Immunomodulatory and anti-inflammatory therapeutic potential of gingerols and their nanoformulations.

Ginger (Zingiber officinale Roscoe), a member of the Zingiberaceae family, is one of the most popular spices worldwide, known since ancient times, and used both as a spice and a medicinal plant. The phenolic compounds found in ginger are predominantly gingerols, shogaols, and paradols. Gingerols are the major phenolic compounds found in fresh ginger and contain mainly 6-gingerol as well as 4-, 5-, 8-, 10-, and 12-gingerols. Gingerols possess a wide array of bioactivities, such as antioxidant and anticancer, among others. Regarding the different array of biological activities and published data on the mechanisms underlying its action, the complex interaction between three key events, including inflammation, oxidative stress, and immunity, appears to contribute to a plethora of pharmacological activities of this compound. Among these, the immunomodulatory properties of these compounds, which attract attention due to their effects on the immune system, have been the focus of many studies. Gingerols can alleviate inflammation given their ability to inhibit the activation of protein kinase B (Akt) and nuclear factor kappa B (NF-κB) signaling pathways, causing a decrease in proinflammatory and an increase in anti-inflammatory cytokines. However, given their low bioavailability, it is necessary to develop new and more effective strategies for treatment with gingerols. In order to overcome this problem, recent studies have addressed new drug delivery systems containing gingerols. In this review, the immunomodulatory activities of gingerol and its underlying mechanisms of action combined with the contributions of developed nanodrug delivery systems to this activity will be examined.

The potential of pumpkin seed oil as a functional food-A comprehensive review of chemical composition, health benefits, and safety.

The growing interest in foods that can be beneficial to human health is bringing into focus some products that have been used locally for centuries but have recently gained worldwide attention. One of these foods is pumpkin seed oil, which has been used in culinary and traditional medicine, but recent data also show its use in the pharmaceutical and cosmetic industries. In addition, some sources refer to it as a potential functional food, mainly because it is obtained from pumpkin seeds, which contain many functional components. However, the production process of the oil may affect the content of these components and consequently the biological activity of the oil. In this review, we have focused on summarizing scientific data that explore the potential of pumpkin seed oil as a functional food ingredient. We provide a comprehensive overview of pumpkin seed oil chemical composition, phytochemical content, biological activity, and safety, as well as the overview of production processes and contemporary use. The main phytochemicals in pumpkin seed oil with health-related properties are polyphenols, phytoestrogens, and fatty acids, but carotenoids, squalene, tocopherols, and minerals may also contribute to health benefits. Most studies have been conducted in vitro and support the claim that pumpkin seed oil has antioxidant and antimicrobial activities. Clinical studies have shown that pumpkin seed oil may be beneficial in the treatment of cardiovascular problems of menopausal women and ailments associated with imbalance of sex hormones.

Regulation of DAPK1 by Natural Products: An Important Target in Treatment of Stroke.

Stroke is a sudden neurological disorder that occurs due to impaired blood flow to an area of the brain. Stroke can be caused by the blockage or rupture of a blood vessel in the brain, called ischemic stroke and hemorrhagic stroke, respectively. Stroke is more common in men than women. Atrial fibrillation, hypertension, kidney disease, high cholesterol and lipids, genetic predisposition, inactivity, poor nutrition, diabetes mellitus, family history and smoking are factors that increase the risk of stroke. Restoring blood flow by repositioning blocked arteries using thrombolytic agents or endovascular therapy are the most effective treatments for stroke. However, restoring circulation after thrombolysis can cause fatal edema or intracranial hemorrhage, and worsen brain damage in a process known as ischemia-reperfusion injury. Therefore, there is a pressing need to find and develop more effective treatments for stroke. In the past, the first choice of treatment was based on natural compounds. Natural compounds are able to reduce the symptoms and reduce various diseases including stroke that attract the attention of the pharmaceutical industry. Nowadays, as a result of the numerous studies carried out in the field of herbal medicine, many useful and valuable effects of plants have been identified. The death-associated protein kinase (DAPK) family is one of the vital families of serine/threonine kinases involved in the regulation of some biological functions in human cells. DAPK1 is the most studied kinase within the DAPKs family as it is involved in neuronal and recovery processes. Dysregulation of DAPK1 in the brain is involved in the developing neurological diseases such as stroke. Natural products can function in a variety of ways, including reducing cerebral edema, reducing brain endothelial cell death, and inhibiting TNFα and interleukin-1ß (IL-1ß) through regulating the DAPK1 signal against stroke. Due to the role of DAPK1 in neurological disorders, the aim of this article was to investigate the role of DAPK1 in stroke and its modulation by natural compounds.

