Prevalence and clinical implications of germline pathogenic variants in cancer predisposing genes in young patients across sarcoma subtypes.

BACKGROUND: Sarcomas are a rare and diverse group of cancers occurring mainly in young individuals for which an underlying germline genetic cause remains unclear in most cases. METHODS: Germline DNA from 177 children, adolescents and young adults with soft tissue or bone sarcomas was tested using multigene panels with 113 or 126 cancer predisposing genes (CPGs) to describe the prevalence of germline pathogenic/likely pathogenic variants (GPVs). Subsequent testing of a subset of tumours for loss of heterozygosity (LOH) evaluation was performed to investigate the clinical and molecular significance of these variants. RESULTS: GPVs were detected in 21.5% (38/177) of the patients (15.8% in children and 21.6% in adolescents and young adults), with dominant CPGs being altered in 15.2% overall. These variants were found in genes previously associated with the risk of developing sarcomas (TP53, RB1, NF1, EXT1/2) but also in genes where that risk is still emerging/limited (ERCC2, TSC2 and BRCA2) or unknown (PALB2, RAD50, FANCM and others). The detection rates of GPVs varied from 0% to 33% across sarcoma subtypes and GPV carriers were more likely to present more than one primary tumour than non-carriers (21.1%×6.5%; p=0.012). Loss of the wild-type allele was detected in 48% of tumours from GPV carriers, mostly in genes definitively associated with sarcoma risk. CONCLUSION: Our findings reveal that a high proportion of young patients with sarcomas presented a GPV in a CPG, underscoring the urgency of establishing appropriate genetic screening strategies for these individuals and their families.

Brazilian red propolis exerts a cytotoxic action against prostate cancer cells and upregulates human monocyte functions.

Different propolis samples can be obtained in Brazil, such as green, brown and red. Studies related to Brazilian red propolis (BRP) have increased in the last few years, so the aim of this study was to investigate its effects on the prostate cell lines LNCaP and PC-3 and on human monocytes. BRP chemical composition was analyzed by HPLC-DAD, the viability of monocyte and cancer cell by MTT assay. Cytokine production (TNF-α, IL-1ß, IL-6, IL-10) by monocytes was quantitated by ELISA, the expression of cell markers (TLR-2, TLR-4, HLA-DR, CD80) and reactive oxygen species by flow cytometry. The candidacidal activity and the effects of supernatant of treated monocytes on tumor cells were assessed. BRP affected LNCaP viability after 48 and 72 h, while PC-3 cells were more resistant over time. BRP upregulated CD80 and HLA-DR expression, and stimulated TNF-α, IL-6 and IL-10 production. BRP enhanced the fungicidal activity of monocytes, displayed an antioxidant action and the supernatant of BRP-treated monocytes diminished LNCaP viability. In the search for new immunomodulatory and antitumoral agents, BRP exerted a selective cytotoxic activity on prostate cancer cells and an immunomodulatory action, suggesting its potential for clinical trials with oncological patients and for the discovery of new immunomodulatory and antitumor drugs.

How Does Brazilian Green Propolis Act in Normal and Tumor Cells? Identification of Compounds in or out Monocytes or HEp-2 Cells.

The aim of this study was to identify propolis compounds after incubation of normal and tumor cells (monocytes and HEp-2 cells, respectively) with Brazilian green propolis, in the lysate and supernatant of cell cultures and within these cells by gas chromatography-mass spectrometry (GC/MS). Cinnamic acid derivatives were generally localized in the lysate of both cell lines after incubation, suggesting these compounds are actively transported across the membrane into the cytoplasm. Terpenes were also found in the lysate. Artepillin C, in contrast, was localised only in the supernatant. Some constituents were unobservable after incubation, especially in monocytes, suggesting the compounds had been degraded. Our findings shed light on the possible sites of action (intracellular or via a cell membrane protein) and the bioavailability of various constituents of propolis, as well as possible modes of delivery of bioactive constituents.

Brazilian green propolis: A novel tool to improve the cytotoxic and immunomodulatory action of docetaxel on MCF-7 breast cancer cells and on women monocyte.

