Cognitive Decline in Early and Premature Menopause.

Early and premature menopause, or premature ovarian insufficiency (POI), affects 1% of women under the age of 40 years. This paper reviews the main aspects of early and premature menopause and their impact on cognitive decline. Based on the literature, cognitive complaints are more common near menopause: a phase marked by a decrease in hormone levels, especially estrogen. A premature reduction in estrogen puts women at a higher risk for cardiovascular disease, parkinsonism, depression, osteoporosis, hypertension, weight gain, midlife diabetes, as well as cognitive disorders and dementia, such as Alzheimer's disease (AD). Experimental and epidemiological studies suggest that female sex hormones have long-lasting neuroprotective and anti-aging properties. Estrogens seem to prevent cognitive disorders arising from a cholinergic deficit in women and female animals in middle age premature menopause that affects the central nervous system (CNS) directly and indirectly, both transiently and in the long term, leads to cognitive impairment or even dementia, mainly due to the decrease in estrogen levels and comorbidity with cardiovascular risk factors, autoimmune diseases, and aging. Menopausal hormone therapy from menopause to the age of 60 years may provide a "window of opportunity" to reduce the risk of mild cognitive impairment (MCI) and AD in later life. Women with earlier menopause should be taken care of by various specialists such as gynecologists, endocrinologists, neurologists, and psychiatrists in order to maintain their mental health at the highest possible level.

New therapeutic targeting of Alzheimer's disease with the potential use of proline-rich polypeptide complex to modulate an innate immune response - preliminary study.

BACKGROUND: The lack of effective treatment for Alzheimer's disease (AD) stems mainly from the incomplete understanding of AD causes. Neuroinflammation has emerged as an important component of AD pathology, and a vast number of experimental and clinical data indicated a crucial role for the activation of the innate immune system in disease promotion and symptom progression. METHODS: Clinical examinations of AD patients in a different stage of disease severity in correlation with the measurement of two innate immune reactions, i.e., peripheral blood leukocyte (PBLs) resistance to viral infection (vesicular stomatitis virus, VSV) ex vivo, and cytokines: TNF-α, IFN-γ, IL-1ß, and IL-10, production with enzyme-linked immunosorbent assay (ELISA), have been investigated during this preliminary study before and after 4 weeks of oral treatment with dietary supplement proline-rich polypeptide complex (PRP) (120 µg of PRP/day). The potential effect of PRP on the distribution of PBLs' subpopulations has been specified. RESULTS: We have found a deficiency in innate immune response in AD patients. It was demonstrated for the first time that the degree of PBLs resistance to VSV infection was closely related to the stage of clinical severity of AD. Our study showed significant differences in cytokine production which pointed that in AD patients innate immune mechanisms are impaired. Administration of PRP to our patients increased innate immune response of PBLs and declined pro- and anti-inflammatory cytokine production, thus subduing the excessively developed inflammatory response, especially among patients with high severity of AD. PRP did not exhibit a pro-proliferative activity. It was showed, however, significant influence of PRP on the distribution of PBLs' subpopulations. CONCLUSION: The findings mentioned above might be crucial in the context of potential application of immunomodulatory therapy in AD patients and indicated PRP as a potential target for future treatments in neuroinflammatory diseases like AD.

Sex Differences in Innate Immune Response of Peripheral Blood Leukocytes of Alzheimer's Disease Patients.

Neurodegenerative disorders, including Alzheimer's disease (AD), are associated with a disruption of normal immune function that could potentially impact the brain. In AD sex and gender have been noted as relevant to disease prevalence or clinical manifestation. It is suggested that disease progression could vary as a result of the different inflammation state among males and females. The objective was to investigate sex-dependent difference in innate immunity of AD patients and healthy, age-matched controls. The level of innate immunity was measured with test based on peripheral blood leukocytes (PBLs) resistance to viral infection (vesicular stomatitis virus, VSV) ex vivo. Cytokine: TNF-α, IFN-γ, IL-1ß, IL-10 production by uninfected and VSV-infected PBLs ex vivo with enzyme-linked immunosorbent assay were examined. In contrast to controls, women with AD exhibit lower average level of innate immunity than AD men. The mean level of TNF-α, IL-10 and IL-1ß was higher in AD men than in AD women whereas such changes were not observed among controls. The level of IFN-γ was higher in AD than in controls. PBLs from AD did not increase IFN-γ production after viral infection in contrast to controls. Leukocytes from women with AD exhibited a weaker response to viral infection and much less cytokine production compared to men with AD. It is important to consider sex as a biological variable in AD as it shows promises to advance our understanding of mechanisms of AD pathology and may be the basis for future treatment of AD.

