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Frontiers in Endocrinology 2023In zebrafish, estrogens produced in the ovaries via Cyp19a1a activity are required for both sexual differentiation of the ovary during early development as well as...
In zebrafish, estrogens produced in the ovaries via Cyp19a1a activity are required for both sexual differentiation of the ovary during early development as well as maintenance of the ovarian state during adulthood. The importance of Cyp19a1b that is highly expressed in the brain for female reproduction is still under study. We previously reported that female mutant zebrafish have significantly lower brain estradiol levels and impaired spawning behavior characterized by an increased latency to oviposition during dyadic sexual behavior encounters. In the current study, we provide evidence that the delayed oviposition in female mutants is linked to impaired arginine vasopressin (Avp) signaling. Droplet digital PCR experiments revealed that levels of the estrogen receptors, , and () are lower in the hypothalamus of mutant females compared to wildtype fish. We then used acute intraperitoneal injections of Avp and Oxt, along with mixtures of their respective receptor antagonists, to determine that Avp can uniquely rescue the delayed oviposition in female mutants. Using immunohistochemistry, we demonstrated that Cyp19a1b-expressing radial glial cell (RGC) fibers surround and are in contact with Avp-immunopositive neurons in the preoptic areas of the brain. This could provide the neuroanatomical proximity for RGC-derived estrogens to diffuse to and activate estrogen receptors and regulate expression levels. Together these findings identify a positive link between Cyp19a1b and Avp for female zebrafish sexual behavior. They also suggest that the female mutant behavioral phenotype is likely a consequence of impaired processing of Avp-dependent social cues important for mate identification and assessment.
Topics: Animals; Female; Arginine Vasopressin; Estrogens; Oviposition; Oxytocin; Receptors, Estrogen; Zebrafish
PubMed: 38144569
DOI: 10.3389/fendo.2023.1308675 -
Comprehensive Psychoneuroendocrinology Nov 2023The neuropeptide hormone oxytocin is involved in many processes in our bodies, linking our social lives to our internal states. I started out my career studying primate... (Review)
Review
The neuropeptide hormone oxytocin is involved in many processes in our bodies, linking our social lives to our internal states. I started out my career studying primate families, an interest that expanded into the role of oxytocin in family-oriented behaviors such as pair bonding and parenting in prairie voles, humans, and other primates. Starting as a post-doc with Dr. C. Sue Carter, I also became interested in the role of oxytocin during development and the way that we manipulate oxytocin clinically. During that post-doc and then as a faculty member at the University of California, Davis, I have worked on a number of these questions.
PubMed: 38108037
DOI: 10.1016/j.cpnec.2023.100203 -
Comprehensive Psychoneuroendocrinology Nov 2023In this article, I am going through my scientific and personal journey using my work on oxytocin as a compass. I recount how my scientific questions were shaped over the... (Review)
Review
In this article, I am going through my scientific and personal journey using my work on oxytocin as a compass. I recount how my scientific questions were shaped over the years, and how I studied them through the lens of different fields ranging from linguistics and neuroscience to comparative and population genomics in a wide range of vertebrate species. I explain how my evolutionary findings and proposal for a universal gene nomenclature in the oxytocin-vasotocin ligand and receptor families have impacted relevant fields, and how my studies in the oxytocin and vasotocin system in songbirds, humans and non-human primates have led me to now be testing intranasal oxytocin as a candidate treatment for speech deficits. I also discuss my projects on the neurobiology of dance and where oxytocin fits in the picture of studying speech and dance in parallel. Lastly, I briefly communicate the challenges I have been facing as a woman and an international scholar in science and academia, and my personal ways to overcome them.
PubMed: 38108035
DOI: 10.1016/j.cpnec.2023.100193 -
World Journal of Oncology Dec 2023Colorectal cancer (CRC) is a leading cause of cancer-associated mortality worldwide. Despite being an essential component of systemic chemotherapy for advanced CRC,...