The Role of Natural Products in Treatment of Depressive Disorder.

Depressive disorder is one of the most common psychiatric syndromes that, if left untreated, can cause many disturbances in a person's life. Numerous factors are involved in depression, including inflammation, brain-derived neurotrophic factor (BDNF), GABAergic system, hypothalamic- pituitary-adrenal (HPA) Axis, monoamine neurotransmitters (serotonin (5-HT), noradrenaline, and dopamine). Common treatments for depression are selective serotonin reuptake inhibitors, tricyclic antidepressants, and monoamine oxidase inhibitors, but these drugs have several side effects such as anxiety, diarrhea, constipation, weight loss, and sexual dysfunctions. These agents only reduce the symptoms and temporarily reduce the rate of cognitive impairment associated with depression. As a result, extensive research has recently been conducted on the potential use of antidepressant and sedative herbs. According to the available data, herbs used in traditional medicine can be significantly effective in reducing depression, depressive symptoms and improving patients' performance. The present study provides a summary of biomarkers and therapeutic goals of depression and shows that natural products such as saffron or genipin have antidepressant effects. Some of the useful natural products and their mechanisms were evaluated. Data on various herbs and natural isolated compounds reported to prevent and reduce depressive symptoms is also discussed.

Garlic (Allium sativum L.): Its Chemistry, Nutritional Composition, Toxicity, and Anticancer Properties.

The current review discuss the chemistry, nutritional composition, toxicity, and biological functions of garlic and its bioactive compounds against various types of cancers via different anticancer mechanisms. Several scientific documents were found in reliable literature and searched in databases viz Science Direct, PubMed, Web of Science, Scopus, and Research Gate were carried out using keywords such as "garlic", "garlic bioactive compounds", "anticancer mechanisms of garlic", "nutritional composition of garlic", and others. Garlic contains several phytoconstituents with activities against cancer, and compounds such as diallyl trisulfide (DATS), allicin, and diallyl disulfide (DADS), diallyl sulfide (DAS), and allyl mercaptan (AM). The influence of numerous garlic- derived products, phytochemicals, and nanoformulations on the liver, oral, prostate, breast, gastric, colorectal, skin, and pancreatic cancers has been studied. Based on our search, the bioactive molecules in garlic were found to inhibit the various phases of cancer. Moreover, the compounds in this plant also abrogate the peroxidation of lipids, activity of nitric oxide synthase, epidermal growth factor (EGF) receptor, nuclear factor-kappa B (NF-κB), protein kinase C, and regulate cell cycle and survival signaling cascades. Hence, garlic and its bioactive molecules exhibit the aforementioned mechanistic actions, and thus, they could be used to inhibit the induction, development, and progression of cancer. The review describes the nutritional composition of garlic, its bioactive molecules, and nanoformulations against various types of cancers, as well as the potential for developing these agents as antitumor drugs.

Therapeutic Effects of Hydroalcoholic Extracts from the Ancient Apple Mela Rosa dei Monti Sibillini in Transient Global Ischemia in Rats.

