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Anorexia nervosa (AN) is an eating disorder (ED) that has seen an increase in its incidence in the last thirty years. Compared to other psychosomatic disorders, ED can be responsible for many major medical complications, moreover, in addition to the various systemic impairments, patients with AN undergo morphological and physiological changes affecting the cerebral cortex. Through immunohistochemical studies on portions of postmortem human brain of people affected by AN and healthy individuals, and western blot studies on leucocytes of young patients and healthy controls, this study investigated the role in the afore-mentioned processes of altered redox state. The results showed that the brain volume reduction in AN could be due to an increase in the rate of cell death, mainly by apoptosis, in which mitochondria, main cellular organelles affected by a decreased dietary intake, and a highly compromised intracellular redox balance, may play a pivotal role.
Assuntos
Anorexia Nervosa , Encéfalo , Estresse Oxidativo , Humanos , Anorexia Nervosa/metabolismo , Anorexia Nervosa/patologia , Estresse Oxidativo/fisiologia , Encéfalo/metabolismo , Encéfalo/patologia , Feminino , Adulto , Adulto Jovem , Adolescente , Apoptose/fisiologiaRESUMO
Breast cancer (BC) is the most commonly diagnosed tumor, remaining one of the leading causes of morbidity and mortality in females worldwide, with the highest rates in Western countries. Among metastatic BC (MBC), triple-negative breast cancer (TNBC) is characterized by the lack of expression of specific receptors, and differs from other subgroups of BC for its increased growth and fast spreading, with reduced treatment possibilities and a worse outcome. Actually, MBC patients are extremely prone to metastasis and consequent relapses, which affect distant target organs (e.g., brain, lung, bone and liver). Hence, the comprehension of biological mechanisms underlying the BC metastatization process is a key requirement to conceive/set up innovative medicinal strategies, with the goal to achieve long-lasting therapeutic efficacy, reducing adverse effects, and also ameliorating Quality of Life (QoL). Bioactive metabolites isolated from medicinal mushrooms (MMs) used as a supportive treatment, combined with conventional oncology, have recently gained wide interest. In fact, mounting evidence has revealed their peculiar promising immunomodulatory, anti-inflammatory and anticancer activities, even though these effects have to be further clarified. Among the group of most promising MMs are Lentinula edodes, Grifola frondosa, Ganoderma lucidum, Ophiocordyceps sinensis and Agaricus blazei, which are already employed in conventional cancer protocols in Asia and China. Recently, a growing number of studies have focused on the pharmacology and feasibility of MM-derived bioactive compounds as a novel valuable approach to propose an effective adjuvant therapy for MBC patients' management. In this review, we summarized the current state of knowledge on the abovementioned MM-derived bioactive compounds and their therapeutic potential in clinical settings.
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The current standard oncotherapy for glioblastoma is limited by several adverse side effects, leading to a short-term patient survival rate paralleled by a worsening quality of life (QoL). Recently, Complementary and Integrative Medicine's (CIM) innovative approaches have shown positive impacts in terms of better response to treatment, side effect reduction, and QoL improvement. In particular, promising potential in cancer therapy has been found in compounds coming from phyto- and mycotherapy. The objective of this study was to demonstrate the beneficial effects of a new phyto-mycotherapy supplement, named Ganostile, in the human glioblastoma cell line U251, in combination with chemotherapeutic agents, i.e., Cisplatin and a new platinum-based prodrug. Choosing a supplement dosage that mimicked oral supplementation in humans (about 1 g/day), through in vitro assays, microscopy, and cytometric analysis, it has emerged that the cells, after 48hr continuous exposure to Ganostile in combination with the chemical compounds, showed a higher mortality and a lower proliferation rate than the samples subjected to the different treatments administered individually. In conclusion, our data support the use of Ganostile in integrative oncology protocols as a promising adjuvant able to amplify conventional and new drug effects and also reducing resistance mechanisms often observed in brain tumors.
