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Current evidence suggests a beneficial role of herbal products in free radical-induced diseases. Panax notoginseng (Burk.) F. H. Chen has long occupied a leading position in traditional Chinese medicine because of the ergogenic, nootropic, and antistress activities, although these properties are also acknowledged in the Western world. The goal of this paper is to review the pharmacological and toxicological properties of P. notoginseng and discuss its potential therapeutic effect. A literature search was carried out on Pubmed, Scopus, and the Cochrane Central Register of Controlled Trials databases. The following search terms were used: "notoginseng", "gut microbiota", "immune system", "inflammation", "cardiovascular system", "central nervous system", "metabolism", "cancer", and "toxicology". Only peer-reviewed articles written in English, with the full text available, have been included. Preclinical evidence has unraveled the P. notoginseng pharmacological effects in immune-inflammatory, cardiovascular, central nervous system, metabolic, and neoplastic diseases by acting on several molecular targets. However, few clinical studies have confirmed the therapeutic properties of P. notoginseng, mainly as an adjuvant in the conventional treatment of cardiovascular disorders. Further clinical studies, which both confirm the efficacy of P. notoginseng in free radical-related diseases and delve into its toxicological aspects, are mandatory to broaden its therapeutic potential.

Biliverdin is one of the three by-products of heme oxygenase (HO) activity, the others being ferrous iron and carbon monoxide. Under physiological conditions, once formed in the cell, BV is reduced to bilirubin (BR) by the biliverdin reductase (BVR). However, if BVR is inhibited by either genetic variants, as occurs in the Inuit ethnicity, or dioxin intoxication, BV accumulates in cells giving rise to a clinical syndrome known as green jaundice. Preclinical studies have demonstrated that BV not only has a direct antioxidant effect by scavenging free radicals, but also targets many signal transduction pathways, such as BVR, soluble guanylyl cyclase, and the aryl hydrocarbon receptor. Through these direct and indirect mechanisms, BV has shown beneficial roles in ischemia/reperfusion-related diseases, inflammatory diseases, graft-versus-host disease, viral infections and cancer. Unfortunately, no clinical data are available to confirm these potential therapeutic effects and the kinetics of exogenous BV in humans is unknown. These limitations have so far excluded the possibility of transforming BV from a mere by-product of heme degradation into a disease-modifying agent. A closer collaboration between basic and clinical researchers would be advantageous to overcome these issues and promote translational research on BV in free radical-induced diseases.

Although the anticancer role of curcumin has been extensively addressed in preclinical research, only a few studies were carried out in humans, with conflicting results. The aim of this systematic review is to collate together the results of the therapeutic effect of curcumin in cancer patients. A literature search was carried out in Pubmed, Scopus, and the Cochrane Central Register of Controlled Trials up to 29 January 2023. Only randomized controlled trials (RCTs) designed to evaluate the effects of curcumin on cancer progression, patient survival, or surgical/histological response were included. Seven out of 114 articles, published between 2016 and 2022, were analyzed. They evaluated patients with locally advanced and/or metastatic prostate, colorectal, and breast cancers, as well as multiple myeloma and oral leucoplakia. Curcumin was given as an add-on therapy in five studies. Cancer response was the most investigated primary endpoint and curcumin issued some positive results. On the contrary, curcumin was ineffective in improving overall or progression-free survival. The curcumin safety profile was favorable. In conclusion, available clinical evidence is not strong enough to support the therapeutic use of curcumin in cancer. New RCTs exploring the effects of different curcumin formulations in early-stage cancers would be welcome.

Heme oxygenase (HO-2) is an enzyme mainly involved in the physiologic turnover of heme and intracellular gas sensing, and it is very abundant in the brain, testes, kidneys and vessels. Since 1990, when HO-2 was discovered, the scientific community has underestimated the role of this protein in health and disease, as attested by the small amount of articles published and citations received. One of the reason that have contributed to the lack of interest in HO-2 was the difficulty in upregulating or inhibiting this enzyme. However, over the last 10 years, novel HO-2 agonists and antagonists have been synthesized, and the availability of these pharmacological tools should increase the appeal of HO-2 as drug target. In particular, these agonists and antagonists could help explain some controversial aspects, such as the neuroprotective versus neurotoxic roles of HO-2 in cerebrovascular diseases. Furthermore, the discovery of HO-2 genetic variants and their involvement in Parkinson's disease, in particular in males, opens new avenues for pharmacogenetic studies in gender medicine.

