantly expressed in human carcinomas and can act with either tumor-promoting or tumor-suppressing functions. miR-19a is one of the most investigated miRNAs, whose dysregulated expression is involved in different types of tumors and has been potentially associated with the prognosis of cancer patients. The aim of this review is to investigate the role of miR-19a in cancer, highlighting its involvement in cell proliferation, cell growth, cell death, tissue invasion and migration, as well as in angiogenesis. On these bases, miR-19a could prove to be truly useful as a potential diagnostic, prognostic, and therapeutic marker.


Assuntos
MicroRNAs/genética , Neoplasias/diagnóstico , Neoplasias/genética , Biomarcadores Tumorais/genética , Proliferação de Células/genética , Detecção Precoce de Câncer/métodos , Feminino , Regulação Neoplásica da Expressão Gênica , Genes Supressores de Tumor , Humanos , Masculino , Modelos Genéticos , Invasividade Neoplásica/genética , Neoplasias/patologia , Oncogenes , Prognóstico
20.
Int J Mol Sci ; 22(8)2021 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-33920318

RESUMO

Chemotherapy-induced neuropathy is a common, dose-dependent adverse effect of several antineoplastics, such as oxaliplatin (L-OHP). The aim of the present work was to evaluate the potential beneficial effects of 2-pentadecyl-2-oxazoline (PEA-OXA) in a murine model of oxaliplatin-induced peripheral neuropathy (OIPN). OIPN was induced by an intraperitoneally injection of L-OHP in rats on five consecutive days (D0-4) for a final cumulative dose of 10 mg/kg. PEA-OXA and ultramicronized palmitoylethanolamide (PEAum), both 10 mg/kg, were given orally 15-20 min prior (L-OHP) and sacrifice was made on day 25. Our results demonstrated that PEA-OXA, more than PEAum, reduced the development of hypersensitivity in rats; this was associated with the reduction in hyperactivation of glia cells and the increased production of proinflammatory cytokines in the dorsal horn of the spinal cord, accompanied by an upregulation of neurotrophic factors in the dorsal root ganglia (DRG). Moreover, we showed that PEA-OXA reduced L-OHP damage via a reduction in NF-κB pathway activation and a modulation of Nrf-2 pathways. Our findings identify PEA-OXA as a therapeutic target in chemotherapy-induced painful neuropathy, through the biomolecular signaling NF-κB/Nrf-2 axis, thanks to its abilities to counteract L-OHP damage. Therefore, we can consider PEA-OXA as a promising adjunct to chemotherapy to reduce chronic pain in patients.


Assuntos
Fator 2 Relacionado a NF-E2/genética , Oxaliplatina/farmacologia , Oxazóis/farmacologia , Dor/tratamento farmacológico , Doenças do Sistema Nervoso Periférico/tratamento farmacológico , Animais , Modelos Animais de Doenças , Gânglios Espinais/efeitos dos fármacos , Gânglios Espinais/patologia , Humanos , Camundongos , NF-kappa B/genética , Neoplasias/complicações , Neoplasias/tratamento farmacológico , Oxaliplatina/efeitos adversos , Dor/induzido quimicamente , Dor/genética , Dor/patologia , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/genética , Doenças do Sistema Nervoso Periférico/patologia , Ratos , Transdução de Sinais/efeitos dos fármacos
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