Search Results (88)

Diabetes is a risk factor for periodontitis. Increasing evidence suggests that a central player in this link is the vacuolar H+-ATPase (V-ATPase), which provides a physical and functional core for regulation by the catabolic lysosomal AMP-activated protein kinase complex (L-AMPK) and the anabolic mammalian target of rapamycin complex 1 (mTORC1). These complexes detect levels of various cellular nutrients, including glucose at the lysosome, and promote cellular responses to restore homeostasis. The high-glucose conditions of diabetes foster anabolic mTORC1 signaling that increases inflammation and inflammatory bone resorption in response to periodontal infections. Here, we review the structure and composition of V-ATPase, L-AMPK, mTORC1, and other elements of the energy-sensing platform. Mechanisms by which V-ATPase passes signals to the complexes are examined and recent data are reviewed. Current anti-bone resorptive therapeutics, bisphosphonates and denosumab, enhance the risk of medicine-related osteonecrosis of the jaw (MRONJ) and are not used to treat periodontal bone loss. Accumulating data suggest that it may be possible to target inflammatory bone resorption through agents that stimulate L-AMPK, including metformin and glucagon-like peptide-1 agonists. This approach may reduce inflammatory bone resorption without major effects on overall bone remodeling or increased risk of MRONJ. Full article

Background: The blood–brain barrier (BBB) plays a critical role in protecting the central nervous system (CNS) but also limits drug delivery. Insufficient knowledge of how the CNS promotes the onset and maintenance of peripheral neuropathic pain limits therapeutic methods for the treatment of persistent neuropathic pain. Thus, this study aimed to evaluate the ability of a novel combination of Palmitoylethanolamide (PEA) and Equisetum arvense L. (Equisetum A.L.) to cross the BBB and modulate nociceptive pathways. Methods: Using a humanised in vitro BBB tri-culture model, the permeability, cytotoxicity, and integrity of the barrier were assessed after exposure to two different PEA forms, PEA ultramicronized (PEA-um) and PEA80mesh, Equisetum A.L., and a combination of the last two samples. The samples exhibited no cytotoxicity, maintained tight junction integrity, and efficiently crossed the blood–brain barrier (BBB), with the combination displaying the highest permeability. The eluate from the BBB model was then used to stimulate the co-culture of CCF-STTG1 astrocytes and SH-SY5Y neurons pre-treated with H₂O₂ 200 µM. Results: Treatment with the combination significantly increased cell viability (1.8-fold, p < 0.05), reduced oxidative stress (2.5-fold, p < 0.05), and decreased pro-inflammatory cytokines (TNFα, IL-1β) compared to single agents. Mechanistic analysis revealed modulation of key targets involved in pain pathways, including decreased FAAH and NAAA activity, increased levels of endocannabinoids (AEA and 2-AG), upregulation of CB2 receptor expression, enhanced PPARα activity, and reduced phosphorylation of PKA and TRPV1. Conclusions: These findings suggest that the combination of PEA and Equisetum A.L. effectively crosses the BBB and exerts combined anti-inflammatory and analgesic effects at the CNS level, suggesting a possible role in modulating neuroinflammatory and nociception responses. Full article

Inflammation plays a central role in various pathological conditions, necessitating the search for safer and more effective anti-inflammatory agents. This study investigates the anti-inflammatory activity of caulerpin, a bisindolic alkaloid isolated from Caulerpa racemosa. In vitro assays demonstrated that caulerpin significantly reduced nitric oxide, TNF-α, IL-6, and IL-12 levels in macrophages stimulated with LPS + IFN-γ, without affecting cell viability. In silico toxicity predictions using Protox 3.0 reinforce a favorable safety profile of caulerpin. Molecular docking and molecular dynamics simulations revealed its high-affinity binding to the glucocorticoid receptor ligand-binding domain (GR-LBD), suggesting a mechanism of action similar to dexamethasone. The involvement of the glucocorticoid receptor was confirmed by the partial reversal of caulerpin’s effects upon RU486 treatment. In vivo, caulerpin exhibited a favorable safety profile, with no signs of acute toxicity at an oral dose of 100 mg/kg. Moreover, in a mouse model of endotoxic shock, caulerpin administration significantly improved survival rates in a dose-dependent manner, providing complete protection at 4 mg/kg. These findings highlight caulerpin as a promising candidate for the development of novel anti-inflammatory therapies. Further studies are warranted to explore its pharmacokinetics, optimize its structure, and evaluate its efficacy in chronic inflammatory diseases. Full article