Introduction: The heme oxygenase/biliverdin reductase (HO/BVR) system is involved in heme metabolism. The inducible isoform of HO (HO-1) and BVR both exert cytoprotective effects by enhancing cell stress response. In this context, some xenobiotics, which target HO-1, including herbal products, behave as neuroprotectants in several experimental models of neurodegeneration. Despite this, no drug having either HO-1 or BVR as a main target is currently available. Areas covered: After a description of the brain HO/BVR system, the paper analyzes the main classes of drugs acting on the nervous system, with HO as second-level target, and their neuroprotective potential. Finally, the difficulties that exist for the development of drugs acting on HO/BVR and the possible ways to overcome these hurdles are examined. Expert opinion: Although the limited clinical evidence has restricted the translational research on the HO/BVR system, mainly because of the dual nature of its by-products, there has been growing interest in the therapeutic potential of these enzymes. Scientists should boost the translational research on the HO/BVR system which could be supported by the significant evidence provided by preclinical studies.

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by progressive and irreversible worsening of cognitive functions, inability to perform everyday activities, and mood disorders. Currently, AD is considered the leading cause of dementia and hospitalization of older adults in nursing homes. In the United States, 5.8 million people has been calculated to suffer from AD in 2019, 81% being 75 years or older; the percentage of individuals with AD increases with age, from 3% of people aged 65–74 to 32% of people aged 85 and older. Women are more affected by AD than men (M/F 2/1) probably because of their longer lifespan. Finally, African Americans and Hispanics are about twice likely to develop AD as older Whites (Alzheimer’s Association, 2019). The lack of any updated epidemiologic survey about AD in Europe is quite disappointing; the most accurate analysis dates back 2017 and reveals an estimated prevalence at 5.05% (men 3.31% and women 7.13%) increasing with age (Niu et al., 2017). In Europe, about 3 million people was estimated to suffer from AD (Mayer et al., 2018).

Recent studies have shown the role of gut microbiota in favoring the absorption of herbal products and the transformation of their active principles into metabolites endowed with biological activity. This review focuses on the evidence supporting the changes occurring, after metabolic reactions by specific bacteria that colonize the human gut, to ginseng-derived ginsenosides, green tea-derived catechins, and quercetin, this latter being a flavonoid aglycon bound to sugars and abundant in some vegetables and roots. Furthermore, the results of several studies demonstrating the potential beneficial effects of the active metabolites generated by these biotransformations on ginsenosides, catechins and quercetin will be reported.

Biliverdin reductase-A (BVR) catalyzes the reduction of heme-derived biliverdin into bilirubin, this latter being a powerful endogenous free radical scavenger. Furthermore, BVR is also endowed with both serine/threonine/tyrosine kinase and scaffold activities, through which it interacts with the insulin receptor kinase, conventional and atypical protein kinase C isoforms, mitogen-activated protein kinases as well as the phosphatidylinositol-3 kinase/Akt system. By regulating this complex array of signal transduction pathways, BVR is involved in the pathogenesis of neurodegenerative, metabolic, cardiovascular and immune-inflammatory diseases as well as in cancer. In addition, both BVR and BVR-B, this latter being an alternate isozyme predominant during fetal development but sometimes detectable through adulthood, have been studied as peripheral biomarkers for an early detection of Alzheimer's disease, atherosclerosis and some types of cancer. However, despite these interesting lines of evidence, to date BVR has not been considered as an appealing drug target. Only limited evidence supports the neuroprotective effects of atorvastatin and ferulic acid through BVR regulation in the aged canine brain and human neuroblastoma cells, whereas interesting results have been reported regarding the use of BVR-based peptides in preclinical models of cardiac diseases and cancer.