The Mela Rosa dei Monti Sibillini is an ancient apple variety cultivated by Romans in the foothills of the Sibillini Mountains, central Italy, showing potential as a source of nutraceuticals. The purpose of this study was to evaluate the protective effects of the hydroalcoholic extracts from the peel (APE) and pulp (APP) of this fruit in an animal model of transient global ischemia. Chemical constituents were analyzed by liquid chromatography-mass spectrometry (LC-DAD-MSn) indicating several polyphenols such as B-type procyanidins, quercetin derivatives and hydroxycinnamic acids as the main bioactive components. Acute pre-treatment of extracts (30 mg/kg, i.p.) significantly decreased the brain levels of the pro-inflammatory cytokines IL-1ß (p < 0.01) and TNF-α (p < 0.001 and p < 0.01 for APE and APP, respectively), the expression of caspase-3 (p < 0.01, For APE) and MDA (p < 0.05), a lipid peroxidation biomarker in rats. Both extracts restricted the pathological changes of the brain induced by ischemic stroke in hematoxylin and eosin assay. Moreover, they improved the scores of behavioral tests in grid-walking and modified neurological severity scores (mNSS) tests. In conclusion, these results proved this ancient Italian apple is a source of nutraceuticals able to protect/prevent damage from brain ischemia.

Role of natural products for the treatment of Alzheimer's disease.

Negative psychological and physiological consequences of neurodegenerative disorders represent a high social and health cost. Among the neurodegenerative disorders Alzheimer's disease (AD) is recognized as a leading neurodegenerative condition and a primary cause of dementia in the elderlys. AD is considered as neurodegenerative disorder that progressively impairs cognitive function and memory. According to current epidemiological data, about 50 milLion people worldwide are suffering from AD. The primary symptoms of AD are almost inappreciable and usually comprise forgetfulness of recent events. Numerous processes are involved in the development of AD, for example oxidative stress (OS) mainly due to mitochondrial dysfunction, intracellular the accumulation of hyperphosphorylated tau (τ) proteins in the form of neurofibrillary tangles, excessive the accumulation of extracellular plaques of beta-amyloid (Aß), genetic and environmental factors. Running treatments only attenuate symptoms and temporarily reduce the rate of cognitive progression associated with AD. This means that most treatments focus only on controlLing symptoms, particularly in the initial stages of the disease. In the past, the first choice of treatment was based on natural ingredients. In this sense, diverse natural products (NPs) are capable to decrease the symptoms and alleviate the development of several diseases including AD attracting the attention of the scientific community and the pharmaceutical industry. Specifically, numerous NPs including flavonoids, gingerols, tannins, anthocyanins, triterpenes and alkaloids have been shown anti-inflammatory, antioxidant, anti-amyloidogenic, and anti-choLinesterase properties. This review provide a summary of the pathogenesis and the therapeutic goals of AD. It also discusses the available data on various plants and isolated natural compounds used to prevent and diminish the symptoms of AD.

Hepatoprotective Effects of Standardized Extracts from an Ancient Italian Apple Variety (Mela Rosa dei Monti Sibillini) against Carbon Tetrachloride (CCl4)-Induced Hepatotoxicity in Rats.

The aim of this research was to examine the effect of the hydroalcoholic extracts from the peel (APE) and pulp (APP) of a traditional apple cultivar from central Italy (Mela Rosa dei Monti Sibillini) on CCl4-induced hepatotoxicity in rats. Phytoconstituents were determined by liquid chromatography-mass spectrometry (LC-MS) analysis showing an abundance of proanthocyanidins and flavonol derivatives together with the presence of annurcoic acid in APE. Wistar rats received APE/APP (30 mg/kg oral administration) for three days before CCl4 injection (2 mL/kg intraperitoneal once on the third day). Treatment with both APE and APP prior to CCl4 injection significantly decreased the serum levels of aspartate aminotransferase (AST), alkaline phosphatase (ALP) and alanine aminotransferase (ALT) compared to the CCl4 group. Besides, pretreatment with APE reversed the CCl4 effects on superoxide dismutase (SOD), myeloperoxidase (MPO), tumor necrosis factor-α (TNF-α) and interleukin-1beta (IL-1ß) levels in liver tissue in rats and reduced tissue damage as shown in hematoxylin and eosin staining. These results showed that this ancient Italian apple is worthy of use in nutraceuticals and dietary supplements to prevent and/or protect against liver disorders.

Collateral sensitivity of natural products in drug-resistant cancer cells.

