Highlights d Mitochondrial ATP is necessary to sustain Wnt signaling d Respiratory chain complex inhibition leads to reduced calcium uptake into the ER d A defect in complex III assembly causes impairments in Wnt signaling

Glucocorticoids (GCs) play important roles in developmental and physiological processes through the transcriptional activity of their cognate receptor (Gr). Using CRISPR/Cas9 technology, we established a zebrafish null Gr mutant line and compared its phenotypes with wild type and a zebrafish line with partially silenced gr (grs357/s357). Homozygous gr−/− larvae are morphologically inconspicuous and, in contrast to GR−/− knockout mice, viable through adulthood, although with reduced fitness and early life survival. Mutants gr−/− are fertile, but their reproductive capabilities fall at around 10 months of age, when, together with cardiac and intestinal abnormalities already visible at earlier stages, increased fat deposits are also observed. Mutants show higher levels of whole-body cortisol associated with overstimulated basal levels of crh and pomca transcripts along the HPI axis, which is unresponsive to a mechanical stressor. Transcriptional activity linked to immune response is also hampered in the gr−/− line: after intestinal damage by dextran sodium sulphate exposure, there are neither inflammatory nor anti-inflammatory cytokine gene responses, substantiating the hypothesis of a dual-action of the GC-GR complex on the immune system. Hence, the zebrafish gr mutant line appears as a useful tool to investigate Gr functions in an integrated in vivo model.

Mitochondria are key intracellular organelles involved not only in the metabolic state of the cell, but also in several cellular functions, such as proliferation, Calcium signaling, and lipid trafficking. Indeed, these organelles are characterized by continuous events of fission and fusion which contribute to the dynamic plasticity of their network, also strongly influenced by mitochondrial contacts with other subcellular organelles. Nevertheless, mitochondria release a major amount of reactive oxygen species (ROS) inside eukaryotic cells, which are reported to mediate a plethora of both physiological and pathological cellular functions, such as growth and proliferation, regulation of autophagy, apoptosis, and metastasis. Therefore, targeting mitochondrial ROS could be a promising strategy to overcome and hinder the development of diseases such as cancer, where malignant cells, possessing a higher amount of ROS with respect to healthy ones, could be specifically targeted by therapeutic treatments. In this review, we collected the ultimate findings on the blended interplay among mitochondrial shaping, mitochondrial ROS, and several signaling pathways, in order to contribute to the dissection of intracellular molecular mechanisms involved in the pathophysiology of eukaryotic cells, possibly improving future therapeutic approaches.

Loss of lysosomal glucocerebrosidase (GBA1) function is responsible for several organ defects, including skeletal abnormalities in type 1 Gaucher disease (GD). Enhanced bone resorption by infiltrating macrophages has been proposed to lead to major bone defects. However, while more recent evidences support the hypothesis that osteoblastic bone formation is impaired, a clear pathogenetic mechanism has not been depicted yet. Here, by combining different molecular approaches, we show that Gba1 loss of function in zebrafish is associated with defective canonical Wnt signaling, impaired osteoblast differentiation and reduced bone mineralization. We also provide evidence that increased reactive oxygen species production precedes the Wnt signaling impairment, which can be reversed upon human GBA1 overexpression. Type 1 GD patient fibroblasts similarly exhibit reduced Wnt signaling activity, as a consequence of increased β-catenin degradation. Our results support a novel model in which a primary defect in canonical Wnt signaling antecedes bone defects in type 1 GD.

BackgroundOverweight and obesity are associated with pregnancy complications and adverse perinatal outcomes, posing short and long-term risks for maternal and child health. This study evaluated maternal, delivery and neonatal outcomes in pregnancies complicated by overweight and obesity.MethodsThis prospective cross-sectional study included 258 pregnant women. According to prepregnancy body mass index (BMI), participants were classified as normal weight, overweight, or obese. Data were analyzed using the chi-square test and analysis of variance followed by the Tukey test. Logistic regression was performed to calculate odds ratios and 95 % confidence intervals (p < 0.05).ResultsMost women ≥ 35 years old were overweight (22.7 %) and obese (27.6 %). Prepregnancy diabetes was significantly associated with obesity (15.7 %, p < 0.000). Obese women showed the lowest weight gain (9.6 ± 7.5Kg). Overweight and obese women practiced physical exercise more frequently (p = 0.010) than normal weight women. A greater proportion of obese mothers (13.4 %) had large for gestational age babies (p = 0.021), with higher thoracic circumference (33.6 ± 2.0 cm) and abdominal circumference (31.6 ± 2.3 cm). Obesity increased the risk of developing hypertension (OR = 7.0; 3.1-15.9), hyperglycemic disturbances (OR = 5.5; 2.9-10.6) and HbA1c ≥ 6.5 % (OR = 3.7; 1.2-11.1). The infants born to obese mothers had longer hospital stay (3.9 ± 3.9 days) (p = 0.005).ConclusionOur results confirm that obesity in pregnancy can lead to adverse outcomes, and underscore the importance of identifying and treating inadequate weight status during pregnancy.