Docetaxel (DTX) is used against breast cancer despite its side effects such as toxicity and immunosuppression. Here we investigated the cytotoxic and immunomodulatory effects of the ethanol solution extract of propolis (EEP) in combination with DTX on MCF-7 breast cancer cells and on women's monocyte. The cytotoxic potential of EEP + DTX was assessed by MTT assay and the type of tumor cell death was evaluated by flow cytometry. The effects of EEP + DTX on the migration and invasion of MCF-7 cells were analyzed. Cytokine production by monocytes was assessed by ELISA and the expression of cell surface markers was evaluated by flow cytometry. We also assessed the fungicidal activity of monocytes against Candida albicans and the generation of reactive oxygen species (ROS). Finally, the impact of the supernatants of treated monocytes in the viability, migration, and invasiveness of tumor cells was assessed. EEP enhanced the cytotoxicity of DTX alone against MCF-7 cells by inducing necrosis and inhibiting their migratory ability. EEP + DTX exerted no cytotoxic effects on monocytes and stimulated HLA-DR expression, TNF-α, and IL-6 production, exerted an immunorestorative action in the fungicidal activity, and reduced the oxidative stress. Our findings have practical implications and reveal new insights for complementary medicine.

Variable population prevalence estimates of germline TP53 variants: A gnomAD-based analysis.

Reports of variable cancer penetrance in Li-Fraumeni syndrome (LFS) have raised questions regarding the prevalence of pathogenic germline TP53 variants. We previously reported higher-than-expected population prevalence estimates in sequencing databases composed of individuals unselected for cancer history. This study aimed to expand and further evaluate the prevalence of pathogenic and likely pathogenic germline TP53 variants in the gnomAD dataset (version r2.0.2, n = 138,632). Variants were selected and classified based on our previously published algorithm and compared with alternative estimates based on three different classification databases: ClinVar, HGMD, and the UMD_TP53 database. Conservative prevalence estimates of pathogenic and likely pathogenic TP53 variants were within the range of one carrier in 3,555-5,476 individuals. Less stringent classification increased the approximate prevalence to one carrier in every 400-865 individuals, mainly due to the inclusion of the controvertible p.N235S, p.V31I, and p.R290H variants. This study shows a higher-than-expected population prevalence of pathogenic and likely pathogenic germline TP53 variants even with the most conservative estimates. However, these estimates may not necessarily reflect the prevalence of the classical LFS phenotype, which is based upon family history of cancer. Comprehensive approaches are needed to better understand the interplay of germline TP53 variant classification, prevalence estimates, cancer penetrance, and LFS-associated phenotype.

The chemical composition and events related to the cytotoxic effects of propolis on osteosarcoma cells: A comparative assessment of Colombian samples.

Osteosarcoma (OSA) is a type of bone cancer showing an aggressive biological behavior with metastatic progression. Because propolis potential for the development of new antitumoral drugs has been indicated, we evaluated the chemical composition of Colombian propolis samples and the mechanisms involved in their cytotoxic effects on OSA cells. The chemical composition was analyzed by GC-MS and the DPPH free radical scavenging activity was measured. Cluster and principal components analysis were used to establish an association with their inhibitory concentration 50% (IC50 ). Cell viability was analyzed by MTT assay; apoptosis was determined by flow cytometry; mitochondrial membrane permeability and reactive oxygen species were evaluated by rhodamine 123 and DCFH-DA. Transwell assay was used to evaluate the invasiveness of propolis-treated cells. Samples were grouped: Cluster 1 contained diterpenes and benzophenones and showed the highest antiradical activity; Cluster 2 was characterized by triterpenes, fatty acid, and diterpenes. Usm contained diterpenes and triterpenes different of the other samples and Sil contained triterpenes and flavonoids. Apoptosis, mitochondrial membrane alteration, and suppression of cell invasion were the main mechanisms involved in the inhibition of OSA cells in vitro, suggesting the potential of Colombian propolis to discover new antitumor drugs.

Early-onset breast cancer patients in the South and Southeast of Brazil should be tested for the TP53 p.R337H mutation.

Germline TP53 mutations are associated with Li-Fraumeni syndrome (LFS), a disease that predisposes carriers to a wide variety of early onset tumors. In southern and southeastern Brazil, a high frequency of a germline TP53 mutation, p.R337H, was diagnosed in 0,3% of the population due to a founder effect. Carriers are at risk for developing cancer but the penetrance is lower than in typical DNA binding domain mutations. To date, only a few families were detected and diagnosis of carriers remains a challenge. Therefore, the inclusion of additional criteria to detect p.R337H carriers is necessary for the Brazilian population. We assessed the A.C. Camargo Cancer Center Oncogenetics Department database in search of common characteristics associated with p.R337H families that did not fulfill LFS/LFL clinical criteria. Among 42 p.R337H families, three did not meet any LFS/LFL criteria. All cases were young female patients with breast cancer diagnosed before age 45 and with no family history of LFS linked-cancers. Our results suggest that screening for the germline TP53 p.R337H mutation should be indicated, along with BRCA1 and BRCA2 genetic testing, for this group of patients, especially in the South and Southeast of Brazil.

