TRAIL-R Deficient Mice Are Protected from Neurotoxic Effects of Amyloid-ß.

TRAIL, a member of TNF superfamily, is a potent inducer of neuronal death. Neurotoxic effects of TRAIL appear mediated by its death receptor TRAIL-R2/DR5. To assess the role of TRAIL/TRAIL-R2 pathway in AD-related neurodegeneration, we studied the impact of the treatment with amyloid-ß (Aß) upon cell viability and inflammation in TRAIL-R-deficient mice (TRAIL-R-/-). Here, we demonstrate that the lack of TRAIL-R2 protects from death cultured TRAIL-R-/- mouse embryonic hippocampal cells after treatment with either Aß1-42 or TRAIL. Consistently, stereotaxic injection of Aß1-42 resulted in blunted caspase activation, as well as in reduction of JNK phosphorylation and increased AKT phosphorylation in TRAIL-R-/- mice. Moreover, the lack of TRAIL-R2 was associated with blunted constitutive p53 expression in mice that have undergone Aß1-42 treatment, as well as in decrease of phosphorylated forms of tau and GSK3ß proteins. Likewise, TRAIL-R2 appears essential to both TRAIL and Aß-mediated neurotoxicity and inflammation. Indeed, hippocampi of TRAIL-R-/- mice challenged with Aß1-42, showed a slight expression of microglial (Iba-1) and astrocytic (GFAP) markers along with attenuated levels of IL-1ß, TNF-α, NOS2 and COX2. In conclusion, the bulk of these results demonstrate that the constitutive lack of TRAIL-R2 is associated with a substantial reduction of noxious effects of Aß1-42, providing further evidence on the prominent role played by TRAIL in course of Aß-related neurodegeneration and confirming that the TRAIL system represents a potential target for innovative AD therapy.

In search of an ideal drug for safer treatment of obesity: The false promise of pseudoephedrine.

Obesity is a major public health problem worldwide. Only relatively few treatment options are, at present, available for the management of obese patients. Furthermore, treatment of obesity is affected by the widespread misuse of drugs and food supplements. Ephedra sinica is an old medicinal herb, commonly used in the treatment of respiratory tract diseases. Ephedra species contain several alkaloids, including pseudoephedrine, notably endowed with indirect sympathomimetic pharmacodynamic properties. The anorexigenic effect of pseudoephedrine is attributable primarily to the inhibition of neurons located in the hypothalamic paraventricular nucleus (PVN), mediating satiety stimuli. Pseudoephedrine influences lipolysis and thermogenesis through interaction with ß3 adrenergic receptors and reduces fat accumulation through down-regulation of transcription factors related to lipogenesis. However, its use is associated with adverse events that involve to a large extent the cardiovascular and the central nervous system. Adverse events of pseudoephedrine also affect the eye, the intestine, and the skin, and, of relevance, sudden cardiovascular death related to dietary supplements containing Ephedra alkaloids has also been reported. In light of the limited availability of clinical data on pseudoephedrine in obesity, along with its significantly unbalanced risk/benefit profile, as well as of the psychophysical susceptibility of obese patients, it appears reasonable to preclude the prescription of pseudoephedrine in obese patients of any order and degree.

The immune system on the TRAIL of Alzheimer's disease.

Alzheimer's disease (AD) is the most common form of dementia, characterized by progressive degeneration and loss of neurons in specific regions of the central nervous system. Chronic activation of the immune cells resident in the brain, peripheral immune cell trafficking across the blood-brain barrier, and release of inflammatory and neurotoxic factors, appear critical contributors of the neuroinflammatory response that drives the progression of neurodegenerative processes in AD. As the neuro-immune network is impaired in course of AD, this review is aimed to point out the essential supportive role of innate and adaptive immune response either in normal brain as well as in brain recovery from injury. Since a fine-tuning of the immune response appears crucial to ensure proper nervous system functioning, we focused on the role of the TNF superfamily member, TNF-related apoptosis-inducing ligand (TRAIL), which modulates both the innate and adaptive immune response in the pathogenesis of several immunological disorders and, in particular, in AD-related neuroinflammation. We here summarized mounting evidence of potential involvement of TRAIL signaling in AD pathogenesis, with the aim to provide clearer insights about potential novel therapeutic approaches in AD.

The Biochemical and Pharmacological Properties of Ozone: The Smell of Protection in Acute and Chronic Diseases.

Ozone therapy has been widely used in everyday clinical practice over the last few years, leading to significant clinical results in the treatment of herniated discs and pain management. Nevertheless, further studies have demonstrated its potential efficacy and safety under other clinical and experimental conditions. However, some of these studies showed controversial results regarding the safety and efficacy of ozone therapy, thus mining its potential use in an everyday clinical practice. To this regard, it should be considered that extensive literature review reported the use of ozone in a significant different dose range and with different delivery systems. The aim of the present review is to describe the various pharmacological effects of ozone in different organs and clinical conditions and to provide possible biochemical and molecular insights for ozone biological properties, thus providing a possible explanation for various controversial clinical outcomes described in the scientific literature.

