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1.
Artigo em Inglês | MEDLINE | ID: mdl-34628475

RESUMO

Data regarding the safety and efficacy of COVID-10 vaccines among cancer patients are lacking. Factors such as age, underlying disease and antineoplastic treatment confer negatively to the immune response due to vaccination. The degree of immunosuppression though may be lessen by targeted treatments like the androgen receptor-targeted agents (ARTA) that are commonly used in patients with metastatic prostate cancer. Herein, we report our data on 25 patients with prostate cancer under treatment with ARTA who were vaccinated for COVID-19. Our data suggest that these patients develop neutralizing antibodies against SARS-CoV-2 similarly to healthy volunteers. No safety issues were noted.

2.
Blood Adv ; 2021 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-34529762

RESUMO

The urgency of the COVID-19 pandemic has led to accelerated vaccine development within less than a year. Immunocompromised patients with hematological malignancies are more susceptible to COVID-19 and at higher risk of severe complications and worse outcomes compared with general population. In this context, we evaluated the humoral response by determining the titers of neutralizing antibodies (NAbs) against SARS-CoV-2 in patients with Waldenstrom Macroglobulinemia (WM) after vaccination with the BNT162b2 or AZD1222 vaccine. An FDA-approved, ELISA-based methodology was implemented to evaluate NAbs on the day of the first vaccine shot, as well as on day 22 and 50 afterwards. 106 patients with WM (43% males, median age 73 years) and 212 healthy controls (46% males, median age 66 years) who were vaccinated during the same period, at the same center were enrolled in the study (which is registered at www.clinicaltrials.gov as NCT04743388). Our data indicate that vaccination with either 2 doses of the BNT162b2 or 1 dose of the AZD1222 vaccine leads to lower production of NAbs against SARS-CoV-2 in patients with WM compared with controls both on day 22 and on day 50 (P<0.001 for all comparisons). Disease-related immune dysregulation and therapy-related immunosuppression are involved in the low humoral response. Importantly, active treatment with either Rituximab or Bruton's Tyrosine Kinase inhibitors was proven as an independent prognostic factor for suboptimal antibody response following vaccination. In conclusion, patients with WM have low humoral response following COVID-19 vaccination, which underlines the need for timely vaccination ideally during a treatment-free period and for continuous vigilance on infection control measures.

3.
Br J Haematol ; 2021 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-34528249

RESUMO

Patients with multiple myeloma (MM) have a suboptimal antibody response following vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and lower seroconversion rates following coronavirus disease 2019 (COVID-19) compared with healthy individuals. In this context, we evaluated the development of neutralising antibodies (NAbs) against SARS-CoV-2 in non-vaccinated patients with MM and COVID-19 compared with patients after vaccination with two doses of the BNT162b2 vaccine. Serum was collected either four weeks post confirmed diagnosis or four weeks post a second dose of BNT162b2. NAbs were measured with a Food and Drug Administration-approved enzyme-linked immunosorbent assay methodology. Thirty-five patients with COVID-19 and MM along with 35 matched patients were included. The two groups did not differ in age, sex, body mass index, prior lines of therapy, disease status, lymphocyte count, immunoglobulin levels and comorbidities. Patients with MM and COVID-19 showed a superior humoral response compared with vaccinated patients with MM. The median (interquartile range) NAb titre was 87·6% (71·6-94%) and 58·7% (21·4-91·8%) for COVID-19-positive and vaccinated patients, respectively (P = 0·01).Importantly, there was no difference in NAb production between COVID-19-positive and vaccinated patients who did not receive any treatment (median NAb 85·1% vs 91·7%, P = 0·14). In conclusion, our data indicate that vaccinated patients with MM on treatment without prior COVID-19 should be considered for booster vaccine doses.