Recent studies have suggested the role of an infectious component in the pathogenesis of Alzheimer's disease (AD). In light of this, research has focused on some bacteria constituting the intestinal microbial flora which can produce amyloid. Once generated, the latter hypothetically triggers a systemic inflammatory response which compromises complex brain functions, such as learning and memory. Clinical studies have shown that, in cognitively impaired elderly patients with brain amyloidosis, there is lower abundance in the gut of E. rectale and B. fragilis, two bacterial species which have an anti-inflammatory activity, versus a greater amount of pro-inflammatory genera such as Escherichia/Shigella. According to these findings, some clinical studies have demonstrated that supplementation with Lactobacilli- and Bifidobacteria- based probiotics has improved cognitive, sensory and emotional functions in subjects with AD. Moreover, certain herbal products, in particular dietetic polyphenols, have proved capable of restoring dysbiosis and, therefore, their prebiotic role could be effective in counteracting the onset of AD regardless of their activity of free radical scavenging or enhancement of the cell stress response. One of the recent greatest novelties in the field of neurodegenerative diseases is the chance to prevent or slow down AD progression with agents, such as probiotics and prebiotics, acting outside the central nervous system.

The use of Panax ginseng and Panax quinquefolius in traditional Chinese medicine dates back to about 5000 years ago thanks to its several beneficial and healing properties. Over the past few years, extensive preclinical and clinical evidence in the scientific literature worldwide has supported the beneficial effects of P. ginseng and P. quinquefolius in significant central nervous system, metabolic, infectious and neoplastic diseases. There has been growing research on ginseng because of its favorable pharmacokinetics, including the intestinal biotransformation which is responsible for the processing of ginsenosides - contained in the roots or extracts of ginseng - into metabolites with high pharmacological activity and how such principles act on numerous cell targets. The aim of this review is to provide a simple and extensive overview of the pharmacokinetics and pharmacodynamics of P. ginseng and P. quinquefolius, focusing on the clinical evidence which has shown particular effectiveness in specific diseases, such as dementia, diabetes mellitus, respiratory infections, and cancer. Furthermore, the review will also provide data on toxicological factors to support the favorable safety profile of these medicinal plants.

For many decades, the world scientific literature has accounted for a number of works on the biological effects of bilirubin-IXalpha (BR). The first studies focused on the neurotoxic effects of the excessive production of BR, in particular regarding both physiological neonatal jaundice and the more severe ones, typically as consequences of severe hemolysis or other underlying diseases. Only since 1987, has significant evidence, however, underlined the neuroprotective role of BR linked to the scavenging effect of free radicals as reactive oxygen species and nitric oxide and its congeners. Despite the presence in the literature of many excellent papers dealing with the multiple roles played by BR in health and disease, there were very few and somewhat dated reviews that summarize the key findings related to the neuroprotective and neurotoxic effects of the bile pigment and underlying mechanisms. In light of the previous statements, the aim of this review is to provide a summary of the main discoveries in the last years on the effects of BR on the central nervous system. An analytical description about the synthesis of BR, its distribution in the systemic circulation, liver metabolism and elimination through feces and urine will be provided, together with the main mechanisms claimed to describe the neurotoxicity and neuroprotection by the bile pigment. Finally, the possible translational aspects of pharmacological modulation in the production of BR in order to prevent or counteract toxic effects or enhance the protective actions, will be discussed.

Over the last few years, several papers have become available in the literature on both the main hallmarks of Alzheimer’s disease (AD) and the several intracellular pathways whose alteration is responsible for its onset and progression. The use of transgenic and nontransgenic animal models has played a key role in achieving such a remarkable amount of preclinical data, allowing researchers to dissect the cellular changes occurring in the AD brain. In addition, the huge amount of preclinical evidence arising from these animal models was necessary for the further clinical development of pharmacological agents capable of interfering with most of the impaired neural pathways in AD patients. In this respect, a significant role is played by the dysfunction of excitatory and inhibitory neurotransmission responsible for the cognitive and behavioral symptoms described in AD patients. The aim of this review is to summarize the main animal models that contributed toward unraveling the pathological changes in neurotransmitter synthesis, release, and receptor binding in AD preclinical studies. The review also provides an updated description of the current pharmacological agents – still under clinical development – acting on the neurotransmitter systems.