Assuntos
Neoplasias Encefálicas , Glioblastoma , Humanos , Glioblastoma/tratamento farmacológico , Glioblastoma/patologia , Linhagem Celular Tumoral , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/patologia , Proliferação de Células/efeitos dos fármacos , Cisplatino/farmacologia , Cisplatino/uso terapêutico , Suplementos Nutricionais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Sobrevivência Celular/efeitos dos fármacos , Apoptose/efeitos dos fármacosRESUMO
Malignant primary brain tumors remain among the most difficult cancers to treat, in particular, Glioblastoma Multiforme (GBM) is the deadliest brain tumor. The standard therapies currently used are not efficient enough in improving patients' survival and quality of life. Cisplatin (CDDP), a platinum-based drug, has shown efficacy against different solid neoplasms, but it is also associated to different forms of off-target toxicity. To overcome the limitation in the use of CDDP in the treatment of GBM patients, fourth generation platinum compounds are been synthesized, one of them is the Pt(IV)Ac-POA, a prodrug with a medium-chain fatty acid as axial ligand, which acts as a histone 3 deacetylase inhibitor. Moreover, recently, the antioxidant effects of medicinal mushrooms have been shown to induce a lowering of the toxicity of chemotherapy drugs, inducing greater therapeutic efficiency, thus the combined therapy of chemotherapy and micotherapy could be helpful in the treatment of GBM reducing the adverse effects of the former thanks to phytotherapy's antioxidant, anti-inflammatory, immunomodulatory and antitumoral activities. Here, through immunoblotting, ultrastructural and immunofluorescence analysis, we evaluated the contribution in the activation of different cell death pathway of Micotherapy U-Care, a medicinal blend supplement, used together with platinum-based compounds on human glioblastoma U251 cells.
Assuntos
Antineoplásicos , Neoplasias Encefálicas , Glioblastoma , Humanos , Glioblastoma/tratamento farmacológico , Glioblastoma/genética , Apoptose , Qualidade de Vida , Morte Celular , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Cisplatino/farmacologia , Cisplatino/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/patologia , Antineoplásicos Alquilantes/uso terapêutico , Inibidores de Histona Desacetilases/farmacologia , Linhagem Celular TumoralRESUMO
In the present study, the potential functional properties of the extracts from the edible part of Capsicum annuum L. var. Peperone di Voghera (VP) were studied. The phytochemical analysis revealed a high amount of ascorbic acid, paralleled by a low carotenoid content. Normal human diploid fibroblasts (NHDF) were chosen as the in vitro model models to investigate the effects of the VP extract on oxidative stress and aging pathways. The extract of Carmagnola pepper (CP), another important Italian variety, was used as the reference vegetable. The cytotoxicity evaluation was performed firstly, using a 3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide (MTT) assay, while the VP potential antioxidant and antiaging activity was investigated by immunofluorescence staining focusing on specifically selected proteins. The MTT data revealed the highest cell viability at a concentration of up to 1 mg/mL. The immunocytochemical analyses highlighted an increased expression of transcription factors and enzymes involved in redox homeostasis (Nrf2, SOD2, catalase), improved mitochondrial functionality, and the up-regulation of the longevity gene SIRT1. The present results supported the functional role of the VP pepper ecotype, suggesting a feasible use of its derived products as valuable food supplements.
Assuntos
Capsicum , Humanos , Capsicum/metabolismo , Antioxidantes/metabolismo , Estresse Oxidativo , Extratos Vegetais/metabolismo , EnvelhecimentoRESUMO
The effects of ferrocene (Fc) and ferrocenium (Fc+) induced in triple negative human breast cancer MCF-7 cells were explored by immunofluorescence, flow cytometry, and transmission electron microscopy analysis. The different abilities of Fc and Fc+ to produce reactive oxygen species and induce oxidative stress were clearly observed by activating apoptosis and morphological changes after treatment, but also after tests performed on the model organism D. discoideum, particularly in the case of Fc+. The induction of ferroptosis, an iron-dependent form of regulated cell death driven by an overload of lipid peroxides in cellular membranes, occurred after 2 h of treatment with Fc+ but not Fc. However, the more stable Fc showed its effects by activating necroptosis after a longer-lasting treatment. The differences observed in terms of cell death mechanisms and timing may be due to rapid interconversion between the two oxidative forms of internalized iron species (from Fe2+ to Fe3+ and vice versa). Potential limitations include the fact that iron metabolism and mitophagy have not been investigated. However, the ability of both Fc and Fc+ to trigger different and interregulated types of cell death makes them suitable to potentially overcome the shortcomings of traditional apoptosis-mediated anticancer therapies.