Neuroinflammatory responses are central to the pathogenesis of neurodegenerative diseases, affecting cells of both neuronal and glial origin that respond to immune-driven inflammatory stimuli. The PI3K/mTOR signaling pathway is essential for the regulation of these neuroinflammatory processes and is therefore a promising target for therapeutic intervention. Here, we investigated the consequences of PI3K/mTOR pathway inhibition on neuroinflammation employing PF-04691502, an agent with combined PI3K and mTOR inhibitory activity. We treated SH-SY5Y, C6, BV-2, and Mo3.13 cell lines with PF-04691502 at concentrations of 0.1, 0.5, and 1 µM to assess the modulation of neuroinflammatory responses. To induce inflammation, cells were stimulated with lipopolysaccharide (LPS, 1 μg/mL) and interferon-gamma (IFN-γ, 100 U/mL). The results from the MTT assays demonstrated that PI3K/mTOR inhibition preserved cell viability at 0.5 and 1 µM across all of the cell lines, indicating its potential to mitigate inflammation-driven cytotoxicity. Subsequent ELISA assays revealed a marked decrease in the NF-κB and pro-inflammatory cytokine levels, confirming the effective suppression of inflammation through PI3K/mTOR inhibition. In addition, the SH-SY5Y cell line was exposed to MPP+ to simulate Parkinson’s disease (PD)-like toxicity; then, cell viability, PD-associated markers, and apoptotic indicators were assessed. Our results indicate that inhibition of the PI3K/mTOR signaling axis may alleviate neurodegenerative processes by modulating both neuroinflammatory responses and apoptotic pathways. These findings highlight the therapeutic promise of targeting PI3K/mTOR in the context of neurodegenerative disorders and support the need for further validation through in vivo and clinical investigations. Full article

Introduction: Craniopharyngiomas are rare sellar embryonic malformational tumors of low-grade histological malignancy. Despite high overall survival rates (92%), quality of life is frequently reduced due to adverse late effects caused by hypothalamic obesity. It is well known that morbid hypothalamic obesity is associated with the grade of hypothalamic damage. Accordingly, craniopharyngioma should be considered a paradigmatic disease, reflecting challenges in the diagnosis and treatment of acquired hypothalamic obesity. Methods: A narrative review was performed after searching the MEDLINE/PubMed, Embase, and Web of Science databases for initial identifying articles. The search terms childhood-onset craniopharyngioma and hypothalamic obesity were used. Results: Despite the availability of promising therapeutic approaches, such as medication with central stimulating agents, antidiabetic drugs, glucagon-like peptide 1 (GLP1) receptor agonists, and Setmelanotide, it must be emphasized that there is currently no pharmaceutical treatment for hypothalamic obesity in craniopharyngioma proven to be effective in randomized controlled trials. For Setmelanotide, a prospective blinded randomized trial over a 12-month treatment period is ongoing. Bariatric interventions are effective, but non-reversible procedures such as bypass operations are controversial in the pediatric age group due to legal and ethical concerns. Recently, a treatment algorithm was introduced to improve the management of hypothalamic syndrome/obesity by offering more personalized treatment. Decisions on treatment strategies focusing on the preservation of visual, neuroendocrine, and hypothalamic integrity should be made by experienced multidisciplinary teams. Conclusions: Treatment approaches for hypothalamic obesity are limited. Further research on novel treatment approaches for hypothalamic obesity is warranted to improve the quality of life after childhood-onset craniopharyngioma. Full article

