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Cardiovascular Research Oct 2023Pulmonary arterial hypertension (PAH) is a rare cardiovascular disorder leading to pulmonary hypertension and, often fatal, right heart failure. Sex differences in PAH... (Review)
Review
Pulmonary arterial hypertension (PAH) is a rare cardiovascular disorder leading to pulmonary hypertension and, often fatal, right heart failure. Sex differences in PAH are evident, which primarily presents with a female predominance and increased male severity. Disturbed signalling of the transforming growth factor-β (TGFβ) family and gene mutations in the bone morphogenetic protein receptor 2 (BMPR2) are risk factors for PAH development, but how sex-specific cues affect the TGFβ family signalling in PAH remains poorly understood. In this review, we aim to explore the sex bias in PAH by examining sex differences in the TGFβ signalling family through mechanistical and translational evidence. Sex hormones including oestrogens, progestogens, and androgens, can determine the expression of receptors (including BMPR2), ligands, and soluble antagonists within the TGFβ family in a tissue-specific manner. Furthermore, sex-related genetic processes, i.e. Y-chromosome expression and X-chromosome inactivation, can influence the TGFβ signalling family at multiple levels. Given the clinical and mechanistical similarities, we expect that the conclusions arising from this review may apply also to hereditary haemorrhagic telangiectasia (HHT), a rare vascular disorder affecting the TGFβ signalling family pathway. In summary, we anticipate that investigating the TGFβ signalling family in a sex-specific manner will contribute to further understand the underlying processes leading to PAH and likely HHT.
Topics: Female; Male; Humans; Pulmonary Arterial Hypertension; Transforming Growth Factor beta; Familial Primary Pulmonary Hypertension; Hypertension, Pulmonary; Signal Transduction; Bone Morphogenetic Protein Receptors, Type II
PubMed: 37595264
DOI: 10.1093/cvr/cvad129 -
Frontiers in Endocrinology 2023Polycystic ovarian syndrome (PCOS) is a metabolic, reproductive, and psychological disorder affecting 6-20% of reproductive women worldwide. However, there is still no... (Review)
Review
Polycystic ovarian syndrome (PCOS) is a metabolic, reproductive, and psychological disorder affecting 6-20% of reproductive women worldwide. However, there is still no cure for PCOS, and current treatments primarily alleviate its symptoms due to a poor understanding of its etiology. Compelling evidence suggests that hyperandrogenism is not just a primary feature of PCOS. Instead, it may be a causative factor for this condition. Thus, figuring out the mechanisms of androgen synthesis, conversion, and metabolism is relatively important. Traditionally, studies of androgen excess have largely focused on classical androgen, but in recent years, adrenal-derived 11-oxygenated androgen has also garnered interest. Herein, this Review aims to investigate the origins of androgen excess, androgen synthesis, how androgen receptor (AR) signaling mediates adverse PCOS traits, and the role of 11-oxygenated androgen in the pathophysiology of PCOS. In addition, it provides therapeutic strategies targeting hyperandrogenism in PCOS.
Topics: Female; Humans; Polycystic Ovary Syndrome; Hyperandrogenism; Androgens; Phenotype
PubMed: 38152131
DOI: 10.3389/fendo.2023.1273542 -
Redox Biology Sep 2023Mitoquinone (MitoQ), a mitochondria-targeted antioxidant, has been used to treat several diseases. The present study aimed to investigate the therapeutic effects of...
Mitoquinone (MitoQ), a mitochondria-targeted antioxidant, has been used to treat several diseases. The present study aimed to investigate the therapeutic effects of MitoQ in benign prostatic hyperplasia (BPH) models and their underlying molecular mechanisms. In this study, we determined that MitoQ inhibited dihydrotestosterone (DHT)-induced cell proliferation and mitochondrial ROS by inhibiting androgen receptor (AR) and NOD-like receptor family pyrin domain-containing 3 (NLRP3) signaling in prostate epithelial cells. Molecular modeling revealed that DHT may combine with AR and NLRP3, and that MitoQ inhibits both AR and NLRP3. AR and NLRP3 downregulation using siRNA showed the linkage among AR, NLRP3, and MitoQ. MitoQ administration alleviated pathological prostate enlargement and exerted anti-proliferative and antioxidant effects by suppressing the AR and NLRP3 signaling pathways in rats with BPH. Hence, our findings demonstrated that MitoQ is an inhibitor of NLPR3 and AR and a therapeutic agent for BPH treatment.
