Protective effect of a hydromethanolic extract from Fraxinus excelsior L. bark against a rat model of aluminum chloride-induced Alzheimer's disease: Relevance to its anti-inflammatory and antioxidant effects.

ETHNOPHARMACOLOGICAL RELEVANCE: Fraxinus excelsior L. (FE), commonly known as the ash, belongs to the Oleaceae family and has shown several pharmacological and biological properties, such as antioxidant, immunomodulatory, neuroprotective, and anti-inflammatory effects. It has also attracted the most attention toward neuroinflammation. Moreover, FE bark and leaves have been used to treat neurological disorders, aging, neuropathic pain, urinary complaints, and articular pain in traditional and ethnomedicine. Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder resulting from the involvement of amyloid-beta, metal-induced oxidative stress, and neuroinflammation. AIM OF THE STUDY: The objective of the current study was to assess the neuroprotective effects of hydromethanolic extract from FE bark in an AlCl3-induced rat model of AD. MATERIALS AND METHODS: The maceration process was utilized to prepare the hydromethanolic extract of FE bark, and characterized by LC-MS/MS. To assess the anti-AD effects of the FE extract, rats were categorized into five different groups, AlCl3; normal control; FE-treated groups at 50, 100, and 200 mg/kg. Passive avoidance learning test, Y-maze, open field, and elevated plus maze behavioral tests were evaluated on days 7 and 14 to analyze the cognitive impairments. Zymography analysis, biochemical tests, and histopathological changes were also followed in different groups. RESULTS: LC-MS/MS analysis indicated the presence of coumarins, including isofraxidin7-O-diglucoside in the methanolic extract of FE as a new isofraxidin derivative in this genus. FE significantly improved memory and cognitive function, maintained weight, prevented neuronal damages, and preserved the hippocampus's histological features, as demonstrated by behavioral tests and histopathological analysis. FE increased anti-inflammatory MMP-2 activity, whereas it decreased that of inflammatory MMP-9. Moreover, FE increased plasma antioxidant capacity by enhancing CAT and GSH while decreasing nitrite levels in the serum of treated groups. In comparison between the treated groups, the rats that received high doses of the FE extract (200 mg/kg) showed the highest therapeutic effect. CONCLUSION: FE rich in coumarins could be an effective anti-AD adjunct agent, passing through antioxidant and anti-inflammatory pathways. These results encourage further studies for the development of this extract as a promising agent in preventing, managing, or treating AD and related diseases.

Therapeutic targeting of Ras/Raf/MAPK pathway by natural products: A systematic and mechanistic approach for neurodegeneration.

BACKGROUND: Multiple dysregulated pathways are behind the pathogenesis of neurodegenerative diseases (NDDs); however, the crucial targets are still unknown. Oxidative stress, apoptosis, autophagy, and inflammation are the most dominant pathways that strongly influence neurodegeneration. In this way, targeting the Ras/Raf/mitogen-activated protein kinases (MAPKs) pathway appears to be a developing strategy for combating NDDs like Parkinson's disease, Alzheimer's disease, stroke, aging, and other NDDs. Accordingly, plant secondary metabolites have shown promising potentials for the simultaneous modulation of the Ras/Raf/MAPKs pathway and play an essential role in NDDs. MAPKs include p38 MAPK, extracellular signal-regulated kinase 1/2 (ERK 1/2), and c-Jun N-terminal kinase (JNK), which are important molecular players in neurodegeneration. Ras/Raf, which is located the upstream of MAPK pathway influences the initiation and progression of neurodegeneration and is regulated by natural products. PURPOSE: Thus, the present study aimed to investigate the neuroprotective roles of plant- and marine-derived secondary metabolites against several NDDs through the modulation of the Ras/Raf/MAPK signaling pathway. STUDY DESIGN AND METHODS: A systematic and comprehensive review was performed to highlight the modulatory roles of natural products on the Ras/Raf/MAPK signaling pathway in NDDs, according to the PRISMA guideline, using scholarly electronic databases, including PubMed, Scopus, and Web of Sciences. Associated reference lists were also searched for the literature review. RESULTS: From a total of 1495 results, finally 107 articles were included in the present study. The results show that several natural compounds such as alkaloid, phenolic, terpenoids, and nanoformulation were shown to have modulatory effects on the Ras/Raf/MAPKs pathway. CONCLUSION: Natural products are promising multi-targeted agents with on NDDs through Ras/Raf/MAPKs pathway. Nevertheless, additional and complementary studies are necessary to check its efficacy and potential side effects.