Xeroderma pigmentosum: low prevalence of germline XPA mutations in a Brazilian XP population.

Xeroderma pigmentosum (XP) is a rare autosomal recessive disorder characterized by DNA repair defects that cause photophobia, sunlight-induced cancers, and neurodegeneration. Prevalence of germline mutations in the nucleotide excision repair gene XPA vary significantly in different populations. No Brazilian patients have been reported to carry a germline mutation in this gene. In this study, the germline mutational status of XPA was determined in Brazilian patients exhibiting major clinical features of XP syndrome. The study was conducted on 27 unrelated patients from select Brazilian families. A biallelic inactivating transition mutation c.619C>T (p.Arg207Ter) was identified in only one patient with a history of neurological impairment and mild skin abnormalities. These findings suggest that XP syndrome is rarely associated with inherited disease-causing XPA mutations in the Brazilian population. Additionally, this report demonstrates the effectiveness of genotype-phenotype correlation as a valuable tool to guide direct genetic screening.

Anti-inflammatory action of geopropolis produced by stingless bees on human peripheral blood mononuclear cells.

Natural products have been used to treat inflammatory reactions and led to the discovery of new anti-inflammatory drugs. Geopropolis (GEO) is produced by stingless bees and has been used by indigenous people to improve the immune functions. Here, a possible synergism between GEO and dexamethasone (DEX) was assessed on human peripheral blood mononuclear cells (PBMC) stimulated by lipopolysaccharide (LPS). PBMC viability was evaluated by the MTT, apoptosis/necrosis by flow cytometry, cytokine and eicosanoids production by ELISA, and intracellular pathways by polymerase chain reaction. GEO and DEX alone or in combination did not affect cell viability. GEO in combination with lower concentrations of DEX inhibited cytokine production (TNF-α, IL-1ß, and IL-10). No effects were seen on eicosanoids nor in intracellular pathways. Despite not always being more efficient than the isolated treatments, GEO + DEX seemed to be promising and allow the use of DEX in lower concentrations, reducing adverse effects.

Misclassification of a frequent variant from PMS2CL pseudogene as a PMS2 loss of function variant in Brazilian patients.

PMS2, a Lynch Syndrome gene, presents challenges in genetic testing due to the existence of multiple pseudogenes. This study aims to describe a series of cases harboring a variant in the PMS2CL pseudogene that has been incorrectly assigned to PMS2 with different nomenclatures. We reviewed data from 647 Brazilian patients who underwent multigene genetic testing at a single center to identify those harboring the PMS2 V1:c.2186_2187delTC or V2:c.2182_2184delACTinsG variants, allegedly located at PMS2 exon 13. Gene-specific PCR and transcript sequencing was performed. Among the 647 individuals, 1.8% (12) carried the investigated variants, with variant allele frequencies ranging from 15 to 34%. By visually inspecting the alignments, we confirmed that both V1 and V2 represented the same variant and through gene-specific PCR and PMS2 transcript analysis, we demonstrated that V1/V2 is actually located in the PMS2CL pseudogene. Genomic databases (ExAC and gnomAD) report an incidence of 2.5 - 5.3% of this variant in the African population. Currently, V1 is classified as "uncertain significance" and V2 as "conflicting" in ClinVar, with several laboratories classifying them as "pathogenic". We identified a frequent African PMS2CL variant in the Brazilian population that is misclassified as a PMS2 variant. It is likely that V1/V2 have been erroneously assigned to PMS2 in several manuscripts and by clinical laboratories, underscoring a disparity-induced matter. Considering the limitations of short-read NGS differentiating between certain regions of PMS2 and PMS2CL, using complementary methodologies is imperative to provide an accurate diagnosis.

Propolis anti-inflammatory effects on MAGE-1 and retinoic acid-treated dendritic cells and on Th1 and T regulatory cells.