Assuntos
Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Células MCF-7 , Metalocenos/farmacologia , Apoptose/fisiologia , Ferro/metabolismo , Espécies Reativas de Oxigênio/metabolismoRESUMO
Cisplatin (CDDP) is one of the most effective chemotherapeutic agents, used for the treatment of diverse tumors, including neuroblastoma and glioblastoma. CDDP induces cell death through different apoptotic pathways. Despite its clinical benefits, CDDP causes several side effects and drug resistance.[Pt(O,O'-acac)(γ-acac)(DMS)], namely PtAcacDMS, a new platinum(II) complex containing two acetylacetonate (acac) and a dimethylsulphide (DMS) in the coordination sphere of metal, has been recently synthesized and showed 100 times higher cytotoxicity than CDDP. Additionally, PtAcacDMS was associated to a decreased neurotoxicity in developing rat central nervous system, also displaying great antitumor and antiangiogenic activity both in vivo and in vitro. Thus, based on the knowledge that several chemotherapeutics induce cancer cell death through an aberrant increase in [Ca2+]i, in the present in vitro study we compared CDDP and PtAcacDMS effects on apoptosis and intracellular Ca2+ dynamics in human glioblastoma T98G cells, applying a battery of complementary techniques, i.e., flow cytometry, immunocytochemistry, electron microscopy, Western blotting, qRT-PCR, and epifluorescent Ca2+ imaging. The results confirmed that (i) platinum compounds may induce cell death through an aberrant increase in [Ca2+]i and (ii) PtAcacDMS exerted stronger cytotoxic effect than CDDP, associated to a larger increase in resting [Ca2+]i. These findings corroborate the use of PtAcacDMS as a promising approach to improve Pt-based chemotherapy against gliomas, either by inducing a chemosensitization or reducing chemoresistance in cell lineages resilient to CDDP treatment.
Assuntos
Neoplasias Encefálicas/patologia , Cisplatino/efeitos adversos , Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos , Glioma/patologia , Compostos Organoplatínicos/farmacologia , Apoptose/efeitos dos fármacos , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/ultraestrutura , Cálcio/metabolismo , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Citoesqueleto/efeitos dos fármacos , Citoesqueleto/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Retículo Endoplasmático/efeitos dos fármacos , Retículo Endoplasmático/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glioma/genética , Glioma/ultraestrutura , Homeostase/efeitos dos fármacos , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Proteínas do Tecido Nervoso/metabolismo , Proteína ORAI1/genética , Proteína ORAI1/metabolismo , ATPases Transportadoras de Cálcio da Membrana Plasmática/metabolismo , Poli(ADP-Ribose) Polimerases/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismoRESUMO
Frailty is a geriatric syndrome associated with both locomotor and cognitive decline, typically linked to chronic systemic inflammation, i.e., inflammaging. In the current study, we investigated the effect of a two-month oral supplementation with standardized extracts of H. erinaceus, containing a known amount of Erinacine A, Hericenone C, Hericenone D, and L-ergothioneine, on locomotor frailty and cerebellum of aged mice. Locomotor performances were monitored comparing healthy aging and frail mice. Cerebellar volume and cytoarchitecture, together with inflammatory and oxidative stress pathways, were assessed focusing on senescent frail animals. H. erinaceus partially recovered the aged-related decline of locomotor performances. Histopathological analyses paralleled by immunocytochemical evaluation of specific molecules strengthened the neuroprotective role of H. erinaceus able to ameliorate cerebellar alterations, i.e., milder volume reduction, slighter molecular layer thickness decrease and minor percentage of shrunken Purkinje neurons, also diminishing inflammation and oxidative stress in frail mice while increasing a key longevity regulator and a neuroprotective molecule. Thus, our present findings demonstrated the efficacy of a non-pharmacological approach, based on the dietary supplementation using H. erinaceus extract, which represent a promising adjuvant therapy to be associated with conventional geriatric treatments.