4.
Blood Cancer J ; 11(8): 138, 2021 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-34341335

RESUMO

Recent data suggest a suboptimal antibody response to COVID-19 vaccination in patients with hematological malignancies. Neutralizing antibodies (NAbs) against SARS-CoV-2 were evaluated in 276 patients with plasma cell neoplasms after vaccination with either the BNT162b2 or the AZD1222 vaccine, on days 1 (before the first vaccine shot), 22, and 50. Patients with MM (n = 213), SMM (n = 38), and MGUS (n = 25) and 226 healthy controls were enrolled in the study (NCT04743388). Vaccination with either two doses of the BNT162b2 or one dose of the AZD1222 vaccine leads to lower production of NAbs in patients with MM compared with controls both on day 22 and on day 50 (p < 0.001 for all comparisons). Furthermore, MM patients showed an inferior NAb response compared with MGUS on day 22 (p = 0.009) and on day 50 (p = 0.003). Importantly, active treatment with either anti-CD38 monoclonal antibodies (Mabs) or belantamab mafodotin and lymphopenia at the time of vaccination were independent prognostic factors for suboptimal antibody response following vaccination. In conclusion, MM patients have low humoral response following SARS-CoV-2 vaccination, especially under treatment with anti-CD38 or belamaf. This underlines the need for timely vaccination, possibly during a treatment-free period, and for continuous vigilance on infection control measures in non-responders.


Assuntos
Anticorpos Neutralizantes , Anticorpos Antivirais , Vacinas contra COVID-19 , COVID-19 , Mieloma Múltiplo , SARS-CoV-2 , Idoso , Idoso de 80 Anos ou mais , Anticorpos Neutralizantes/sangue , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , COVID-19/sangue , COVID-19/imunologia , COVID-19/prevenção & controle , Vacinas contra COVID-19/administração & dosagem , Vacinas contra COVID-19/imunologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/sangue , Mieloma Múltiplo/imunologia , Estudos Prospectivos , SARS-CoV-2/imunologia , SARS-CoV-2/metabolismo
5.
Cell Rep ; 36(6): 109504, 2021 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-34352226

RESUMO

Early responses to vaccination are important for shaping both humoral and cellular protective immunity. Dissecting innate vaccine signatures may predict immunogenicity to help optimize the efficacy of mRNA and other vaccine strategies. Here, we characterize the cytokine and chemokine responses to the 1st and 2nd dose of the BNT162b2 mRNA (Pfizer/BioNtech) vaccine in antigen-naive and in previously coronavirus disease 2019 (COVID-19)-infected individuals (NCT04743388). Transient increases in interleukin-15 (IL-15) and interferon gamma (IFN-γ) levels early after boost correlate with Spike antibody levels, supporting their use as biomarkers of effective humoral immunity development in response to vaccination. We identify a systemic signature including increases in IL-15, IFN-γ, and IP-10/CXCL10 after the 1st vaccination, which were enriched by tumor necrosis factor alpha (TNF-α) and IL-6 after the 2nd vaccination. In previously COVID-19-infected individuals, a single vaccination results in both strong cytokine induction and antibody titers similar to the ones observed upon booster vaccination in antigen-naive individuals, a result with potential implication for future public health recommendations.


Assuntos
Vacinas contra COVID-19/imunologia , COVID-19/imunologia , Quimiocina CXCL10/imunologia , Interferon gama/imunologia , Interleucina-15/imunologia , SARS-CoV-2/imunologia , Adulto , Idoso , Anticorpos Antivirais/imunologia , COVID-19/metabolismo , Vacinas contra COVID-19/administração & dosagem , Feminino , Humanos , Imunidade/imunologia , Masculino , Pessoa de Meia-Idade , RNA Mensageiro/imunologia
6.
Cells ; 10(8)2021 07 30.
Artigo em Inglês | MEDLINE | ID: mdl-34440710

