Melatonin effect on breast and ovarian cancers by targeting the PI3K/Akt/mTOR pathway.

Melatonin, the hormone of the pineal gland, possesses a range of physiological functions, and recently, its anticancer effect has become more apparent. A more thorough understanding of molecular alterations in the components of several signaling pathways as new targets for cancer therapy is needed because of current innate restrictions such as drug toxicity, side effects, and acquired or de novo resistance. The PI3K/Akt/mTOR pathway is overactivated in many solid tumors, such as breast and ovarian cancers. This pathway in normal cells is essential for growth, proliferation, and survival. However, it is an undesirable characteristic in malignant cells. We have reviewed multiple studies about the effect of melatonin on breast and ovarian cancer, focusing on the PI3K/Akt/mTOR pathway. Melatonin exerts its inhibitory effects via several mechanisms. A: Downregulation of downstream or upstream components of the signaling pathway such as phosphatase and tensin homolog (PTEN), phosphatidylinositol (3,4,5)-trisphosphate kinase (PI3K), p-PI3K, Akt, p-Akt, mammalian target of rapamycin (mTOR), and mTOR complex1 (mTORC1). B: Apoptosis induction by decreasing MDM2 expression, a downstream target of Akt, and mTOR, which leads to Bad activation in addition to Bcl-XL and p53 inhibition. C: Induction of autophagy in cancer cells via activating ULK1 after mTOR inhibition, resulting in Beclin-1 phosphorylation. Beclin-1 with AMBRA1 and VPS34 promotes PI3K complex I activity and autophagy in cancer cells. The PI3K/Akt/mTOR pathway overlaps with other intracellular signaling pathways and components such as AMP-activated protein kinase (AMPK), Wnt/ß-catenin, mitogen-activated protein kinase (MAPK), and other similar pathways. Cancer therapy can benefit from understanding how these pathways interact and how melatonin affects these pathways.

Cytotoxic and apoptotic effects of Ferula gummosa Boiss: extract on human breast adenocarcinoma cell line.

PURPOSE: Ferula gummosa Boiss. is a well-known and valuable medicinal plant in Iran. Research has shown that this plant has several pharmacological properties, including anti-bacterial, anti-cancer and etc. In the present study, we investigated the cytotoxic properties of F. gummosa Boiss. extract in MCF-7 breast adenocarcinoma cells. METHODS: The cytotoxicity and pro-apoptotic properties of the extract were assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) test and propidium iodide (PI) stained cells, respectively. Apoptosis and necrosis were evaluated by annexin V-PI staining. The levels of reactive oxygen species (ROS),malondialdehyde (MDA), glutathione (GSH), and superoxide dismutase (SOD) was determined to evaluate oxidative stress. The cell migration and the gene expression were assessed by scratch assay and quantitative real-time polymerase chain reaction (q-RT-PCR), respectively. RESULTS: The extract of F. gummosa decreased the viability and cell cycle progression of MCF-7 cells by inducing apoptosis and necrosis, increasing ROS and MDA levels, and decreasing GSH levels and SOD activity. It also lowered the cells' migration capability by enhancing p53 mRNA levels and reducing MMP-9 mRNA expression. CONCLUSION: F. gummosa exhibited pro-apoptotic, anti-proliferative, and anti-metastatic effects on MCF-7 cells. It is therefore recommended that detailed future research be done on different parts of the plant or its secondary metabolites to find anti-cancer lead compounds.

Evaluating the Protective Effects of Thymoquinone on Methamphetamine-induced Toxicity in an In Vitro Model Based on Differentiated PC12 Cells.

Methamphetamine (Meth) is a highly addictive stimulant. Its potential neurotoxic effects are mediated through various mechanisms, including oxidative stress and the initiation of the apoptotic process. Thymoquinone (TQ), obtained from Nigella sativa seed oil, has extensive antioxidant and anti-apoptotic properties. This study aimed to investigate the potential protective effects of TQ against Meth-induced toxicity by using an in vitro model based on nerve growth factor-differentiated PC12 cells. Cell differentiation was assessed by detecting the presence of a neuronal marker with flow cytometry. The effects of Meth exposure were evaluated in the in vitro neuronal cell-based model via the determination of cell viability (in an MTT assay) and apoptosis (by annexin/propidium iodide staining). The generation of reactive oxygen species (ROS), as well as the levels of glutathione (GSH) and dopamine, were also determined. The model was used to determine the protective effects of 0.5, 1 and 2 µM TQ against Meth-induced toxicity (at 1 mM). The results showed that TQ reduced Meth-induced neurotoxicity, possibly through the inhibition of ROS generation and apoptosis, and by helping to maintain GSH and dopamine levels. Thus, the impact of TQ treatment on Meth-induced neurotoxicity could warrant further investigation.