The pivotal role of JAK/STAT and IRS/PI3K signaling pathways in neurodegenerative diseases: Mechanistic approaches to polyphenols and alkaloids.

BACKGROUND: Neurodegenerative diseases (NDDs) are characterized by progressive neuronal dysfunctionality which results in disability and human life-threatening events. In recent decades, NDDs are on the rise. Besides, conventional drugs have not shown potential effectiveness to attenuate the complications of NDDs. So, exploring novel therapeutic agents is an urgent need to combat such disorders. Accordingly, growing evidence indicates that polyphenols and alkaloids are promising natural candidates, possessing several beneficial pharmacological effects against diseases. Considering the complex pathophysiological mechanisms behind NDDs, Janus kinase (JAK), insulin receptor substrate (IRS), phosphoinositide 3-kinase (PI3K), and signal transducer and activator of transcription (STAT) seem to play critical roles during neurodegeneration/neuroregeneration. In this line, modulation of the JAK/STAT and IRS/PI3K signaling pathways and their interconnected mediators by polyphenols/alkaloids could play pivotal roles in combating NDDs, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), stroke, aging, multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), depression and other neurological disorders. PURPOSE: Thus, the present study aimed to investigate the neuroprotective roles of polyphenols/alkaloids as multi-target natural products against NDDs which are critically passing through the modulation of the JAK/STAT and IRS/PI3K signaling pathways. STUDY DESIGN AND METHODS: A systematic and comprehensive review was performed to highlight the modulatory roles of polyphenols and alkaloids on the JAK/STAT and IRS/PI3K signaling pathways in NDDs, according to the PRISMA guideline, using scholarly electronic databases, including Scopus, PubMed, ScienceDirect, and associated reference lists. RESULTS: In the present study 141 articles were included from a total of 1267 results. The results showed that phenolic compounds such as curcumin, epigallocatechin-3-gallate, and quercetin, and alkaloids such as berberine could be introduced as new strategies in combating NDDs through JAK/STAT and IRS/PI3K signaling pathways. This is the first systematic review that reveals the correlation between the JAK/STAT and IRS/PI3K axis which is targeted by phytochemicals in NDDs. Hence, this review highlighted promising insights into the neuroprotective potential of polyphenols and alkaloids through the JAK/STAT and IRS/PI3K signaling pathway and interconnected mediators toward neuroprotection. CONCLUSION: Amongst natural products, phenolic compounds and alkaloids are multi-targeting agents with the most antioxidants and anti-inflammatory effects possessing the potential of combating NDDs with high efficacy and lower toxicity. However, additional reports are needed to prove the efficacy and possible side effects of natural products.

Naringenin Improves Ovalbumin-Induced Allergic Asthma in Rats through Antioxidant and Anti-Inflammatory Effects.