RESUMO

The aim of this study was to investigate the kinetics of neutralizing antibodies (NAbs) and anti-SARS-CoV-2 anti-S-RBD IgGs up to three months after the second vaccination dose with the BNT162b2 mRNA vaccine. NAbs and anti-S-RBD levels were measured on days 1 (before the first vaccine shot), 8, 22 (before the second shot), 36, 50, and three months after the second vaccination (D111) (NCT04743388). 283 health workers were included in this study. NAbs showed a rapid increase from D8 to D36 at a constant rate of about 3% per day and reached a median (SD) of 97.2% (4.7) at D36. From D36 to D50, a slight decrease in NAbs values was detected and it became more prominent between D50 and D111 when the rate of decline was determined at -0.11 per day. The median (SD) NAbs value at D111 was 92.7% (11.8). A similar pattern was also observed for anti-S-RBD antibodies. Anti-S-RBDs showed a steeper increase during D22-D36 and a lower decline rate during D36-D111. Prior COVID-19 infection and younger age were associated with superior antibody responses over time. In conclusion, we found a persistent but declining anti-SARS-CoV-2 humoral immunity at 3 months following full vaccination with BNT162b2 in healthy individuals.


Assuntos
Anticorpos Antivirais/imunologia , Vacinas contra COVID-19/imunologia , COVID-19/prevenção & controle , SARS-CoV-2/imunologia , Adulto , Idoso , Anticorpos Antivirais/metabolismo , Formação de Anticorpos , Feminino , Humanos , Cinética , Masculino , Pessoa de Meia-Idade , Adulto Jovem
7.
BMC Med ; 19(1): 208, 2021 08 23.
Artigo em Inglês | MEDLINE | ID: mdl-34420521

RESUMO

BACKGROUND: Coronavirus SARS-CoV-2, the causative agent of COVID-19, has caused a still evolving global pandemic. Given the worldwide vaccination campaign, the understanding of the vaccine-induced versus COVID-19-induced immunity will contribute to adjusting vaccine dosing strategies and speeding-up vaccination efforts. METHODS: Anti-spike-RBD IgGs and neutralizing antibodies (NAbs) titers were measured in BNT162b2 mRNA vaccinated participants (n = 250); we also investigated humoral and cellular immune responses in vaccinated individuals (n = 21) of this cohort 5 months post-vaccination and assayed NAbs levels in COVID-19 hospitalized patients (n = 60) with moderate or severe disease, as well as in COVID-19 recovered patients (n = 34). RESULTS: We found that one (boosting) dose of the BNT162b2 vaccine triggers robust immune (i.e., anti-spike-RBD IgGs and NAbs) responses in COVID-19 convalescent healthy recipients, while naïve recipients require both priming and boosting shots to acquire high antibody titers. Severe COVID-19 triggers an earlier and more intense (versus moderate disease) immune response in hospitalized patients; in all cases, however, antibody titers remain at high levels in COVID-19 recovered patients. Although virus infection promotes an earlier and more intense, versus priming vaccination, immune response, boosting vaccination induces antibody titers significantly higher and likely more durable versus COVID-19. In support, high anti-spike-RBD IgGs/NAbs titers along with spike (vaccine encoded antigen) specific T cell clones were found in the serum and peripheral blood mononuclear cells, respectively, of vaccinated individuals 5 months post-vaccination. CONCLUSIONS: These findings support vaccination efficacy, also suggesting that vaccination likely offers more protection than natural infection.


Assuntos
Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Vacinas contra COVID-19/uso terapêutico , COVID-19 , Glicoproteína da Espícula de Coronavírus/imunologia , COVID-19/prevenção & controle , COVID-19/terapia , Humanos , Cinética , Leucócitos Mononucleares , RNA Mensageiro , SARS-CoV-2
8.
Clin Exp Med ; 2021 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-34283338