Recovery from traumatic spinal cord injury (tSCI) is challenging due to the limited regenerative capacity of the central nervous system to restore cells, myelin, and neural connections. At the clinical level, the fundamental pillars of treatment are the reduction in secondary damage (neuroprotection) and rehabilitation; these are the tools we have to mitigate the disability caused by spinal cord injury (SCI). To date, the treatments on which neuroprotection has been based are the prevention of acute respiratory failure to avoid hypoxia, early hemodynamic control, neuroprotective drugs and surgical management. Optimizing early hemodynamic control to ensure adequate spinal cord perfusion may be key to the management of SCI. While neuroprotective agents like methylprednisolone have fallen into disuse, several promising therapies are currently being tested in clinical trials. In terms of surgical treatment, although their impact on neurological recovery remains debated, appropriate early bone decompression followed by duroplasty in selected cases is increasingly recommended. Advances in cell therapies hold significant potential for enhancing both clinical and functional outcomes in SCI patients. Moreover, emerging neuromodulation techniques, such as transcutaneous and epidural stimulation, along with innovations in rehabilitation technologies—such as robotic systems and exoskeletons—are becoming indispensable tools for improving locomotion and overall mobility in individuals with SCI. This article provides an update on the advances in neuroprotection against secondary damage caused by tSCI, in cellular therapies, and in new rehabilitation therapies. Full article

GABA (γ-Aminobutyric Acid), a well-established inhibitory neurotransmitter in the central nervous system, has garnered considerable interest for its potential role in diabetes management, particularly due to its presence in pancreatic islets. This review aims to explore the therapeutic role of GABA in diabetes management and its potential mechanisms for antidiabetic effects. Relevant studies were searched across databases such as PubMed and ScienceDirect, applying strict eligibility criteria focused on GABA administration methods and diabetic models. The collective results showed that the administration of GABA in diabetic models resulted in remarkable enhancements in glucose and insulin homeostasis, favorable modifications in lipid profiles, and amelioration of dysfunctions across neural, hepatic, renal, and cardiac systems. The findings from the literature demonstrated that GABAergic signaling within pancreatic tissues can significantly contribute to the stimulation of β cell proliferation through the facilitation of a sustained trans-differentiation process, wherein glucagon-secreting α cells are converted into insulin-secreting β-like cells. In addition, activated GABAergic signaling can trigger the initiation of the PI3K/AKT signaling pathway within pancreatic tissues, leading to improved insulin signaling and maintained glucose homeostasis. GABAergic signaling can further function within hepatic tissues, promoting inhibitory effects on the expression of genes related to gluconeogenesis and lipogenesis. Moreover, GABA may enhance gut microbiota diversity by attenuating gut inflammation, attributable to its anti-inflammatory and immunomodulatory properties. Furthermore, the neuroprotective effects of GABA play a significant role in ameliorating neural disorders associated with diabetes by facilitating a substantial reduction in neuronal apoptosis. In conclusion, GABA emerges as a promising candidate for an antidiabetic agent; however, further research is highly encouraged to develop a rigorously designed framework that comprehensively identifies and optimizes the appropriate dosages and intervention methods for effectively managing and combating diabetes. Full article

Obesity has emerged as a global epidemic, creating an increased burden of weight-related diseases and straining healthcare systems worldwide. While the fundamental principle of energy balance—caloric intake versus expenditure—remains central to weight regulation, real-world outcomes often deviate from simplistic predictions due to a multitude of physiological and environmental factors. Genetic predispositions, variations in basal metabolic rates, adaptive thermogenesis, physical activity, and nutrient losses via fecal and urinary excretion contribute to interindividual differences in energy homeostasis. Additionally, factors such as meal timing, macronutrient composition, gut microbiota dynamics, and diet-induced thermogenesis (DIT) further modulate energy utilization and metabolic efficiency. This Perspective explores key physiological determinants of the energy balance, while also highlighting the clinical significance of thrifty versus spendthrifty metabolic phenotypes. Key strategies for individualized weight management include precision calorimetry, circadian-aligned meal timing, the use of protein- and whole food diets to enhance DIT, and increases in non-exercise activity, as well as mild cold exposure and the use of thermogenic agents (e.g., capsaicin-like compounds) to stimulate brown adipose tissue activity. A comprehensive, personalized approach to obesity management that moves beyond restrictive caloric models is essential to achieving sustainable weight control and improving long-term metabolic health. Integrating these multifactorial insights into clinical practice will enhance obesity treatment strategies, fostering more effective and enduring interventions. Full article