Background: Propolis exhibits huge potential in the pharmaceutical industry. In the present study, its effects were investigated on dendritic cells (DCs) stimulated with a tumor antigen (MAGE-1) and retinoic acid (RA) and on T lymphocytes to observe a possible differential activation of T lymphocytes, driving preferentially to Th1 or Treg cells. Methods: Cell viability, lymphocyte proliferation, gene expression (T-bet and FoxP3), and cytokine production by DCs (TNF-α, IL-10, IL-6 and IL-1ß) and lymphocytes (IFN-γ and TGF-ß) were analyzed. Results: MAGE-1 and RA alone or in combination with propolis inhibited TNF-α production and induced a higher lymphoproliferation compared to control, while MAGE-1 + propolis induced IL-6 production. Propolis in combination with RA induced FoxP3 expression. MAGE-1 induced IFN-γ production while propolis inhibited it, returning to basal levels. RA inhibited TGF-ß production, what was counteracted by propolis. Conclusion: Propolis affected immunological parameters inhibiting pro-inflammatory cytokines and favoring the regulatory profile, opening perspectives for the control of inflammatory conditions.

Propolis consumption by asymptomatic HIV-individuals: Better redox state? A prospective, randomized, double-blind, placebo-controlled trial.

Propolis is a natural product has many biological properties of clinical interest, such as anti-inflammatory and antioxidant. Considering that people living with HIV/aids (PLWHA) on effective combined antiretroviral therapy (cART) present early aging due to an intense immune activation, inflammation, and redox imbalance, propolis consumption could offer a benefit to such patients. This double-blind longitudinal study evaluated whether Brazilian green propolis pills intake (500 mg/day for three months) would decrease the oxidative stress of virological suppressed HIV-individuals. To compare each group (propolis, n = 20 versus placebo, n = 20) in both moments (M0, before and M1, after the intervention), the following markers were assessed: plasma malondialdehyde (MDA), carbonylation, total oxide nitric, total antioxidant capacity (TAP), superoxide dismutase, catalase, and NFkB and NRF2 gene expression. Data were analyzed using Poisson, Gamma distribution and ANOVA followed by Tukey-Kramer. The groups were homogeneous regarding age, gender, time of diagnosis/ treatment, cART scheme, CD4+ T cell count, and no changes were observed in the diet food, or patients' lifestyles. A decreased MDA concentration was seen in the propolis group (M0 = 0.24 ± 0.13, M1 = 0.20 ± 0.10 protein nmol/mg; p = 0.005) as well as a slight but non-significant increase of TAP (M0 = 49.07 ± 13.26, M1 = 52.27 ± 14.86%; p = 0.06). One may conclude that propolis promoted a lower lipid peroxidation and improved the antioxidant system, suggesting that its use may be beneficial to PLWHA in an attempt to contain the intense inflammatory and oxidant activity.

Germline pathogenic variants in patients with early-onset neuroendocrine neoplasms.

Neuroendocrine neoplasms (NENs) are a rare group of cancers with heterogeneous behaviour and mostly of unknown aetiology. Excluding some infrequent hereditary cancer syndromes, the extent and clinical significance of mutations in other cancer predisposing genes (CPGs) are not known. We aimed to investigate the frequency of pathogenic and likely germline pathogenic variants (GPVs) in known CPGs in young adults with NEN and the clinical and molecular characteristics of these patients. We recruited 108 patients with lung or digestive NEN diagnosed between 18 and 50 years and performed targeted sequencing of 113 CPGs on germline DNA. For some patients, tumour features such as loss of heterozygosity (LOH), tumour mutation burden and microsatellite instability were evaluated. GPVs were detected in 17 patients (15.7%). Median age, sex, stage at diagnosis, family history of NENs or any personal history of neoplasm were similar between patients with or without GPVs. GPV carriers had more gastric (P = 0.084), functioning NEN (P = 0.041), positive family history of cancer (P = 0.015) and exclusively well-differentiated histology. Genes affected were mostly involved in DNA repair (CHEK2, ERCC2, ERCC3, XPC, MSH6, POLE and SLX4), with most GPVs found in MUTYH (four cases). LOH was performed in eight tumours and detected only in an SLX4-positive case. Overall, our findings indicate a role of inherited genetic alterations, particularly in DNA repair genes, in NEN carcinogenesis in young adults. These patients more often had a family history of cancer and functioning NENs.

Risk of metastasis in BRCA2 carriers diagnosed with triple-negative breast cancer.