The efficacy of an association of palmitoylethanolamide and alpha-lipoic acid in patients with chronic prostatitis/chronic pelvic pain syndrome: A randomized clinical trial.

BACKGROUND: Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a complex condition, characterized by uncertain etiology and by limited response to therapy. The definition of CP/CPPS includes genitourinary pain with or without voiding symptoms in the absence of uropathogenic bacteria, as detected by standard microbiological methods, or another identifiable cause such as malignancy. The efficacy of various medical therapies, has been evaluated in clinical studies, but evidence is lacking or conflicting. We compared Serenoa Repens in monotherapy versus Palmitoylethanolamide (PEA) in combination with Alpha-lipoic acid (ALA) and evaluated the efficacy of these treatments in patients with CP/CPPS. METHODS: We conducted a randomized, single-blind trial. 44 patients diagnosed with CP/CPPS (mean age 41.32 ± 1.686 years) were randomly assigned to treatment with Palmitoylethanolamide 300 mg plus Alpha-lipoic acid 300 mg (Peanase®), or Serenoa Repens at 320 mg. Three questionnaires (NIH-CPSI, IPSS and IIEF5) were administered at baseline and after 12 weeks of treatment in each group. RESULTS: 12 week treatment with Peanase significantly improved the IPSS score compared to the same period of treatment with Serenoa Repens, and significantly reduced NIH-CPSI score. Similar results were observed in the different NIH-CPSI subscores break down. However, the same treatment did not result in significant improvement of the IIEF5 score. Both treatments did not produce undesired effects. CONCLUSIONS: The present results document the efficacy of an association of Palmitoylethanolamide (PEA) and Alpha-lipoic acid (ALA) administered for 12 weeks for treating patients with CP/CPPS, compared with Serenoa Repens monotherapy.

Disease Modifying Strategies in Multiple Sclerosis: New Rays of Hope to Combat Disability?

Multiple sclerosis (MS) is the most prevalent chronic autoimmune inflammatory- demyelinating disorder of the central nervous system (CNS). It usually begins in young adulthood, mainly between the second and fourth decades of life. Usually, the clinical course is characterized by the involvement of multiple CNS functional systems and by different, often overlapping phenotypes. In the last decades, remarkable results have been achieved in the treatment of MS, particularly in the relapsing- remitting (RRMS) form, thus improving the long-term outcome for many patients. As deeper knowledge of MS pathogenesis and respective molecular targets keeps growing, nowadays, several lines of disease-modifying treatments (DMT) are available, an impressive change compared to the relative poverty of options available in the past. Current MS management by DMTs is aimed at reducing relapse frequency, ameliorating symptoms, and preventing clinical disability and progression. Notwithstanding the relevant increase in pharmacological options for the management of RRMS, research is now increasingly pointing to identify new molecules with high efficacy, particularly in progressive forms. Hence, future efforts should be concentrated on achieving a more extensive, if not exhaustive, understanding of the pathogenetic mechanisms underlying this phase of the disease in order to characterize novel molecules for therapeutic intervention. The purpose of this review is to provide a compact overview of the numerous currently approved treatments and future innovative approaches, including neuroprotective treatments as anti-LINGO-1 monoclonal antibody and cell therapies, for effective and safe management of MS, potentially leading to a cure for this disease.

Insight into Risk Factors, Pharmacogenetics/Genomics, and Management of Adverse Drug Reactions in Elderly: A Narrative Review.

The European Medicine Agency (EMA) has defined Adverse Drug Reactions (ADRs) as "a noxious and unintended response to a medicine", not including poisoning, accidental, or intentional overdoses. The ADR occurrence differs based on the approach adopted for defining and detecting them, the characteristics of the population under study, and the research setting. ADRs have a significant impact on morbidity and mortality, particularly among older adults, and represent a financial burden for health services. Between 30% and 60% of ADRs might be predictable and preventable, emerging as a result of inappropriate prescription, drug chemistry inherent toxicity, cell-specific drug toxicity, age- and sex-related anomalies in drug absorption, distribution, metabolism, and elimination (ADME), and drug-drug interactions (DDIs) in combination therapies or when a patient is treated with different drugs for concomitant disorders. This is particularly important in chronic diseases which require long-term treatments. Rapid developments in pharmacogenetics/genomics have improved the understanding of ADRs accompanied by more accurate prescriptions and reduction in unnecessary costs. To alleviate the burden of ADRs, especially in the elderly, interventions focused on pharmaceutical principles, such as medication review and reconciliation, should be integrated into a broader assessment of patients' characteristics, needs, and health priorities. Digital health interventions could offer valuable solutions to assist healthcare professionals in identifying inappropriate prescriptions and promoting patient adherence to pharmacotherapies.

Ampicillin plus ceftriaxone therapy against Enterococcus faecalis endocarditis: A case report, guidelines considerations, and literature review.