Viruses can manipulate the host metabolism to achieve optimal replication conditions, and central carbon metabolism (CCM) pathways are often crucial in determining viral infections. Feline calicivirus (FCV), a diminutive RNA viral agent, induces upper respiratory tract infections in feline hosts, with highly pathogenic strains capable of precipitating systemic infections and subsequent host cell necrosis, thereby presenting a formidable challenge to feline survival and protection. However, the relationship between FCV and host cell central carbon metabolism (CCM) remains unclear, and the precise pathogenic mechanisms of FCV are yet to be elucidated. Upon FCV infection of Crandell-Rees Feline Kidney (CRFK) cells, an enhanced cellular uptake of glucose and glutamine was observed. Metabolomics analyses disclosed pronounced alterations in the central carbon metabolism of the infected cells. FCV infection was found to augment glycolytic activity while sustaining the tricarboxylic acid (TCA) cycle flux, with cellular ATP levels remaining invariant. Concurrently, both glutamine metabolism and the flux of the pentose phosphate pathway (PPP) were noted to be intensified. The application of various inhibitory agents targeting glycolysis, glutamine metabolism, and the PPP resulted in a significant suppression of FCV proliferation. Experiments involving glucose and glutamine deprivation demonstrated that the absence of either nutrient markedly curtailed FCV replication. Collectively, these findings suggest a critical interplay between central carbon metabolism and FCV proliferation. FCV infection stimulates CRFK cells to augment glucose and glutamine uptake, thereby supplying the necessary metabolic substrates and energy for viral replication. During the infection, glutamine emerges as the primary energy substrate, ensuring ATP production and energy homeostasis, while glucose is predominantly channeled into the pentose phosphate pathway to facilitate nucleotide synthesis. Full article

Inflammation has always been considered a trigger or consequence of neurodegenerative diseases, and the inhibition of inflammation in the central nervous system can effectively protect nerve cells. Several studies have indicated that various natural products inhibit neuroinflammation. Among these, Antarctic fungal metabolites have pharmacological activities and a developmental value. Therefore, this study aimed to evaluate the anti-neuroinflammatory activity of an Antarctic fungus belonging to Aspergillus (strain SF-7367). Secondary metabolites of SF-7367 were isolated using high-performance liquid chromatography followed by validation of their anti-inflammatory effects in lipopolysaccharide-stimulated BV2 microglia and RAW264.7 macrophages. Chemical analysis of metabolites from the fungal strain revealed five known compounds: epideoxybrevianamide E (1), brevianamide V/W (2), brevianamide K (3), brevianamide Q (4), and brevianamide R (5). Among these compounds, brevianamide K showed significant anti-inflammatory activity against both cell types. Results of Western blotting and molecular docking showed that brevianamide K could regulate the activation of nuclear factor kappa-light-chain-enhancer of activated B cell (NF-κB) signaling. This indicates that brevianamide K present in Aspergillus sp. (strain SF-7367) can inhibit inflammatory responses by reducing lipopolysaccharide-induced nuclear translocation of NF-κB (p65). These findings suggest that Aspergillus sp. (strain SF-7367) and brevianamide K are candidate agents for treating neurodegenerative diseases. Full article