Assuntos
Envelhecimento Saudável/fisiologia , Hericium/metabolismo , Neuroproteção , Animais , Ciclo-Oxigenase 2/metabolismo , Fragilidade/metabolismo , Fragilidade/fisiopatologia , Proteína Glial Fibrilar Ácida/metabolismo , Envelhecimento Saudável/efeitos dos fármacos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Inflamação/patologia , Interleucina-6/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Atividade Motora/efeitos dos fármacos , Neuroproteção/efeitos dos fármacos , Óxido Nítrico Sintase Tipo II/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/farmacologia , Sirtuína 1/metabolismo , Superóxido Dismutase/metabolismoRESUMO
In the present study, the functional role of the inwardly rectifying K+ channel, Kir4.1, and large-conductance Ca2+-activated K+ (BK) channel during cell migration in U251 cell line was investigated. We focused on polarised cells which are positive for the active-Cdc42 migration marker. The perforated patch technique was used to avoid intracellular dialysis and to maintain physiological changes in intracellular calcium. Wound healing was employed to assay migration after 24 h. Polarised cells recorded displayed different hallmarks of undifferentiated glial cells: depolarised resting membrane potential and high membrane resistance. Cells recorded outside wounded area did not display either constitutive inward or outward rectification. After migration, U251 cells were characterised by a constitutively smaller Kir4.1 and larger BK currents with a linearly related amplitude. Menthol modulation increased both currents in a linearly dependent manner, indicating a common mechanism triggered by activation of transient receptor potential melastatin 8 (TRPM8), a Ca2+-permeable non-selective cation channel. We hypothesised that both migration and menthol modulation would share an increase of intracellular calcium triggering the increase in Kir4.1 and BK channels. Immunocytochemistry demonstrated the cytoplasmic expression of both Kir4.1 and BK channels and a mislocation in the nucleus under basal conditions. Before and after migration, polarised cells increased the expression of Kir4.1 and BK channels both in the cytoplasm and nucleus. TEM ultrastructural analysis displayed a different nuclear distribution of Kir4.1 and BK channels. In the present study, the physiological role of Kir4.1 and BK currents at membrane potential, their involvement in migration, and the functional role of nuclear channels were discussed.
Assuntos
Neoplasias Encefálicas/patologia , Movimento Celular , Glioblastoma/patologia , Canais de Potássio Ativados por Cálcio de Condutância Alta/metabolismo , Canais de Potássio Corretores do Fluxo de Internalização/metabolismo , Neoplasias Encefálicas/metabolismo , Cálcio/metabolismo , Linhagem Celular Tumoral , Glioblastoma/metabolismo , Humanos , Potenciais da Membrana , Canais de Cátion TRPM/metabolismoRESUMO
Although medicinal mushroom extracts have been proposed as promising anti-cancer agents, their precise impacts on metastatic breast cancer are still to be clarified. For this purpose, the present study exploited the effect of a novel medicinal mushroom blend, namely Micotherapy U-care, in a 4T1 triple-negative mouse breast cancer model. Mice were orally administered with Micotherapy U-care, consisting of a mixture of Agaricus blazei, Ophiocordyceps sinensis, Ganoderma lucidum, Grifola frondosa, and Lentinula edodes. The syngeneic tumor-bearing mice were generated by injecting 4T1 cells in both supplemented and non-supplemented mice. After sacrifice 25 days later, specific endpoints and pathological outcomes of the murine pulmonary tissue were evaluated. (i) Histopathological and ultrastructural analysis and (ii) immunohistochemical assessment of TGF-ß1, IL-6 and NOS2, COX2, SOD1 as markers of inflammation and oxidative stress were performed. The QoL was comparatively evaluated. Micotherapy U-care supplementation, starting before 4T1 injection and lasting until the end of the experiment, dramatically reduced the pulmonary metastases density, also triggering a decrease of fibrotic response, and reducing IL-6, NOS, and COX2 expression. SOD1 and TGF-ß1 results were also discussed. These findings support the valuable potential of Micotherapy U-care as adjuvant therapy in the critical management of triple-negative breast cancer.
