The Involvement of Prolactin in Stress-Related Disorders.

The most important and widely studied role of prolactin (PRL) is its modulation of stress responses during pregnancy and lactation. PRL acts as a neuropeptide to support physiological reproductive responses. The effects of PRL on the nervous system contribute to a wide range of changes in the female brain during pregnancy and the inhibition of the hypothalamic-pituitary axis. All these changes contribute to the behavioral and physiological adaptations of a young mother to enable reproductive success. PRL-driven brain adaptations are also crucial for regulating maternal emotionality and well-being. Hyperprolactinemia (elevated PRL levels) is a natural and beneficial phenomenon during pregnancy and lactation. However, in other situations, it is often associated with serious endocrine disorders, such as ovulation suppression, which results in a lack of offspring. This introductory example shows how complex this hormone is. In this review, we focus on the different roles of PRL in the body and emphasize the results obtained from animal models of neuropsychiatric disorders.

The crucial role of prolactin-lactogenic hormone in Covid-19.

Prolactin (PRL) is a peptide hormone secreted from anterior pituitary involved in milk production in the females and regulation of sex drive in both sexes. PRL has pro-inflammatory and anti-inflammatory functions. High PRL serum level or hyperprolactinemia is associated with different viral infections. In coronavirus disease 2019 (Covid-19), which caused by positive-sense single-strand RNA virus known as severe acute respiratory distress syndrome coronavirus type 2 (SARS-CoV-2), PRL serum level is increased. PRL in Covid-19 may exacerbate the underlying inflammatory status by induction release of pro-inflammatory cytokines. However, PRL through its anti-inflammatory effects may reduce the hyperinflammatory status in Covid-19. The underlying mechanism of increasing PRL in Covid-19 is poorly understood. Therefore, in this review we try to find the potential anti-inflammatory or pro-inflammatory role of PRL in Covid-19. As well, this review was aimed to discuss the underlying causes and mechanisms for Covid-19-induced hyperprolactinemia.

Metabolic syndrome in the era of COVID-19 outbreak: impact of lockdown on cardiometabolic health.

PURPOSE: COVID-19 pandemics and cardiometabolic health are mutually interconnected. Chronic metabolic diseases are known risk factors for increased mortality after SARS-CoV-2 infection. In turn, COVID pandemics imposed sudden changes in lifestyle and social isolation with consequent potential cardiometabolic sequelae. The present study aimed at investigating the impact of changes in lifestyle and social life on metabolic profile in hyperprolactinemic or osteoporotic patients without pre-existing cardiometabolic diseases at the time of COVID-19. METHODS: The primary study outcome measurement was the prevalence of obesity, arterial hypertension, impaired glucose tolerance (IGT) or diabetes mellitus (DM), dyslipidemia and metabolic syndrome after COVID-19 outbreak. Seventy-four patients (21 men and 53 women, aged 51.8 ± 17.8 years) were admitted to the outpatient clinic of the Neuroendocrine Disease Unit at University "Federico II" of Naples, Italy, as per their routine clinical practice because of tumoral and non-tumoral hyperprolactinemia in 52 patients (70.3%), and osteoporosis/osteopenia in 22 (29.7%). Among female patients, 25 (47.2%) were at menopausal age. RESULTS: At the end of lockdown, prevalence of obesity (from 37.8% to 51.3%, p < 0.0001), dyslipidemia (from 28.4 to 48.6%, p = 0.003) and metabolic syndrome (from 14.9 to 27%, p < 0.0001) significantly increased compared to pre-COVID evaluation. No significant change was found in the prevalence of arterial hypertension and IGT/DM. CONCLUSION: SARS-CoV-2 outbreak has led to a rapid increase in the prevalence of metabolic syndrome, potentially contributing to the increased COVID-19 related mortality.

Guidance on the treatment of antipsychotic-induced hyperprolactinemia when switching the antipsychotic is not an option.

PURPOSE: This article aims to evaluate management options for antipsychotic-induced hyperprolactinemia and associated treatment considerations such as efficacy, tolerability, drug interactions, contraindications, and dosing regimens. SUMMARY: Hyperprolactinemia is a common adverse effect of antipsychotics. First-line management includes reducing the dose of the offending antipsychotic, discontinuing the antipsychotic, or switching to another antipsychotic associated with a lower risk of hyperprolactinemia. However, these options are not always practical and are associated with a risk of relapse of the psychiatric illness. Other management options include adjunctive aripiprazole, dopamine agonists (cabergoline and bromocriptine), metformin, and herbal supplements. A search of Embase, PubMed, and Google Scholar using key terms such as hyperprolactinemia, prolactin, antipsychotic, treatment guidelines, aripiprazole, dopamine agonist, cabergoline, bromocriptine, metformin, herbals, supplements, and medications was conducted for literature retrieval. Upon evaluation of the available literature we found the following: (1) aripiprazole is safe and effective in lowering prolactin levels within normal limits; (2) adjunctive cabergoline and bromocriptine decrease elevated prolactin levels, while cabergoline may be more effective in reducing prolactin but can also be associated with a more serious adverse effect of cardiac valvular abnormalities; (3) metformin causes a mild reduction of prolactin levels; and (4) there are limited data to support use of herbal medications (chamomile, Peony-Glycyrrhiza decoction, and shakuyaku-kanzo-to) in antipsychotic-induced hyperprolactinemia. CONCLUSION: There are treatments available for antipsychotic-induced hyperprolactinemia in patients who are unable to alter their current antipsychotic regimen. However, there remains a need for additional short- and long-term studies to determine the efficacy and safety of these treatment strategies, given that patients taking antipsychotics typically require chronic, life-long treatment for their illnesses.