RESUMO

Vaccination against SARS-CoV-2 is considered as the most important preventive strategy against COVID-19, but its efficacy in patients with hematological malignancies is largely unknown. We investigated the development of neutralizing antibodies (NAbs) against SARS-CoV-2 in patients with Waldenstrom Macroglobulinemia (WM), Chronic Lymphocytic Leukemia (CLL) and Non-Hodgkin Lymphoma (NHL). After the first dose of the vaccine, on D22, WM/CLL/NHL patients had lower NAb titers compared to controls: the median NAb inhibition titer was 17% (range 0-91%, IQR 8-27%) for WM/CLL/NHL patients versus 32% (range 2-98%, IQR 19-48%) for controls (P < 0.001). Only 8 (14%) patients versus 114 (54%) controls developed NAb titers ≥ 30% on D22 (p < 0.001). Our data indicate that the first dose of both BNT162b2 and AZD1222 leads to lower production of NAbs against SARS-CoV-2 in patients with WM/CLL/NHL compared to controls of similar age and gender and without malignant disease. Even though the response rates were not optimal, vaccination is still considered essential and if possible should be performed before treatment initiation. These patients with suboptimal responses should be considered to be prioritized for booster doses.

9.
Cell Death Dis ; 12(7): 671, 2021 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-34218254

RESUMO

The balanced functionality of cellular proteostatic modules is central to both proteome stability and mitochondrial physiology; thus, the age-related decline of proteostasis also triggers mitochondrial dysfunction, which marks multiple degenerative disorders. Non-functional mitochondria are removed by mitophagy, including Parkin/Pink1-mediated mitophagy. A common feature of neuronal or muscle degenerative diseases, is the accumulation of damaged mitochondria due to disrupted mitophagy rates. Here, we exploit Drosophila as a model organism to investigate the functional role of Parkin/Pink1 in regulating mitophagy and proteostatic responses, as well as in suppressing degenerative phenotypes at the whole organism level. We found that Parkin or Pink1 knock down in young flies modulated proteostatic components in a tissue-dependent manner, increased cell oxidative load, and suppressed mitophagy in neuronal and muscle tissues, causing mitochondrial aggregation and neuromuscular degeneration. Concomitant to Parkin or Pink1 knock down cncC/Nrf2 overexpression, induced the proteostasis network, suppressed oxidative stress, restored mitochondrial function, and elevated mitophagy rates in flies' tissues; it also, largely rescued Parkin or Pink1 knock down-mediated neuromuscular degenerative phenotypes. Our in vivo findings highlight the critical role of the Parkin/Pink1 pathway in mitophagy, and support the therapeutic potency of Nrf2 (a druggable pathway) activation in age-related degenerative diseases.


Assuntos
Proteínas de Drosophila/deficiência , Proteínas de Drosophila/metabolismo , Mitocôndrias Musculares/enzimologia , Mitofagia , Músculo Esquelético/enzimologia , Degeneração Neural , Neurônios/enzimologia , Proteínas Serina-Treonina Quinases/deficiência , Proteínas Repressoras/metabolismo , Ubiquitina-Proteína Ligases/deficiência , Animais , Animais Geneticamente Modificados , Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Regulação da Expressão Gênica , Técnicas de Silenciamento de Genes , Mitocôndrias Musculares/genética , Mitocôndrias Musculares/patologia , Músculo Esquelético/patologia , Neurônios/patologia , Estresse Oxidativo , Fenótipo , Proteínas Serina-Treonina Quinases/genética , Proteostase , Proteínas Repressoras/genética , Transdução de Sinais , Ubiquitina-Proteína Ligases/genética
10.
Neurobiol Aging ; 105: 137-147, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34062489

RESUMO

Alzheimer's disease (AD) is the prevailing form of dementia. Protein degradation and antioxidant pathways have a critical role in preventing the accumulation of protein aggregation; thus, failure of proteostasis in neurons along with redox imbalance mark AD. Herein, we exploited an AD Drosophila model expressing human amyloid precursor (hAPP) and beta-secretase 1 (hBACE1) proteins, to better understand the role of proteostatic or antioxidant pathways in AD. Ubiquitous expression of hAPP, hBACE1 in flies caused more severe degenerative phenotypes versus neuronal targeted expression; it also, suppressed proteasome activity, increased oxidative stress and significantly enhanced stress-sensitivity. Overexpression of Prosß5 proteasomal subunit or Nrf2 transcription factor in AD Drosophila flies partially restored proteasomal activity but did not rescue hAPP, hBACE1 induced neurodegeneration. On the other hand, expression of autophagy-related Atg8a in AD flies decelerated neurodegeneration, increased stress-resistance, and improved flies' health-/lifespan. Overall, our data suggest that the noxious effects of amyloid-beta aggregates can be alleviated by enhanced autophagy, thus dietary or pharmacological interventions that target autophagy should be considered in AD therapeutic approaches.