The role of transient receptor potential (TRP) channels in phagocytosis: A comprehensive review.

When host cells are exposed to foreign particles, dead cells, or cell hazards, a sophisticated process called phagocytosis begins. During this process, macrophages, dendritic cells, and neutrophils engulf the target by expanding their membranes. Phagocytosis of apoptotic cells is called efferocytosis. This process is of significant importance as billions of cells are eliminated daily without provoking inflammation. Both phagocytosis and efferocytosis depend on Ca2+ signaling. A big family of Ca2+ permeable channels is transient receptor potentials (TRPs) divided into nine subfamilies. We aimed to review their roles in phagocytosis. The present review article shows that various TRP channels such as TRPV1, 2, 3, 4, TRPM2, 4, 7, 8, TRPML1, TRPA1, TRPC1, 3, 5, 6 have roles at various stages of phagocytosis. They are involved in the phagocytosis of amyloid ß, α-synuclein, myelin debris, bacteria, and apoptotic cells. In particular, TRPC3 and TRPM7 contribute to efferocytosis. These effects are mediated by changing Ca2+ signaling or targeting intracellular enzymes such as Akt. In addition, they contribute to the chemotaxis of phagocytic cells towards targets. Although a limited number of studies have assessed the role of TRP channels in phagocytosis and efferocytosis, their findings indicate that they have critical roles in these processes. In some cases, their ablation completely abolished the phagocytic function of the cells. As a result, TRP channels are potential targets for developing new therapeutics that modulate phagocytosis.

An overview on the protective effects of ellagic acid against heavy metals, drugs, and chemicals.

Ellagic acid (EA) is a polyphenol extracted from many plants. EA modulates inflammatory mediators via antioxidant mechanisms, such as catalase (CAT) activities, superoxide dismutase (SOD), enhancement, increase in glutathione (GSH), and lipid peroxidation (LPO) suppression. EA has anti-apoptotic properties that are thought to be mediated by regulating the expression of B-cell lymphoma 2 (Bcl-2), Bcl-2-associated X protein (Bax), and caspase-3. In this article, we surveyed the literature dealing with the protective effects of EA against different heavy metals, drugs, and natural toxins. The findings indicated that EA has remarkable protective properties against various toxicants. Its protective effects were mostly mediated via normalizing lipid metabolism, oxidative stress, and inflammatory mediators, for example, tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and IL-1ß. The results of this study showed that EA has significant protective effects against a varied range of compounds, either chemical or natural. These effects are mainly mediated via intensifying the antioxidant defense system. However, other mechanisms such as inhibition of inflammatory responses and suppression of apoptosis are important.

The role of the ATP-Binding Cassette A1 (ABCA1) in neurological disorders: a mechanistic review.

INTRODUCTION: Cholesterol homeostasis is critical for normal brain function. It is tightly controlled by various biological elements. ATP-binding cassette transporter A1 (ABCA1) is a membrane transporter that effluxes cholesterol from cells, particularly astrocytes, into the extracellular space. The recent studies pertaining to ABCA1's role in CNS disorders were included in this study. AREAS COVERED: In this comprehensive literature review, preclinical and human studies showed that ABCA1 has a significant role in the following diseases or disorders: Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis, neuropathy, anxiety, depression, psychosis, epilepsy, stroke, and brain ischemia and trauma. EXPERT OPINION: ABCA1 via modulating normal and aberrant brain functions such as apoptosis, phagocytosis, BBB leakage, neuroinflammation, amyloid ß efflux, myelination, synaptogenesis, neurite outgrowth, and neurotransmission promotes beneficial effects in aforementioned diseases. ABCA1 is a key molecule in the CNS. By boosting its expression or function, some CNS disorders may be resolved. In preclinical studies, liver X receptor agonists have shown promise in treating CNS disorders via ABCA1 and apoE enhancement.