Topics: Male; Humans; Rats; Animals; Prostatic Hyperplasia; Antioxidants; Receptors, Androgen; NLR Family, Pyrin Domain-Containing 3 Protein
PubMed: 37454529
DOI: 10.1016/j.redox.2023.102816 -
Proceedings of the National Academy of... Jul 2023Early in the COVID-19 pandemic, data suggested that males had a higher risk of developing severe disease and that androgen deprivation therapy might be associated with...
Early in the COVID-19 pandemic, data suggested that males had a higher risk of developing severe disease and that androgen deprivation therapy might be associated with protection. Combined with the fact that (), a host entry factor for the SARS-CoV-2 virus, was a well-known androgen-regulated gene, this led to an upsurge of research investigating androgen receptor (AR)-targeting drugs. Proxalutamide, an AR antagonist, was shown in initial clinical studies to benefit COVID-19 patients; however, further validation is needed as one study was retracted. Due to continued interest in proxalutamide, which is in phase 3 trials, we examined its ability to impact SARS-CoV-2 infection and downstream inflammatory responses. Proxalutamide exerted similar effects as enzalutamide, an AR antagonist prescribed for advanced prostate cancer, in decreasing AR signaling and expression of and , the SARS-CoV-2 receptor. However, proxalutamide led to degradation of AR protein, which was not observed with enzalutamide. Proxalutamide inhibited SARS-CoV-2 infection with an IC value of 97 nM, compared to 281 nM for enzalutamide. Importantly, proxalutamide inhibited infection by multiple SARS-CoV-2 variants and synergized with remdesivir. Proxalutamide protected against cell death in response to tumor necrosis factor alpha and interferon gamma, and overall survival of mice was increased with proxalutamide treatment prior to cytokine exposure. Mechanistically, we found that proxalutamide increased levels of NRF2, an essential transcription factor that mediates antioxidant responses, and decreased lung inflammation. These data provide compelling evidence that proxalutamide can prevent SARS-CoV-2 infection and cytokine-induced lung damage, suggesting that promising clinical data may emerge from ongoing phase 3 trials.
Topics: Male; Humans; Animals; Mice; COVID-19; SARS-CoV-2; Androgens; Androgen Antagonists; Pandemics; Peptidyl-Dipeptidase A; Prostatic Neoplasms; Interferon-gamma
PubMed: 37459541
DOI: 10.1073/pnas.2221809120 -
Cancers Sep 2023Triple-negative breast cancer (TNBC) is considered one of the most aggressive forms of breast cancer with poor survival rates compared to other breast cancer subtypes.... (Review)
Review
Triple-negative breast cancer (TNBC) is considered one of the most aggressive forms of breast cancer with poor survival rates compared to other breast cancer subtypes. TNBC is characterized by the absence of the estrogen receptor alpha, progesterone receptor, and the human epidermal growth factor receptor 2, limiting those viable treatment options available to patients with other breast cancer subtypes. Furthermore, due to the particularly high heterogeneity of TNBC, conventional treatments such as chemotherapy are not universally effective, leading to drug resistance and intolerable side effects. Thus, there is a pressing need to discover new therapies beneficial to TNBC patients. This review highlights current findings regarding the roles of three steroid hormone receptors, estrogen receptor beta, the androgen receptor, and the glucocorticoid receptor, in the progression of TNBC. In addition, we discussed several ongoing and completed clinical trials targeting these hormone receptors in TNBC patients.
PubMed: 37835396
DOI: 10.3390/cancers15194702 -
Current Oncology Reports Sep 2023There have been increasing reports of cardiovascular complications of androgen deprivation therapy (ADT) leading to worse outcomes among patients with prostate cancer.... (Review)
Review
PURPOSE OF THE REVIEW
There have been increasing reports of cardiovascular complications of androgen deprivation therapy (ADT) leading to worse outcomes among patients with prostate cancer. While this may result from the direct effects of androgen suppression in the cardiovascular systems, there are ADT-type-specific distinct cardiovascular complications suggestive of mechanisms beyond androgen-mediated. Thus, it is critical to understand the biological and clinical impact of ADT on the cardiovascular system.