Curcumin is a natural polyphenol component of Curcuma longa Linn, which is currently considered one of the most effective nutritional antioxidants for counteracting free radical-related diseases. Several experimental data have highlighted the pleiotropic neuroprotective effects of curcumin, due to its activity in multiple antioxidant and anti-inflammatory pathways involved in neurodegeneration. Although its poor systemic bioavailability after oral administration and low plasma concentrations represent restrictive factors for curcumin therapeutic efficacy, innovative delivery formulations have been developed in order to overwhelm these limitations. This review provides a summary of the main findings involving the heme oxygenase/biliverdin reductase system as a valid target in mediating the potential neuroprotective properties of curcumin. Furthermore, pharmacokinetic properties and concerns about curcumin’s safety profile have been addressed.

Curcumin is a polyphenol compound extracted from the rhizome of Curcuma longa Linn (family Zingiberaceae) commonly used as a spice to color and flavor food. Several preclinical studies have suggested beneficial roles for curcumin as an adjuvant therapy in free radical-based diseases, mainly neurodegenerative disorders. Indeed, curcumin belongs to the family of hormetins and the enhancement of the cell stress response, mainly the heme oxygenase-1 system, is actually considered the common denominator for this dual response. However, evidence-based medicine has clearly demonstrated the lack of any therapeutic effect of curcumin to contrast the onset or progression of neurodegeneration and related diseases. Finally, the curcumin safety profile imposes a careful analysis of the risk/benefit balance prior to proposing chronic supplementation with curcumin.

Over the last few years, several preclinical studies have shown that some herbal products, such as ferulic acid, Ginkgo biloba, and resveratrol, exert neuroprotective effects through the modulation of the heme oxygenase/biliverdin reductase system. Unfortunately, sufficient data supporting the shift of knowledge from preclinical studies to humans, particularly in neurodegenerative diseases, are not yet available in the literature. The purpose of this review is to summarize the studies and the main results achieved on the potential therapeutic role of the interaction between the heme oxygenase/biliverdin reductase system with ferulic acid, G. biloba, and resveratrol. Some critical issues have also been reported, mainly concerning the safety profile and the toxicological sequelae associated to the supplementation with the herbs mentioned above, based on both current literature and specific reports issued by the competent Regulatory Authorities.

For many years now the world's scientific literature has been perfused with articles on the therapeutic potential of natural products, the vast majority of which have herbal origins, as in the case of free radical-induced diseases. What is often overlooked is the effort of researchers who take into consideration the preclinical and clinical evaluation of these herbal products, in order to demonstrate the therapeutic efficacy and safety. The first critical issue to be addressed in the early stages of the preclinical studies is related to pharmacokinetics, which is sometimes not very favorable, of some of these products, which limits the bioavailability after oral intake. In this regard, it is worthy underlining how it is often unethical to propose the therapeutic efficacy of a compound on the basis of preclinical results obtained with far higher concentrations to those which, hopefully, could be achieved in organs and tissues of subjects taking these products by mouth. The most widely used approach to overcome the problem related to the low bioavailability involves the complexation of the active ingredients of herbal products with non-toxic carriers that facilitate the absorption and distribution. Even the induction or inhibition of drug metabolizing enzymes by herbal products, and the consequent variations of plasma concentrations of co-administered drugs, are phenomena to be carefully evaluated as they can give rise to side-effects. This risk is even greater when considering that people lack the perception of the risk arising from an over use of herbal products that, by their very nature, are considered risk-free.

Modulation of endogenous cellular defense mechanisms via the vitagene system represents an innovative approach to therapeutic intervention in diseases causing chronic tissue damage, such as in neurodegeneration. The possibility of high-throughoutput screening using proteomic techniques, particularly redox proteomics, provide more comprehensive overview of the interaction of proteins, as well as the interplay among processes involved in neuroprotection. Here by introducing the hormetic dose response concept, the mechanistic foundations and applications to the field of neuroprotection, we discuss the emerging role of heat shock protein as prominent member of vitagene network in neuroprotection and redox proteomics as a tool for investigating redox modulation of stress responsive vitagenes. Hormetic mechanisms are reviewed as possibility of targeted therapeutic manipulation in a cell-, tissue- and/or pathway-specific manner at appropriate points in the neurodegenerative disease process.

