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ABSTRACT Objective: To determine circulating endothelial progenitor cells (EPC) counts and levels of inflammatory markers in individuals with and without type 1 diabetes mellitus (T1DM) in response to an intense aerobic exercise session. Subjects and methods: In total, 15 adult men with T1DM and 15 healthy individuals underwent a 30-minute aerobic exercise session on a cycle ergometer at 60% of the peak heart rate. The EPC count (CD45dim/CD34+/KDR+), tumor necrosis factor-alpha (TNF-α) and interleukin 6 (IL-6) levels were measured before and 60 minutes after the session. Results: We found no difference within or between groups regarding EPC counts before and after the aerobic exercise: healthy individuals, 0.02% change (95% confidence interval [CI] −0.04%-0.08%); individuals with T1DM, 0.00% (95%CI −0.01%-0.01%). We also found no difference in TNF-α levels before and after exercise in healthy individuals (210.2, interquartile range [IQR] 142.1-401.2 pg/mL and 191.3, IQR 136.4-350.5 pg/mL, respectively) and in patients with T1DM (463.8, IQR 201.4-4306.0 pg/mL and 482.7, IQR 143.8-4304.3 pg/mL, respectively). Similarly, no difference in IL-6 levels was observed before and after exercise in healthy individuals (148.2, IQR 147.5-148.6 pg/mL and 148.2, IQR 147.7-148.6 pg/mL, respectively) and individuals with T1DM (147.2, IQR 145.9-147.7 pg/mL and 147.2, IQR 146.8-147.8 pg/mL, respectively). Conclusions: Patients with T1DM and healthy controls had comparable EPC responses to aerobic exercise, most likely due to the absence of a chronic inflammatory state.

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ABSTRACT Objective: This study aims to explore the role of estrogen in providing cardioprotective benefits to premenopausal women, examining how hormonal differences between sexes influence the prevalence of cardiovascular diseases (CVDs) in women. Materials and methods: Eighteen female Wistar rats were equally distributed into three treatment groups. Animals in Group I (sham-operated) and Group II (ovariectomized [OVX]) received oral saline solution at a dose of 2 mL/kg. Group III (OVX+E2) received oral E2 2 µg/mL/kg after ovariectomy. Hemodynamic parameters and baroreflex sensitivity were determined in all groups. Plasma levels of malondialdehyde (MDA), superoxide dismutase (SOD), and nitric oxide (NO) were measured, along with those of the inflammatory markers tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and high mobility group box-1 (HMGB-1). Results: The OVX group, compared with the sham-operated group, displayed significantly altered hemodynamic parameters and baroreflex sensitivity, along with elevated MDA levels and decreased SOD and NO levels. This group also had higher levels of inflammatory cytokines than the sham-operated group. In the absence of estrogen, these factors led to the advancement of cardiovascular abnormalities. In the OVX+E2 group, estrogen treatment considerably improved baroreflex sensitivity and hemodynamic profile while reducing the expression of inflammatory cytokines compared with the OVX group, demonstrating anti-inflammatory actions of estrogen. Conclusion: Estrogen mediates cardioprotection by improving baroreflex sensitivity in ovariectomized Wistar rats through modulation of the NO pathway.

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ABSTRACT Objective: Nitrate is ubiquitously found in the environment and is one of the main components of nitrogen fertilizers. Previous studies have shown that nitrate disrupts the reproductive system in aquatic animals, but no study has evaluated the impact of nitrate exposure on the uterus in mammals. This study aimed to evaluate the impact of maternal exposure to nitrate during the prenatal period on uterine morphology and gene expression in adult female F1 rats. Materials and methods: Pregnant Wistar rats were either treated with sodium nitrate 20 mg/L or 50 mg/L dissolved in drinking water from the first day of pregnancy until the birth of the offspring or were left untreated. On postnatal day 90, the uteri of female offspring rats were collected for histological and gene expression analyses. Morphometric analyses of the uterine photomicrographs were performed to determine the thickness of the layers of the uterine wall (endometrium, myometrium, and perimetrium) and the number of endometrial glands. Results: The highest nitrate dose increased the myometrial thickness of the exposed female rats. Treatment with both nitrate doses reduced the number of endometrial glands compared with no treatment. Additionally, nitrate treatment significantly increased the expression of estrogen receptors and reduced the expression of progesterone receptors in the uterus. Conclusion: Our results strongly suggest that prenatal exposure to nitrate programs gene expression and alters the uterine morphology in female F1 rats, potentially increasing their susceptibility to developing uterine diseases during adulthood.