Cannabidiol goes nuclear: The role of PPARγ.

BACKGROUND: Cannabidiol (CBD) is one of the main phytocannabinoids found in Cannabis sativa. In contrast to Δ9-tetrahydrocannabinol, it has a low affinity for cannabinoid receptors CB1 and CB2, thereby it does not induce significant psychoactive effects. However, CBD may interact with other receptors, including peroxisome proliferator-activated receptor gamma (PPARγ). CBD is a PPARγ agonist and changes its expression. There is considerable evidence that CBD's effects are mediated by its interaction with PPARγ. So, we reviewed studies related to the interaction of CBD and PPARγ. METHODS: In this comprehensive literature review, the term 'cannabidiol' was used in combination with the following keywords including 'PPARγ', 'Alzheimer's disease', 'Parkinson's disease', 'seizure', 'multiple sclerosis', 'immune system', 'cardiovascular system', 'cancer', and 'adipogenesis'. PubMed, Web of Science, and Google Scholar were searched until December 20, 2022. A total of 78 articles were used for the reviewing process. RESULTS: CBD, via activation of PPARγ, promotes significant pharmacological effects. The present review shows that the effects of CBD on Alzheimer's disease and memory, Parkinson's disease and movement disorders, multiple sclerosis, anxiety and depression, cardiovascular system, immune system, cancer, and adipogenesis are mediated, at least in part, via PPARγ. CONCLUSION: CBD not only activates PPARγ but also affects its expression in the body. It was suggested that the late effects of CBD are mediated via PPARγ activation. We suggested that CBD's chemical structure is a good backbone for developing new dual agonists. Combining it with other chemicals enhances their biological effectiveness while reducing their dosage. The present study indicated that PPARγ is a key target for CBD, and its activation by CBD should be considered in all future studies.

Pharmacological effects of cannabidiol by transient receptor potential channels.

Cannabidiol (CBD), as a major phytocannabinoid of Cannabis sativa, has emerged as a promising natural compound in the treatment of diseases. Its diverse pharmacological effects with limited side effects have promoted researchers to pursue new therapeutic applications. It has little affinity for classical cannabinoid receptors (CB1 and CB2). Considering this and its diverse pharmacological effects, it is logical to set up studies for finding its putative potential targets other than CB1 and CB2. A class of ion channels, namely transient potential channels (TRP), has been identified during two recent decades. More than 30 members of this family have been studied, so far. They mediate diverse physiological functions and are associated with various pathological conditions. Some have been recognized as key targets for natural compounds such as capsaicin, menthol, and CBD. Studies show that CBD has agonistic effects for TRPV1-4 and TRPA1 channels with antagonistic effects on the TRPM8 channel. In this article, we reviewed the recent findings considering the interaction of CBD with these channels. The review indicated that TRP channels mediate, at least in part, the effects of CBD on seizure, inflammation, cancer, pain, acne, and vasorelaxation. This highlights the role of TRP channels in CBD-mediated effects, and binding to these channels may justify part of its paradoxical effects in comparison to classical phytocannabinoids.

Protective effect of Toll-like receptor 4 antagonist on inflammation, EEG, and memory changes following febrile seizure in Wistar rats.

Neuroinflammation and fever are the main triggers in febrile seizures (FS). Focusing on inflammatory pathways and anti-inflammatory drugs could compensate for the limitations of existing medications. The aim of this study is to evaluate the neuroprotective effect of specific antagonizing Toll-like receptor 4 (TLR4), as a prominent inflammatory axis, on the consequences of FS and adulthood using animal models. Complex FS was induced on 9-11 day old male rat pups using a heated chamber. TAK-242, as a specific TLR4 inhibitor, was injected intraperitoneally before seizure induction. Seizure threshold, duration, and spike number were measured by electrocorticography. The levels of inflammatory cytokines, TLR4 protein expression, and oxidative stress markers were detected by enzyme-linked immunosorbent assay, western blotting, malondialdehyde (MDA), catalase (CAT), and superoxide dismutase (SOD) assessments in the cortex and hippocampus. Also, spatial and non-spatial memory were evaluated using the novel object recognition test (NORT) and double Y-maze test during adulthood. The results revealed that provoked inflammatory responses in neonate rats, after FS, were associated with the increase of the tumor necrosis factor alpha, interleukin-1ß, and enhanced TLR4 protein expression. Meanwhile, based on performed behavioral tests, the inflammatory process was also involved in adulthood memory deficit. Pretreatment with TAK-242 reduced the inflammatory cytokines and TLR4 protein expression in the cortex and hippocampus of neonate rats and improvement in memory deficit in NORT and double Y-maze tasks. Also, pretreatment with TAK-242 elevated seizure threshold, SOD, and CAT activities, and decreased seizure duration and MDA level with no significant change in spike number. TAK-242 possibly controlled FS via inhibiting inflammation.