Asthma is a chronic disease with eosinophilic inflammation and oxidative damages leading to airway obstruction. Naringenin is a phytochemical possessing strong antioxidant and anti-inflammatory activities against chronic destructive conditions. The current study is devoted to evaluating naringenin's effects on the attenuation of inflammation and oxidative stress in lung tissue in a rat model of ovalbumin-induced asthma. Male Wistar rats were allocated to five groups of six: normal control (NC, receiving 1 ml/day of normal saline, orally), asthmatic (AS, receiving ovalbumin (1 mg/mL), and alum (1 mg/mL in saline) on days 0 and 14. Then, on days 21, 22, and 23, they were sensitized with the inhalation of ovalbumin), AS treated with dexamethasone (AS, 1 mg/kg/day, orally) [AS + D1], AS treated with naringenin (20 mg/kg/day, orally) [AS + N20], and AS treated with naringenin (40 mg/kg/day, orally) [AS + N40]. All the groups received associated drugs/agents for 28 days. Finally, bronchoalveolar lavage fluid (BALF) and lung tissue samples were taken off from the animals. The eosinophil count in BALF and malondialdehyde (MDA), glutathione (GSH), interleukin-13 and -4 (IL-13 and IL-4) levels were measured. Besides, the expression of urocortin (UCN) and surfactant protein-D (SP-D) were evaluated in the lung tissue using immunohistochemistry (IHC) and western blotting methods, respectively. Hematoxylin and eosin (H&E) staining were utilized to conduct histopathological analysis. Naringenin treatment significantly reduced MDA, remarkably increased GSH, and meaningfully reduced IL-4 and IL-13 levels in lung tissue. The count of eosinophils in the BALF of AS + N20 and AS + N40 was significantly reduced in comparison with the AS group. The UCN and SP-D protein levels were significantly decreased in the AS + N20 and AS + N40 groups compared to the AS group, using the IHC and western blot methods, respectively. Histopathological analysis data also confirm the results. Naringenin improves the symptoms of allergic asthma through antioxidant and anti-inflammatory effects.

Cellular senescence signaling in cancer: A novel therapeutic target to combat human malignancies.

Senescence is a special state of tumor suppression induced by cell cycle arrest. However, releasing senescence-associated secretory phenotypes by senescent cells could provide tumorigenic conditions and epigenetic changes in neighboring cells. The conventional anticancer drugs activate therapy-induced senescence by several mechanisms which include an increase in mitochondrial biogenesis and reactive oxygen species, up-regulation of tumor suppressor proteins (e.g., p53, p21, p38, and p16) and modulation of dysregulated signaling mediators, including senescence-associated ß-galactosidase, ataxia-telangiectasia mutated/ATM and Rad3-related, checkpoint kinase1/2, phosphatidylinositol 3-kinases/Akt, Ras/Raf pathway, and extracellular signal-regulated kinase/mitogen-activated protein kinase. On the other hand, conventional anticancer agents induce the secretion of procarcinogenic molecules, including inflammatory mediators, such as nuclear factor-κB, tumor necrosis factor-α, and interleukins, and angiogenic mediators, namely vascular endothelial growth factor, in the tumor microenvironment. This condition urges the need for finding novel alternative therapies, novel senolytics, senescence inducers and combination therapies in the regulation of senescence towards the regulation of multiple tumorigenic conditions. This comprehensive review highlights the therapeutic targets and signaling pathways in the senescence of tumor cells. The critical roles of anticancer drug-induced senescence, senolytics, and associated combined administrations are evaluated in the attenuation of cellular senescence pathways to achieve cancer prevention and efficient treatment. Current challenges/pitfalls, limitations, and future research are also discussed.

Targeting lactate metabolism and glycolytic pathways in the tumor microenvironment by natural products: A promising strategy in combating cancer.

Anticancer drugs are not purely effective because of their toxicity, side effects, high cost, inaccessibility, and associated resistance. On the other hand, cancer is a complex public health problem that could intelligently adopt different signaling pathways and alter the body's metabolism to escape from the immune system. One of the cancer strategies to metastasize is modifying pH in the tumor microenvironment, ranging between 6.5 and 6.9. As a powerful determiner, lactate is responsible for this acidosis. It is involved in immune stimulation, including innate and adaptive immunity, apoptotic-related factors (Bax/Bcl-2, caspase), and glycolysis pathways (e.g., GLUT-1, PKM2, PFK, HK2, MCT-1, and LDH). Lactate metabolism, in turn, is interconnected with several dysregulated signaling mediators, including PI3K/Akt/mTOR, AMPK, NF-κB, Nrf2, JAK/STAT, and HIF-1α. Because of lactate's emerging and critical role, targeting lactate production and its transporters is important for preventing and managing tumorigenesis. Hence, exploring and developing novel promising anticancer agents to minimize human cancers is urgent. Based on numerous studies, natural secondary metabolites as multi-target alternative compounds with health-promoting properties possess more high effectiveness and low side effects than conventional agents. Besides, the mechanism of multi-targeted natural sources is related to lactate production and cancer-associated cross-talked factors. This review focuses on targeting the lactate metabolism/transporters, and lactate-associated mediators, including glycolytic pathways. Besides, interconnected mediators to lactate metabolism are also targeted by natural products. Accordingly, plant-derived secondary metabolites are introduced as alternative therapies in combating cancer through modulating lactate metabolism and glycolytic pathways.