13.
Vaccines (Basel) ; 9(3)2021 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-33801380

RESUMO

Between June and November 2020, we assessed plasma antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nucleocapsid protein in 4996 participants (aged 18-82 years, 34.5% men) from the National and Kapodistrian University of Athens. The weighted overall prevalence was 1.6% and monthly prevalence correlated with viral RNA-confirmed SARS-CoV-2 infections in Greece, in the same period. Notably, 49% of seropositive cases reported no history of SARS-CoV-2 infection-related clinical symptoms and 33% were unsuspected of their previous infection. Additionally, levels of anti-SARS-CoV-2 antibodies against the spike-protein receptor-binding domain were similar between symptomatic and asymptomatic individuals, irrespective of age and gender. Using Food and Drug Administration Emergency Use Authorization-approved assays, these results support the need for such studies on pandemic evaluation and highlight the development of robust humoral immune responses even among asymptomatic individuals. The high percentage of unsuspected/asymptomatic active cases, which may contribute to community transmission for more days than that of cases who are aware and self-isolate, underscores the necessity of measures across the population for the efficient control of the pandemic.

14.
Nat Prod Res ; : 1-4, 2021 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-33706628

RESUMO

Three known compounds were isolated from Virgaria nigra CF-231658; 2,7-dihydroxy naphthalene (1), virgaricin B (2) and virgaricin (3). The isolated compounds was obtained from liquid-state and agar-supported fermentation using Amberlite XAD-16 solid-phase extraction during the cultivation step. Their structures were elucidated on the basis of 1D and 2D NMR as well as HRMS spectroscopic analyses. The isolated compounds were examined for their ability to inhibit elastase using normal human diploid fibroblasts. Compound 2 displayed the most potent activity with 76.7 ± 2.12% inhibition of the enzyme activity at 5 µM concentration.

15.
Life (Basel) ; 10(9)2020 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-32967110

RESUMO

Due to early implementation of public health measures, Greece had low number of SARS-CoV-2 infections and COVID-19 severe incidents in hospitalized patients. The National and Kapodistrian University of Athens (ΝΚUA), especially its health-care/medical personnel, has been actively involved in the first line of state responses to COVID-19. To estimate the prevalence of antibodies (Igs) against SARS-CoV-2 among NKUA members, we designed a five consecutive monthly serosurvey among randomly selected NKUA consenting volunteers. Here, we present the results from the first 2500 plasma samples collected during June-July 2020. Twenty-five donors were tested positive for anti-SARS-CoV-2 Igs; thus, the overall seroprevalence was 1.00%. The weighted overall seroprevalence was 0.93% (95% CI: 0.27, 2.09) and varied between males [1.05% (95% CI: 0.18, 2.92)] and females [0.84% (95% CI: 0.13, 2.49)], age-groups and different categories (higher in participants from the School of Health Sciences and in scientific affiliates/faculty members/laboratory assistants), but no statistical differences were detected. Although focused on the specific population of NKUA members, our study shows that the prevalence of anti-SARS-CoV-2 Igs for the period June-July 2020 remained low and provides knowledge of public health importance for the NKUA members. Given that approximately one in three infections was asymptomatic, continuous monitoring of the progression of the pandemic by assessing Ig seroprevalence is needed.