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ABSTRACT Objective: The aim of this study was to characterize the parameters of reproductive anatomy and pituitary hormone expression levels in ames dwarf mice (Prop1df/df). Materials and methods: Male Prop1df/df mice aged 30 days received daily intraperitoneal injections of recombinant human GH and levothyroxine three times weekly for 60 days. The sexual maturation of these animals was compared with that of their wild-type (Prop+/+) and untreated (Prop1df/df) siblings. Results: The Prop1df/df treated group developed sexual maturation 2 weeks later than the Prop+/+ group and presented an increase in testicular weight, complete spermatogenesis, and enhanced LH and FSH expression. The Prop1df/df untreated group had low FSH expression and no offspring; most animals in this group did not develop sexual maturation during the study period. Conclusion: Replacement with GH and levothyroxine appeared to play a crucial role in restoring peripheral reproductive parameters and increasing pituitary hormone expression in Prop1df/df mice.

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ABSTRACT Objective: To assess the genotypic and allelic distribution of the rs10046 polymorphism in the CYP19A1 gene and evaluate whether this aromatase gene variant is associated with cardiovascular risk in postmenopausal women. Materials and methods: This cross-sectional study analyzed repository-stored samples from 370 postmenopausal women aged 44-72 years. Clinical, metabolic, and hormonal data were collected. The patients’ estimated 10-year atherosclerotic cardiovascular disease (ASCVD) risk was calculated using the ASCVD Risk Estimator Plus, as recommended by the American College of Cardiology/American Heart Association. Genotyping of the rs10046 polymorphism of the CYP19A1 gene was carried out using real-time polymerase chain reaction with allelic discrimination assays. Results: The participants had a mean age of 56.07 ± 5.58 years and a mean body mass index (BMI) of 27.73 ± 5.41 kg/m². The 10-year ASCVD risk was estimated to be low, borderline, intermediate, and high in 64.7%, 12.8%, 19.8%, and 2.7% of the participants, respectively. The CC genotype of the rs10046 polymorphism was associated with low estradiol levels (p = 0.003) and high ASCVD scores (p = 0.014). In a multivariate model, age (p < 0.001) and CC genotype (p = 0.021) were independently associated with higher ASCVD risk. Conclusion: The present study found that the CC genotype of the rs10046 polymorphism in the CYP19A1 gene is associated with low estradiol levels and an increased ASCVD risk. Additionally, the results indicated that, among postmenopausal women, age and the CC genotype of rs10046 were associated with a high prevalence of ASCVD risk, independent of BMI.

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ABSTRACT Objective: Considering that the αvβ3 integrin plays an important role in tumor metastasis, this study investigated the involvement of these pathways in mediating the triiodothyronine (T3) effects on amphiregulin (AREG) expression. Materials and methods: We treated MCF-7 cells with T3 (10 nM) for 1 hour in the presence or absence of inhibitors for αvβ3 integrin (RGD peptide), MAPK (PD98059), PI3K (LY294002), and protein synthesis (cycloheximide [CHX]). A control group (C) received no T3 or inhibitors. Analyses of mRNA and protein expression were done using RT-qPCR and Western blot, respectively. Results: We observed that T3 increased AREG expression, an effect that was suppressed by all inhibitors. This finding indicates that the activation of the αvβ3 integrin signaling pathway, via PI3K, MAPK/ERK, is necessary for the T3-mediated effects on AREG expression and highlights the involvement of nongenomic mechanisms. In addition, CHX completely abolished T3-induced AREG mRNA expression, indicating that this effect requires prior protein synthesis. Conclusion: The identification that T3 acts through this signaling pathway holds considerable potential for clinical application, as it could lead to the development of specific drugs to block it.