Antioxidant and anticancer potentials of edible flowers: where do we stand?

Edible flowers are attracting special therapeutic attention and their administration is on the rise. Edible flowers play pivotal modulatory roles on oxidative stress and related interconnected apoptotic/inflammatory pathways toward the treatment of cancer. In this review, we highlighted the phytochemical content and therapeutic applications of edible flowers, as well as their modulatory potential on the oxidative stress pathways and apoptotic/inflammatory mediators, resulting in anticancer effects. Edible flowers are promising sources of phytochemicals (e.g., phenolic compounds, carotenoids, terpenoids) with several therapeutic effects. They possess anti-inflammatory, anti-diabetic, anti-microbial, anti-depressant, anxiolytic, anti-obesity, cardioprotective, and neuroprotective effects. Edible flowers potentially modulate oxidative stress by targeting erythroid nuclear transcription factor-2/extracellular signal-regulated kinase/mitogen-activated protein kinase (Nrf2/ERK/MAPK), reactive oxygen species (ROS), nitric oxide (NO), malondialdehyde (MDA) and antioxidant response elements (AREs). As the interconnected pathways to oxidative stress, inflammatory mediators, including tumor necrosis factor (TNF)-α, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), interleukins (ILs) as well as apoptotic pathways such as Bcl-2-associated X protein (Bax), Bcl-2, caspase and cytochrome C are critical targets of edible flowers in combating cancer. In this regard, edible flowers could play promising anticancer effects by targeting oxidative stress and downstream dysregulated pathways.

Targeting Mitochondria by Plant Secondary Metabolites: A Promising Strategy in Combating Parkinson's Disease.

Parkinson's disease (PD) is one of the most prevalent and debilitating neurodegenerative conditions, and is currently on the rise. Several dysregulated pathways are behind the pathogenesis of PD; however, the critical targets remain unclear. Accordingly, there is an urgent need to reveal the key dysregulated pathways in PD. Prevailing reports have highlighted the importance of mitochondrial and cross-talked mediators in neurological disorders, genetic changes, and related complications of PD. Multiple pathophysiological mechanisms of PD, as well as the low efficacy and side effects of conventional neuroprotective therapies, drive the need for finding novel alternative agents. Recently, much attention has been paid to using plant secondary metabolites (e.g., flavonoids/phenolic compounds, alkaloids, and terpenoids) in the modulation of PD-associated manifestations by targeting mitochondria. In this line, plant secondary metabolites have shown promising potential for the simultaneous modulation of mitochondrial apoptosis and reactive oxygen species. This review aimed to address mitochondria and multiple dysregulated pathways in PD by plant-derived secondary metabolites.

Natural products attenuate PI3K/Akt/mTOR signaling pathway: A promising strategy in regulating neurodegeneration.