Noise induced hearing loss depends on the progressive increase of reactive oxygen species and lipoperoxidative damage in conjunction with the imbalance of antioxidant defenses. The redox-sensitive transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) plays a critical role in the regulation of cellular defense against oxidative stress including heme oxygenase-1 (HO-1) activation. In this work we describe a link between cochlear oxidative stress damage, induced by noise exposure, and the activation of Nrf2/HO-1 pathway. In our model, noise induces superoxide production and overexpression of the lipid peroxidation marker, 4-hydroxy-nonenals (4-HNE). To face the oxidative stress, the endogenous defense system is as well activated as shown by the slight activation of superoxide dismutases (SODs). In addition, we also observed the activation of the Nrf2/HO-1 pathway after noise exposure. In doing so, Nrf2 appears to promote the maintenance of cellular homeostasis under stress conditions. However, in this model the endogenous antioxidant system fails to counteract noise-induced cell damage and its activation is not enough effective in preventing the cochlear damage. The herb-derived phenol rosmarinic acid (RA) attenuates noise-induced hearing loss reducing threshold shift and promotes hair cell survival. In fact, RA enhances the endogenous antioxidant defenses as shown by the decreased superoxide production, the reduced expression of 4-HNE and the up-regulation of SODs. Interestingly, RA potentiates the Nrf2/OH-1 signaling pathway as shown by immunohistochemical and western blot analyses. Thus, protective effects of RA are associated with the induction/activation of Nrf2-ARE signaling pathway in addition to RA direct scavenging capability.

Bach1, among the genes encoded on chromosome 21, is a transcription repressor, which binds to antioxidant response elements of DNA thus inhibiting the transcription of specific genes involved in the cell stress response including heme oxygenase-1 (HO-1). HO-1 and its partner, biliverdin reductase-A (BVR-A), are upregulated in response to oxidative stress in order to protect cells against further damage. Since oxidative stress is an early event in Down syndrome (DS) and might contribute to the development of multiple deleterious DS phenotypes, including Alzheimer's disease (AD) pathology, we investigated the status of the Bach1/HO-1/BVR-A axis in DS and its possible implications for the development of AD. In the present study, we showed increased total Bach1 protein levels in the brain of all DS cases coupled with reduced induction of brain HO-1. Furthermore, increased oxidative stress could, on one hand, overcome the inhibitory effects of Bach1 and, on the other hand, promote BVR-A impairment. Our data show that the development of AD in DS subjects is characterized by (i) increased Bach1 total and poly-ubiquitination; (ii) increased HO-1 protein levels; and (iii) increased nitration of BVR-A followed by reduced activity. To corroborate our findings, we analyzed Bach1, HO-1, and BVR-A status in the Ts65Dn mouse model at 3 (young) and 15 (old) months of age. The above data support the hypothesis that the dysregulation of HO-1/BVR-A system contributes to the early increase of oxidative stress in DS and provide potential mechanistic paths involved in the neurodegenerative process and AD development.

The heme oxygenase/biliverdin reductase (HO/BVR) pathway enhances cell stress response by degrading excess heme or producing antioxidant and cytoprotective molecules. Recently, members of the HO/BVR system have been proposed as biomarkers for the early diagnosis of free radical-related diseases. In this study, the presence of both the inducible and constitutive HO isoforms (HO-1 and HO-2, respectively) and BVR was evaluated by immunohistochemistry in human skin cancer samples. Moderate/strong immunoreactivities against HO-1, HO-2 and BVR were detected in 100% of the nodular malignant melanoma samples, whereas in basal cell carcinoma specimens these figures were 62%, 88% and 60%, respectively, with a faint/moderate degree of expression. Faint/moderate HO-1, HO-2 and BVR immunoreactivities were detected in 33%, 66% and 100% of melanocytic nevi samples, respectively. In conclusion, HO-1 and HO-2 and BVR were expressed in the cytosols of skin cancer cells, whereas perilesional normal epidermis showed only faint staining, thus leading to the hypothesis that the HO/BVR system is activated in skin cancers.