Zataria multiflora and Pioglitazone Affect Systemic Inflammation and Oxidative Stress Induced by Inhaled Paraquat in Rats.

The effects of Zataria multiflora (Z. multiflora) and pioglitazone (a PPAR-γ agonist) alone and in combination, on systemic inflammation and oxidative stress induced by inhaled paraquat (PQ) as a herbicide, which induced inflammation in rats, were examined. Rats were exposed to (1) saline (control) and (2) 54 mg/m3 PQ aerosols (8 times, every other day, each time for 30 min) without treatment or treated with (3 and 4) two doses of Z. multiflora (200 and 800 mg/kg/day), (5 and 6) two doses of pioglitazone (5 and 10 mg/kg/day), (7) low doses of Z.multiflora + pioglitazone, (Pio-5+Z-200 mg/kg/day) or (8) dexamethasone (0.03 mg/kg/day) for 16 days, after the last PQ exposure. Different variables were measured at the end of the treatment period. Exposure to PQ significantly increased total and differential white blood cells (WBC) counts, serum levels of nitrite (NO2), malondialdehyde (MDA), interleukin- (IL) 17, and tumor necrosis factor alpha (TNF-α), but reduced thiol, superoxide dismutase (SOD), catalase (CAT), IL-10, and interferon-gamma (INF-γ) (p < 0.05 to p < 0.001). Most measured parameters were significantly improved in groups treated with either doses of the extract, pioglitazone, Pio-5+Z-200 mg/kg/day, or dexamethasone compared to the PQ group (p < 0.05 to p < 0.001). The combination of low doses of Pio-5+Z-200 mg/kg/day showed significantly higher effects compared to each one alone (p < 0.05 to p < 0.001). Systemic oxidative stress and inflammation due to inhaled PQ were improved by Z. multiflora and pioglitazone. Higher effects of Pio-5+Z-200 mg/kg/day compared to each one alone suggest modulation of PPAR-γ receptors by the plant extract, but further studies using PPAR-γ antagonists need to be done in this regard.

Protective effects of maternal administration of curcumin and hesperidin in the rat offspring following repeated febrile seizure: Role of inflammation and TLR4.

Neuroinflammation has a key role in seizure generation and perpetuation in the neonatal period, and toll-like receptor 4 (TLR4) pathway has a prominent role in neuroinflammatory diseases. Administration of antioxidants and targeting TLR4 in the embryonic period may protect rat offspring against the next incidence of febrile seizure and its harmful effects. Curcumin and hesperidin are natural compounds with anti-inflammatory and antioxidant properties and have an inhibitory action on TLR4 receptors. We evaluated the effect of maternal administration of curcumin and hesperidin on infantile febrile seizure and subsequent memory dysfunction in adulthood. Hyperthermia febrile seizure was induced on postnatal days 9-11 on male rat pups with 24 h intervals, in a Plexiglas box that was heated to ~45 °C by a heat lamp. We used enzyme-linked immunosorbent assay, Western blotting, malondialdehyde (MDA), and glutathione (GSH) assessment for evaluation of inflammatory cytokine levels, TLR4 protein expression, and oxidative responses in the hippocampal tissues. For assessing working memory and long-term potentiation, the double Y-maze test and Schaffer collateral-CA1 in vivo electrophysiological recording were performed, respectively Our results showed that curcumin and hesperidin decreased TNF-α, IL-10, and TLR4 protein expression and reversed memory dysfunction. However, they did not provoke a significant effect on GSH content or amplitude and slope of recorded fEPSPs in the hippocampus. In addition, curcumin, but not hesperidin, decreased interleukin-1ß (IL-1ß) and MDA levels. These findings imply that curcumin and hesperidin induced significant protective effects on febrile seizures, possibly via their anti-inflammatory and antioxidant properties and downregulation of TLR4.