BACKGROUND: As common, progressive, and chronic causes of disability and death, neurodegenerative diseases (NDDs) significantly threaten human health, while no effective treatment is available. Given the engagement of multiple dysregulated pathways in neurodegeneration, there is an imperative need to target the axis and provide effective/multi-target agents to tackle neurodegeneration. Recent studies have revealed the role of phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) in some diseases and natural products with therapeutic potentials. PURPOSE: This is the first systematic and comprehensive review on the role of plant-derived secondary metabolites in managing and/or treating various neuronal disorders via the PI3K/Akt/mTOR signaling pathway. STUDY DESIGN AND METHODS: A systematic and comprehensive review was done based on the PubMed, Scopus, Web of Science, and Cochrane electronic databases. Two independent investigators followed the PRISMA guidelines and included papers on PI3K/Akt/mTOR and interconnected pathways/mediators targeted by phytochemicals in NDDs. RESULTS: Natural products are multi-target agents with diverse pharmacological and biological activities and rich sources for discovering and developing novel therapeutic agents. Accordingly, recent studies have shown increasing phytochemicals in combating Alzheimer's disease, aging, Parkinson's disease, brain/spinal cord damages, depression, and other neuronal-associated dysfunctions. Amongst the emerging targets in neurodegeneration, PI3K/Akt/mTOR is of great importance. Therefore, attenuation of these mediators would be a great step towards neuroprotection in such NDDs. CONCLUSION: The application of plant-derived secondary metabolites in managing and/or treating various neuronal disorders through the PI3K/Akt/mTOR signaling pathway is a promising strategy towards neuroprotection.

Alkaloids as Potential Phytochemicals against SARS-CoV-2: Approaches to the Associated Pivotal Mechanisms.

Since its inception, the coronavirus disease 2019 (COVID-19) pandemic has infected millions of people around the world. Therefore, it is necessary to find effective treatments against Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), as it is the viral source of COVID-19. Alkaloids are one of the most widespread plant-derived natural compounds with prominent antiviral effects. Accordingly, these phytochemicals have been promising candidates towards discovering effective treatments for COVID-19. Alkaloids have shown potential anti-SARS-CoV activities via inhibiting pathogenesis-associated targets of the Coronaviridae family that are required for the virus life cycle. In the current study, the chemistry, plant sources, and antiviral effects of alkaloids, as well as their anti-SARS-CoV-2 effect with related mechanisms, are reviewed towards discovering an effective treatment against COVID-19.

The effects of anticancer medicinal herbs on vascular endothelial growth factor based on pharmacological aspects: a review study.

As a complicated process of forming new blood vessels from the present vasculature endothelium, angiogenesis plays a critical role in the progression of cancer, through developing new blood vessels in tumor cells. Angiogenesis is regulated by proteins known as inhibitor or activator molecules, affected by different medicinal herbs and small molecules. In the present review, the molecular mechanisms of tumor angiogenesis are outlined, focusing on the pharmacological aspects and molecular mechanisms of natural compounds used in chemotherapy and their effects on angiogenesis, focusing on vascular endothelial growth factor (VEGF).Our findings show that a significant number of drugs used in the treatment of cancer are antiangiogenic small molecules and phytochemicals which inhibit VEGF and angiogenesis. Besides, medicinal herbs are potential multi-target agents with more covering mechanisms, lower costs and lower toxicity to develop novel anticancer drugs through targeting the VEGF signaling pathway and receptor tyrosine kinases (RTKs) in the angiogenesis. For this reason, herbal anti-VEGF agents are considered as imperative targets to be used for cancer treatment in clinical applications.The findings reveal a promising perspective for medicinal herbs and natural compounds acting on VEGF and angiogenesis to find new targets and potential therapeutic use in the treatment of cancer.

Ginger and Heart Health: From Mechanisms to Therapeutics.