BACKGROUND: Triple-negative breast cancer (TNBC) is the neoplasia most associated with BRCA1 germline pathogenic variants (PV) and is more likely to develop metastases than the other breast cancer (BC) subtypes, mainly in the lungs and the central nervous system (CNS). Recently, BRCA2 carriers were shown to have a higher risk for developing CNS metastases. However, the patterns of recurrence and metastases of BRCA2 carriers with TNBC are unknown. METHODS: TNBC patient data attending the A.C. Camargo Cancer Center, from 1998 through 2020, were verified either by medical records or by BRCA1/2 genetic testing carried out. Multivariable logistic regression models were fit to the data to assess the independent factors for bone and CNS metastases. Adjustment was done using all independent variables with p < 0.2 in the univariable Cox model to describe the relationship between the independent variables until time of death. RESULTS: A total of 388 TNBC patients were evaluated. We identified PV in BRCA1/2 genes in 21% (82/388), being 17.7% (69/388) in BRCA1 and only 3.3% (13/388) in BRCA2. A total of 120 patients (31%) developed distant metastases. Bone or CNS metastases were observed in 40% and 60% of BRCA2 PV carriers (p = 0.155), respectively. The BRCA2 carriers tended to have a higher likelihood of developing bone metastases (OR, 4.06; 95% CI, 0.82-20.01; p = 0.085), when compared to BRCA1 carriers (OR, 0.6; 95% CI, 0.12-2.87; p = 0.528). BRCA2 carriers had an OR of 1.75 (95% CI, 0.33-9.14; p = 0.503) for CNS metastasis development, while BRCA1 carriers had an OR of 0.72 (95% CI, 0.23-2.23; p = 0.574). CONCLUSIONS: Patients with TNBC and PV in the BRCA2 gene had higher frequencies of secondary bone involvement and CNS in the course of the disease. However, the BRCA2 PV did not represent an independent outcome predictor of metastases and overall survival. Efforts to increase the number of BRCA2 carriers among TNBC patients are crucial for determining their risk of developing bone and CNS metastases compared to BRCA2 noncarriers.

Characterization of genetic predisposition to molecular subtypes of breast cancer in Brazilian patients.

Introduction: BRCA1 and BRCA2 germline pathogenic variants (GPVs) account for most of the 5-10% of breast cancer (BC) that is attributable to inherited genetic variants. BRCA1 GPVs are associated with the triple negative subtype, whereas BRCA2 GPVs are likely to result in higher grade, estrogen-receptor positive BCs. The contribution of other genes of high and moderate risk for BC has not been well defined and risk estimates to specific BC subtypes is lacking, especially for an admixed population like Brazilian. Objective: The aim of this study is to evaluate the value of a multigene panel in detecting germline mutations in cancer-predisposing genes for Brazilian BC patients and its relation with molecular subtypes and the predominant molecular ancestry. Patients and methods: A total of 321 unrelated BC patients who fulfilled NCCN criteria for BRCA1/2 testing between 2016-2018 were investigated with a 94-genes panel. Molecular subtypes were retrieved from medical records and ancestry-specific variants were obtained from off-target reads obtained from the sequencing data. Results: We detected 83 GPVs in 81 patients (positivity rate of 25.2%). Among GPVs, 47% (39/83) were identified in high-risk BC genes (BRCA1/2, PALB2 and TP53) and 18% (15/83) in moderate-penetrance genes (ATM, CHEK2 and RAD51C). The remainder of the GPVs (35% - 29/83), were identified in lower-risk genes. As for the molecular subtypes, triple negative BC had a mutation frequency of 31.6% (25/79), with predominance in BRCA1 (12.6%; 10/79). Among the luminal subtypes, except Luminal B HER2-positive, 18.7% (29/155) had GPV with BRCA1/2 genes contributing 7.1% (11/155) and non-BRCA1/2 genes, 12.9% (20/155). For Luminal B HER2-positive subtype, 40% (16/40) had GPVs, with a predominance of ATM gene (15% - 6/40) and BRCA2 with only 2.5% (1/40). Finally, HER2-enriched subtype presented a mutation rate of 30.8% (4/13) with contribution of BRCA2 of 7.5% (1/13) and non-BRCA1/2 of 23% (3/13). Variants of uncertain significance (VUS) were identified in 77.6% (249/321) of the patients and the number of VUS was increased in patients with Asian and Native American ancestry. Conclusion: The multigene panel contributed to identify GPVs in genes other than BRCA1/2, increasing the positivity of the genetic test from 9.6% (BRCA1/2) to 25.2% and, considering only the most clinically relevant BC predisposing genes, to 16.2%. These results indicate that women with clinical criteria for hereditary BC may benefit from a multigene panel testing, as it allows identifying GPVs in genes that directly impact the clinical management of these patients and family members.