16.
Bioorg Med Chem Lett ; 30(6): 126952, 2020 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-32005414

RESUMO

In the course of a primary screening of 614 microbial actinomycete extracts for the discovery of tyrosinase inhibitors, the EtOAc extract of the fermentation broth of the strain Streptomyces sp. CA-129531 isolated from a Martinique sample, exhibited in cell free and cell-based assays the most promising activity (IC50 value of 63 µg/mL). Scaled-up production in a bioreactor led to the isolation of one new trichostatic acid analogue, namely trichostatic acid B (1), along with six known trichostatin derivatives (2-7), four diketopiperazines (8-11), two butyrolactones (12-13) and one hydroxamic acid siderophore (14). Among them, trichostatin A (4) showed a Ki value of 6.1 µM and six times stronger anti-tyrosinase activity (IC50 2.18 µΜ) than kojic acid (IC50 14.07 µΜ) used as a positive control. Deoxytrichostatin A (6) displayed also strong inhibitory activity against tyrosinase (IC50 19.18 µΜ). Trichostatin A production in bioreactor started together with the exponential phase of growth (day 4) and the maximum concentration was reached at day 9 (2.67 ± 0.13 µg/mL). Despite the cytotoxicity of some individual components, the EtOAc extract showed no cytotoxic effect on HepG2, A2058, A549, MCF-7 and MIA PaCa-2 cell lines, (IC50 >2.84 mg/mL) and against BG fibroblasts at the concentrations where the whitening effect was exerted, reassuring its safety and great tyrosinase inhibitory potential.


Assuntos
Actinobacteria/química , Misturas Complexas/química , Inibidores Enzimáticos/química , Ácidos Hidroxâmicos/química , Monofenol Mono-Oxigenase/antagonistas & inibidores , Streptomyces/química , Reatores Biológicos , Sobrevivência Celular/efeitos dos fármacos , Misturas Complexas/metabolismo , Dicetopiperazinas/química , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/metabolismo , Fermentação , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Humanos , Ácidos Hidroxâmicos/metabolismo , Lactonas/química , Programas de Rastreamento , Pironas/química , Metabolismo Secundário/efeitos dos fármacos
17.
Molecules ; 25(3)2020 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-32033190

RESUMO

Abstract: A main cellular functional module that becomes dysfunctional during aging is the proteostasis network. In the present study, we show that benzoic acid derivatives isolated from Bjerkandera adusta promote the activity of the two main protein degradation systems, namely the ubiquitin-proteasome (UPP) and especially the autophagy-lysosome pathway (ALP) in human foreskin fibroblasts. Our findings were further supported by in silico studies, where all compounds were found to be putative binders of both cathepsins B and L. Among them, compound 3 (3-chloro-4-methoxybenzoic acid) showed the most potent interaction with both enzymes, which justifies the strong activation of cathepsins B and L (467.3 ± 3.9%) on cell-based assays. Considering that the activity of both the UPP and ALP pathways decreases with aging, our results suggest that the hydroxybenzoic acid scaffold could be considered as a promising candidate for the development of novel modulators of the proteostasis network, and likely of anti-aging agents.


Assuntos
Autofagia/fisiologia , Coriolaceae/química , Hidroxibenzoatos/farmacologia , Lisossomos/fisiologia , Proteostase/efeitos dos fármacos , Ácido Benzoico/farmacologia , Catepsinas/metabolismo , Extratos Celulares/farmacologia , Linhagem Celular , Coriolaceae/metabolismo , Humanos , Hidroxibenzoatos/química , Simulação de Acoplamento Molecular , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteólise , Ubiquitina-Proteína Ligases/metabolismo
18.
Front Neurosci ; 13: 1202, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31803000