Ginkgo Biloba Leaf Extract Improves an Innate Immune Response of Peripheral Blood Leukocytes of Alzheimer's Disease Patients.

BACKGROUND: One of the main features of Alzheimer's disease (AD) pathology is failure in innate immune response and chronic inflammation. Lack of effective AD treatment means that more attention is paid to alternative therapy and drugs of natural origin, such as extract of Ginkgo biloba (EGb). The purpose of this study was to investigate the effect of EGb on the mechanisms of innate immune response of peripheral blood leukocytes (PBLs) in AD patients. METHODS: In AD patients and healthy-age matched controls, the effect of EGb on two of innate immune reactions, i.e., PBLs resistance to viral infection ex vivo and production of cytokines, namely TNF-α, IFN-γ, IL-1ß, IL-10, IL-15, and IFN-α, were investigated. The influence of EGb on inflammatory-associated genes expression that regulate innate immune response to viral infection and cytokine production, namely IRF-3, IRF-7, tetherin, SOCS1, SOCS3, NFKB1, p65, and MxA was also examined. RESULTS: A beneficial effect of EGb especially in AD women was observed. EGb decreased production of TNF-α, IFN-γ, and IL-10 and increased IL-15 and IL-1ß. The effect was more pronouncement in AD group. EGb also downregulated expression of investigated genes. CONCLUSIONS: EGb may have an advantageous properties for health management in elderly and AD sufferers but especially in women with AD. Improving peripheral innate immune cells' activity by adding EGb as accompanying treatment in AD may be, in the long term, a good course to modify the disease progression.

Inhibition of Human Respiratory Influenza A Virus and Human Betacoronavirus-1 by the Blend of Double-Standardized Extracts of Aronia melanocarpa (Michx.) Elliot and Sambucus nigra L.

Viral and bacterial diseases are among the greatest concerns of humankind since ancient times. Despite tremendous pharmacological progress, there is still a need to search for new drugs that could treat or support the healing processes. A rich source of bioactive compounds with antiviral potency include plants such as black chokeberry and elderberry. The aim of this study was to assess the in vitro antiviral ability of an originally designed double-standardized blend of extracts from Aronia melanocarpa (Michx.) Elliot and Sambucus nigra L. (EAM-ESN) or separated extracts of A. melanocarpa (EAM) or S. nigra (ESN) against four human respiratory tract viruses: influenza A virus (A/H1N1), betacoronavirus-1 (HCoV-OC43) belonging to the same ß-coronaviruses as the current pandemic SARS-CoV-2, human herpesvirus type 1 (HHV-1), and human adenovirus type 5 (HAdV-5). Antiviral assays (AVAs) were used to evaluate the antiviral activity of the plant extracts in a cell-present environment with extracts tested before, simultaneously, or after viral infection. The virus replication was assessed using the CPE scale or luminescent assay. The EAM-ESN blend strongly inhibited A/H1N1 replication as well as HCoV-OC43, while having a limited effect against HHV-1 and HAdV-5. This activity likely depends mostly on the presence of the extract of S. nigra. However, the EAM-ESN blend possesses more effective inhibitory activity toward virus replication than its constituent extracts. A post-infection mechanism of action of the EAM-ESN make this blend the most relevant for potential drugs and supportive treatments; thus, the EAM-ESN blend might be considered as a natural remedy in mild, seasonal respiratory viral infections.

Current and Near-Future Treatment of Alzheimer's Disease.

Recent findings have improved our understanding of the multifactorial nature of AD. While in early asymptomatic stages of AD, increased amyloid-ß synthesis and tau hyperphosphorylation play a key role, while in the latter stages of the disease, numerous dysfunctions of homeostatic mechanisms in neurons, glial cells, and cerebrovascular endothelium determine the rate of progression of clinical symptoms. The main driving forces of advanced neurodegeneration include increased inflammatory reactions in neurons and glial cells, oxidative stress, deficiencies in neurotrophic growth and regenerative capacity of neurons, brain insulin resistance with disturbed metabolism in neurons, or reduction of the activity of the Wnt-ß catenin pathway, which should integrate the homeostatic mechanisms of brain tissue. In order to more effectively inhibit the progress of neurodegeneration, combination therapies consisting of drugs that rectify several above-mentioned dysfunctions should be used. It should be noted that many widely-used drugs from various pharmacological groups, "in addition" to the main therapeutic indications, have a beneficial effect on neurodegeneration and may be introduced into clinical practice in combination therapy of AD. There is hope that complex treatment will effectively inhibit the progression of AD and turn it into a slowly progressing chronic disease. Moreover, as the mechanisms of bidirectional communication between the brain and microbiota are better understood, it is expected that these pathways will be harnessed to provide novel methods to enhance health and treat AD.

