Chiara Sasia

Background/Objectives: Chronic stress leads to sustained elevations in cortisol levels, which promote neuronal damage and impair memory. Prolonged stress also enhances proinflammatory signaling. Adaptogens are plant-derived compounds associated with the ability to increase the body’s resistance to stress, thereby improving mental and physical performance. To identify potential interventions capable of attenuating stress-related memory alterations, this study investigated a formulation combining the adaptogen Bacopa monnieri L. with phosphatidylserine and choline (BPC). Methods: An in vitro model of stress-related neuroinflammation was established by exposing BV2 microglial cells to corticotropin-releasing hormone (CRH, 100 nM). SH-SY5Y cells exposed to conditioned medium from CRH-stimulated BV2 cells or to iron(II) sulfate and L-ascorbic acid (Fe/Asc) were used as models of neurotoxicity. Results: BPC attenuated CRH-induced proinflammatory microglial morphology, as well as the reduction in cell viability and cell number. BPC treatment restored the levels of stress-related markers, including SIRT-1, Nrf-2, and phosphorylated JNK (p-JNK). Furthermore, BPC protected against neurotoxicity induced by CRH and Fe/Asc and promoted cholinergic activation by restoring basal acetylcholinesterase (AChE) levels. The combined BPC formulation showed superior efficacy compared with its individual components across all experimental assays. Conclusions: Collectively, these findings indicate that the BPC formulation developed in this study effectively attenuates stress-related neuroinflammation and neurotoxicity. BPC may represent a promising strategy to help limit the progression of early cognitive dysfunction under conditions of prolonged stress.

Activation of microglia and resulting neuroinflammation are central processes that significantly contribute to neurodegenerative disease progression. Treatments capable of attenuating neuroinflammation are therefore an urgent medical need. Vitis vinifera L., cultivated since ancient times for its fruits, is known for its antioxidant and anti-inflammatory activities. However, polyphenols, the main bioactive molecules in V. vinifera extracts, exhibit considerable variability due to numerous hard-to-control factors, which complicates the production of standardized extracts with consistent biological activity. To address this issue, plant cell culture biotechnology was used to produce a highly standardized V. vinifera phytocomplex (VP), and its anti-neuroinflammatory profile was investigated in LPS-stimulated microglial cells, an in vitro model of neuroinflammation. VP reduced the LPS-induced pro-inflammatory phenotype, improved cell viability and cell number, attenuated NF-κB activation and ERK1/2 phosphorylation, and increased SIRT1 levels. To overcome VP’s poor water solubility, water-soluble cellulose nanocrystal (CNC)-based formulations were developed and tested. VP-CNC formulations markedly reduced the BV2 pro-inflammatory phenotype and increased cell viability under both basal and LPS-stimulated conditions. The nanoformulations also decreased pERK1/2 levels and increased SIRT1 expression, exhibiting biological activities comparable to VP alone. V. vinifera phytocomplex derived from plant cell cultures represents an innovative and standardized product with promising anti-neuroinflammatory properties.

Activation of microglia and resulting neuroinflammation are central processes that significantly contribute to neurodegenerative disease progression. Treatments capable of attenuating neuroinflammation are therefore an urgent medical need. Vitis vinifera L., cultivated since ancient times for its fruits, is known for its antioxidant and anti-inflammatory activities. However, polyphenols, the main bioactive molecules in V. vinifera extracts, vary considerably due to numerous hard-to-control factors, making it difficult to obtain standardized extracts with consistent biological activity. To address this issue, plant cell culture biotechnology was used to produce a highly standardized V. vinifera phytocomplex (VP), and its anti-neuroinflammatory profile was investigated in LPS-stimulated microglial cells, an in vitro model of neuroinflammation. VP reduced the LPS-induced pro-inflammatory phenotype, improved cell viability and cell number, attenuated NF-κB activation and ERK1/2 phosphorylation, and increased SIRT1 levels. To overcome VP’s poor water solubility, water-soluble, nanocellulose-based formulations containing cellulose nanocrystal (CNC) were developed and tested. VP-CNC formulations markedly reduced the BV2 pro-inflammatory phenotype and increased cell viability under both basal and LPS-stimulated conditions. The nanoformulations also decreased pERK1/2 levels and increased SIRT1 expression, exhibiting biological activities comparable to VP alone. V. vinifera phytocomplex derived from plant cell cultures represents an innovative and standardized product with promising antineuroinflammatory properties.

Diabetic patients experience hyperglycemia, which can affect multiple organs, including brain function, leading to disabling neurological complications. Hyperglycemia plays a key role in promoting neuroinflammation, the most common complication in diabetic individuals, through the activation of microglia. Attenuating hyperglycemia-related neuroinflammation in microglia may reduce diabetes-associated neurological comorbidities. Natural remedies containing phenolic compounds have shown efficacy in mitigating microglia-mediated neuroinflammation. The aim of this study was to investigate the potential of a Melissa officinalis L. (MO) phytocomplex, obtained from plant cell cultures and enriched in its main polyphenolic constituent, rosmarinic acid (RA), in attenuating hyperglycemia-induced neuroinflammation in microglia. A time-course morphological analysis of BV2 microglial cells exposed to high glucose (HG) levels showed a shift towards a proinflammatory phenotype, peaking after 48 h, which was reversed by pretreatment with MO. Biochemical assays revealed increased expression of the microglial marker CD11b (187%), activation of the NF-κB pathway (179%), expression of iNOS (225%), enhanced phosphorylation of ERK1/2 (180%), and increased expression of the proinflammatory cytokine IL-6 (173%). Pretreatment with MO prevented the aberrant expression of these proinflammatory mediators and restored SIRT1 levels. Exposure of neuronal SH-SY5Y cells to the conditioned medium from HG-exposed microglia significantly reduced cell viability. MO counteracted this effect, exhibiting neuroprotective activity. RA showed efficacy comparable to that of MO. In conclusion, MO and RA attenuated microglia-mediated oxidative imbalance and neuroinflammation under HG exposure by inhibiting the morphological shift toward a proinflammatory phenotype induced by HG and abrogating the subsequent activation of the downstream ERK1/2–NF-κB–iNOS pathway.

