Modulation of inflammation and immunity by omega-3 fatty acids: a possible role for prevention and to halt disease progression in autoimmune, viral, and age-related disorders.

Omega-3 polyunsaturated fatty acids (PUFA) have demonstrated anti-inflammatory properties, while Omega-6 have pro-inflammatory effects, and the balance between the two is an important aspect of healthy nutrition. Over the last 30 years, however, the Western diet has shifted largely from Omega-3 to Omega-6 consumption. Uncontrolled aberrant and chronic inflammation is a leading component of many common diseases, including arthritis, cardiovascular diseases, neurodegenerative diseases, cancer, obesity, autoimmune diseases, and infective diseases. Eicosanoids derived from Omega-6 participate in the inflammatory process, while Omega-3 PUFA have the opposite effect. Many favorable effects of Omega-3 are believed to result from their anti-inflammatory properties, but eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) also have inhibitory effects on immune cells and reduce proinflammatory cytokine release. All these mechanisms can be beneficial in autoimmunity. No effective preventions or definite cures for autoimmune diseases are yet known because pathophysiology is also unclear. Omega-3 fatty acid supplementation is associated with a significant reduction in disease activity in several autoimmune diseases, like type 1 diabetes (T1D), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and multiple sclerosis (MS). Studies of viral diseases, including COVID-19, show improvement in symptom severity, recovery prognosis, and probability of survival with the use of Omega-3. Finally, the evidence of the beneficial effect of Omega-3 on metabolic diseases associated with aging is persuasive; various studies have demonstrated that their consumption improves lipids, fatty liver disease, obesity, cognitive function, and cardiovascular complications of chronic kidney disease (CKD). Omega-3 PUFA have also been shown to support an anti-inflammatory effect in older age and to have favorable effects on age-related disease's complications, frailty, and mortality. A healthy Omega-6/3 PUFA ratio should be targeted for the modulation of low-grade inflammation, as well as for the prevention of immune dysregulation and complications of uncontrolled inflammation triggered by infections, development, and progression of autoimmune disorders, and the consequences of oxidative stress due to aging. There is still a need for randomized clinical studies to validate current evidence supporting supplementation with correct doses of Omega-3 PUFA in autoimmune and chronic disease prevention.

Umbilical Cord-derived Mesenchymal Stem Cells for COVID-19 Patients with Acute Respiratory Distress Syndrome (ARDS).

The coronavirus SARS-CoV-2 is cause of a global pandemic of a pneumonia-like disease termed Coronavirus Disease 2019 (COVID-19). COVID-19 presents a high mortality rate, estimated at 3.4%. More than 1 out of 4 hospitalized COVID-19 patients require admission to an Intensive Care Unit (ICU) for respiratory support, and a large proportion of these ICU-COVID-19 patients, between 17% and 46%, have died. In these patients COVID-19 infection causes an inflammatory response in the lungs that can progress to inflammation with cytokine storm, Acute Lung Injury (ALI), Acute Respiratory Distress Syndrome (ARDS), thromboembolic events, disseminated intravascular coagulation, organ failure, and death. Mesenchymal Stem Cells (MSCs) are potent immunomodulatory cells that recognize sites of injury, limit effector T cell reactions, and positively modulate regulatory cell populations. MSCs also stimulate local tissue regeneration via paracrine effects inducing angiogenic, anti-fibrotic and remodeling responses. MSCs can be derived in large number from the Umbilical Cord (UC). UC-MSCs, utilized in the allogeneic setting, have demonstrated safety and efficacy in clinical trials for a number of disease conditions including inflammatory and immune-based diseases. UC-MSCs have been shown to inhibit inflammation and fibrosis in the lungs and have been utilized to treat patients with severe COVID-19 in pilot, uncontrolled clinical trials, that reported promising results. UC-MSCs processed at our facility have been authorized by the FDA for clinical trials in patients with an Alzheimer's Disease, and in patients with Type 1 Diabetes (T1D). We hypothesize that UC-MSC will also exert beneficial therapeutic effects in COVID-19 patients with cytokine storm and ARDS. We propose an early phase controlled, randomized clinical trial in COVID-19 patients with ALI/ARDS. Subjects in the treatment group will be treated with two doses of UC-MSC (l00 × 106 cells). The first dose will be infused within 24 hours following study enrollment. A second dose will be administered 72 ± 6 hours after the first infusion. Subject in the control group will receive infusion of vehicle (DPBS supplemented with 1% HSA and 70 U/kg unfractionated Heparin, delivered IV) following the same timeline. Subjects will be evaluated daily during the first 6 days, then at 14, 28, 60, and 90 days following enrollment (see Schedule of Assessment for time window details). Safety will be determined by adverse events (AEs) and serious adverse events (SAEs) during the follow-up period. Efficacy will be defined by clinical outcomes, as well as a variety of pulmonary, biochemical and immunological tests. Success of the current study will provide a framework for larger controlled, randomized clinical trials and a means of accelerating a possible solution for this urgent but unmet medical need. The proposed early phase clinical trial will be performed at the University of Miami (UM), in the facilities of the Diabetes Research Institute (DRI), UHealth Intensive Care Unit (ICU) and the Clinical Translational Research Site (CTRS) at the University of Miami Miller School of Medicine and at the Jackson Memorial Hospital (JMH).