Spices and aromatic herbs are important components of everyday nutrition in several countries and cultures, thanks to their capability to enhance the flavor of many dishes and convey significant emotional contributions by themselves. Indeed, spices as well as aromatic herbs are to be considered not only for their important values of antimicrobial agents or flavor enhancers everybody knows, but also, thanks to their olfactory and gustatory spectrum, as drivers to stimulate the consumers’ memories and, in a stronger way, emotions. Considering these unique characteristics, spices and aromatic herbs have caught the attention of consumer scientists and experts in sensory analysis for their evaluation using semi-quantitative approaches, with interesting evidence. In this pilot study as a first step, each studied botanical, belonging to Piperaceae or aromatic herbs, has been subjected to headspace solid phase micro-extraction (HS-SPME) coupled with gas-chromatography mass spectrometry (GC-MS) analysis to assess their spontaneous volatile emission, representing the complex chemical pattern, which encounters the consumers’ olfactory perception. Furthermore, the present investigation, performed on 12 individuals, outlines the administration of a pilot study, merging the typical sensory analysis with emotional data collection and the innovative contribution related to the study around the Autonomic and Central Nervous System activation in consumers, performed using wearable technologies and related signal processing. The results obtained by our study, beyond demonstrating the feasibility of the approach, confirmed, both in terms of emotional responses and biomedical signals, the significant emotional potential of spices and aromatic herbs, most of which featuring an overall positive valence, yet with inter-subjects’ variations. Future investigations should aim to increase the number of volunteers evaluated with such an approach to draw more stable conclusions and attempting a customization of product preferences based on both implicit and explicit sensory responses. Full article

The brain contains many interconnected and complex cellular and molecular mechanisms. Injury to the brain causes permanent dysfunctions in these mechanisms. So, it continues to be an area where surgical intervention cannot be performed except for the removal of tumors and the repair of some aneurysms. Some agents that can cross the blood–brain barrier and reach neurons show neuroprotective effects in the brain due to their anti-apoptotic, anti-inflammatory and antioxidant properties. In particular, some agents act by reducing or modulating the accumulation of protein aggregates in neurodegenerative diseases (Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, Amyotrophic lateral sclerosis, and prion disease) caused by protein accumulation. Substrate accumulation causes increased oxidative stress and stimulates the brain’s immune cells, microglia, and astrocytes, to secrete proinflammatory cytokines. Long-term or chronic neuroinflammatory response triggers apoptosis. Brain damage is observed with neuronal apoptosis and brain functions are impaired. This situation negatively affects processes such as motor movements, memory, perception, and learning. Neuroprotective agents prevent apoptosis by modulating molecules that play a role in apoptosis. In addition, they can improve impaired brain functions by supporting neuroplasticity and neurogenesis. Due to the important roles that these agents play in central nervous system damage or neurodegenerative diseases, it is important to elucidate many mechanisms. This review provides an overview of the mechanisms of flavonoids, which constitute a large part of the agents with neuroprotective effects, as well as vitamins, neurotransmitters, hormones, amino acids, and their derivatives. It is thought that understanding these mechanisms will enable the development of new therapeutic agents and different treatment strategies. Full article

Background. Acetyl phosphate (AcP) is a microbial intermediate involved in the central bacterial metabolism. In bacteria, it also functions as a donor of acetyl and phosphoryl groups in the nonenzymatic protein acetylation and signal transduction. In host, AcP was detected as an intermediate of the pyruvate dehydrogenase complex, and its appearance in the blood was considered as an indication of mitochondrial breakdown. In vitro experiments showed that AcP is a powerful agent of nonenzymatic acetylation of proteins. The influence of AcP on isolated mitochondria has not been previously studied. Methods. In this work, we tested the influence of AcP on the opening of the mitochondrial permeability transition pore (mPTP), respiration, and succinate dehydrogenase (SDH) activity under neutral and alkaline conditions stimulating the nonenzymatic acetylation using polarographic, cation-selective, and spectrophotometric methods. Results. It was found that AcP slowed down the opening of the mPTP by calcium ions and decreased the efficiency of oxidative phosphorylation and the activity of SDH. These effects were observed only at neutral pH, whereas alkaline pH by itself caused a decrease in these functions to a much greater extent than AcP. AcP at a concentration of 0.5–1 mM decreased the respiratory control and the swelling rate by 20–30%, while alkalization decreased them twofold, thereby masking the effect of AcP. Presumably, the acetylation of adenine nucleotide translocase involved in both the opening of mPTP and oxidative phosphorylation underlies these changes. The intermediate electron carrier phenazine methosulfate (PMS), removing SDH inhibition at the ubiquinone-binding site, strongly activated SDH under alkaline conditions and, partially, in the presence of AcP. It can be assumed that AcP weakly inhibits the oxidation of succinate, while alkalization slows down the electron transfer from the substrate to the acceptor. Conclusions. The results show that both AcP and alkalization, by promoting nonmetabolic and nonenzymatic acetylation from the outside, retard mitochondrial functions. Full article