Background/Objectives: Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system characterized by demyelination and neuronal damage. Current MS therapies are unsatisfactory, and new therapies are encouraged. A correlation between nutritional intake and MS has been speculated. Supplementation of approved immunomodulatory therapy with herbal medicines possessing antioxidant and anti-inflammatory activities could provide benefits to MS patients. Ginger is one of the most widely consumed dietary supplements in the world, commonly used in traditional medicine. Studies demonstrated that ginger may also be beneficial in the management of neurodegenerative diseases. The aim of this study is to investigate the MS therapeutic potential of ginger. Methods: A standardized Zingiber officinale Roscoe extract (ZOE) was orally administered for 14 days. Two experimental autoimmune encephalomyelitis (EAE) models in mice were used. The PLP_139-151-EAE relapsing-remitting model and MOG_35–55-EAE chronic model. Clinical score, von Frey, hot plate, and rotarod tests were used for behavioral tests. ELISA and Western blotting were used to measure cytokines levels. Evans Blue content was determined spectrophotometrically. Results: ZOE attenuated motor disability and pain hypersensitivity in both models had no effect on body weight loss. ZOE reduced the blood–brain barrier (BBB) permeability in the PLP-EAE models and reduced levels of circulating cytokines (Il-6, IL-17) in the MOG-EAE model. ZOE attenuated spinal cytokines overexpression in both models. Conclusions: ZOE improves EAE symptoms and attenuates the proinflammatory response in both models, representing a promising nutraceutical support to the conventional therapeutic approach to MS.

Microglia-mediated neuroinflammation has been linked to neurodegenerative disorders. Inflammation and aging contribute to microglial senescence. Microglial senescence promotes the development of neurodegenerative disorders, including Alzheimer’s disease (AD). In this study, we investigated the anti-neuroinflammatory and anti-senescence activity of Honokiol (HNK), a polyphenolic neolignane from Magnolia officinalis Rehder & E.H Wilson, in comparison with its synthetic analogue Honokiol Hexafluoro (CH). HNK reduced the pro-inflammatory cell morphology of LPS-stimulated BV2 microglia cells and increased the expression of the anti-inflammatory cytokine IL-10 with an efficacy comparable to CH. HNK and CH were also able to attenuate the alterations in cell morphology associated with cellular senescence in BV2 cells intermittently stimulated with LPS and significantly reduce the activity and expression of the senescence marker ß-galactosidase and the expression of p21 and pERK1/2. The treatments reduced the expression of senescence-associated secretory phenotype (SASP) factors IL-1ß and NF-kB, decreased ROS production, and abolished H2AX over phosphorylation (γ-H2AX) and acetylated H3 overexpression. Senescent microglia cells showed an increased expression of the Notch ligand Jagged1 that was reduced by HNK and CH with a comparable efficacy to the Notch inhibitor DAPT. Overall, our data illustrate a protective activity of HNK and CH on neuroinflammation and cellular senescence in microglia cells involving a Notch-signaling-mediated mechanism and suggesting a potential therapeutic contribution in aging-related neurodegenerative diseases.

Growing evidence indicates chronic low-grade systemic inflammation as a major pathophysiological mechanism of obesity. Systemic inflammation provokes an immune response in the brain through the activation of microglia that results in the development of neuroinflammation, cellular senescence, and occurrence of neurological dysfunction. In the efforts to identify an innovative intervention with potential efficacy on obesity and associated complications, our aim was to study the capability of the dietary supplement Dekosilhue^® (DKS), successfully used for improving the control of body weight, to attenuate microglia senescent phenotype. Microglia senescence was induced by intermittent stimulation of BV2 cells with LPS 500 ng/mL every 72 h for 4 h/day, over a period of 10 days. DKS (100 µg/mL) treatment reduced ß-galactosidase activity and expression, the formation of senescence-associated heterochromatin foci to control levels, and increased cell viability of senescent BV2 (2 folds of control). DSK reduced the expression of Nuclear Factor-kB (NF-kB) (20% lower than control), a key molecule involved in the acquisition of the senescence-associated secretory phenotype (SASP). DKS promoted a neuroprotective effect by increasing the cell viability of SH-SY5Y neuronal cells exposed to the senescent BV2 conditioned medium to values of non-senescent cells. In conclusion, DKS attenuated the senescent microglia phenotype, showing senotherapeutic activity that might be further investigated as adjunctive intervention for obesity and obesity-related neurological disturbances.