Assuntos
Agaricales/química , Proliferação de Células/efeitos dos fármacos , Oncologia Integrativa , Neoplasias de Mama Triplo Negativas/dietoterapia , Animais , Linhagem Celular Tumoral , Suplementos Nutricionais , Modelos Animais de Doenças , Feminino , Humanos , Camundongos , Plantas Medicinais/química , Neoplasias de Mama Triplo Negativas/patologiaRESUMO
Bioactive metabolites isolated from medicinal mushrooms (MM) used as supportive treatment in conventional oncology have recently gained interest. Acting as anticancer agents, they interfere with tumor cells and microenvironment (TME), disturbing cancer development/progression. Nonetheless, their action mechanisms still need to be elucidated. Recently, using a 4T1 triple-negative mouse BC model, we demonstrated that supplementation with Micotherapy U-Care, a MM blend, produced a striking reduction of lung metastases density/number, paralleled by decreased inflammation and oxidative stress both in TME and metastases, together with QoL amelioration. We hypothesized that these effects could be due to either a direct anticancer effect and/or to a secondary/indirect impact of Micotherapy U-Care on systemic inflammation/immunomodulation. To address this question, we presently focused on apoptosis/proliferation, investigating specific molecules, i.e., PARP1, p53, BAX, Bcl2, and PCNA, whose critical role in BC is well recognized. We revealed that Micotherapy U-Care is effective to influence balance between cell death and proliferation, which appeared strictly interconnected and inversely related (p53/Bax vs. Bcl2/PARP1/PCNA expression trends). MM blend displayed a direct effect, with different efficacy extent on cancer cells and TME, forcing tumor cells to apoptosis. Yet again, this study supports the potential of MM extracts, as adjuvant supplement in the TNBC management.
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Agaricales/química , Antineoplásicos/uso terapêutico , Neoplasias Pulmonares/secundário , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/patologia , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Feminino , Camundongos Endogâmicos BALB C , Proteínas de Neoplasias/metabolismo , Proteína Supressora de Tumor p53/metabolismoRESUMO
Cisplatin is one of the most active chemotherapeutic agents used in the treatment of childhood and adult malignancies. Cisplatin induces cell death through different pathways. Despite its effectiveness, the continued clinical use of cisplatin is limited by onset of severe side effects (nephrotoxicity, ototoxicity and neurotoxicity) and drug resistance. Therefore, one of the main experimental oncology purpose is related to the search for new platinum-based drugs to create different types of adducts or more specific and effective subcellular targets. Thus, [Pt(O,O'-acac)(γ-acac)(DMS)], which reacts preferentially with protein thiols or thioether, was synthesized. In our research, different approaches were used to compare cisplatin and [Pt(O,O'-acac)(γ-acac)(DMS)] effects in B50 rat neuroblastoma cells. Our results, using immunocytochemical, cytometric and morphological techniques, showed that these compounds exert a cytostatic action and activate apoptosis with different pathways. Long-term effects demonstrated that [Pt(O,O'-acac)(γ-acac)(DMS)] exerts cytotoxic effects in neuronal B50 cell line not inducing drug resistance. Analysis was performed both to compare the ability of these platinum compounds to induce cell death and to investigate the intracellular mechanisms at the basis of their cytotoxicity.
Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Cisplatino/farmacologia , Neuroblastoma/tratamento farmacológico , Neuroblastoma/patologia , Compostos Organoplatínicos/farmacologia , Animais , Antineoplásicos/química , Ciclo Celular/efeitos dos fármacos , Cisplatino/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Compostos Organoplatínicos/química , Ratos , Relação Estrutura-Atividade , Células Tumorais CultivadasRESUMO
Aging and its related disorders are important issues nowadays and the first cause of this physio-pathological condition is the overproduction of ROS. Ascorbic acid is an antioxidant mediator and its anti-aging proprieties are well known. Our previous data demonstrated that Voghera sweet pepper (VP), a distinctive type of pepper cultivated in Italy, is particularly rich in ascorbic acid. Based on these data, the anti-aging effect mediated by extracts of the edible part of VP was evaluated on an in vitro model of both young and old Normal Human Diploid Fibroblasts (NHDF). Using phase contrast microscopy, we observed that VP may help cells in the maintenance of physiological morphology during aging. Cytofluorimetric analyses revealed that VP extracts led to an increase in DNA synthesis and percentage of living cells, linked to a consequent increase in mitotic events. This hypothesis is supported by the enhancement of PCNA expression levels observed in old, treated fibroblasts, corroborating the idea that this extract could recover a young phenotype in adult fibroblasts, confirmed by the study of p16 and p53 expression levels and TEM analyses. Based on these results, we may suppose that VP can lead to the partial recovery of "young-like" phenotypes in old fibroblasts.
Assuntos
Ácido Ascórbico , Capsicum , Proliferação de Células , Senescência Celular , Fibroblastos , Extratos Vegetais , Proteína Supressora de Tumor p53 , Humanos , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Capsicum/química , Senescência Celular/efeitos dos fármacos , Extratos Vegetais/farmacologia , Proliferação de Células/efeitos dos fármacos , Ácido Ascórbico/farmacologia , Proteína Supressora de Tumor p53/metabolismo , Antígeno Nuclear de Célula em Proliferação/metabolismo , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Envelhecimento/fisiologia , Antioxidantes/farmacologia , Diploide , Células Cultivadas , ItáliaRESUMO
[Pt(O,O'-acac)(γ-acac)(DMS)] (PtAcacDMS) is a new platinum compound showing low reactivity with nucleobases and specific reactivity with sulfur ligands intracellularly. It induces apoptosis in breast cancer cells, but appears to be less neurotoxic to the developing cerebellum than cisplatin (cisPt). The aim of this study was to assess the neurotoxicity of platinum compounds on calcium homeostasis in the dentate gyrus and Cornu Ammonis regions of the hippocampal formation during rat postnatal development. Two intracellular calcium homeostasis systems were taken for measurement, calbindin, a calcium buffer protein, and a plasma membrane calcium ATPase (PMCA1). The platinum compounds showed different effects on these markers in the two areas. One day after injection (PD11), cisPt decreased calbindin immunoreactivity and PMCA1 labeling in both regions; at PD17, the downregulation of PMCA1 persisted. Instead, PtAcacDMS produced varying effects on calbindin immunoreactivity in the two regions at PD11 and PD17; but in all cases, the changes incurred in calbindin immunoreactivity were counterbalanced by changes produced in PMCA1 expression. In conclusion, PtAcacDMS seems to affect calcium homeostasis in the central nervous system differently than cisPt. Both the platinum compounds act early to alter the calbindin buffering system. However, the most important difference between cisPt and PtAcacDMS is that, in vivo, the latter acts early to stimulate calcium efflux from nerve cells as reflected by its effect on PMCA1. The rapid onset of an activated calcium pump appears to be essential to cope with the excessive intracellular calcium concentration stemming from the downregulation of calbindin which could damage neuron function and morphology.