RESUMO

Defects in the endoplasmic reticulum (ER) membrane shaping and interaction with other organelles seem to be a crucial mechanism underlying Hereditary Spastic Paraplegia (HSP) neurodegeneration. REEP1, a transmembrane protein belonging to TB2/HVA22 family, is implicated in SPG31, an autosomal dominant form of HSP, and its interaction with Atlastin/SPG3A and Spastin/SPG4, the other two major HSP linked proteins, has been demonstrated to play a crucial role in modifying ER architecture. In addition, the Drosophila ortholog of REEP1, named ReepA, has been found to regulate the response to ER neuronal stress. Herein we investigated the role of ReepA in ER morphology and stress response. ReepA is upregulated under stress conditions and aging. Our data show that ReepA triggers a selective activation of Ire1 and Atf6 branches of Unfolded Protein Response (UPR) and modifies ER morphology. Drosophila lacking ReepA showed Atf6 and Ire1 activation, expansion of ER sheet-like structures, locomotor dysfunction and shortened lifespan. Furthermore, we found that naringenin, a flavonoid that possesses strong antioxidant and neuroprotective activity, can rescue the cellular phenotypes, the lifespan and locomotor disability associated with ReepA loss of function. Our data highlight the importance of ER homeostasis in nervous system functionality and HSP neurodegenerative mechanisms, opening new opportunities for HSP treatment.

19.
J Biotechnol ; 301: 88-96, 2019 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-31152756

RESUMO

From a large screening of microbial extracts for the discovery of proteasome modulating natural products, the fungal strain Cercospora sp. (CF-223709) was selected as the most promising for further investigation. Different liquid cultures of the strain were initially screened for their anti-oxidant activity (DPPH, ABTS) and for their cytotoxicity against the A2058, HepG2 and CCD25sk cell lines. A detailed chemical analysis and evaluation of the capacity to activate 26S-proteasome was followed for the most active extract. Three main polyketides were isolated and characterized by extensive analysis of NMR and HRMS spectra data as penialidine F (1), fulvic acid (2), and SB238569 (3). Fulvic acid showed the most significant anti-oxidant activity. Its IC50 value (8.16 µM) against the ABTS radical resulted 3-fold lower than the standard trolox. Fulvic acid also demonstrated a significant effect on proteasome by enhancing the chymotrypsin- and caspase-like activities of the 26S proteasome of human fibroblasts by 71.43% and 37.5% at 1 µM, respectively. Furthermore by scaling up the culture in a 30 L submerged bioreactor, Cercospora sp. produced up to 162.6 ±â€¯1.3 mg of fulvic acid/L. Our findings suggest that CF-223709 can be a promising source of proteasome activating natural compounds.


Assuntos
Ascomicetos/metabolismo , Produtos Biológicos , Reatores Biológicos/microbiologia , Policetídeos , Complexo de Endopeptidases do Proteassoma/efeitos dos fármacos , Antioxidantes , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Humanos , Complexo de Endopeptidases do Proteassoma/metabolismo
20.
Molecules ; 24(12)2019 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-31208056

RESUMO

The strain Streptomyces osmaniensis CA-244599 isolated from the Comoros islands was submitted to liquid-state fermentation coupled to in situ solid-phase extraction with amberlite XAD-16 resin. Elution of the trapped compounds on the resin beads by ethyl acetate afforded seven metabolites, osmanicin (1), streptazolin (2), streptazone C (3), streptazone B1 (4), streptenol C (5), nocardamine (6) and desmethylenylnocardamine (7). Osmanicin (1) is a newly reported unusual scaffold combining streptazolin (2) and streptazone C (3) through a Diels-Alder type reaction. Experimental evidence excluded the spontaneous formation of 1 from 2 and 3. The isolated compounds were evaluated for their ability to inhibit elastase using normal human diploid fibroblasts. Compound 1 exhibited the most potent activity with an IC50 of 3.7 µM.


Assuntos
Alcaloides/farmacologia , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Elastase Pancreática/antagonistas & inibidores , Policetídeos/farmacologia , Streptomyces/química , Alcaloides/biossíntese , Alcaloides/química , Alcaloides/isolamento & purificação , Vias Biossintéticas , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Fermentação , Humanos , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Conformação Molecular , Estrutura Molecular , Policetídeos/química , Policetídeos/isolamento & purificação , Policetídeos/metabolismo , RNA Ribossômico 16S/genética , Streptomyces/classificação , Streptomyces/genética
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