Cancer chemotherapy is frequently hampered by drug resistance. Concepts to combine anticancer drugs with different modes of action to avoid the development of resistance did not provide the expected success in the past, because tumors can be simultaneously non-responsive to many drugs (e.g. the multidrug resistance phenotype). However, tumors may be specifically hypersensitive to other drugs - a phenomenon also termed collateral sensitivity. This seems to be a general biological mechanism, since it also occurs in drug-resistant Escherichia coli and Saccharomyces cerevisiae. Here, we give a timely and comprehensive overview on hypersensitivity in resistant cancer cells towards natural products and their derivatives. Since the majority of clinically established anticancer drugs are natural products or are in one way or another derived from them, it is worth hypothesizing that natural products may deliver promising lead compounds for the development of collateral sensitive anticancer drugs. Hypersensitivity occurs not only in classical ABC transporter-mediated multidrug resistance, but also in many other resistance phenotypes. Resistant cancers can be hypersensitive to natural compounds from diverse classes and origins (i.e. mitotic spindle poisons, DNA topoisomerase 1 and 2 inhibitors, diverse phytochemicals isolated from medicinal plants, (semi)synthetic derivatives of phytochemicals, antibiotics, marine drugs, recombinant therapeutic proteins and others). Molecular mechanisms of collateral sensitivity include (1) increased ATP hydrolysis and reactive oxygen species production by futile cycling during ABC transporter-mediated drug efflux, (2) inhibition of ATP production, and (3) alterations of drug target proteins (e.g. increased expression of topoisomerases and heat shock proteins, inhibition of Wnt/ß-catenin pathway, mutations in ß-tubulin). The phenomenon of hypersensitivity needs to be exploited for clinical oncology by the development of (1) novel combination protocols that include collateral sensitive drugs and (2) novel drugs that specifically exhibit high degrees of hypersensitivity in resistant tumors.

Protective effects of hydroalcoholic extracts from an ancient apple variety 'Mela Rosa dei Monti Sibillini' against renal ischemia/reperfusion injury in rats.

The purpose of this work was to investigate the effect of hydroalcoholic extracts from the peel (APE) and pulp (APP) of a traditional apple variety of central Italy, the 'Mela Rosa dei Monti Sibillini', on the damage caused by renal ischemia/reperfusion injury (IRI) in rats. Thirty mg per kg b.w. of the extracts were administered intraperitoneally to male adult Wistar rats 3 days before the induction of IRI by pedicle clamping. A significant decrease in the levels of malondialdehyde (MDA), tumor necrosis factor-α (TNFα), interleukin 1 beta (IL-1ß) and nuclear factor-κB (NF-κB) was observed in the groups pre-treated with APE when compared with IRI rats. The chemical composition of APE was determined by HPLC-DAD-MSn highlighting a significant amount of proanthocyanidins (52.9 mg g-1), flavonols (42.27 mg g-1) and dihydrochalcones (11.75 mg g-1). These findings indicated that this ancient apple variety is a promising source of nutraceuticals and functional foods helpful to manage complications of renal disorders.

Toll-like receptors as novel therapeutic targets for herpes simplex virus infection.

Seropositivity for HSV reaches more than 70% within the world population, and yet no approved vaccine exists. While HSV1 is responsible for keratitis, encephalitis, and labialis, HSV2 carriers have a high susceptibility to other STD infections, such as HIV. Induction of antiviral innate immune responses upon infection depends on a family of pattern recognition receptors called Toll-like receptors (TLR). TLRs bridge innate and adaptive immunity by sensing virus infection and activating antiviral immune responses. HSV adopts smart tricks to evade innate immunity and can also manipulate TLR signaling to evade the immune system or even confer destructive effects in favor of virus replication. Here, we review mechanisms by which HSV can trick TLR signaling to impair innate immunity. Then, we analyze the role of HSV-mediated molecular cues, in particular, NF-κB signaling, in promoting protective versus destructive effects of TLRs. Finally, TLR-based therapeutic opportunities with the goal of preventing or treating HSV infection will be discussed.

Antidepressive effects of a chemically characterized maqui berry extract (Aristotelia chilensis (molina) stuntz) in a mouse model of Post-stroke depression.