Cognitive impairment is a core feature of neurodevelopmental (schizophrenia) and aging-associated (mild cognitive impairment and Alzheimer’s dementia) neurodegenerative diseases. Limited efficacy of current pharmacological treatments warrants further search for new targets for nootropic interventions. The breakdown of myelin, a phospholipids axonal sheath that protects the conduction of nerve impulse between neurons, was proposed as a neuropathological abnormality that precedes and promotes the deposition of amyloid-β in neuritic plaques. The present review of the recent literature and our own pre- and clinical data suggest (for the first time) that the anthranilic acid (AA)-induced activation of microglial-expressed G-protein coupled receptor (GPR109A) inhibits cytosolic phospholipase A2 (cPLA2), an enzyme that triggers the degradation of myelin and consequently attenuates cognitive impairment. The present review suggests that the up-regulation of AA formation is a sex-specific compensatory (adaptive) reaction aimed to prevent/treat cognitive impairment. The AA–GPR109A–cPLA2–myelin–cognition cascade suggests new nootropic interventions, e.g., the administration of pegylated kynureninase, an enzyme that catalyzes AA formation from Kynurenine (Kyn), a tryptophane catabolite; pegylated interferon-alpha; central and peripheral Kyn aminotransferase inhibitors that increase availability of Kyn as a substrate for AA formation; and vagus nerve stimulation. The cascade predicts nootropic activity of exogenous GPR109A agonists that were designed and underwent clinical trials (unsuccessful) as anti-dyslipidemia agents. The proposed cascade might contribute to the pathogenesis of cognitive impairment. Data on AA in neurodegenerative disorders are scarce, and the proposed cascade needs further exploration in pre- and clinical studies Full article

Post-traumatic trigeminal neuropathy (PTTN) is a sensory abnormality caused by injury to the trigeminal nerve during orofacial surgery. However, existing analgesics are ineffective against PTTN. Abnormal microglial activation in the caudal part of the spinal trigeminal nucleus caudal part (Sp5C), where the central trigeminal nerve terminals reside, plays an important role in PTTN pathogenesis. Therefore, regulating microglial activity in Sp5C appears to be an important approach to controlling pain in PTTN. Cannabinoid receptor 2 (CB₂) is expressed in immune cells including microglia, and its activation has anti-inflammatory effects. The current study demonstrates that the repeated intranasal administration of CB₂ agonist HU-308 ameliorates the infraorbital nerve cut (IONC)-induced hyperresponsiveness to acetone (cutaneous cooling). The therapeutic efficacy of oral HU-308 was found to be less pronounced in alleviating cold hypersensitivity in IONC mice compared to intranasal administration, indicating the potential advantages of the intranasal route. Furthermore, repeated intranasal administration of HU-308 suppressed the activation of Sp5C microglia in IONC mice. Additionally, pretreatment with the CB₂ antagonist, SR 144528, significantly blocked the anti-nociceptive effect of repeated intranasal administration of HU-308 on cold hypersensitization in IONC mice. These data suggest that the continuous stimulation of CB₂ ameliorates PTTN-induced pain via the inhibition of microglial activation. Thus, CB₂ agonists are potential candidates for novel therapeutic agents against PTTN. Full article