POSEIDON study: a pilot, safety and feasibility trial of high-dose omega3 fatty acids and high-dose cholecalciferol supplementation in type 1 diabetes.

The anti-inflammatory and immunomodulatory properties of high-dose omega-3 fatty acids and Vitamin D, and the initial encouraging results from case reports on the use of this supplementation in new-onset Type 1 Diabetes (T1D), support further testing of this combination strategy. This intervention appears to be well tolerated, affordable, and sufficiently safe to be further tested in randomized prospective trials to determine whether this combination therapy may be of assistance to halt progression of autoimmunity and/or preserve residual beta-cell function in subjects with new onset and established T1D of up to 10 years duration. In addition, the 1st PreDiRe T1D conference (Preventing Disease and its Recurrence in Type 1 Diabetes - see Editorial in this issue) was organized to discuss initial results and possible alternative/complementary strategies, for collaborative international expansion of these trials, to include strategies for disease prevention. Our POSEIDON clinical trial will test the use of high dose vitamin D3 and highly purified Omega-3 fatty acids in new onset and established T1D. The draft of the study protocol, in addition to the informed consent and assent, is now shared open access to facilitate its international implementation by interested physicians and centers that would like to further test this approach through clinical trials.

Agmatine in the hypothalamic paraventricular nucleus stimulates feeding in rats: involvement of neuropeptide Y.

BACKGROUND AND PURPOSE: Agmatine, a multifaceted neurotransmitter, is abundantly expressed in the hypothalamic paraventricular nucleus (PVN). Our aim was to assess (i) the effect of agmatine on feeding behaviour and (ii) its association, if any, with neuropeptide Y (NPY). EXPERIMENTAL APPROACH: Satiated rats fitted with intra-PVN cannulae were administered agmatine, alone or jointly with (i) α2-adrenoceptor agonist, clonidine, or antagonist, yohimbine; (ii) NPY, NPY Y1 receptor agonist, [Leu³¹, Pro³4]-NPY, or antagonist, BIBP3226; or (iii) yohimbine and NPY. Cumulative food intake was monitored at different post-injection time points. Furthermore, the expression of hypothalamic NPY following i.p. treatment with agmatine, alone or in combination with yohimbine (i.p.), was evaluated by immunocytochemistry. KEY RESULTS: Agmatine robustly increased feeding in a dose-dependent manner. While pretreatment with clonidine augmented, yohimbine attenuated the orexigenic response to agmatine. Similarly, NPY and [Leu³¹, Pro³4]-NPY potentiated the agmatine-induced hyperphagia, whereas BIBP3226 inhibited it. Moreover, yohimbine attenuated the synergistic orexigenic effect induced by the combination of NPY and agmatine. Agmatine increased NPY immunoreactivity in the PVN fibres and in the cells of the hypothalamic arcuate nucleus (ARC) and this effect was prevented by pretreatment with yohimbine. NPY immunoreactivity in the fibres of the ARC, dorsomedial, ventromedial and lateral nuclei of the hypothalamus was not affected by any of the above treatments. CONCLUSIONS AND IMPLICATIONS: The orexigenic effect of agmatine is coupled to increased NPY activity mediated by stimulation of α2-adrenoceptors within the PVN. This signifies the importance of agmatine or α2-adrenoceptor modulators in the development of novel therapeutic agents to treat feeding-related disorders.

Reversal of caffeine-induced anxiety by neurosteroid 3-alpha-hydroxy-5-alpha-pregnane-20-one in rats.

