Vitamins and Hormones最新文献

The hypothalamus plays a central role in regulating energy expenditure and maintaining energy homeostasis, crucial for an organism's survival. Located in the ventral diencephalon, it is a dynamic and adaptable brain region capable of rapid responses to environmental changes, exhibiting high anatomical and cellular plasticity and integrates a myriad of sensory information, internal physiological cues, and humoral factors to accurately interpret the nutritional state and adjust food intake, thermogenesis, and energy homeostasis. Key hypothalamic nuclei contain distinct neuron populations that respond to hormonal, nutrient, and neural inputs and communicate extensively with peripheral organs like the gastrointestinal tract, liver, pancreas, and adipose tissues to regulate energy production, storage, mobilization, and utilization. The hypothalamus has evolved to enhance energy storage for survival in famine and scarce environments but contribute to obesity in modern contexts of caloric abundance. It acts as a master regulator of whole-body energy homeostasis, rapidly adapting to ensure energy supplies for cellular functions. Understanding hypothalamic function, pertaining to energy expenditure, is crucial for developing targeted interventions to address metabolic disorders, offering new insights into the neural control of metabolic states and potential therapeutic strategies.

The discovery of Kisspeptin (Kiss) has opened a new direction in research on neuroendocrine control of reproduction in vertebrates. Belonging to the RF amide family of peptides, Kiss and its cognate receptor Gpr54 (Kissr) have a long and complex evolutionary history. Multiple forms of Kiss and Kissr are identified in non-mammalian vertebrates, with the exception of birds, and monotreme mammals. However, only a single form of the ligand (KISS1/Kiss1) and receptor (KISS1R/Kiss1r) is retained in higher mammals. Kiss1 is distributed in the hypothalamus-pituitary-gonadal (HPG) axis and its primary function is to stimulate gonadotropin-releasing hormone (GnRH) secretion. Kiss1 neurons are distributed in the rostral periventricular area of the third ventricle (RP3V) and arcuate/infundibular nucleus (ARN/IFN). The ARN/IFN is considered the GnRH pulse generator controlled by steroid negative feedback, and the RP3V neurons is concerned with GnRH surge induced by steroid positive feedback in females. The Kiss1-Kiss1r signaling is important in all aspects of reproduction: puberty onset, maintenance of adult gonadal functions and reproductive aging, and hence assumes therapeutic potentials in the treatment of reproductive dysfunctions and induction of artificial reproduction. This chapter reviews involvement of Kiss1 in the control of the HPG axis functions in female mammals.

Opioid use disorder (OUD) is considered a global health issue that affects various aspects of patients' lives and poses a considerable burden on society. Due to the high prevalence of remissions and relapses, novel therapeutic approaches are required to manage OUD. Deep brain stimulation (DBS) is one of the most promising clinical breakthroughs in translational neuroscience. It involves stereotactically implanting electrodes inside the brain and transmitting electrical pulses to targeted areas. To date, the nucleus accumbens has been recognized as the most successful DBS target for treating different types of drug addiction. Nevertheless, further preclinical research is required to determine the optimal brain target and stimulation parameters. On the other hand, the lateral hypothalamic area (LHA) plays a crucial role in many motivated behaviors including food intake and drug-seeking. Additionally, it projects widely throughout the brain to reward-related areas like the ventral tegmental area. Therefore, this chapter reviews studies investigating the potential positive effects of DBS administration in the LHA in animal models of opioid dependence and other pathological conditions. Findings reveal that LHA has the potential to be targeted for DBS application to treat a wide variety of disorders such as opioid dependence, obesity, and sleep disorders without significant adverse events. However, in the context of opioid dependence, more studies are needed, based on more valid animal models of addiction, including self-administration paradigms and varying stimulation patterns, to indicate that LHA is a safe and effective target for DBS in subjects with refractory opioid dependence.

