Metformin increases APP expression and processing via oxidative stress, mitochondrial dysfunction and NF-κB activation: Use of insulin to attenuate metformin's effect

AbstractClinical and experimental biomedical studies have shown Type 2 diabetes mellitus (T2DM) to be a risk factor for the development of Alzheimer's disease (AD). This study demonstrates the effect of metformin, a therapeutic biguanide administered for T2DM therapy, on β-amyloid precursor protein (APP) metabolism in in vitro, ex vivo and in vivo models. Furthermore, the protective role of insulin against metformin is also demonstrated. In LAN5 neuroblastoma cells, metformin increases APP and presenilin levels, proteins involved in AD. Overexpression of APP and presenilin 1 (Pres 1) increases APP cleavage and intracellular accumulation of β-amyloid peptide (Aβ), which, in turn, promotes aggregation of Aβ. In the experimental conditions utilized the drug causes oxidative stress, mitochondrial damage, decrease of Hexokinase-II levels and cytochrome C release, all of which lead to cell death. Several changes in oxidative stress-related genes following metformin treatment were detected by PCR arrays specific for the oxidative stress pathway. These effects of metformin were found to be antagonized by the addition of insulin, which reduced Aβ levels, oxidative stress, mitochondrial dysfunction and cell death. Similarly, antioxidant molecules, such as ferulic acid and curcumin, are able to revert metformin's effect. Comparable results were obtained using peripheral blood mononuclear cells. Finally, the involvement of NF-κB transcription factor in regulating APP and Pres 1 expression was investigated. Upon metformin treatment, NF-κB is activated and translocates from the cytoplasm to the nucleus, where it induces increased APP and Pres 1 transcription. The use of Bay11-7085 inhibitor suppressed the effect of metformin on APP and Pres 1 expression

An extreme negative sea level in the Mediterranean Basin: San Giorgio case study compared with Adriatic Sea

The aim of this paper is to discuss the case of an extreme negative sea level phenomenon that occurred along Sicily Island’s coasts (Italy). Sea level time series associated to six stations that are part of the Italian tide gauge network have been analysed. By deriving the tidal residual and by evaluating meteorological parameters’ trends, it was possible to give an explanation to this phenomenon

Neurological Consequences, Mental Health, Physical Care, and Appropriate Nutrition in Long-COVID-19

SARS-CoV-2 pandemic has caused a collapse of the world health systems. Now, vaccines and more effective therapies have reversed this crisis but the scenario is further aggravated by the appearance of a new pathology, occurring as SARS-CoV-2 infection consequence: the long-COVID-19. This term is commonly used to describe signs and symptoms that continue or develop after acute infection of COVID-19 up to several months. In this review, the consequences of the disease on mental health and the neurological implications due to the long-COVID are described. Furthermore, the appropriate nutritional approach and some recommendations to relieve the symptoms of the pathology are presented. Data collected indicated that in the next future the disease will affect an increasing number of individuals and that interdisciplinary action is needed to counteract it

Moringa oleifera Leaf Powder as Functional Additive in Cookies to Protect SH-SY5Y Cells

The aim of this work is the evaluation of the addition of Moringa leaf powder (MLP) in cookies in terms of antioxidant properties, dough processability and sensorial properties of the cookies. The total content of biophenols and flavonoids in MLP was detected and the identification of the bioactive molecules was performed by HPLC-ESI-TOF-MS measurements, before and after oven treatment at 180 ◦C for 20 min. After a preliminary evaluation of the MLP water soluble fraction (MLPsf) cytotoxicity, its protective effect against an oxidative injury induced in the SH-SY5Y cells was assessed. Data evidence that the bioactive molecules present in MLPsf are effective in preventing ROS production and in protecting neuronal cells against oxidative stress. Prototypes of cookies containing MLP in different concentrations were then produced and evaluated by a consumer panel. Selected doughs containing MLP were analysed to determine the total content of biophenols in the cookies after baking and their enrichment in terms of valuable chemical elements. The influence of MLP on the viscoelastic behaviour and morphology of the doughs was also assessed. Finally, the potential role in counteracting the insurgence of not treatable neurodegenerative pathologies of two main MLP components, glucomoringin and kaempferol derivatives, present also after the thermal treatment, was discussed

Imaging features of pancreatic metastases: A comparison with pancreatic ductal adenocarcinoma

Purpose: To compare imaging features of pancreatic metastases (PM) with those of pancreatic ductal adenocarcinomas (PDAC). Methods: CT and MR scans of 24 patients with 54 PM and 30 patients with PDAC were reviewed to evaluate the imaging features, which were compared by using a Chi square test. Results: We found a statistically significant difference between PM and PDAC based on location (P < 0.001), margins (P < 0.001), arterial enhancement (P = 0.004), rim enhancement (P < 0.001), pancreatic duct dilatation (P = 0.01), common bile duct dilatation (P = 0.003), vascular involvement (P = 0.02), parenchymal atrophy (P < 0.001), peripancreatic fluid (P = 0.03). Conclusion: Imaging features might be helpful to differentiate PM from PDAC