BACKGROUND: As a major cause of morbidity and mortality, cardiovascular diseases (CVDs) are globally increasing. In spite of recent development in the management of cardiovascular complications, CVDs have remained a medical challenge. Numerous conventional drugs are used to play cardioprotective roles; however, they are associated with several side effects. Considering the rich phytochemistry and fewer side effects of herbal medicines, they have gained particular attention to develop novel herbal drugs with cardioprotective potentials. Amongst natural entities, ginger is an extensively used and well-known functional food and condiment, possessing plentiful bioactivities, like anti-inflammatory, antioxidant, and antimicrobial properties in several disorders management. OBJECTIVE: The current review deliberated phytochemical properties as well as the ginger/ginger constituents' biological activities and health benefits in several diseases, with particular attention to cardiovascular complications. METHODS: A comprehensive search was conducted using multiple databases, including Scopus, PubMed, Medline, Web of Science, national database (Irandoc and SID), and related articles in terms of the health benefits and cardioprotective effects of ginger/ginger constituents. These data were collected from inception until August 2019. RESULTS: In recent years, several herbal medicines were used to develop new drugs with more potency and also minor side effects. Amongst natural entities, ginger is used as a traditional medicine in several diseases. The crude extract, along with related pungent active constituents, is mostly attributed to heart health. The cardioprotective effects of ginger are contributed to its cardiotonic, anti- hypertensive, anti-hyperlipidemia, and anti-platelet effects. The signaling pathways and molecular mechanisms of ginger regarding its cardioprotective effects are also clarified. CONCLUSION: This study revealed the biological activities, health benefits, and cardioprotective properties of ginger/ginger constituents along with related mechanisms of action, which gave new insights to show new avenues in the treatment of CVDs.

Attenuation of Nrf2/Keap1/ARE in Alzheimer's Disease by Plant Secondary Metabolites: A Mechanistic Review.

Alzheimer's disease (AD) is a progressive neuronal/cognitional dysfunction, leading to disability and death. Despite advances in revealing the pathophysiological mechanisms behind AD, no effective treatment has yet been provided. It urges the need for finding novel multi-target agents in combating the complex dysregulated mechanisms in AD. Amongst the dysregulated pathophysiological pathways in AD, oxidative stress seems to play a critical role in the pathogenesis progression of AD, with a dominant role of nuclear factor erythroid 2-related factor 2 (Nrf2)/Kelch-like ECH-associated protein-1 (Keap1)/antioxidant responsive elements (ARE) pathway. In the present study, a comprehensive review was conducted using the existing electronic databases, including PubMed, Medline, Web of Science, and Scopus, as well as related articles in the field. Nrf2/Keap1/ARE has shown to be the upstream orchestrate of oxidative pathways, which also ameliorates various inflammatory and apoptotic pathways. So, developing multi-target agents with higher efficacy and lower side effects could pave the road in the prevention/management of AD. The plant kingdom is now a great source of natural secondary metabolites in targeting Nrf2/Keap1/ARE. Among natural entities, phenolic compounds, alkaloids, terpene/terpenoids, carotenoids, sulfur-compounds, as well as some other miscellaneous plant-derived compounds have shown promising future accordingly. Prevailing evidence has shown that activating Nrf2/ARE and downstream antioxidant enzymes, as well as inhibiting Keap1 could play hopeful roles in overcoming AD. The current review highlights the neuroprotective effects of plant secondary metabolites through targeting Nrf2/Keap1/ARE and downstream interconnected mediators in combating AD.

Targeting Multiple Signaling Pathways in Cancer: The Rutin Therapeutic Approach.

Multiple dysregulated signaling pathways are implicated in the pathogenesis of cancer. The conventional therapies used in cancer prevention/treatment suffer from low efficacy, considerable toxicity, and high cost. Hence, the discovery and development of novel multi-targeted agents to attenuate the dysregulated signaling in cancer is of great importance. In recent decades, phytochemicals from dietary and medicinal plants have been successfully introduced as alternative anticancer agents due to their ability to modulate numerous oncogenic and oncosuppressive signaling pathways. Rutin (also known as rutoside, quercetin-3-O-rutinoside and sophorin) is an active plant-derived flavonoid that is widely distributed in various vegetables, fruits, and medicinal plants, including asparagus, buckwheat, apricots, apples, cherries, grapes, grapefruit, plums, oranges, and tea. Rutin has been shown to target various inflammatory, apoptotic, autophagic, and angiogenic signaling mediators, including nuclear factor-κB, tumor necrosis factor-α, interleukins, light chain 3/Beclin, B cell lymphoma 2 (Bcl-2), Bcl-2 associated X protein, caspases, and vascular endothelial growth factor. A comprehensive and critical analysis of the anticancer potential of rutin and associated molecular targets amongst various cancer types has not been performed previously. Accordingly, the purpose of this review is to present an up-to-date and critical evaluation of multiple cellular and molecular mechanisms through which the anticancer effects of rutin are known to be exerted. The current challenges and limitations as well as future directions of research are also discussed.