Prostate cancer (PCa) is a multifaceted and heterogeneous disease that affects men globally. PCa incidences and related deaths in men are a major clinical challenge that needs immediate attention to prevent, manage, or treat the disease to improve overall health in patients. Activation of androgen receptor (AR) signaling and subsequent transactivation of downstream genes play a predominant role in PCa development, progression, and metastasis. Over the last few decades, the role of epigenetics has been much appreciated in the pathogenesis of PCa. There is widespread involvement of several epigenetic changes (such as DNA modifications by methylation, histone modifications by acetylation, chromatin remodellers, and non-coding RNAs, etc.) in the regulation of PCa initiation, progression, as well as the emergence of androgen-insensitive castration-resistant PCa (CRPC) phenotype, which has improved our understanding of disease etiology. Moreover, targeting selective epigenetic marks has raised immense opportunities to target PCa, owing to the possibilities of reversal of epigenetic changes involved in the disease progression. Several epigenetic inhibitors (e.g., DNMT inhibitors, HDAC inhibitors) have been investigated in preclinical studies as well as in clinical trials to establish effective epigenetic-based therapies against PCa, and indeed, few of them have already made their way to the clinic. Epigenetics also plays a role in the reactivation of AR signaling in CRPC; though hormonal therapies are ineffective in these tumors, epigenetic inhibitors combined with other therapies are considered important in targeting CRPC. Here, we have summarized epigenetics in the regulation of AR signaling, progress in understanding epigenetics' role in etiology, and the importance of designing effective therapies for PCa, including CRPC. We have also discussed the limitations and challenges in epigenetics therapies and strategies to overcome obstacles in improving existing therapies to better manage PCa disease in clinics.

Many studies, from in-vitro and in-vivo to population-based studies, demonstrate undesirable effects of higher thyroid hormone levels on the development of cancer, as well as its prognosis and consequently an outcome of cancer patients. Thyroid hormones mediate cancer cells' growth, proliferation, and metastatic diffusion. Current data demonstrate an increased risk of solid as well as hematologic malignancies in patients with higher serum thyroid hormone levels and/or lower thyrotropin levels (TSH). However, the results are sparse. The present chapter will summarize studies investigating the correlation between hyperthyroidism, higher upper reference range triiodothyronine (T3) and thyroxine (T4) levels, and normal-low TSH with cancer risk and prognosis, respectively. The diagnostics, clinical management, and treatment of hyperthyroidism in cancer patients will also be illustrated. Finally, the importance of a prompt restoration of euthyroidism in cancer patients and the priority role of radioiodine (RAI) therapy to permanently eliminate hyperthyroidism in most cancer patients will be discussed.

Prolactin-secreting adenomas comprise approximately 50 % of all clinically relevant pituitary adenomas. Most men with prolactinomas present with large and invasive tumors. Despite effective medical therapy with dopamine agonists and prolactin normalization, over 20 % of men with prolactinomas will remain with hypogonadism. There are two suggested mechanisms for hypogonadism: central suppression of the hypothalamic-pituitary-gonadal axis caused by elevated prolactin levels leading to inhibition of the kisspeptin neurons in the hypothalamus and loss of pulsatile luteinizing hormone secretion, and tumor mass effect with compression of the normal pituitary tissue and destruction of gonadotroph cells. Hypogonadism in men results in sexual dysfunction, low libido, anemia, fatigue, and infertility. Identification of patients who are likely to recover the damaged gonadal axis upon prolactin suppression is important. These are men that harbor smaller tumors, with higher testosterone levels at diagnosis, no visual field defects, and without impairment in the secretion of other pituitary hormones. Testosterone replacement should be offered to patients with lower chance of restoring normal function of the gonadal axis. However, most men will achieve spontaneous recovery of the hypothalamic-pituitary-gonadal axis within 12 months after prolactin normalization. For men with prolactinoma and hypogonadism persistence who wish to restore fertility, treatment with gonadotropins or with clomiphene citrate has been found to be safe and effective. In the present review, we propose an algorithm for the management of hypogonadism persistence in men with macroprolactinomas.