The protective effect of modafinil on vincristine-induced peripheral neuropathy in rats: A possible role for TRPA1 receptors.

Vincristine (VCR) induces peripheral neuropathy. We aimed to assess the efficacy of modafinil on VCR-induced neuropathy in rats. Neuropathy was induced by intraperitoneal (i.p.) injections of VCR (0.1 mg/kg). Neuropathic groups received modafinil (5, 25 and 50 mg/kg); gabapentin (20 mg/kg); and a combination of modafinil (5 and 50 mg/kg) and gabapentin (20 mg/kg,). Then, electrophysiological, behavioural, biochemical and pathological evaluations were performed. Latencies of tail-flick and von Frey filament tests, motor nerve conduction velocity (MNCV) and excitation of nerve conduction were decreased. Moreover, the transient receptor potential cation channel ankyrin 1 (TRPA1) level was increased, while TRPV1 and N-Methyl-D-aspartate (NMDA) levels remained unchanged. Tumour necrosis factor-alpha (TNF-α) and interleukin-1beta (IL-1ß) levels were markedly elevated. Pre-treatment with modafinil prevented sensorimotor neuropathy by raising latencies, MNCV and excitation, reducing TRPA1, TNF-α and IL-1ß levels. Modafinil improved behavioural, electrophysiological and pathological disturbances. The results showed that TRPA1 has a more important role than NMDA and TRPV1, in VCR-induced neuropathic pain. In addition, inflammatory mediators, TNF-α and IL-1ß, were involved. Further, the combination of modafinil and gabapentin improved the neuroprotective effect of gabapentin. So, modafinil might be a neuroprotective agent in the prevention of VCR-induced neuropathy.

Transient receptor potential ankyrin 1 (TRPA1)-mediated toxicity: friend or foe?

Transient receptor potential (TRP) channels have been widely studied during the last decade. New studies uncover new features and potential applications for these channels. TRPA1 has a huge distribution all over the human body and has been reported to be involved in different physiological and pathological conditions including cold, pain, and damage sensation. Considering its role, many studies have been devoted to evaluating the role of this channel in the initiation and progression of different toxicities. Accordingly, we reviewed the most recent studies and divided the role of TRPA1 in toxicology into the following sections: neurotoxicity, cardiotoxicity, dermatotoxicity, and pulmonary toxicity. Acetaminophen, heavy metals, tear gases, various chemotherapeutic agents, acrolein, wood smoke particulate materials, particulate air pollution materials, diesel exhaust particles, cigarette smoke extracts, air born irritants, sulfur mustard, and plasticizers are selected compounds and materials with toxic effects that are, at least in part, mediated by TRPA1. Considering the high safety of TRPA1 antagonists and their efficacy to resolve selected toxic or adverse drug reactions, the future of these drugs looks promising.

Anticonvulsant and ameliorative effects of pioglitazone on cognitive deficits, inflammation and apoptosis in the hippocampus of rat pups exposed to febrile seizure.

OBJECTIVES: Pioglitazone (PGZ), a peroxisome proliferator-activated receptor gamma (PPAR-γ) agonist, has significant neuroprotective effects and has been reported to regulate inflammatory processes. MATERIALS AND METHODS: We evaluated the effects of PGZ on febrile seizure (FS) in rat pups. Three groups of male rat pups received intraperitoneal (IP) injections of PGZ (5, 10, and 20 mg/kg). Lipopolysaccharide (LPS) and kainic acid (KA) were injected to induce FS. The rat pups behaviors were recorded and analyzed. Seizure latency, duration, and severity were recorded to evaluate the effect of PGZ on FS. Novel object recognition task (NORT) was used to evaluate the effect of PGZ on cognitive deficits induced by FS. At the end of the experimental protocol, molecular and histological tests were done. RESULTS: PGZ significantly increased seizure latency and decreased seizure duration and median of seizure scores (P<0.05, P<0.01, and P<0.001) after induction of FS. Rat pups exposed to FS had memory deficits both in short-term and long-term memories in the NORT that were reversed by PGZ-treatment (P<0.01 and P<0.001). PGZ significantly reduced interleukin-1ß, tumor necrosis factor-α, and inducible nitric oxide synthase concentration in the hippocampus (P<0.05 and P<0.01). In addition, PGZ decreased the number of degenerating and TUNEL positive neurons in CA1, CA3, and DG subfields of the hippocampus (P<0.05, P<0.01 and P<0.001). CONCLUSION: The present results indicated that PGZ had anticonvulsant, anti-inflammatory, and anti-apoptotic effects with ameliorative effects on cognitive deficits induced by FS in rat pups.