Ferulic acid (FA) belongs to the family of phenolic acids and is very abundant in fruits and vegetables. Over the past years, several studies have shown that FA acts as a potent antioxidant by scavenging free radicals and enhancing the cell stress response through the up-regulation of cytoprotective systems, e.g. heme oxygenase-1, heat shock protein 70, extracellular signal-regulated kinase 1/2 and the proto-oncogene Akt. Furthermore, FA was shown to inhibit the expression and/or activity of cytotoxic enzymes, including inducible nitric oxide synthase, caspases and cyclooxygenase-2. Based on this evidence, FA has been proposed as a potential treatment for many disorders including Alzheimer's disease, cancer, cardiovascular diseases, diabetes mellitus and skin disease. However, despite the great abundance of preclinical research, only a few studies were carried out in humans, the majority of which used foods containing FA, and therefore the clinical efficacy of this mode of administration needs to be further documented. New efforts and resources are needed in clinical research for the complete evaluation of FA therapeutic potential in chronic diseases.

No abstract available.

Alzheimer disease (AD) is the most common form of dementia among the elderly and is characterized by progressive loss of memory and cognition. These clinical features are due in part to the increase of reactive oxygen and nitrogen species that mediate neurotoxic effects. The up-regulation of the heme oxygenase-1/biliverdin reductase-A (HO-1/BVR-A) system is one of the earlier events in the adaptive response to stress. HO-1/BVR-A reduces the intracellular levels of pro-oxidant heme and generates equimolar amounts of the free radical scavengers biliverdin-IX alpha (BV)/bilirubin-IX alpha (BR) as well as the pleiotropic gaseous neuromodulator carbon monoxide (CO) and ferrous iron. Two main and opposite hypotheses for a role of the HO-1/BVR-A system in AD propose that this system mediates neurotoxic and neuroprotective effects, respectively. This apparent controversy was mainly due to the fact that for over about 20years HO-1 was the only player on which all the analyses were focused, excluding the other important and essential component of the entire system, BVR. Following studies from the Butterfield laboratory that reported alterations in BVR activity along with decreased phosphorylation and increased oxidative/nitrosative post-translational modifications in the brain of subjects with AD and amnestic mild cognitive impairment (MCI) subjects, a debate was opened on the real pathophysiological and clinical significance of BVR-A. In this paper we provide a review of the main discoveries about the HO/BVR system in AD and MCI, and propose a mechanism that reconciles these two hypotheses noted above of neurotoxic and the neuroprotective aspects of this important stress responsive system.

Alzheimer s disease (AD) is a neurodegenerative disorder characterized by the progressive loss of cognitive function, the inability to perform the activities of daily living and psychiatric symptoms. The formation of toxic aggregates of amyloid-beta-peptide (Abeta), through the activities of beta - and gamma- secretases, is considered as the earlier event in the pathogenesis of the disease. The deposition of both Abeta and the following hyperphosphorylation of tau protein, trigger an exaggerate immune-inflammatory response culminating with the production of excess reactive oxygen and nitrogen species responsible for damage on cellular nucleic acids, proteins and lipids. One of the mechanisms used by neural cells to counteract oxidative/nitrosative damage in AD is the enhancement of the cell stress response. Among the main components of the cell stress response is the heme oxygenase/biliverdin reductase (HO/BVR) axis, which catalyzes the degradation of heme which is toxic if produced in excess or under redox unbalanced conditions. However, the HO/BVR system and its by-products, carbon monoxide and bilirubin, have also been shown to be neuroprotective by activating pro-survival pathways and scavenging free radicals. Nevertheless, recent research demonstrated as both the inducible isoform of HO, known as HO-1, and BVR undergo oxidative/nitrosative/phosphorylative post-translational modifications in AD brain which alter the ability of HO-1 and BVR to activate the cell stress response. In this light, naturally occurring substances or drugs (e.g. statins) that prevent the post-translational modifications leading to a controlled up-regulation of the HO/BVR system have been proposed as potential new tools for the treatment of AD.

In this study, stearic acid- and stearyl ferulate-based solid lipid nanoparticles containing trans-ferulic acid (SLN-FA and SLN-SF-FA, respectively), were prepared and characterized for loading efficiency, size and shape. In addition, by using rat brain microsomes, we evaluated in vitro the antioxidant activity of these formulations against three well known initiators of lipid peroxidation, such as AAPH, NADPH/ADP-Fe(3+) and SIN-1 which in turn generate the peroxyl and perferryl radicals as well as peroxynitrite, respectively. Commercially available FA and its ethyl ester (FAEE) were used as comparators. Both SLN-FA and SLN-SF-FA dose-dependently reduced lipid peroxidation induced by the three oxidants. Interestingly, SLN-SF-FA displayed greater efficacy (EC50) and potency (maximal activity) against AAPH- and NADPH/ADP-Fe(3+)-induced lipid peroxidation. Our results support the idea that this new formulations could facilitate the uptake of FA by the cells because of their lipophilic structure, thus increasing FA bioavailability. Furthermore, stearyl ferulate-based nanoparticles could prevent the degradation of FA entrapped on their structure, making FA almost entirely available to explicate its antioxidant power once released.