BACKGROUND
Colorectal cancer (CRC) is a leading cause of cancer-associated mortality worldwide. Despite being an essential component of systemic chemotherapy for advanced CRC, 5-fluorouracil (5-FU) clinical use has severe limitations, such as high toxicity, low selectivity and drug resistance. [VQ]dDAVP (1-deamino-4-valine-5-glutamine-8-D-arginine vasopressin) is a peptide vasopressin analog and a selective agonist of the arginine vasopressin type 2 membrane receptor (AVPR2), expressed in microvascular and tumor tissue. This synthetic compound has well-proven antitumor and antimetastatic activity in different tumor types, including metastatic CRC. The objective of this work was to assess the potential combinational benefits in preclinical CRC models after [VQ]dDAVP addition to 5-FU.
METHODS
Effects on cellular viability, cell cycle progression, apoptosis and molecular mechanisms associated to [VQ]dDAVP treatment in combination with 5-FU were evaluated in murine CT-26 and human COLO-205 cell lines. , impact of dual therapy was explored on CRC tumor growth and metastatic spread.
RESULTS
In CRC cells, [VQ]dDAVP (1 µM) addition to sub-IC 5-FU concentrations resulted in the enhancement of cytostatic effects induced by chemotherapy. Reduction of cell viability after combined treatment was associated with cell cycle arrest in the G/G phase, induction of apoptosis and increased gene expression of the cyclin-dependent kinase inhibitor p21 (CDKN1A) and the tumor suppressor p53 (TP53) in malignant cells, as assessed by flow cytometry, terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate (dUTP) nick end labeling (TUNEL), and quantitative reverse transcription polymerase chain reaction (qRT-PCR), respectively. , intravenous administration of [VQ]dDAVP (0.3 µg/kg) in combination with safe low doses of 5-FU (50 or 80 mg/kg for CT-26 or COLO-205 tumor models, respectively) effectively abrogated CRC growth, reducing aggressiveness of primary lesions and increasing survival of tumor-bearing mice. In addition, concomitant administration of [VQ]dDAVP and 5-FU inhibited pulmonary metastasis formation by CT-26 cells in immunocompetent mice, especially reducing macrometastatic disease.
CONCLUSIONS
[VQ]dDAVP seems to enhance the efficacy of 5-FU-based chemotherapy in CRC by modulating tumor progression, as well as metastatic dissemination, suggesting its potential role as a safe and cost-effective co-adjuvant agent for the management of advanced CRC.
PubMed: 38022396
DOI: 10.14740/wjon1715 -
Medicine Nov 2023Angiotensin II receptor blockers (ARBs) are currently considered first-line antihypertensive drugs, effectively inhibiting the renin-angiotensin-aldosterone system....
RATIONALE
Angiotensin II receptor blockers (ARBs) are currently considered first-line antihypertensive drugs, effectively inhibiting the renin-angiotensin-aldosterone system. However, ARBs have been associated with intraoperative hypotension during general anesthesia. Although it is recommended to discontinue ARBs for 24 hours before surgery, the optimal duration of discontinuation remains unclear. We present a severe refractory hypotension encountered during general anesthesia despite discontinuing ARBs for 48 hours before anesthesia.
PATIENT CONCERNS
A severe refractory hypotension occurred during the induction of general anesthesia for cranioplasty in a 66-year-old male patient (170 cm/75 kg). The patient was taking azilsartan, angiotensin receptor blocker, for hypertension, which was discontinued 48 hours before anesthesia induction. Despite repeated administration of ephedrine and continuous infusion of norepinephrine, hemodynamic instability did not improve. Therefore, the surgery was postponed.
DIAGNOSIS
The patient was diagnosed with angiotensin receptor blocker-induced refractory hypotension.
INTERVENTIONS
Before the second surgery, the angiotensin receptor blocker was discontinued 96 hours prior to the surgery. Invasive blood pressure monitoring was performed before anesthesia induction, and vasopressin was prepared. General anesthesia was induced using remimazolam and maintained with desflurane.
OUTCOMES
The surgery was completed successfully without occurrence of refractory hypotension.
LESSONS
Refractory hypotension induced by Angiotensin receptor blockers can still occur even after discontinuing the medication for 48 hours before induction of general anesthesia. Despite withholding the medication, caution should be practiced regarding hypotension during general anesthesia in patient taking ARBs.