SIRT1 and microRNAs: The role in breast, lung and prostate cancers.

Breast cancer and prostate cancer are the most common malignant tumors in female and men, respectively. Furthermore, lung cancer is the leading cause of cancer deaths worldwide. It is an emergency to develop a powerful strategy to treat these threatening cancers more effectively, because of low efficacy and high rates of chemotherapy effects. MicroRNAs (miRNAs), a class of small non-coding RNAs, are key regulators of gene expression via induction of translational repression or mRNA degradation. MiRNA deregulation has been linked to cancer initiation and progression. Silent Inflammation Regulator 2 (SIR2) proteins-sirtuins- are a family of histone deacetylases (HDACs) that catalyze deacetylation of both histone and non- histone lysine residues. SIRT1 can act as an oncogene. It plays a role in tumorigenesis by anti-apoptotic activity and is implicated in diverse cellular process including autophagy, senescence, apoptosis, proliferation, and aging. MicroRNAs and SIRT1 serve as tumor suppressors or tumor promotors depending on the oncogenic pathway specific to particular tumors. MicroRNAs modulate cancer development by targeting SIRT1. In this review, we underlie the specific mechanisms involved in these threatening cancers by microRNAs/SIRT1 pathways.

The effect of exercise preconditioning on stroke outcome in ovariectomized mice with permanent middle cerebral artery occlusion.

Exercise preconditioning has been shown to be effective in improving behavioral and neuropathological indices after cerebral ischemia. We evaluated the effect of exercise preconditioning, 17ß-estradiol, and their combination on stroke outcome using an experimental model of stroke in ovariectomized (OVX) mice. OVX mice were randomly assigned to 4 groups as follows: control (stroke), exercise (exercise and stroke), estradiol (17ß-estradiol and stroke), and exercise+estradiol (exercise and 17ß-estradiol and stroke). Exercise preconditioning was performed on a treadmill 5 days/week, 40 min/day, at a speed of 18 m/min for 4 weeks. 17ß-estradiol was gavaged (40 µg/kg per day) for 4 weeks. Stroke was induced by permanent middle cerebral artery occlusion (pMCAO), and neurological deficits were evaluated 1, 2, and 7 days after stroke. Then, the serum concentrations of matrix metalloproteinase-9 (MMP-9) and interleukin-10 (IL-10) and infarct volumes were assessed. Exercise preconditioning and 17ß-estradiol induced a better outcome compared with the control ischemic mice, which was manifested by decrease in MMP-9, increase in IL-10, diminished infarct volume, and improved neurological deficits. Concomitant administration of 17ß-estradiol and exercise also significantly improved these parameters. Exercise preconditioning or administration of 17ß-estradiol alone or in combination before pMCAO induced significant neuroprotection in OVX mice.

Carotenoids in the treatment of diabetes mellitus and its complications: A mechanistic review.

Carotenoids are a large class of natural antioxidants that occur in many vegetables, foods and other natural sources. To date, a large number of biological properties have been reported from carotenoids, particularly protective effects against diabetes mellitus (DM), cancer, and neurodegenerative, metabolic and cardiovascular diseases. However, recent studies including clinical evidences, have shown that carotenoids play a role in the treatment of diabetes via enhancing insulin sensitivity. They are also able to protect the body from long-term consequences of diabetes including infectious diseases, nephropathy, neuronal and eye abnormalities. In this review, we try to discuss the mechanisms behind the biological effects of carotenoids for the prevention and treatment of DM and its complications. The authors believe that carotenoids will have a prominent place in the treatment of DM and its complications in the future.

Inhibition of transient receptor potential vanilloid-1 confers neuroprotection, reduces tumor necrosis factor-alpha, and increases IL-10 in a rat stroke model.