Mood disorders occur in 30% of stroke patients, and of these post-stroke depression (PSD) is the most significant. This study aimed to evaluate the antidepressive-like effects and in vivo antioxidant activity of a chemically characterized maqui berry (Aristotelia chilensis (Molina) Stuntz) extract obtained from an optimized extraction method, on a murine PSD model. The extraction process was optimized to maximize anthocyanin content, and the phytochemical profile of the extract was evaluated using a multi-methodological approach including a liquid chromatographic method coupled with mass spectrometry and nuclear magnetic resonance spectroscopy. The antidepressive-like activity was investigated through despair swimming and tail suspension tests. The in vivo antioxidant activity was evaluated in mouse brain tissue by measuring the activity of antioxidant enzymes and lipid peroxidation products. A number of compounds have been first identified in maqui berry here, including malvidin-glucoside, GABA, choline and trigonelline. Moreover, the results showed that the antidepressive-like activity exerted by the extract, which was found to restore normal mouse behavior in both despair swimming and tail suspension tests, could be linked to its antioxidant activity, leading to the conclusion that maqui berries might be useful for supporting pharmacological therapy of PSD by modulating oxidative stress.

Anti-inflammatory effects of Melatonin: A mechanistic review.

N-acetyl-5-methoxy-tryptamine (melatonin) is a natural substance produced both by plants, as a secondary metabolite, and animals, by the pineal gland and other tissues. In humans, melatonin participates in numerous functions including the regulation of mood, sleep, reproduction, promotion of immunomodulation, antioxidant defense and as an anti-inflammatory agent. The anti-inflammatory activity of melatonin could yield beneficial effects on intake, particularly against the chronic inflammation which underlies many chronic diseases. This review aims to provide an assessment of the literature data on the anti-inflammatory activity of melatonin, with a particular focus on the mechanisms responsible for this behavior. We can conclude that many in vitro studies and in vivo studies in experimental animal model systems show that melatonin exerts anti-inflammatory activity in a number of chronic diseases which affect different organs in different circumstances. Clinical trials, however, often fail to reach positive results and are thus far inconclusive. Thus, in the future, long-term well-designed investigations on melatonin-rich foods or melatonin food supplements could provide valuable information towards public health recommendations on melatonin, taking into account both the nature of the compound and the optimal dose, for protection from long-term inflammation linked to chronic diseases.

Targeting STATs in neuroinflammation: The road less traveled!

JAK/STAT transduction pathway is a highly conserved pathway implicated in regulating cellular proliferation, differentiation, survival and apoptosis. Dysregulation of this pathway is involved in the onset of autoimmune, haematological, oncological, metabolic and neurological diseases. Over the last few years, the research of anti-neuroinflammatory agents has gained considerable attention. The ability to diminish the STAT-induced transcription of inflammatory genes is documented for both natural compounds (such as polyphenols) and chemical drugs. Among polyphenols, quercetin and curcumin directly inhibit STAT, while Berberis vulgaris L. and Sophora alopecuroides L extracts act indirectly. Also, the Food and Drug Administration has approved several JAK/STAT inhibitors (direct or indirect) for treating inflammatory diseases, indicating STAT can be considered as a therapeutic target for neuroinflammatory pathologies. Considering the encouraging data obtained so far, clinical trials are warranted to demonstrate the effectiveness and potential use in the clinical practice of STAT inhibitors to treat inflammation-associated neurodegenerative pathologies.

Targeting mTORs by omega-3 fatty acids: A possible novel therapeutic strategy for neurodegeneration?

Neurodegenerative diseases (NDs) such as Parkinson's (PD), Alzheimer's (AD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS) cause significant world-wide morbidity and mortality. To date, there is no drug of cure for these, mostly age-related diseases, although approaches in delaying the pathology and/or giving patients some symptomatic relief have been adopted for the last few decades. Various studies in recent years have shown the beneficial effects of omega-3 poly unsaturated fatty acids (PUFAs) through diverse mechanisms including anti-inflammatory effects. This review now assesses the potential of this class of compounds in NDs therapy through specific action against the mammalian target of rapamycin (mTOR) signaling pathway. The role of mTOR in neurodegenerative diseases and targeted therapies by PUFAs are discussed.