This case study reports a fatal subarachnoid hemorrhage (SAH) with concomitant accidental carbon monoxide (CO) exposure in 32-year-old man. Autopsy results indicated an antemortem aspiration of smoke, and a massive SAH was identified as the cause of death. Intriguingly, the carboxyhemoglobin level was 30%, suggesting that CO could have played a specific role. Intracranial hemorrhages following CO exposure in brain areas and tissues such as the basal ganglia, globus pallidus, or white matter are rare, but well characterized, whereas SAH related to CO exposure has not been previously described. In this case report, the possible role of CO, either as a primary cause or as a facilitating factor, in the pathogenesis of SAH is discussed. In particular, we propose the hypothesis that the excessive vasodilating effects produced by CO on the cerebral endothelium results in consequential loss of microvascular integrity.

The tumor suppressor protein p53 has been described "as the guardian of the genome" for its crucial role in regulating the transcription of numerous genes responsible for cells cycle arrest, senescence, or apoptosis in response to various stress signals. Although p53 promotes longevity by decreasing the risk of cancer through activation of apoptosis or cellular senescence, several findings suggest that an increase of its activity may have deleterious effects leading to selected aspects of the aging phenotype and neurodegenerative diseases. There is the link between p53 and oxidative stress, the latter a crucial factor that contributes to neurodegenerative processes like Alzheimer disease (AD). In the present study, using a proteomics approach, we analyzed the impact of lack of p53 on the expression of several brain mitochondrial proteins involved in different pathways, and how lack of p53 may present a target to restore neuronal impairments. Our investigation on isolated brain mitochondria from p53((-/-)) mice also provides a better understanding of the p53-mitochondria relationship and its involvement in the development of many diseases.

Alzheimer disease (AD) is a neurodegenerative disorder characterized by progressive cognitive impairment and neuropathology. Oxidative and nitrosative stress plays a principal role in the pathogenesis of AD. The induction of the heme oxygenase-1/biliverdin reductase-A (HO-1/BVR-A) system in the brain represents one of the earliest mechanisms activated by cells to counteract the noxious effects of increased reactive oxygen species and reactive nitrogen species. Although initially proposed as a neuroprotective system in AD brain, the HO-1/BVR-A pathophysiological features are under debate. We previously reported alterations in BVR activity along with decreased phosphorylation and increased oxidative/nitrosative posttranslational modifications in the brain of subjects with AD and those with mild cognitive impairment (MCI). Furthermore, other groups proposed the observed increase in HO-1 in AD brain as a possible neurotoxic mechanism. Here we provide new insights about HO-1 in the brain of subjects with AD and MCI, the latter condition being the transitional phase between normal aging and early AD. HO-1 protein levels were significantly increased in the hippocampus of AD subjects, whereas HO-2 protein levels were significantly decreased in both AD and MCI hippocampi. In addition, significant increases in Ser-residue phosphorylation together with increased oxidative posttranslational modifications were found in the hippocampus of AD subjects. Interestingly, despite the lack of oxidative stress-induced AD neuropathology in cerebellum, HO-1 demonstrated increased Ser-residue phosphorylation and oxidative posttranslational modifications in this brain area, suggesting HO-1 as a target of oxidative damage even in the cerebellum. The significance of these findings is profound and opens new avenues into the comprehension of the role of HO-1 in the pathogenesis of AD.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive impairment and neuropathology. Only acetylcholinesterase inhibitors and the NMDA antagonist memantine are approved for AD treatment. Recent preclinical and epidemiological studies proposed statins as novel therapeutics for AD, but the mechanisms of action are still unknown. Here, we demonstrate that atorvastatin (80 mg/d for 14.5 months) treatment resulted in an up-regulation of the inducible isoform of haem oxygenase (HO-1), an enzyme with significant neuroprotective activity. Atorvastatin selectively increased HO-1 in the parietal cortex but not cerebellum. In contrast, HO-2 was increased in cerebellum but not parietal cortex. No changes were observed in HO-1 or HO-2 in the liver. Significant negative correlations between HO-1 and oxidative stress indices and positive correlations with glutathione levels in parietal cortex were found. HO-1 up-regulation significantly correlated with lower discrimination learning error scores in aged beagles. Reference to therapeutic applications of atorvastatin in AD is discussed.