From Small Peptides to Large Proteins against Alzheimer'sDisease

Alzheimer's disease (AD) is the most common neurodegenerative disorder in the elderly. The two cardinal neuropathological hallmarks of AD are the senile plaques, which are extracellular deposits mainly constituted by beta-amyloids, and neurofibrillary tangles formed by abnormally phosphorylated Tau (p-Tau) located in the cytoplasm of neurons. Although the research has made relevant progress in the management of the disease, the treatment is still lacking. Only symptomatic medications exist for the disease, and, in the meantime, laboratories worldwide are investigating disease-modifying treatments for AD. In the present review, results centered on the use of peptides of different sizes involved in AD are presented

Protective, Antioxidant and Antiproliferative Activity of Grapefruit IntegroPectin on SH-SY5Y Cells

Tested in vitro on SH-SY5Y neuroblastoma cells, grapefruit IntegroPectin is a powerful protective, antioxidant and antiproliferative agent. The strong antioxidant properties of this new citrus pectin, and its ability to preserve mitochondrial membrane potential and morphology, severely impaired in neurodegenerative disorders, make it an attractive therapeutic and preventive agent for the treatment of oxidative stress-associated brain disorders. Similarly, the ability of this pectic polymer rich in RG-I regions, as well as in naringin, linalool, linalool oxide and limonene adsorbed at the outer surface, to inhibit cell proliferation or even kill, at high doses, neoplastic cells may have opened up new therapeutic strategies in cancer research. In order to take full advantage of its vast therapeutic and preventive potential, detailed studies of the molecular mechanism involved in the antiproliferative and neuroprotective of this IntegroPectin are urgently needed

Systemic Immune Responses in Alzheimer’s Disease: In Vitro Mononuclear Cell Activation and Cytokine Production

To investigate the systemic signs of immune-inflammatory responses in Alzheimer’s disease (AD), in the present study we have analyzed blood lymphocyte subsets and the expression of activation markers on peripheral blood mononuclear cells (PBMCs) fromADpatients and age-matched healthy controls (HC) activated in vitro by recombinant amyloid-β peptide (rAβ42). Our study of AD lymphocyte subpopulations confirms the already described decrease of the absolute number and percentage of B cells when compared to HC lymphocytes, whereas the other subsets are not significantly different in patients and controls. We report the increased expression of the activation marker CD69 and of the chemokine receptors CCR2 and CCR5 on T cells but no changes of CD25 after activation. B cells are also activated by rAβ42 as demonstrated by the enhanced expression of CCR5. Moreover, rAβ42 induces an increased expression of the scavenger receptor CD36 on monocytes. Some activation markers and chemokine receptors are overexpressed in unstimulated AD cells when compared to controls. This is evidence of the pro-inflammatory status of AD. Stimulation by rAβ42 also induces the production of the pro-inflammatory cytokines IL-1β, IL-6, IFN-γ, and TNF-α, and of the anti-inflammatory cytokines IL-10 and IL-1Ra. The chemokines RANTES, MIP-1β, and eotaxin as well as some growth factors (GM-CSF, G-CSF) are also overproduced by AD-derived PBMC activated by rAβ42. These results support the involvement of systemic immunity in AD patients. However, our study is an observational one so we cannot draw a conclusion about its contribution to the pathophysiology of the disease

NMR Studies on Structure and Dynamics of the Monomeric Derivative of BS-RNase: New Insights for 3D Domain Swapping

Three-dimensional domain swapping is a common phenomenon in pancreatic-like ribonucleases. In the aggregated state, these proteins acquire new biological functions, including selective cytotoxicity against tumour cells. RNase A is able to dislocate both N- and C-termini, but usually this process requires denaturing conditions. In contrast, bovine seminal ribonuclease (BS-RNase), which is a homo-dimeric protein sharing 80% of sequence identity with RNase A, occurs natively as a mixture of swapped and unswapped isoforms. The presence of two disulfides bridging the subunits, indeed, ensures a dimeric structure also to the unswapped molecule. In vitro, the two BS-RNase isoforms interconvert under physiological conditions. Since the tendency to swap is often related to the instability of the monomeric proteins, in these paper we have analysed in detail the stability in solution of the monomeric derivative of BS-RNase (mBS) by a combination of NMR studies and Molecular Dynamics Simulations. The refinement of NMR structure and relaxation data indicate a close similarity with RNase A, without any evidence of aggregation or partial opening. The high compactness of mBS structure is confirmed also by H/D exchange, urea denaturation, and TEMPOL mapping of the protein surface. The present extensive structural and dynamic investigation of (monomeric) mBS did not show any experimental evidence that could explain the known differences in swapping between BS-RNase and RNase A. Hence, we conclude that the swapping in BS-RNase must be influenced by the distinct features of the dimers, suggesting a prominent role for the interchain disulfide bridges