Topics: Male; Humans; Aged; Angiotensin-Converting Enzyme Inhibitors; Angiotensin Receptor Antagonists; Hypotension; Anesthesia, General
PubMed: 38013296
DOI: 10.1097/MD.0000000000036126 -
Genes Nov 2023The neurobiological systems of maintenance and control of behavioral responses result from natural selection. We have analyzed the selection signatures for single...
The neurobiological systems of maintenance and control of behavioral responses result from natural selection. We have analyzed the selection signatures for single nucleotide variants (SNV) of the genes of oxytocin (, ) and vasopressin (, , ) systems, which are associated with the regulation of social and emotional behavior in distinct populations. The analysis was performed using original WGS (whole genome sequencing) data on Eastern Slavs (SlEast), as well as publicly available data from the 1000 Genomes Project on GBR, FIN, IBR, PUR, BEB, CHB, and ACB populations (the latter were taken as reference). To identify selection signatures, we rated the integrated haplotype scores (iHS), the numbers of segregating sites by length (nSl), and the integrated haplotype homozygosity pooled (iHH12) measures; the fixation index Fst was implemented to assess genetic differentiation between populations. We revealed that the strongest genetic differentiation of populations was found with respect to the gene, with the greatest differentiation observed in GRB (Fst = 0.316) and CHB (Fst = 0.325) in comparison to ACB. Also, high Fst values were found for SNVs of the gene rs28499431, rs33940624, rs28477649, rs3883899, and rs28452187 in most of the populations. Selection signatures have also been identified in the , , , and genes. Our analysis shows that the , , , , and genes were subject to positive selection in a population-specific process, which was likely contributing to the diversity of adaptive emotional response types and social function realizations.
Topics: Humans; Oxytocin; Vasopressins; Genomics; Receptors, Oxytocin; Receptors, Vasopressin
PubMed: 38002996
DOI: 10.3390/genes14112053 -
A vasopressin circuit that modulates sex-specific social interest and anxiety-like behavior in mice.BioRxiv : the Preprint Server For... Nov 2023One of the largest sex differences in brain neurochemistry is the male-biased expression of the neuropeptide arginine vasopressin (AVP) within the vertebrate social...
One of the largest sex differences in brain neurochemistry is the male-biased expression of the neuropeptide arginine vasopressin (AVP) within the vertebrate social brain. Despite the long-standing implication of AVP in social and anxiety-like behavior, the precise circuitry and anatomical substrate underlying its control are still poorly understood. By employing optogenetic manipulation of AVP cells within the bed nucleus of the stria terminalis (BNST), we have unveiled a central role for these cells in promoting social investigation, with a more pronounced role in males relative to females. These cells facilitate male social investigation and anxiety-like behavior through their projections to the lateral septum (LS), an area with the highest density of sexually-dimorphic AVP fibers. Blocking the vasopressin 1a receptor (V1aR) in the LS eliminated stimulation-mediated increases in these behaviors. Together, these findings establish a distinct BNST AVP → LS V1aR circuit that modulates sex-specific social interest and anxiety-like behavior.
PubMed: 37986987
DOI: 10.1101/2023.11.06.564847 -
Kidney360 Dec 2023In a analysis, short-term reduction in spot urine osmolality (Uosm) was associated with decreased kidney volume growth in autosomal dominant polycystic kidney disease...
KEY POINTS
In a analysis, short-term reduction in spot urine osmolality (Uosm) was associated with decreased kidney volume growth in autosomal dominant polycystic kidney disease for both tolvaptan and instruction to increase hydration alone. For the same spot Uosm reduction, however, the kidney volume benefit was greater with tolvaptan, possibly because of greater cumulative 24-hour Uosm suppression by tolvaptan.
BACKGROUND
In addition to decreasing water excretion and increasing urinary concentration, the antidiuretic hormone vasopressin plays a role in the pathophysiology of autosomal dominant polycystic kidney disease. It has been hypothesized that by suppressing vasopressin release, drinking large amounts of water might exert therapeutic effects in autosomal dominant polycystic kidney disease similar to those of tolvaptan, an antagonist of the vasopressin type 2 receptor, but evidence is lacking. We analyzed data from tolvaptan clinical trials to evaluate relationships among water intake, urine osmolality (Uosm), and change in total kidney volume (TKV).