Stroke is a major cause of mortality and long-term disability in adults. Transient receptor potential vanilloid-1 (TRPV1) plays a crucial role in neuroinflammation. In this study, the effects of TRPV1 agonist (capsaicin) and antagonist (AMG9810) on cerebral ischemia were investigated. Forty male Wistar rats were assigned to the following experimental groups: sham, vehicle) ischemic), AMG9810 (selective TRPV1 antagonist, 0.5 mg/kg; 3 h after stroke), and capsaicin (1 mg/kg; 3 h after stroke). Stroke was induced by permanent middle cerebral artery occlusion and neurological deficits were evaluated 1, 3, and 7 days after stroke. Then, infarct volume, brain edema, body temperature, mRNA expression of TRPV1, and serum concentrations of tumor necrosis factor-alpha (TNF-α) and IL-10 were measured. Compared to the vehicle group, AMG9810 significantly decreased the infarct volume (P < 0.01). Latency for the removal of sticky labels from the forepaw and the hanging time were significantly decreased and increased, respectively, following administration of AMG9810 (P < 0.01 and P < 0.001 vs. vehicle) 3 and 7 days after stroke. Compared to the sham group, the mRNA expression of TRPV1 was significantly increased in vehicle group (P < 0.01). Administration of AMG9810 significantly increased the anti-inflammatory cytokine IL-10 and decreased the inflammatory cytokine TNF-α (P < 0.05). Moreover, our results indicate that AMG9810 might a promising candidate for the hypothermic treatment of stroke. The findings also suggest a key role for AMG9810 in reducing inflammation after stroke and imply that TRPV1 could be a potential target for the treatment of ischemic stroke.

Glycyrrhetinic Acid and Its Derivatives: Anti-Cancer and Cancer Chemopreventive Properties, Mechanisms of Action and Structure- Cytotoxic Activity Relationship.

The anti-cancer properties of liquorice have been attributed, at least in part, to glycyrrhizin (GL). However, GL is not directly absorbed through the gastrointestinal tract. It is hydrolyzed to 18-ß-glycyrrhetinic acid (GA), the pharmacologically active metabolite, by human intestinal microflora. GA exhibits remarkable cytotoxic and anti-tumor properties. The pro-apoptotic targets and mechanisms of action of GA have been extensively studied over the past decade. In addition, GA is an inexpensive and available triterpene with functional groups (COOH and OH) in its structure, which make it an attractive lead compound for medicinal chemists to prepare a large number of analogues. To date, more than 400 cytotoxic derivatives have been prepared on the basis of GA scaffold, including 128 cytotoxic derivatives with IC50 values less than 30 µM. Researchers have also succeeded in synthesizing very potent cytotoxic derivatives with IC50s ≤ 1 µM. Studies have shown that the introduction of a double bound at the C1-C2 position combined with an electronegative functional group, such as CN, CF3 or iodine at C2 position, and the oxidation of the hydroxyl group of C3 to the carbonyl group, significantly increased cytotoxicity. This review describes the cytotoxic and anti-tumor properties of GA and its derivatives, targets and mechanisms of action and provides insight into the structure-activity relationship of GA derivatives.

Protective effects of flavonoids against microbes and toxins: The cases of hesperidin and hesperetin.

Many plants produce flavonoids as secondary metabolites. These organic compounds may be involved in the defense against plant-threatening factors, such as microbes and toxins. Certain flavonoids protect their origin source against plant pathogens, but they also exhibit potential healthy properties in human organisms. Hesperidin (Hsd) and its aglycone, hesperetin (Hst), are two flavonoids from the Citrus species that exhibit various biological properties, including antioxidant, antiinflammatory and anticancer effects. Recent studies indicated that Hst and Hsd possess antimicrobial activity. Although the exact mechanisms behind their antimicrobial properties are not fully understood, several mechanisms such as the activation of the host immune system, bacterial membrane disruption, and interference with microbial enzymes, have been proposed. Hsd and Hst may also have protective effects against toxicity induced by various agents. These natural substances may contribute to the protection of cells and tissues through their antioxidant and radical scavenging activities. This review discusses the protective activities of Hsd and Hst against microbes and several toxicities induced by oxidants, chemicals, toxins, chemotherapy and radiotherapy agents, which were reported in vitro and in vivo. Furthermore, the probable mechanisms behind these activities are discussed.