Caffeine has been shown to increase brain and plasma content of neurosteroid 3alpha-hydroxy-5alpha-pregnan-20-one (3alpha,5alpha-THP) that allosterically modulates GABA(A) receptors. The present study evaluated the role of neurosteroid 3alpha,5alpha-THP in the caffeine-induced anxiogenic-like effect using the elevated plus-maze (EPM) test in rats. Acute administration of caffeine (50 or 100mg/kg, i.p.) produced anxiogenic-like activity that was reversed by pretreatment with the neurosteroid 3alpha,5alpha-THP or progesterone, the GABA(A) agonist muscimol, or the benzodiazepine receptor agonist diazepam. On the contrary, caffeine produced higher anxiety in animals previously treated with the GABA(A) receptor antagonist, bicuculline or either of the various neurosteroid biosynthesis enzyme inhibitors viz. trilostane, finasteride or indomethacin. Furthermore, pretreatment with DHEAS, a neurosteroid that negatively modulates GABA(A) receptors also enhanced the caffeine-induced anxiety. Moreover, adrenalectomy potentiated the anxiogenic-like response of caffeine indicating the contributory role of peripheral steroidogenesis. Thus, it is speculated that neurosteroid 3alpha,5alpha-THP through positive modulation of GABA(A) receptor activity may serve as a counter-regulatory mechanism against caffeine-induced anxiety.

Behavioral action of ethanol in Porsolt's forced swim test: modulation by 3 alpha-hydroxy-5 alpha-pregnan-20-one.

Ethanol is known to increase cortical and plasma content of GABAergic neurosteroid 3alpha-hydroxy-5alpha-pregnan-20-one (3alpha,5alpha-THP) which is responsible for some of its behavioral and electrophysiological effects. We have previously demonstrated the antidepressant like effect of 3alpha,5alpha-THP in mice. This study investigated the role of 3alpha,5alpha-THP in acute, chronic and withdrawal effects of ethanol using mouse forced swim test (FST) paradigm. While acute systemic ethanol (2 or 2.5 g/kg) administration exhibited an antidepressant like effect, its prolonged consumption produced tolerance to this effect and its withdrawal, on the other hand, elicited enhanced behavioral despair (depression). The antidepressant like effect of ethanol was potentiated by GABA(A) receptor agonist, muscimol (0.5 mg/kg, i.p.), 3alpha,5alpha-THP (0.5, 1 or 2 microg/mouse, i.c.v.) and by neurosteroidogenic drugs viz. selective serotonin reuptake inhibitor (SSRI), fluoxetine (5 or 20 mg/kg, i.p.), agonist at mitochondrial diazepam binding inhibitor receptor, FGIN 1-27 (0.5 or 1 microg/mouse, i.c.v.), or 11beta-hydroxylase inhibitor, metyrapone (0.5 or 1 microg/mouse, i.c.v.) which are known to increase endogenous 3alpha,5alpha-THP content. Furthermore, inhibition of the endogenous neurosteroid biosynthesis by drugs like 5alpha-reductase inhibitor, finasteride (50 mg/kg, s.c.), 3beta-hydroxysteroid dehydrogenase inhibitor, trilostane (30 mg/kg i.p.) or 3alpha-hydroxysteroid dehydrogenase inhibitor, indomethacin (5 mg/kg, i.p.) and GABA(A) receptor antagonist, bicuculline (1 mg/kg, i.p.) blocked the antidepressant like effect of ethanol. Withdrawal of ethanol from mice consuming it chronically displayed enhanced behavioral despair and elicited tolerance to antidepressant like action of acute ethanol (2.5, 3 or 3.5 g/kg). Moreover, sub-antidepressant doses (0.25 or 0.5 microg/mouse, i.c.v.) of 3alpha,5alpha-THP and fluoxetine (5 mg/kg, i.p.) but not imipramine (1 mg/kg, i.p.) reversed the depression associated with ethanol withdrawal indicating sensitization to their antidepressant action. Thus, 3alpha,5alpha-THP plays a pivotal role in the actions of ethanol and in the depression associated with ethanol withdrawal. These findings may be of potential ramification to contribute to the depression associated with alcoholism and its treatment using neurosteroids.

Dextromethorphan- and pseudoephedrine-induced agitated psychosis and ataxia: case report.

Pseudoephedrine and dextromethorphan are therapeutic constituents of numerous commonly used, over-the-counter cough and cold preparations. Although this drug combination is generally considered quite safe if utilized in recommended doses, overmedication or overdose can result in serious neurologic and cardiovascular abnormalities that occasionally can be life-threatening. We present a case of a 2-year-old child who developed hyperirritability, psychosis, and ataxia after being overmedicated with a pseudoephedrine/dextromethorphan combination cough preparation, and discuss probable mechanisms of toxicity and risk factors for adverse events.