Response to osmotic stress and temperature of the fungus Ustilago maydis.

Ustilago maydis is a fungal pathogen which is exposed during its life cycle to both abiotic and biotic stresses before and after the infection of maize. To cope with extreme environmental changes, microorganisms usually accumulate the disaccharide trehalose. We have investigated both the accumulation of trehalose and the activity of trehalase during the adaptation of U. maydis haploid cells to thermal, sorbitol, and NaCl stresses. Sorbitol and sodium chloride induced sustained accumulation of trehalose, while a transient increase was observed under heat stress. Sorbitol stressed cells showed higher trehalase activity compared with control cells and to those stressed by NaCl and high temperature. Addition of cycloheximide, a protein synthesis inhibitor, did not affect the trehalose accumulation during the first 15 min, but basal levels of trehalose were reached after the second period of 15 min. The proteomic analysis of the response of U. maydis to temperature, sorbitol, and salt stresses indicated a complex pattern which highlights the change of 18 proteins involved in carbohydrate and amino acid metabolism, protein folding, redox regulation, ion homeostasis, and stress response. We hypothesize that trehalose accumulation during sorbitol stress in U. maydis might be related to the adaptation of this organism during plant infection.

Propolis antiviral and immunomodulatory activity: a review and perspectives for COVID-19 treatment.

OBJECTIVES: Viral outbreaks are a frequent concern for humans. A great variety of drugs has been used to treat viral diseases, which are not always safe and effective and may induce adverse effects, indicating the need for new antiviral drugs extracted from natural sources. Propolis is a bee-made product exhibiting many biological properties. An overview of viruses, antiviral immunity, propolis safety and its immunomodulatory and antiviral action is reported, as well as perspectives for coronavirus disease 2019 (COVID-19) treatment. PubMed platform was used for data collection, searching for the keywords "propolis", "virus", "antiviral", "antimicrobial" and "coronavirus". KEY FINDINGS: Propolis is safe and exerts antiviral and immunomodulatory activity; however, clinical trials should investigate its effects on individuals with viral diseases, in combination or not with antiviral drugs or vaccines. SUMMARY: Regarding COVID-19, the effects of propolis should be investigated directly on the virus in vitro or on infected individuals alone or in combination with antiviral drugs, due to its immunomodulatory and anti-inflammatory action. Propolis administration simultaneously with vaccines should be analyzed, due to its adjuvant properties, to enhance the individuals' immune response. The search for therapeutic targets may be useful to find out how propolis can help to control COVID-19.

Sleep deprivation induces oxidative stress in the liver and pancreas in young and aging rats.

The aging process is characterized by a gradual impairment generally caused by oxidative stress and, more specifically, sleep deprivation, which induces oxidative stress in the brain. The objective of this study was to assess the effect of three types of paradoxical sleep deprivation (PSD): 96 h of PSD (96PSD group); 192 h of PSD (192PSD group); 192 h of PSD followed by a recovery period of 20 days (192PSD + Recovery group) on an oral glucose tolerance test (OGTT), lipid peroxidation (LPO), and superoxide dismutase (SOD) and catalase (CAT) activities in the liver and pancreas of young (3-month-old) and adult (14-month-old) rats. The 96PSD and 192PSD groups of young rats showed lower glucose levels on the OGTT than the control group. In the adult rats, only the 96PSD group had lower glucose levels than the control group. However, the areas under the curve for the young and adult 192 and 192PSD + Recovery groups showed significant differences. Both LPO and SOD increased in the 192PSD and 192PSD + Recovery groups, but CAT decreased in the liver of young rats in the 192PSD group. Regarding the pancreas, LPO and SOD levels increased after 96 h of PSD. In adult animals, CAT decreased in the liver after 96 and 192 h of PSD, while LPO and SOD increased in the pancreas of the 192PSD and PSD + Recovery groups. Differences in the SOD and CAT activities in the liver and SOD activities in the pancreas were also observed between the young and adult rats and maintained across all the PSD groups. In conclusion, PSD induced differential responses that appeared to depend on the duration of the induced condition, the animals' age, and the tissue analyzed. It was found that adult rats were more susceptible to the effects of PSD than young rats.