Breast cancer is a widely prevalent and devastating morbidity that affects millions of women around the world. Conventional treatment options for breast cancer include surgery, chemotherapy, and radiotherapy. However, these therapies can frequently have adverse side effects and may not be effective for all patients. In recent years, there has been an increasing interest in the development of targeted therapies for breast cancer. Glut-1, a key glucose transporter that is often overexpressed in breast cancer cells, is a potential candidate for targeted therapies. Glut-1 is crucial for basal glucose transport into cancer cells and is necessary for their rapid growth and survival. Several Glut-1 inhibitors - both natural and synthetic small molecules - have been identified and used as anticancer agents. In this chapter, we summarize the different approaches of Glut-1 inhibition in breast cancer and the mode of inhibition used by various Glut-1 inhibitors. Further understanding of the mechanisms underlying the efficacy of Glut-1 inhibitors in breast cancer treatment may provide crucial insights that can lead to the advancement of current treatment strategies. The functional inhibition of Glut-1 by specific Glut-1 inhibitors is being explored as a potential treatment modality for breast cancer. This approach holds great promise for improving the therapeutic efficacy of breast cancer treatment and minimizing the side effects associated with conventional therapies.

FDA approval of selective CDK4/6 inhibitors (CDK4/6i) marked a groundbreaking development in cancer treatment. Decades of pre-clinical studies elucidated the route that certain cancer cells take to gain the cancer hallmark of uncontrolled proliferation, uncovering CDK4/6 as key players. Further investigation into the molecular underpinnings of this process revealed interconnected signaling between the CDK4/6 and estrogen receptor (ER) signaling axes, providing evidence that CDK4/6i would be particularly relevant in estrogen-driven cancers. Three FDA-approved CDK4/6 inhibitors, palbociclib, ribociclib, and abemaciclib, were independently developed and all exhibited efficacy against in vivo models of ER+ breast cancer. Clinical trials then confirmed the safety and efficacy of these drugs in patients. Ongoing clinical trials are now testing CDK4/6i in several other cancer models, including other hormone-driven cancers. Further mechanistic insights should reveal predictive biomarkers of response, and potential combination therapies to overcome resistance. This chapter provides an overview of the development of these drugs, their current utility, and their potential use in the treatment of multiple malignancies.

The hypothalamus is one of the most complex region in the central nervous system regarding neuroanatomy, neurochemical content, neuropeptide/classical neurotransmitter interactions, physiological actions, and pathophysiology. Hypothalamic neuropeptides have been involved in a large plethora of mechanisms related with obesity, anxiety, feeding, energy metabolism, defensive behavior, mood, and reproduction. The therapeutic potential of these findings is enormous but the physiological complexity occurring in the hypothalamus is huge due in part to the interactions between numerous neuropeptides as well as between neuropeptides and other neuroactive substances. Here, we review the development and neuroanatomy of the hypothalamus as well as the involvement of 31 neuropeptides in hypothalamic functions and pathologies. Alterations in the secretion, release, and/or concentrations of neuropeptides and/or their hypothalamic receptors can trigger different pathologies. Several therapeutic strategies that could be carried out by adjusting neuropeptide levels in the hypothalamus are suggested. The combination of imaging techniques with a detailed neurochemical knowledge of the hypothalamus would be an excellent diagnostic tool, allowing personalized treatment. Several approaches for future research that may contribute to improve or resolve these pathologies are also mentioned.

In this chapter, we describe a potential new approach to treat lymphoproliferative diseases through isoform-specific knockdown of the long form of the prolactin receptor. The chapter includes a summary of the clinical and experimental links between prolactin and such diseases and presents sufficient background about prolactin and its receptors to explain the rationale for our approach. This background also aims to explain why clinical correlations between circulating prolactin and lymphoproliferative diseases may not appear as great as perhaps they are. In the final sections, we summarize our experimental evidence supporting the use of a splice-modulating oligomer that specifically targets the long form of the prolactin receptor. The work used mouse models of systemic lupus erythematosus and diffuse large B-cell lymphoma, human databases, and normal and malignant human cells. We also refer to previous and current studies using the splice-modulating oligomer which demonstrate its lack of toxicity, including in normal immune cells. For each section, we provide a take-home message in bold font so that the reader has the option to focus briefly or delve into details supporting the take-home message.