Metal and bimetallic nanoparticles: Flow synthesis, bioactivity and toxicity.

HYPOTHESIS: Metal nanoparticles are used as additives in commercial products due to their antimicrobial properties. Apart from their high biocidal activity, it is widely observed that silver nanoparticles are toxic. Simultaneously, copper nanoparticles show fungicidal properties, but with limited effectiveness. Hence, it is suggested that a combination of Ag nanoparticles with Cu nanoparticles may decrease the toxic effects of silver while maintaining their high bioactivity. EXPERIMENTS: This paper presents the properties of Ag and Cu metal nanoparticles, and Ag-Cu and Cu-Ag bimetallic nanoparticles, synthesised in a continuous microwave reactor. The size of the metal nanoparticles obtained was in the range of 27-97 nm, and the size of the bimetallic nanoparticles was in the range of 32-184 nm, depending on the microwave irradiation, residence time, pH of the solution and concentrations of the reagents. FINDINGS: Silver nanoparticles of particle size 97 nm revealed the highest antimicrobial activity (MIC = 10 mg/dm3). Simultaneously, silver nanoparticles did not show viral properties, compared to the copper and bimetallic nanoparticles, for which the virus titre was 1.06-1.50 log TCID50/cm3. In contrast to pure metal nanoparticles, the combination of silver and copper in bimetallic systems generated nanoparticles with no genotoxicity (rac(-)/rac(+) < 1.2).

Ligase Pellino3 Regulates Macrophage Action and Survival in Response to VSV Infection in RIG-I-Dependent Path.

Sensing of viral particles and elements that initiate mechanisms of immune response is an intrinsic ability of mammalian cells. Regulatory cytokines and antiviral mediators are released after triggering of complex signaling cascades in response to interaction of pathogen particles with pattern recognition receptors (PRRs) leading to the production of interferons (IFN) and proinflammatory cytokines. Viral RNA in the cytoplasm constitute a potent danger molecule that recognition is performed by RIG-I-like receptors, the most common group of receptors in mammalian cells, capable to recognize a foreign RNA. It is known that the E3 ubiquitin ligase Pellino3 plays an important role in antibacterial and antiviral response, but its involvement in the RLR pathways remains poorly understood. In this study, we investigate the molecular mechanisms of the innate immune response in BMDMs (immortalized macrophages from mouse bone marrow) during VSV infection. Here, we present evidence that the activation of the RIG-I/Pellino3/ERK1/2 pathway in BMDMs is crucial for the protection against VSV. We demonstrate that during infection, viral particles replicate in Pellino3 knockout BMDMs more effectively than in wild-type cells. Increased viral replication resulting in cell lysis and death is aid by impaired synthesis of IFN-I and inflammatory cytokines as a consequence of disturbances in the ERK1/2 pathway regulation.

Hampering Herpesviruses HHV-1 and HHV-2 Infection by Extract of Ginkgo biloba (EGb) and Its Phytochemical Constituents.

Despite the availability of several anti-herpesviral agents, it should be emphasized that the need for new inhibitors is highly encouraged due to the increasing resistant viral strains as well as complications linked with periods of recurring viral replication and reactivation of latent herpes infection. Extract of Ginkgo biloba (EGb) is a common phytotherapeutics around the world with health benefits. Limited studies, however, have addressed the potential antiviral activities of EGb, including herpesviruses such as Human alphaherpesvirus 1 (HHV-1) and Human alphaherpesvirus 2 (HHV-2). We evaluated the antiviral activity of EGb and its phytochemical constituents: flavonoids and terpenes against HHV-1 and HHV-2. Pretreatment of the herpesviruses with EGb prior to infection of cells produced a remarkable anti-HHV-1 and anti-HHV-2 activity. The extract affected the viruses before adsorption to cell surface at non-cytotoxic concentrations. In this work, through a comprehensive anti-HHV-1 and anti-HHV-2 activity study, it was revealed that flavonoids, especially isorhamnetin, are responsible for the antiviral activity of EGb. Such activity was absent in quercetin and kaempferol. However, EGb showed the most potent antiviral potency compared to isorhamnetin. EGb could augment current therapies for herpes labialis and genital herpes. Moreover, the potential use of EGb in multidrug therapy with synthetic anti-herpes compounds might be considered.