The ameliorating effects of anthocyanins on the cross-linked signaling pathways of cancer dysregulated metabolism.

Cancer cells underlie the dysregulated metabolism of carbohydrate, lipid and protein and thereby, employ interconnected cross-linked signaling pathways to supply adequate energy for growth and related biosynthetic procedures. In the present study, a comprehensive review of cancer metabolism and anthocyanin's effect was conducted using the existing electronic databases, including Medline, PubMed, Scopus, and Web of Science, as well as related articles in the field. Such keywords as "cancer", and "cancer metabolism" in the title/abstract/keyword and all the "anthocyanins" in the whole text were used. Data were collected without time restriction until February 2020. The results indicated the involvement of several signaling pathways, including inflammatory PI3K/Akt/mTOR pathway, Bax/Bcl-2/caspases as apoptosis modulators, and NF-κB/Nrf2 as oxidative stress mediators in the cancer dysregulated metabolism. Compelling studies have shown that targeting these pathways, as critical hallmarks of cancer, plays a critical role in combating cancer dysregulated metabolism. The complexity of cancer metabolism signaling pathways, along with toxicity, high costs, and resistance to conventional drugs urge the need to investigate novel multi-target agents. Increasing evidence has introduced plant-derived secondary metabolites as hopeful anticancer candidates which target multiple dysregulated cross-linked pathways of cancer metabolism. Amongst these metabolites, anthocyanins have demonstrated positive anticancer effects by targeting inflammation, oxidative stress, and apoptotic signaling pathways. The current study revealed the cross-linked signaling pathways of cancer metabolism, as well as the promising pharmacological mechanisms of anthocyanins in targeting the aforementioned signaling mediators. To overcome the pharmacokinetic limitations of anthocyanins in cancer treatment, their interactions with gut microbiota and the need to develop related nano-formulations were also considered.

Therapeutic effects of curcumin on the functional disturbances and oxidative stress induced by renal ischemia/reperfusion in rats.

OBJECTIVE: Curcumin has anti-inflammatory and antioxidative properties. The objective of this study was to investigate the therapeutic effects of curcumin on functional disturbances, oxidative stress, and leukocyte infiltration induced by renal ischemia/reperfusion (I/R). MATERIALS AND METHODS: Animals were randomly divided into 9 groups. The groups with 24-h reperfusion consisted of sham-24h, I/R-24h, and three I/R groups treated with curcumin at 10, 20, or 30 mg kg(-1), i.p. after the ischemic period. The 72-h reperfusion groups also included Sham-72h, I/R-72h, I/R treated with curcumin at single dose of 20 mg kg(-1), i.p., and I/R group which received three doses of curcumin at 20 mg kg(-1), i.p., consecutively. Renal functional injury was assessed by measuring serum creatinine and urea-nitrogen concentrations. Oxidative stress was evaluated by assessment tissue malondialdehyde (MDA) and the ferric reducing/antioxidant power (FRAP) levels. Moreover, renal tissue leukocyte infiltration was measured by histopathology examination. RESULTS: Ischemia/reperfusion resulted in a significant increase in serum concentration of creatinine, urea-nitrogen, tissue MDA level, and leukocytes infiltration as well as reduced FRAP level. Treatment with curcumin in 24-h reperfusion groups could only lead to a significant change in the levels of MDA and FRAP. However, in 72-h reperfusion groups, curcumin was able to correct all functional disturbances, oxidative stress, and leukocytes infiltration with more effectiveness in groups that received three doses of curcumin. CONCLUSION: The administration of curcumin during 72-h reperfusion following 30 minutes of ischemia can decrease renal oxidative stress and leukocytes infiltration as well as improve kidney function. However, during first 24-h reperfusion, curcumin only decreased oxidative stress.