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ABSTRACT Objective: This study aimed to investigate the redox balance in subcutaneous and retroperitoneal fat pads of male and female Wistar rats. Materials and methods: The study analyzed the activity and gene expression of the antioxidant enzymes superoxide dismutase, catalase, and glutathione peroxidase, along with the production of NADPH oxidases dependent on H2O2 and gene expression of NOX1, NOX2, and NOX4. Results: The retroperitoneal fat pad in males compared with females had greater NOX2 and NOX4 expression, along with higher superoxide dismutase activity. Additionally, their subcutaneous fat pad had greater NOX4 expression and higher intracellular H2O2 production, together with greater expression and activity of both superoxide dismutase and catalase. Conclusion: The white adipose tissue of male rats had greater reactive oxygen species (ROS) production compared with that of female rats, but also a proportionally greater antioxidant response. These findings are important for ongoing investigations into how sex differences may be linked to the development of metabolic diseases and the unique susceptibilities of each sex.

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ABSTRACT Objective: Diabetic neuropathy (DN) is an important complication of diabetes mellitus. Autophagy is considered to be potentially involved in the regulation of DN. Metformin is broadly utilized in the first-line treatment of diabetes. The present work aimed to assess whether and how metformin exerts protective effects in DN. Materials and methods: A DN rat model induced by streptozotocin (STZ) was established. Metformin was administered to examine its effect on sciatic nerve pathology, and the possible mechanisms involved in this process were explored. Results: Morphological damage was observed in sciatic nerve samples from diabetic animals, accompanied by decreased p-AMPK expression and increased LC-3 levels. Notably, metformin ameliorated the morphological changes in the sciatic nerve by downregulating autophagy via p-AMPK upregulation. Conclusions: These results indicate that metformin attenuates peripheral neuropathy in diabetic rats by regulating autophagy.

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ABSTRACT Modulating the expression of a coding or noncoding gene is a key tool in scientific research. This strategy has evolved methodologically due to advances in cloning approaches, modeling/algorithms in short hairpin RNA (shRNA) design for knockdown efficiency, and biochemical modifications in RNA synthesis, among other developments. Overall, these modifications have improved the ways to either reduce or induce the expression of a given gene with efficiency and facility for implementation in the lab. Allied with that, the existence of various human cell line models for cancer covering different histotypes and biological behaviors, especially for thyroid cancer, has helped improve the understanding of cancer biology. In this review, we cover the most frequently used current techniques for gene modulation in the thyroid cancer field, such as RNA interference (RNAi), short hairpin RNA (shRNA), and gene editing with CRISPR/Cas9 for inhibiting a target gene, and strategies to overexpress a gene, such as plasmid cloning and CRISPRa. Exploring the possibilities for gene modulation allows the improvement of the scientific quality of the studies and the integration of clinicians and basic scientists, leading to better development of translational research.

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ABSTRACT The hypothalamus is a master regulator of energy balance in the body. First-order hypothalamic neurons localized in the arcuate nucleus sense systemic signals that indicate the energy stores in the body. Through distinct projections, arcuate nucleus neurons communicate with second-order neurons, which are mostly localized in the paraventricular nucleus and in the lateral hypothalamus. The signals then proceed to third- and fourth-order neurons that activate complex responses aimed at maintaining whole-body energy homeostasis. During the last 30 years, since the identification of leptin in 1994, there has been a great advance in the unveiling of the hypothalamic and extra-hypothalamic neuronal networks that control energy balance. This has contributed to the characterization of the mechanisms by which glucagon-like peptide-1 receptor agonists promote body mass reduction and has opened new windows of opportunity for the development of drugs to treat obesity. This review presents an overview of the mechanisms involved in the hypothalamic regulation of energy balance and discusses how advancements in this field are contributing to the development of new pharmacological strategies to treat obesity.

