Carbon monoxide (CO) is a gasotransmitter generated by heme oxygenase (HO) isoforms during heme catabolism. The inducible HO-1 produces CO under conditions of redox imbalance, such as oxidative stress and inflammation. On the other hand, HO-2 constitutively generates CO, primarily during the physiological turnover of heme. Extensive evidence indicates that CO exerts autocrine effects by targeting hemoproteins, including soluble guanylyl cyclase, cyclooxygenase, and cytochromes. Furthermore, CO regulates many biological processes within the brain, including mitochondrial biogenesis, potassium channel activity, mitogen-activated protein kinase and phosphatidylinositol-3-kinase/Akt signaling. It also controls the activity of transcription factors, such as hypoxia-inducible factor-1 and peroxisome proliferator-activated receptor-γ. Through these mechanisms, CO modulates inflammatory gene expression, promotes anti-apoptotic signaling, and contributes to local stress responses. Conversely, CO produced in the hypothalamus inhibits the stress-induced release of corticotropin-releasing hormone and arginine vasopressin under pro-inflammatory conditions, resulting in reduced adrenocorticotropin hormone release and cortisol secretion from the anterior pituitary and adrenal cortex, respectively. Moreover, hypothalamic CO acts in a paracrine manner to modulate glucocorticoid release during psychological stress, including restraint or water deprivation. Together, these findings support the view that endogenous CO is a key modulator of the stress axis, exerting pleiotropic effects that integrate neuroendocrine, immune, and metabolic responses.

Heme oxygenase (HO) metabolizes heme into ferrous iron, carbon monoxide (CO), and biliverdin-IXα (BV), the latter being reduced into bilirubin-IXα (BR) by the biliverdin reductase-A (BVR). Heme oxygenase exists as two isoforms, HO-1, inducible and involved in the cell stress response, and HO-2, constitutive and committed to the physiologic turnover of heme and in the intracellular oxygen sensing. Many studies have identified genetic variants of the HO/BVR system and suggested their connection in free radical-induced diseases. The most common genetic variants include (GT)n dinucleotide length polymorphisms and single nucleotide polymorphisms. Gain-of-function mutations in the HO-1 and HO-2 genes foster the ventilator response to hypoxia and reduce the risk of coronary heart disease and age-related macular degeneration but increase the risk of neonatal jaundice, sickle cell disease, and Parkinson’s disease. Conversely, loss-of-function mutations in the HO-1 gene increase the risk of type 2 diabetes mellitus, chronic obstructive pulmonary disease, and some types of cancers. Regarding BVR, the reported loss-of-function mutations increase the risk of green jaundice. Unfortunately, the physiological role of the HO/BVR system does not allow for the hypothesis gene silencing/induction strategies, but knowledge of these mutations can certainly facilitate a medical approach that enables early diagnoses and tailored treatments.

Alzheimer’s disease (AD) is a neurodegenerative disorder involving free radical overload, neuroinflammation, and a deranged cell stress response. In particular, the modulation of the heme oxygenase/biliverdin reductase (HO/BVR) system, a key component of the brain stress response, is currently regarded as a promising therapeutic approach for AD. Cellular senescence, defined as a process of cell cycle arrest due to oxidative stress, DNA damage, mitochondrial dysfunction, and oncogene activation, has been identified as a pivotal factor in the development of AD. A mounting body of research has demonstrated that the accumulation of senescent cells in the brain can lead to a variety of neurotoxic effects, including synaptic dysfunction, the destruction of the blood–brain barrier, and impaired remyelination. Finally, the release of proinflammatory molecules by senescent cells further exacerbates neurodegeneration. A considerable number of xenobiotics, with well-documented neuroprotective effects through the activation of the HO/BVR system, have been shown to modulate pathways involved in cellular senescence outside the brain. Unfortunately, a direct link between HO/BVR and cellular senescence in AD is yet to be established. This compelling evidence should motivate basic and clinical researchers to address such a significant gap in knowledge and conduct novel studies in this field.

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.

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.

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.

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.

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.

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.

The formation and aggregation of amyloid-β-peptide (Aβ) into soluble and insoluble species represent the pathological hallmarks of Alzheimer’s disease (AD). Over the last few years, however, soluble Aβ (sAβ) prevailed over fibrillar Aβ (fAβ) as determinant of neurotoxicity. One of the main therapeutic strategies for challenging neurodegeneration is to fight against neuroinflammation and prevent free radical-induced damage: in this light, the heme oxygenase/biliverdin reductase (HO/BVR) system is considered a promising drug target. The aim of this work was to investigate whether or not celecoxib (CXB), a selective inhibitor of the pro-inflammatory cyclooxygenase-2, modulates the HO/BVR system and prevents lipid peroxidation in SH-SY5Y neuroblastoma cells. Both sAβ (6.25–50 nM) and fAβ (1.25–50 nM) dose-dependently over-expressed inducible HO (HO-1) after 24 h of incubation, reaching statistical significance at 25 and 6.25 nM, respectively. Interestingly, CXB (1–10 μM, for 1 h) further enhanced Aβ-induced HO-1 expression through the nuclear translocation of the transcriptional factor Nrf2. Furthermore, 10 μM CXB counteracted the Aβ-induced ROS production with a mechanism fully dependent on HO-1 up-regulation; nevertheless, 10 μM CXB significantly counteracted only 25 nM sAβ-induced lipid peroxidation damage in SH-SY5Y neurons by modulating HO-1. Both carbon monoxide (CORM-2, 50 nM) and bilirubin (50 nM) significantly prevented ROS production in Aβ-treated neurons and favored both the slowdown of the growth rate of Aβ oligomers and the decrease in oligomer/fibril final size. In conclusion, these results suggest a novel mechanism through which CXB is neuroprotective in subjects with early AD or mild cognitive impairment.

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.

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.

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.

Over the last years, many studies reported on the antioxidant effects of ferulic acid (FA) in preclinical models of dementia through the activation of the heme oxygenase/biliverdin reductase (HO/BVR) system. However, only a few studies evaluated whether FA could improve neurological function under milder conditions, such as psychological stress. The aim of this study was to investigate the effects of FA (150 mg/kg intraperitoneal route) on cognitive function in male Wistar rats exposed to emotional arousal. Animals were randomly assigned to two experimental groups, namely not habituated or habituated to the experimental context, and the novel object recognition test was used to evaluate their cognitive performance. The administration of FA significantly increased long-term retention memory in not habituated rats. Ferulic acid increased the expression of HO-1 in the hippocampus and frontal cortex of not habituated rats only, whereas HO-2 resulted differently modulated in these cognitive brain areas. No significant effects on either HO-1 or HO-2 or BVR were observed in the cerebellum of both habituated and not habituated rats. Ferulic acid activated the stress axis in not habituated rats, as shown by the increase in hypothalamic corticotrophin-releasing hormone levels. Pre-treatment with Sn-protoporphyrin-IX [0.25 μmol/kg, intracerebroventricular route (i.c.v.)], a well-known inhibitor of HO activity through which carbon monoxide (CO) and biliverdin (BV) are generated, abolished the FA-induced improvement of cognitive performance only in not habituated rats, suggesting a role for HO-derived by-products. The CO-donor tricarbonyldichlororuthenium (II) (30 nmol/kg i.c.v.) mimicked the FA-related improvement of cognitive skills only in not habituated rats, whereas BV did not have any effect in any group. In conclusion, these results set the stage for subsequent studies on the neuropharmacological action of FA under conditions of psychological stress.

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. (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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.