ACE2, Circumventricular Organs and the Hypothalamus, and COVID-19.

The SARS-CoV-2 virus gains entry to cells by binding to angiotensin-converting enzyme 2 (ACE2). Since circumventricular organs and parts of the hypothalamus lack a blood-brain barrier, and immunohistochemical studies demonstrate that ACE2 is highly expressed in circumventricular organs which are intimately connected to the hypothalamus, and the hypothalamus itself, these might be easy entry points for SARS-CoV-2 into the brain via the circulation. High ACE2 protein expression is found in the subfornical organ, area postrema, and the paraventricular nucleus of the hypothalamus (PVH). The subfornical organ and PVH are parts of a circuit to regulate osmolarity in the blood, through the secretion of anti-diuretic hormone into the posterior pituitary. The PVH is also the stress response centre in the brain. It controls not only pre-ganglionic sympathetic neurons, but is also a source of corticotropin-releasing hormone, that induces the secretion of adrenocorticotropic hormone from the anterior pituitary. It is proposed that the function of ACE2 in the circumventricular organs and the PVH could be diminished by binding with SARS-CoV-2, thus leading to a reduction in the ACE2/Ang (1-7)/Mas receptor (MasR) signalling axis, that modulates ACE/Ang II/AT1R signalling. This could result in increased presympathetic activity/neuroendocrine secretion from the PVH, and effects on the hypothalamic-pituitary-adrenal axis activity. Besides the bloodstream, the hypothalamus might also be affected by SARS-CoV-2 via transneuronal spread along the olfactory/limbic pathways. Exploring potential therapeutic pathways to prevent or attenuate neurological symptoms of COVID-19, including drugs which modulate ACE signalling, remains an important area of unmet medical need.

Parathyroid allotransplantation to treat post-thyroidectomy hypoparathyroidism: A review of case studies.

OBJECTIVE: Symptomatic long-term hypoparathyroidism following thyroid surgery requires an alternative and permanent therapy that would effectively restore parathyroid function and eliminate the need for substitution drug therapy. The aim of this study was to systematically review the literature on the efficacy and safety of parathyroid allotransplantation to treat post-operative hypoparathyroidism. METHODS: MEDLINE, Embase, BIOSIS and the Cochrane Library were searched for published articles (from inception of each database to September 30, 2018). A total of 9 studies comprising 146 patients (177 allotransplantations) with post thyroidectomy hypoparathyroidism were identified. RESULTS: Parathyroid tissues used for allotransplant were cultured parathyroid cells, cryopreserved parathyroid cells and encapsulated microspheres. Post-transplant immunosuppression was only reported in three studies, mainly with oral prednisolone for 2 weeks to 6 months. Mean graft survival following allotransplantation was 47% (95% CI 24%-71%) when patients were followed-up to 6 months and 41% (95% CI 2.3%-80%) at 12 months. There was significant unexplained heterogeneity observed between studies in both these groups (I2 > 50%). Parathyroid hormone (PTH) levels, and serum calcium levels post intervention was not reported in all studies, but available evidence suggests the levels remains higher (PTH level around 12 pg/ml; Ca level around 8 mg/dl) post-allotransplantation for up to 24 months. CONCLUSIONS: Long-term benefit and harms of allotransplantation is still unclear due to the clinical and statistical heterogeneity observed among the studies. Therefore, conduct of a well-designed controlled clinical trial in the immediate future on allotransplantation is of paramount importance.

Pleotropic Roles of Autotaxin in the Nervous System Present Opportunities for the Development of Novel Therapeutics for Neurological Diseases.

Autotaxin (ATX) is a soluble extracellular enzyme that is abundant in mammalian plasma and cerebrospinal fluid (CSF). It has two known enzymatic activities, acting as both a phosphodiesterase and a phospholipase. The majority of its biological effects have been associated with its ability to liberate lysophosphatidic acid (LPA) from its substrate, lysophosphatidylcholine (LPC). LPA has diverse pleiotropic effects in the central nervous system (CNS) and other tissues via the activation of a family of six cognate G protein-coupled receptors. These LPA receptors (LPARs) are expressed in some combination in all known cell types in the CNS where they mediate such fundamental cellular processes as proliferation, differentiation, migration, chronic inflammation, and cytoskeletal organization. As a result, dysregulation of LPA content may contribute to many CNS and PNS disorders such as chronic inflammatory or neuropathic pain, glioblastoma multiforme (GBM), hemorrhagic hydrocephalus, schizophrenia, multiple sclerosis, Alzheimer's disease, metabolic syndrome-induced brain damage, traumatic brain injury, hepatic encephalopathy-induced cerebral edema, macular edema, major depressive disorder, stress-induced psychiatric disorder, alcohol-induced brain damage, HIV-induced brain injury, pruritus, and peripheral nerve injury. ATX activity is now known to be the primary biological source of this bioactive signaling lipid, and as such, represents a potentially high-value drug target. There is currently one ATX inhibitor entering phase III clinical trials, with several additional preclinical compounds under investigation. This review discusses the physiological and pathological significance of the ATX-LPA-LPA receptor signaling axis and summarizes the evidence for targeting this pathway for the treatment of CNS diseases.

RANKL targeted peptides inhibit osteoclastogenesis and attenuate adjuvant induced arthritis by inhibiting NF-κB activation and down regulating inflammatory cytokines.

Peptides designed from osteoprotegerin (OPG) have previously been shown to inhibit receptor activator of NF-κB ligand (RANKL) and prevent bone loss without significantly inhibiting inflammation. The objective of this study was to develop a novel peptide with dual inhibitory activity against bone loss and inflammation using site-directed mutagenesis. Out of the three putative sites (i.e., Tyr70-Asp78, Tyr82-Glu96, and Leu113-Arg122) available on OPG for RANKL binding, Leu113-Arg122 was used as a template for peptide synthesis. Peptide mutants of the template sequence (112YLEIEFCLKHR122) were synthesized and initially screened for their inhibitory effect on RANK-RANKL binding by competitive ELISA. The most active peptide was further evaluated in vitro for RANKL induced osteoclastogenesis in mouse macrophage cells, and in vivo for Freund's complete adjuvant induced arthritis (AIA) in Lewis rats. The efficacy of the candidate peptide was compared with that of the standard drug celecoxib. The peptide YR-11 (YLEIEFSLKHR), obtained by direct substitution of cysteine with a serine residue in the template sequence, significantly (p<0.05) inhibited RANK-RANKL binding, and RANKL induced TRAP activity and formation of multinucleated osteoclasts without any cytotoxicity. Administration of YR-11 peptide at the dose of 30mg/kg (i.p.) ameliorated both bone loss and inflammation in AIA rats. To elucidate the mechanism for inhibition of inflammation in arthritic rats, serum and tissue cytokines (TNF-α, IL-1ß, and IL-6) were analyzed by ELISA and RT-PCR methods. Results confirmed that YR-11 peptide inhibited pro-inflammatory cytokines in the sera and hind paw tissues of AIA rats through its suppressive effect on RANKL induced nuclear translocation of NF-κB. The results obtained in this study substantiate the therapeutic benefit of this novel peptide in the prevention of bone loss and inflammation in rheumatoid arthritis with reduced side effects.