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ABSTRACT Pyriproxyfen (PPF) acts as a juvenile growth regulator, interfering with normal metamorphosis and blocking the development of insects into adulthood. Although the World Health Organization (WHO) considers the use of PPF at a concentration of 0.01 mg/L as unlikely to pose health risks, recent studies have unveiled potential risks associated with PPF exposure to non-target organisms. Exposure to PPF disrupts insect development primarily by mimicking juvenile hormones; therefore, concerns linger over its impact on unintended species. Studies have highlighted the adverse effects of PPF on aquatic invertebrates, fish, and amphibians and revealed mortality and developmental abnormalities in non-target mosquito species exposed to PPF-treated water. Moreover, PPF may act as an endocrine disruptor, interfering with hormonal pathways crucial for growth, reproduction, and behavior in exposed organisms. Amphibians, for instance, display altered reproductive physiology and developmental abnormalities due to disruptions in endocrine signaling pathways caused by PPF. The ecological ramifications of PPF extend beyond direct toxicity to non-target species. Indirect effects include shifts in food web dynamics and ecosystem functioning. Reductions in insect populations, induced by PPF, can disrupt food availability for higher trophic levels, potentially destabilizing community structure and ecosystem equilibrium. Given mounting evidence of unintended consequences, robust risk assessment and regulatory oversight are imperative. Accurate classification of PPF by regulatory bodies is essential to balancing its role in disease control and pest management benefits with the need to safeguard non-target species and maintain ecosystem health. Future research must prioritize comprehensive assessments of PPF's ecological impact across various habitats and taxa to inform evidence-based policymaking.

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ABSTRACT Tributyltin (TBT) is an organotin compound and a common persistent environmental pollutant with endocrine-disrupting chemical (EDC) actions. It can accumulate in the environment at various concentrations throughout the food chain in the ecosystem, posing a risk to human health, especially during critical periods such as gestation and fetal and offspring development. In this review, we report the results of studies describing the consequences of TBT exposure on placental and reproductive parameters in offspring of both sexes. Results from in vivo and in vitro studies clearly indicate that TBT causes adverse effects on placental development and reproductive parameters in offspring. However, substantial knowledge gaps remain in the literature, requiring further research to better understand the mechanisms behind TBT effects on placental and reproductive disruption in offspring.

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ABSTRACT Gender identity refers to one's psychological sense of their own gender. Establishing gender identity is a complex phenomenon, and the diversity of gender expression challenges simplistic or unified explanations. For this reason, the extent to which it is determined by nature (biological) or nurture (social) is still debatable. The biological basis of gender identity cannot be modeled in animals and is best studied in people who identify with a gender that is different from the sex of their genitals such as transgender people and people with disorders/differences of sex development. Numerous research studies have delved into unraveling the intricate interplay of hormonal, neuroanatomic/neurofunctional, and genetic factors in the complex development of core gender identity. In this review, we explore and consolidate existing research that provides insights into the biological foundations of gender identity, enhancing our understanding of this intriguing human psychological trait.

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SUMMARY The aim of this study is to describe the management and evolution of a patient with the rare condition of double lactotroph tumors and assess the role of intraoperative ultrasonography (IOUS) for their detection and methylation-based liquid biopsy for their diagnosis and monitoring. A 29-year-old woman diagnosed with double lactotroph tumors through hormonal and MRI workup underwent surgical resection due to cabergoline intolerance. To detect a tumor missing through visual inspection, IOUS was performed. Pituitary tumor (PT) and nontumor (NT) tissues and blood were collected for pathological and molecular assessments (genome-wide methylation level profiled using the EPIC array, at surgery and follow-up). Reference methylome data were obtained from publicly available repositories. Both tumors (T1 and T2) were detected via IOUS and confirmed as lactotroph tumors through immunohistochemistry. In tissue specimens, PT-specific markers distinguished T1 from NT tissue, while T2, primarily nontumor cells, clustered with NT specimens. In liquid biopsies, these markers differentiated between T and NT cohorts. During the 12-month follow-up, methylation profiling and prolactin blood assessments showed that methylation markers clustered with NT specimens, which coincided with prolactinemia normalization, indicating successful tumor control after surgery. This case illustrates the translational use of methylation-based liquid biopsy methodologies in detecting and monitoring PTs through the detection of tumor-specific markers in blood specimens. This approach can be useful to distinguish sellar masses mimicking PTs based on nonspecific imaging features and to monitor for early recurrence of PTs, particularly nonfunctioning PTs lacking specific biochemical markers. This case also illustrated the role of IOUS in identifying multiple PTs missed by visual inspection alone, leading to improved patient outcomes through complete tumor resection.