Enterococcus faecalis infective endocarditis (EFIE) continues to be a very serious disease, showing considerable morbidity and mortality rates which are influenced by the spread of multi-drug resistant strains occurred in the last decades. Although aminoglycosides were considered the treatment of choice of EIFE, in recent years several studies have investigated alternative therapeutic approaches, including combinations of beta-lactams, mainly because of the aminoglycoside-renowned nephrotoxicity and the widespread development of high-level aminoglycosides resistance (HLAR). In this scenario, we reported a case involving a prosthetic valve infective endocarditis caused by an aminoglycoside-resistant E. faecalis strain which was successfully treated with ampicillin plus ceftriaxone despite the presence of artificial heart valve and the patient's severe clinical conditions.

Anti-malarial Drugs are Not Created Equal for SARS-CoV-2 Treatment: A Computational Analysis Evidence.

BACKGROUND: The evolution of the pandemic has burdened the national healthcare systems worldwide and at present, there is no preferred antiviral treatment for COVID-19. Recently, the SARS-Cov-2 protease structure was released that may be exploited in in-silico studies in order to conduct molecular docking analysis. METHODS: In particular, we compared the binding of twoantimalarial drugs, already in use, (i.e. chloroquine and hydroxychloroquine), which showed some potential clinical effects on COVID-19 patients, using ritonavir, lopinavir and darunavir as positive control tree antiviral recognized compounds. RESULTS: Our results showed that hydroxychloroquine but not chloroquine exhibited a significant binding activity to the main protease similar to that possessed by protease inhibitors tested for other viral infections. CONCLUSION: Our data suggest that hydroxychloroquine may exert additional direct antiviral activity compared to chloroquine. In the absence of clinical studies comparing the efficacy of these two compounds, hydroxychloroquine may offer additional effects and may be considered as the first choice.

Ampicillin Plus Ceftriaxone Regimen against Enterococcus faecalis Endocarditis: A Literature Review.

Enterococcus faecalis infective endocarditis (EFIE) continues to represent a potentially fatal infectious disease characterized by elevated morbidity and mortality. Despite advances in antimicrobial therapy, changing demographics and the reduced availability of useful antibiotics combined with the dissemination of multi-drug resistant strains, the mortality rate remained unchanged in the last decades. Nowadays, optimizing the antibiotic regimen is still of paramount importance. Historically, aminoglycosides were considered as a cornerstone for treatment even though their use is associated with a high risk of kidney failure. It is against this background that, in recent years, several studies have been carried in order to assess the validity of alternative therapeutic approaches, including combinations of beta-lactams, that, acting synergistically, have yielded useful results in different clinical settings. In this scenario, we searched and critically report clinical studies assessing the efficacy and safety of double beta-lactam therapy in treating EFIE.

Stem Cells: Innovative Therapeutic Options for Neurodegenerative Diseases?

Neurodegenerative diseases are characterized by the progressive loss of structure and/or function of both neurons and glial cells, leading to different degrees of pathology and loss of cognition. The hypothesis of circuit reconstruction in the damaged brain via direct cell replacement has been pursued extensively so far. In this context, stem cells represent a useful option since they provide tissue restoration through the substitution of damaged neuronal cells with exogenous stem cells and create a neuro-protective environment through the release of bioactive molecules for healthy neurons, as well. These peculiar properties of stem cells are opening to potential therapeutic strategies for the treatment of severe neurodegenerative disorders, for which the absence of effective treatment options leads to an increasingly socio-economic burden. Currently, the introduction of new technologies in the field of stem cells and the implementation of alternative cell tissues sources are pointing to exciting frontiers in this area of research. Here, we provide an update of the current knowledge about source and administration routes of stem cells, and review light and shadows of cells replacement therapy for the treatment of the three main neurodegenerative disorders (Amyotrophic lateral sclerosis, Parkinson's, and Alzheimer's disease).

Repositioning of Immunomodulators: A Ray of Hope for Alzheimer's Disease?

Alzheimer's disease (AD) is the most common age-related neurodegenerative disorder characterized by cognitive decline and by the presence of amyloid ß plaques and neurofibrillary tangles in the brain. Despite recent advances in understanding its pathophysiological mechanisms, to date, there are no disease-modifying therapeutic options, to slow or halt the evolution of neurodegenerative processes in AD. Current pharmacological treatments only transiently mitigate the severity of symptoms, with modest or null overall improvement. Emerging evidence supports the concept that AD is affected by the impaired ability of the immune system to restrain the brain's pathology. Deep understanding of the relationship between the nervous and the immune system may provide a novel arena to develop effective and safe drugs for AD treatment. Considering the crucial role of inflammatory/immune pathways in AD, here we discuss the current status of the immuno-oncological, immunomodulatory and anti-TNF-α drugs which are being used in preclinical studies or in ongoing clinical trials by means of the drug-repositioning approach.