Over the last 10 years, the potential therapeutic effects of nutraceuticals to prevent or delay Alzheimer's disease were proposed. Among dietary antioxidants curcumin, Ginkgo biloba and carnitines were extensively studied for their neuroprotective effects. The rationale for this alternative therapeutic approach was based on several preclinical studies which suggested the neuroprotective effects for curcumin, Ginkgo biloba and acetyl-l-carnitine due to either a free radical scavenging activity or the inhibition of pro-inflammatory pathways or the potentiation of the cell stress response. However, although these are interesting premises, clinical studies were not able to demonstrate significant beneficial effects of curcumin, Ginkgo biloba and acetyl-l-carnitine in improving cognitive functions in Alzheimer's disease patients. The aim of this review is to summarize the main pharmacologic features of curcumin, Ginkgo biloba and carnitines as well as to underlie the main outcomes reached by clinical studies designed to demonstrate the efficacy of these natural substances in Alzheimer's disease patients. This article is part of a Special Issue entitled: Antioxidants and Antioxidant Treatment in Disease.

Signal transduction and activator of transcription-3 (STAT3) plays an important role in neuronal survival, regeneration and repair after brain injury. We previously demonstrated that STAT3 is activated in brain after cerebral ischemia specifically in neurons. The effect was sex-specific and modulated by sex steroids, with higher activation in females than males. In the current study, we used a proteomics approach to identify downstream proteins affected by ischemia in male and female wild-type (WT) and neuron-specific STAT3 knockout (KO) mice. We established four comparison groups based on the transgenic condition and the hemisphere analyzed, respectively. Moreover, the sexual variable was taken into account and male and female animals were analyzed independently. Results support a role for STAT3 in metabolic, synaptic, structural and transcriptional responses to cerebral ischemia, indeed the adaptive response to ischemia/reperfusion injury is delayed in neuronal-specific STAT3 KO mice. The differences observed between males and females emphasize the importance of sex-specific neuronal survival and repair mechanisms, especially those involving antioxidant and energy-related activities, often caused by sex hormones.

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Local delivery of chemical agents for brain tumors has offered improved prognosis for patients with brain tumors in recent years. Agents of local delivery are highly desired for their ability to concentrate local, targeted therapeutic agents, including cytotoxic, antiangiogenic, and immunomodulatory agents in the precise location of neoplastic growth. The introduction of polymer drug delivery has offered one such form of local delivery, offering the all the benefits of general local delivery agents, including (1) controlled and (2) sustained release of chemotherapeutic agents over long periods of time, as well as (3) avoidance of the high systemic doses often related to systemic toxicities. Unlike other methods of local delivery, including catheter administration and convection-enhanced delivery (CED), polymer drugs do not rely, respectively, on mechanical function or pressure gradients.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive impairment and neuropathology. Only acetylcholinesterase inhibitors and the NMDA antagonist memantine are approved for AD treatment. Recent preclinical and epidemiological studies proposed statins as novel therapeutics for AD, but the mechanisms of action are still unknown. Here, we demonstrate that atorvastatin (80 mg/d for 14.5 months) treatment resulted in an up-regulation of the inducible isoform of haem oxygenase (HO-1), an enzyme with significant neuroprotective activity. Atorvastatin selectively increased HO-1 in the parietal cortex but not cerebellum. In contrast, HO-2 was increased in cerebellum but not parietal cortex. No changes were observed in HO-1 or HO-2 in the liver. Significant negative correlations between HO-1 and oxidative stress indices and positive correlations with glutathione levels in parietal cortex were found. HO-1 up-regulation significantly correlated with lower discrimination learning error scores in aged beagles. Reference to therapeutic applications of atorvastatin in AD is discussed.