METHODS
Analysis of the Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and Its Outcomes 3:4 clinical trial in which participants were randomized to tolvaptan or placebo and instructed to drink large amounts of water. The relationship between change in spot Uosm from baseline to week 3 and change in TKV to month 12 was assessed using linear regression modeling. Two short-term tolvaptan trials were analyzed to explore relationships between intermittent Uosm sampling and 24-hour Uosm suppression.
RESULTS
With both tolvaptan and placebo (, mandated high water intake alone), Uosm reduction at week 3 was associated with reduction in TKV growth at month 12. However, for the same decrease in spot Uosm, the corresponding reduction in TKV growth was greater for tolvaptan (, a −250 mOsm/kg reduction in Uosm at week 3 was associated with a −1% change in TKV at month 12 for tolvaptan versus +4.5% for placebo). In short-term trials, similar reductions in spot or trough Uosm values were achievable with tolvaptan and high water intake, but cumulative 24-hour suppression was greater with tolvaptan.
CONCLUSIONS
This analysis supports a relationship between effects on Uosm and inhibition of disease progression by tolvaptan and high water intake alone. The findings further suggest that 24-hour Uosm measurement is superior to spot Uosm for assessing suppression of vasopressin activity by tolvaptan.
Topics: Humans; Tolvaptan; Polycystic Kidney, Autosomal Dominant; Drinking; Antidiuretic Hormone Receptor Antagonists; Benzazepines
PubMed: 37986188
DOI: 10.34067/KID.0000000000000302 -
BioRxiv : the Preprint Server For... Nov 2023Internal states drive survival behaviors, but their neural implementation is not well understood. Recently we identified a line attractor in the ventromedial...
Internal states drive survival behaviors, but their neural implementation is not well understood. Recently we identified a line attractor in the ventromedial hypothalamus (VMH) that represents an internal state of aggressiveness. Line attractors can be implemented by recurrent connectivity and/or neuromodulatory signaling, but evidence for the latter is scant. Here we show that neuropeptidergic signaling is necessary for line attractor dynamics in this system, using a novel approach that integrates cell type-specific, anatomically restricted CRISPR/Cas9-based gene editing with microendoscopic calcium imaging. Co-disruption of receptors for oxytocin and vasopressin in adult VMH Esr1 neurons that control aggression suppressed attack, reduced persistent neural activity and eliminated line attractor dynamics, while only modestly impacting neural activity and sex- or behavior-tuning. These data identify a requisite role for neuropeptidergic signaling in implementing a behaviorally relevant line attractor. Our approach should facilitate mechanistic studies in neuroscience that bridge different levels of biological function and abstraction.
PubMed: 37961374
DOI: 10.1101/2023.11.01.565073 -
Cardiovascular Research Dec 2023Cardiovascular disease is the leading cause of death worldwide. Its prevalence is rising due to ageing populations and the increasing incidence of diseases such as... (Review)
Review
Cardiovascular disease is the leading cause of death worldwide. Its prevalence is rising due to ageing populations and the increasing incidence of diseases such as chronic kidney disease, obesity, and diabetes that are associated with elevated cardiovascular risk. Despite currently available treatments, there remains a huge burden of cardiovascular disease-associated morbidity for patients and healthcare systems, and newer treatments are needed. The apelin system, comprising the apelin receptor and its two endogenous ligands apelin and elabela, is a broad regulator of physiology that opposes the actions of the renin-angiotensin and vasopressin systems. Activation of the apelin receptor promotes endothelium-dependent vasodilatation and inotropy, lowers blood pressure, and promotes angiogenesis. The apelin system appears to protect against arrhythmias, inhibits thrombosis, and has broad anti-inflammatory and anti-fibrotic actions. It also promotes aqueous diuresis through direct and indirect (central) effects in the kidney. Thus, the apelin system offers therapeutic promise for a range of cardiovascular, kidney, and metabolic diseases. This review will discuss current cardiovascular disease targets of the apelin system and future clinical utility of apelin receptor agonism.
Topics: Humans; Apelin; Apelin Receptors; Cardiovascular Diseases; Cardiovascular System; Heart
PubMed: 37956047
DOI: 10.1093/cvr/cvad171