RECENT FINDINGS
Gonadotropin-releasing hormone (GnRH) agonists cause increased cardiovascular events compared to GnRH antagonists. Androgen receptor antagonists are linked to an increased risk of long QT syndrome, torsades de pointes, and sudden cardiac death. Androgen synthesis inhibitors are associated with increased rates of hypertension, atrial tachyarrhythmia, and, in rare incidences, heart failure. ADT increases the risk of cardiovascular disease. The risk among ADT drugs differs and must be evaluated to develop a medically optimal plan for prostate cancer patients.
Topics: Male; Humans; Prostatic Neoplasms; Androgens; Androgen Antagonists; Gonadotropin-Releasing Hormone; Cardiovascular System; Biology
PubMed: 37273124
DOI: 10.1007/s11912-023-01424-2 -
Cancers Mar 2024The glycoprotein CD44, with its many isoforms and variations in carbohydrate patterning, participates in a diverse set of cellular functions. This fact leads to the... (Review)
Review
The glycoprotein CD44, with its many isoforms and variations in carbohydrate patterning, participates in a diverse set of cellular functions. This fact leads to the protein playing a role in many normal and pathologic cellular processes including a role in cancer progression and metastasis. These same facts make CD44 a strong therapeutic target in many cancer types, including bladder cancer.
PubMed: 38539529
DOI: 10.3390/cancers16061195 -
Advanced Science (Weinheim,... Jul 2023PRDM16 (PR domain containing protein 16) serves as a dominant activator of brown and beige adipocyte. However, mechanisms underlying the regulation of PRDM16 expression...
PRDM16 (PR domain containing protein 16) serves as a dominant activator of brown and beige adipocyte. However, mechanisms underlying the regulation of PRDM16 expression are incompletely understood. A Prdm16 luciferase knockin reporter mouse model is generated, enabling high throughput monitoring of Prdm16 transcription. Single clonal analysis reveals high heterogeneity of Prdm16 expression in the inguinal white adipose tissue (iWAT) cells. Amongst all transcription factors, androgen receptor (Ar) shows the strongest negative correlation with Prdm16. A sex dimorphism for PRDM16 mRNA expression is present in human WAT, with female individuals exhibiting increased expression than males. Androgen-AR signaling mobilization suppresses Prdm16 expression, accompanied by attenuated beiging in beige adipocytes, but not in brown adipose tissue. The suppressive effect of androgens on beiging is abolished upon overexpression of Prdm16. Cleavage under targets and tagmentation mapping reveals direct binding of AR within the intronic region of Prdm16 locus, whereas no direct binding is detected on Ucp1 and other browning-related genes. Adipocyte-selective deletion of Ar potentiates beige cell biogenesis whereas adipocyte-specific overexpression of AR attenuates white adipose beiging. This study highlights an essential role of AR in negative regulation of PRDM16 in WAT and provides an explanation for the observed sex difference in adipose beiging.
Topics: Animals; Female; Humans; Male; Mice; Adipocytes, Beige; Adipose Tissue, Brown; DNA-Binding Proteins; Obesity; Receptors, Androgen; Transcription Factors
PubMed: 37211698
DOI: 10.1002/advs.202300070 -
Cell Reports Oct 2023Advanced prostate cancers are treated with therapies targeting the androgen receptor (AR) signaling pathway. While many tumors initially respond to AR inhibition, nearly...
Advanced prostate cancers are treated with therapies targeting the androgen receptor (AR) signaling pathway. While many tumors initially respond to AR inhibition, nearly all develop resistance. It is critical to understand how prostate tumor cells respond to AR inhibition in order to exploit therapy-induced phenotypes prior to the outgrowth of treatment-resistant disease. Here, we comprehensively characterize the effects of AR blockade on prostate cancer metabolism using transcriptomics, metabolomics, and bioenergetics approaches. The metabolic response to AR inhibition is defined by reduced glycolysis, robust elongation of mitochondria, and increased reliance on mitochondrial oxidative metabolism. We establish DRP1 activity and MYC signaling as mediators of AR-blockade-induced metabolic phenotypes. Rescuing DRP1 phosphorylation after AR inhibition restores mitochondrial fission, while rescuing MYC restores glycolytic activity and prevents sensitivity to complex I inhibition. Our study provides insight into the regulation of treatment-induced metabolic phenotypes and vulnerabilities in prostate cancer.
Topics: Humans; Male; Androgens; Cell Line, Tumor; Prostatic Neoplasms; Prostatic Neoplasms, Castration-Resistant; Proto-Oncogene Proteins c-myc; Receptors, Androgen; Signal Transduction
PubMed: 37815914
DOI: 10.1016/j.celrep.2023.113221