The Mechanisms Linking Relative Hypercortisolism - The Common Feature Across COVID-19 Risks - To ARDS, Septic Shock, and Cytokine Dysregulation (preprint)

Covid-19 mortality risk factors share a common feature: a high ratio of cortisol to DHEA, referred to as relative hypercortisolism (RHC).Starting from a low just after age 25, adult COVID-19 mortality rates rise in tandem with this ratio as DHEA levels fall by over 80% by age 70. Conversely, juvenile COVID-19 morbidity rates _fall_ with this ratio as DHEA rises to pre-adolescent levels after age 6. Moreover, RHC predicts the severity and likelihood of death for both community acquired pneumonia and septic shock, the primary COVID-19 modes of death. Consistent with this finding, DHEA prevents cytokinedysregulation in a murine leukemia retrovirus model. DHEA, byinhibiting the PI3K/AKT pathway, also inhibits viral replication.DHEA, antagonized by cortisol, maintains intracellular calciumhomeostasis, a critical function during viral infections. The cortisol to DHEA ratio determines the exon splicing of the calcium-sensitive big potassium (BKCa) channel, which exerts predominate control over cell and inner mitochondrial membrane polarization. DHEA increases BKCa calcium sensitivity, and thereby reduces calcium influx into the cell and mitochondrial matrix. This effect–together with vitamin D3/calcitriol promoted calbindin-D9k/28k, magnesium, andubiquinone–protects against mitochondrial calcium overload. Absent these key factors, the COVID-19 virus, SARS-CoV-2, like other viruses disrupts intracellular calcium homeostasis to trigger mitochondrial calcium overload in susceptible hosts. The virus then hijacks the inflammatory ER stress and unfolded protein response (UPR) for its own replication.UPR underlies the virus’s lethality. It splices X-box protein 1(XBP-1) to its active form, which in turn activates the transcription regulator SNAI1. sXBP-1 and SNAI1 shift cellular metabolism from the pentose phosphate pathway to the hexosamine biosynthesis pathway and induce insulin resistance. SNAI1 also causes epidermal-to-mesenchymal transition (EMT). In this process, SNAI1 represses transcription of epithelial and vascular endothelial cadherins along with othercritical proteins forming the tight junction barriers in the lung and vasculature. UPR also inhibits expression of the epithelial sodium channel (ENaC), which maintains alveolar fluid balance. DHEAdose-dependently reduces XBP-1 mRNA splicing in cultured hepatocytes treated with the ER stress/UPR inducer tunicamycin.RHC and insulin resistance also produce a pathological immuneresponse. Insulin resistance via mTORC1 inhibits the cell energy sensor AMPK and, consequently, the first line of defense against the virus, autophagy. Severe mitochondrial calcium overload associated with RHC oxidizes phospholipids and predisposes the cell to necrosis.Upon cell lysis, the oxidized phospholipids trigger sterileinflammation, drawing cytokine-secreting neutrophils and macrophages to the site. Further exacerbating inflammation, insulin resistance and its inhibition of PPAR-γ skews macrophage polarization to thepro-inflammatory M1 phenotype. Meanwhile, RHC promotes glucocorticoid recycling via 11β-HSD1 in thymocytes. This recycling causesactivation-induced cell death, suppresses lymphocyte countproliferation, and leads to IL-1β hypersecretion and worsening RHC.Ultimately, this cytokine storm and severe RHC induce autoimmunity.Evidence suggests this pathological state can be avoided by restoring calcium homeostasis using a combination of DHEA, vitaminD3/calcitriol, magnesium, ubiquinone, and the AMPK/SIRT1 activators, acetyl L-carnitine and alpha lipoic acid.

A bacterial artificial chromosome (BAC)-vectored noninfectious replicon of SARS-CoV-2 (preprint)

Vaccines and antiviral agents are in urgent need to stop the COVID-19 pandemic. To facilitate antiviral screening against SARS-CoV-2 without requirement for high biosafety level facility, we developed a bacterial artificial chromosome (BAC)-vectored replicon of SARS-CoV-2, nCoV-SH01 strain, in which secreted Gaussia luciferase (sGluc) was encoded in viral subgenomic mRNA as a reporter gene. The replicon was devoid of structural genes spike (S), membrane (M), and envelope (E). Upon transfection, the replicon RNA replicated in various cell lines, and was sensitive to interferon alpha (IFN-), remdesivir, but was resistant to hepatitis C virus inhibitors daclatasvir and sofosbuvir. Replication of the replicon was also sensitive overexpression of zinc-finger antiviral protein (ZAP). We also constructed a four-plasmid in-vitro ligation system that is compatible with the BAC system, which makes it easy to introduce desired mutations into the assembly plasmids for in-vitro ligation. This replicon system would be helpful for performing antiviral screening and dissecting virus-host interactions.