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Antineoplásicos/toxicidade , Cálcio/metabolismo , Giro Denteado/efeitos dos fármacos , Homeostase/efeitos dos fármacos , Compostos Organoplatínicos/toxicidade , Animais , Região CA2 Hipocampal/efeitos dos fármacos , Região CA2 Hipocampal/crescimento & desenvolvimento , Região CA2 Hipocampal/metabolismo , Região CA2 Hipocampal/patologia , Região CA3 Hipocampal/efeitos dos fármacos , Região CA3 Hipocampal/crescimento & desenvolvimento , Região CA3 Hipocampal/metabolismo , Região CA3 Hipocampal/patologia , Calbindina 1/metabolismo , Cisplatino/toxicidade , Giro Denteado/crescimento & desenvolvimento , Giro Denteado/metabolismo , Giro Denteado/patologia , ATPases Transportadoras de Cálcio da Membrana Plasmática/metabolismo , Ratos , Ratos WistarRESUMO
Breast cancer (BC) is the second most common cause of brain metastasis onset in patients, with the cerebellum accounting for the 33% of cases. In the current study, using a 4T1 triple-negative mouse BC model, we revealed that an orally administered medicinal mushrooms (MM) blend, rich in ß-glucans, played a direct and specific anti-cancer action on cerebellar metastases, also bettering locomotor performances. The neuroprotective effect of the MM blend plays through (i) a direct and specific inhibition of cerebellar metastatization pattern typical of TNBC (with an induced reduction of about 50% of metastases density) and (ii) the regulation of apoptosis and proliferation-related genes, as suggested by expression changes of specific molecular markers, i.e. PCNA, p53, Bcl2, BAX, CASP9, CASP3, Hsp70 and AIF. Therefore, inhibiting the metastatization process, triggering a significant apoptosis increase, and lessening cell proliferation, this MM supplement, employed as adjuvant treatment in association with conventional therapy, could represent a promising approach, in the field of Integrative Oncology, for patients' management in both prevention and treatment of brain metastases from BC.
Assuntos
Agaricales , Neoplasias Encefálicas , Neoplasias de Mama Triplo Negativas , Humanos , Animais , Camundongos , Neoplasias de Mama Triplo Negativas/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Neoplasias Encefálicas/secundário , ApoptoseRESUMO
Brain aging is a crucial risk factor for several neurodegenerative disorders and dementia. The most affected cognitive function is memory, worsening early during aging. Inflammation and oxidative stress are known to have a role in pathogenesis of cognitive impairments, and a link exists between aging/frailty and immunosenescence/inflammaging. Based on anti-aging properties, medicinal mushrooms represent a source to develop medicines and functional foods. In particular, Hericium erinaceus (He) displays several actions ranging from boosting the immune system to fighting senescence, due to its active ingredients/metabolites. Among these, Ergothioneine (ERGO) is known as the longevity vitamin. Currently, we demonstrated the efficacy of an ERGO-rich He primordium extract (He2) in preventing cognitive decline in a murine model of aging. We focused on recognition memory deterioration during aging, monitored through spontaneous behavioral tests assessing both memory components and frailty index. A parallel significant decrease in key markers of inflammation and oxidative stress, i.e., IL6, TGFß1, GFAP, Nrf2, SOD1, COX2, NOS2, was revealed in the hippocampus by immunohistochemistry, accompanied by an enhancement of NMDAR1and mGluR2, crucially involved in glutamatergic neurotransmission. In summary, we disclosed a selective, preventive and neuroprotective effect of He2 on aged hippocampus, both on recognition memory as well on inflammation/oxidative stress/glutamate receptors expression.
