β3‐Adrenoceptor, a novel player in the round‐trip from neonatal diseases to cancer: Suggestive clues from embryo

Filippi, Luca; Pini, Alessandro; Cammalleri, Maurizio; Bagnoli, Paola; Monte, Massimo Dal

doi:10.1002/med.21874

Cited by 11 publications

(6 citation statements)

References 185 publications

(382 reference statements)

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“…In the meantime, recent studies have demonstrated that β3-AR is rapidly down-regulated upon exposure to a more oxygenated environment (73) confirming the strict dependence of β3-AR expression on oxygen levels. The relevant functional role of β3-AR during fetal life together with its close correlation with oxygen levels explains why it is important to know how oxygen levels change during physiological pregnancies, and at the same time suggests the possibility that its precocious down-regulation after premature birth might affect the newborn health (74).…”

Section: Discussionmentioning

confidence: 99%

“…More detailed knowledge of the fluctuations in oxygen levels starting from conception and throughout pregnancy, their biological effects during intrauterine life, and the mechanisms through which oxygen regulates cell differentiation might help to identify specific time windows on which to intervene to reproduce the effects of oxygen oscillations when, for example, the pregnancy results in a premature birth. Such a perspective would restore the benefits of intrauterine life from which premature infants have been deprived (74).…”

Section: Discussionmentioning

confidence: 99%

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Fetal oxygenation in the last weeks of pregnancy evaluated through the umbilical cord blood gas analysis

et al. 2023

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IntroductionEmbryo and fetus grow and mature over the first trimester of pregnancy in a dynamic hypoxic environment, where placenta development assures an increased oxygen availability. However, it is unclear whether and how oxygenation changes in the later trimesters and, more specifically, in the last weeks of pregnancy.MethodsObservational study that evaluated the gas analysis of the umbilical cord blood collected from a cohort of healthy newborns with gestational age ≥37 weeks. Umbilical venous and arterial oxygen levels as well as fetal oxygen extraction were calculated to establish whether oxygenation level changes over the last weeks of pregnancy. In addition, fetal lactate, and carbon dioxide production were analyzed to establish whether oxygen oscillations may induce metabolic effects in utero.ResultsThis study demonstrates a progressive increase in fetal oxygenation levels from the 37th to the 41st weeks of gestation (mean venous PaO2 approximately from 20 to 25 mmHg; p < 0.001). This increase is largely attributable to growing umbilical venous PaO2, regardless of delivery modalities. In neonates born by vaginal delivery, the increased oxygen availability is associated with a modest increase in oxygen extraction, while in neonates born by cesarean section, it is associated with reduced lactate production. Independently from the type of delivery, carbon dioxide production moderately increased. These findings suggest a progressive shift from a prevalent anaerobic metabolism (Warburg effect) towards a growing aerobic metabolism.ConclusionThis study confirms that fetuses grow in a hypoxic environment that becomes progressively less hypoxic in the last weeks of gestation. The increased oxygen availability seems to favor aerobic metabolic shift during the last weeks of intrauterine life; we hypothesize that this environmental change may have implications for fetal maturation during intrauterine life.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Fetal oxygenation in the last weeks of pregnancy evaluated through the umbilical cord blood gas analysis

et al. 2023

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“…In this regard, studies aimed at the development of artificial placenta technology [75] cannot ignore the physiological levels of oxygenation, which must be respected. But even attempts to mimic the biological effects of intrauterine hypoxemia through the stimulation of β3-adrenoceptor agonists [76] will have to take into consideration that fetal hypoxemia increases only up to the 33-34th week.…”

Section: Discussionmentioning

confidence: 99%

Fetal Oxygenation from the 23rd to the 36th Week of Gestation Evaluated through the Umbilical Cord Blood Gas Analysis

Filippi

Pascarella

Pini

et al. 2023

IJMS

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The embryo and fetus grow in a hypoxic environment. Intrauterine oxygen levels fluctuate throughout the pregnancy, allowing the oxygen to modulate apparently contradictory functions, such as the expansion of stemness but also differentiation. We have recently demonstrated that in the last weeks of pregnancy, oxygenation progressively increases, but the trend of oxygen levels during the previous weeks remains to be clarified. In the present retrospective study, umbilical venous and arterial oxygen levels, fetal oxygen extraction, oxygen content, CO2, and lactate were evaluated in a cohort of healthy newborns with gestational age < 37 weeks. A progressive decrease in pO2 levels associated with a concomitant increase in pCO2 and reduction in pH has been observed starting from the 23rd week until approximately the 33–34th week of gestation. Over this period, despite the increased hypoxemia, oxygen content remains stable thanks to increasing hemoglobin concentration, which allows the fetus to become more hypoxemic but not more hypoxic. Starting from the 33–34th week, fetal oxygenation increases and ideally continues following the trend recently described in term fetuses. The present study confirms that oxygenation during intrauterine life continues to vary even after placenta development, showing a clear biphasic trend. Fetuses, in fact, from mid-gestation to near-term, become progressively more hypoxemic. However, starting from the 33–34th week, oxygenation progressively increases until birth. In this regard, our data suggest that the placenta is the hub that ensures this variable oxygen availability to the fetus, and we speculate that this biphasic trend is functional for the promotion, in specific tissues and at specific times, of stemness and intrauterine differentiation.

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“…The contribution of β3-ARs in promoting embryo properties and functional roles in germ cells, in preimplantation embryos and in the first week of embryogenesis, suggested that the original function of β3-ARs could have been involved in the promotion of proliferation, vascularization, metabolic adaptation and immune tolerance [155]. Since β3-AR was expressed under hypoxia, it has been assumed a relationship between the hypoxic upregulation of β3-ARs, which promoted immune tolerance [156], and the initial mechanisms that were predicted to guarantee fetal tolerance.…”

Section: β3-ar In the Myometrium And Pregnancymentioning

confidence: 99%

Inside the Biology of the β3-Adrenoceptor

Pasha,

Tondo,

Favre

et al. 2024

Biomolecules

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Since the first discovery in 1989, the β3-adrenoceptor (β3-AR) has gained great attention because it showed the ability to regulate many physiologic and metabolic activities, such as thermogenesis and lipolysis in brown and white adipose tissue, respectively (BAT, WAT), negative inotropic effects in cardiomyocytes, and relaxation of the blood vessels and the urinary bladder. The β3-AR has been suggested as a potential target for cancer treatment, both in adult and pediatric tumors, since under hypoxia its upregulation in the tumor microenvironment (TME) regulates stromal cell differentiation, tumor growth and metastases, signifying that its agonism/antagonism could be useful for clinical benefits. Promising results in cancer research have proposed the β3-AR being targeted for the treatment of many conditions, with some drugs, at present, undergoing phase II and III clinical trials. In this review, we report the scientific journey followed by the research from the β3-Ars’ discovery, with focus on the β3-Ars’ role in cancer initiation and progression that elects it an intriguing target for novel antineoplastic approaches. The overview highlights the great potential of the β3-AR, both in physiologic and pathologic conditions, with the intention to display the possible benefits of β3-AR modulation in cancer reality.

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β3‐Adrenoceptor, a novel player in the round‐trip from neonatal diseases to cancer: Suggestive clues from embryo

Cited by 11 publications

References 185 publications

Fetal oxygenation in the last weeks of pregnancy evaluated through the umbilical cord blood gas analysis

Fetal oxygenation in the last weeks of pregnancy evaluated through the umbilical cord blood gas analysis

Fetal Oxygenation from the 23rd to the 36th Week of Gestation Evaluated through the Umbilical Cord Blood Gas Analysis

Inside the Biology of the β3-Adrenoceptor

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