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Increasing reports of neurological and psychiatric outcomes due to psychostimulant synthetic cathinones (SCs) have recently raised public concern. However, the understanding of neurotoxic mechanisms is still lacking, particularly for the under-investigated αPHP, one of the major MDPV derivatives. In particular, its effects on neural stem/progenitor cell cultures (NSPCs) are still unexplored. Therefore, in the current in vitro study, the effects of increasing αPHP concentrations (25-2000 µM), on cell viability/proliferation, morphology/ultrastructure, genotoxicity and cell death pathways, have been evaluated after exposure in murine NSPCs, using a battery of complementary techniques, i.e., MTT and clonogenic assay, flow cytometry, immunocytochemistry, TEM, and patch clamp. We revealed that αPHP was able to induce a dose-dependent significant decrease of the viability, proliferation and clonal capability of the NSPCs, paralleled by the resting membrane potential depolarization and apoptotic/autophagic/necroptotic pathway activation. Moreover, ultrastructural alterations were clearly observed. Overall, our current findings demonstrate that αPHP, damaging NSPCs and the morpho-functional fundamental units of adult neurogenic niches may affect neurogenesis, possibly triggering long-lasting, irreversible CNS damage. The present investigation could pave the way for a broadened understanding of SCs toxicology, needed to establish an appropriate treatment for NPS and the potential consequences for public health.
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Glioblastoma (GBM) is the most common and mortal primary brain tumor in human. After standard therapies, that include surgical resection followed by radiotherapy and chemotherapy, it is difficult to completely remove the tumor and the development of relapses and resistance is almost inevitable. The chemotherapy now available also show important side effects, to overcame those limitation, new platinum-based drugs are being synthetized, Pt(IV)Ac-POA, (OC-6-44)-acetate-diamine-chloride(2-(2-propynyl)octanoato)platinum(IV), a prodrug having an Histone-3-DeAcetylase-Inhibitor as axial ligands, is one of them. Moreover, new compounds of plant origin are increasingly seen as potential sources of benefits in oncological treatments. The aim of the study is to investigate the possible contribution of micotherapy in the fight against GBM, its role in the metabolism of reactive oxygen species (ROS) and its synergic effect with a new platinum-based compound, Pt(IV)Ac-POA, on human glioblastoma U251 cells. Through cytofluorimetric and immunofluorescence analysis, the ability of the micotherapy in study to regulate the cell cycle was assessed, and its importance in controlling the cellular redox state was also revealed, opening to the possibility of a new therapy in which micotherapy can support the activity of new chemotherapy while reducing its side effects controlling inflammatory conditions in the microenvironment. Additionally, the combined therapy appeared able to induce regulated form of necrosis, such as ferroptosis, and to hinder the establishment of resistance mechanisms.
Assuntos
Antineoplásicos , Neoplasias Encefálicas , Glioblastoma , Pró-Fármacos , Humanos , Glioblastoma/tratamento farmacológico , Glioblastoma/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Pró-Fármacos/farmacologia , Ligantes , Linhagem Celular Tumoral , Cloretos/metabolismo , Histonas , Recidiva Local de Neoplasia/tratamento farmacológico , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Inibidores de Histona Desacetilases/uso terapêutico , Diaminas , Neoplasias Encefálicas/patologia , Microambiente TumoralRESUMO
Phenotypic frailty is characterized by a progressive decline in physical functioning. During ageing, morphological and functional alterations involve the brain, and chief theories involve oxidative stress, free radical accumulation, and reduced antioxidant defenses as the most implicated mechanisms. From boosting the immune system to fighting senescence, medicinal mushrooms have been found to have a number of health and longevity benefits. Among them, Hericium erinaceus (He) has been demonstrated to display a variety of physiological effects, including anti-aging properties. Thus, He represents an attractive natural source for developing novel medicines and functional foods, based on the identification of its active ingredients and metabolites. Particularly, H. erinaceus primordium (He2) extract contains a high amount of Ergothioneine (ERGO), the longevity vitamin. Herein, we revealed the preventive effect of ERGO-rich He2 extract in a preclinical model, focusing on locomotor decline during ageing monitored through spontaneous behavioral test. This effect was accompanied by a significant decrease in some oxidative stress markers (NOS2, COX2) paralleled by an increase in P53, showed in cerebellar cortex cells and fibres by immunohistochemistry. In summary, we demonstrated the neuro-protective and preventive effects of He2 extract during aging, probably due to its peculiarly high ERGO content.