A natural flavonoid lawsonaringenin induces cell cycle arrest and apoptosis in HT-29 colorectal cancer cells by targeting multiple signalling pathways.

Colorectal cancer is the third most common malignancy in the world having a high mortality rate. Flavonoids possess many biological activities including anti-cancer activity. lawsonaringenin (LSG) is a flavonoid isolated from leaves of Lawsonia alba Lam. The objective of this study was to demonstrate the anti-cancer potential of LSG in colorectal cancer for the first time. The HT-29 cells were treated with LSG or 5-fluoruracil, as a positive control, to determine its effect on cell cytotoxicity by a MTT cell proliferation assay, and cell cycle progression and apoptosis using flowcytometry. We also determined the mechanisms underlying LSG-mediated growth inhibition of HT-29 cells by by investigating the expression of key oncogenes and apoptosis genes using q-RT PCR and immunocytochemical analysis. The cell cytotoxicity data showed that the IC50 value of LSG was significantly less than the IC50 value of 5-FU (50 µM). The anti-proliferative effect of LSG was mediated by arresting cells in the S phase of the cell cycle which then led to the induction of apoptosis the q-RT PCR and immunocytochemical analysis showed that LSG reduced the expression of ß-catenin (non-phosphorylated) and its downstream signalling target c-Myc, whereas it increased the phosphorylation of ß-catenin. Furthermore, LSG also downregulated the expression of oncogene K-Ras and anti-apoptotic proteins, Bcl-2, and Bcl-xL. In conclusion, our data demonstrates that LSG exerted its anti-tumor activity by arresting the cell cycle in S phase, and by downregulating the expression of oncogenes including ß-catenin, c-Myc, K-Ras and anti-apoptosis proteins Bcl-2 and Bcl-xL. This study suggests a potential use of natural flavonoid, lawsonaringenin, to attenuate colorectal cancer growth; however, further pre-clinical/clinical studies are required to establish its role as a therapeutic agent.

Walnut supplementation reverses the scopolamine-induced memory impairment by restoration of cholinergic function via mitigating oxidative stress in rats: a potential therapeutic intervention for age related neurodegenerative disorders.

The brain is highly susceptible to the damaging effects of oxidative reactive species. The free radicals which are produced as a consequence of aerobic respiration can cause cumulative oxygen damage which may lead to age-related neurodegeneration. Scopolamine, the anti-muscarinic agent, induces amnesia and oxidative stress similar to that observed in the older age. Studies suggest that antioxidants derived from plant products may provide protection against oxidative stress. Therefore, the present study was designed to investigate the attenuation of scopolamine-induced memory impairment and oxidative stress by walnut supplementation in rats. Rats in test group were administrated with walnut suspension (400 mg/kg/day) for four weeks. Both control and walnut-treated rats were then divided into saline and scopolamine-treated groups. Rats in the scopolamine group were injected with scopolamine (0.5 mg/kg dissolved in saline) five minutes before the start of each memory test. Memory was assessed by elevated plus maze (EPM), Morris water maze (MWM), and novel object recognition task (NOR) followed by estimation of regional acetylcholine levels and acetylcholinesterase activity. In the next phase, brain oxidative status was determined by assaying lipid peroxidation, and measuring superoxide dismutase (SOD), glutathione peroxidase (GPx) and catalase (CAT) activities. Results showed that scopolamine-treatment impaired memory function, caused cholinergic dysfunction, and induced oxidative stress in rats compared to that saline-treated controls. These impairments were significantly restored by pre-administration of walnut. This study demonstrates that antioxidant properties of walnut may provide augmented effects on cholinergic function by reducing oxidative stress and thus improving memory performance.

Dietary Supplementation of Almond Prevents Oxidative Stress by Advocating Antioxidants and Attenuates Impaired Aversive Memory in Male Rats.

Scopolamine, an anti-muscarinic agent, has been shown to induce amnesia and oxidative stress similar to that observed in the older age. The present study was designed to determine the relationship between the oxidative status and memory improvement in scopolamine injected rats pre-administered with almonds. Rats (n = 8) in the almond group were administered orally with 400 mg/kg almond suspension for 28 days daily before the intraperitoneal injection of scopolamine (0.5 mg/kg). Passive avoidance task (PAT) was used to assess memory function at the end of treatment. The present study revealed that scopolamine injection significantly impaired the memory function in rats pre-treated with saline which was accompanied by increased oxidative stress as evident by increased brain malondialdehyde (MDA) levels and reduced activities of antioxidant enzymes as compared to healthy controls. Pre-treatment with almond significantly ameliorated scopolamine-induced oxidative stress and memory dysfunction. These findings suggest that dietary supplementation with almonds may have a beneficial effect in reducing the risk of oxidative stress-induced memory loss and delaying or preventing the onset of age-related memory impairment.

The immunomodulation potential of the synthetic derivatives of benzothiazoles: Implications in immune system disorders through in vitro and in silico studies.

Benzothiazole and its natural or synthetic derivatives have been used as precursors for several pharmacological agents for neuroprotective, anti-bacterial, and anti-allergic activities. The objective of the present study was to evaluate effects of benzothiazole analogs (compounds 1-26) for their immunomodulatory activities. Eight compounds (2, 4, 5, 8-10, 12, and 18) showed potent inhibitory activity on PHA-activated peripheral blood mononuclear cells (PBMCs) with IC50 ranging from 3.7 to 11.9 µM compared to that of the standard drug, prednisolone <1.5 µM. Some compounds (2, 4, 8, and 18) were also found to have potent inhibitory activities on the production of IL-2 on PHA/PMA-stimulated PBMCs with IC50 values ranging between <4.0 and 12.8 µM. The binding interaction of these compounds was performed through silico molecular docking. Compounds 2, 8, 9, and 10 significantly suppressed oxidative burst ROS production in phagocytes with IC50 values between <4.0 and 15.2 µM. The lipopolysaccharide (LPS)-induced nitrites in murine macrophages cell line J774 were found to be inhibited by compounds 4, 8, 9, and 18 at a concentration of 25 µg/mL by 56%, 91%, 58%, and 78%, respectively. Furthermore, compounds 5, 8, 12, and 18 showed significant (P<0.05) suppressive activity on Th-2 cytokine, interleukin 4 (IL-4) with an IC50 range of <4.0 to 40.3 µM. Interestingly compound 4 has shown a selective inhibitory activity on IL-2 and T cell proliferation (naïve T cell proliferation stage) rather than on IL-4 cytokine, while compound 12 displayed an interference with T-cell proliferation and IL-4 generation. Moreover compound 8 and 18 exert non-selective inhibition on both IL-2 and IL-4 cytokines, indicating a better interference with stage leading to humoral immune response and hence possible application in autoimmune diseases.

Oxadiazole Derivatives of Diclofenac as an Anti-proliferative Agent for B-cell Non-Hodgkin Lymphoma: An In vitro and In Silico Studies.

BACKGROUND: Non-Hodgkin lymphoma of B cell origin is the common type of lymphoma- related malignancy with poor response rate with conventional front-line therapies. AIM: The aim of the present study was to investigate the potential of new anti-inflammatory oxadiazole derivatives of Diclofenac as an anti-lymphoma agent through in vitro and in silico approaches. METHODS: Anti-lymphoma potential was evaluated by alamar blue technique. MTT assay employed for cytotoxicity. Gene and protein expression studies was performed by qRT-PCR and ELISA respectively. Docking studies was performed by using MOE program. RESULTS: Among five diclofenac derivatives, (II) showed promising anti-lymphoma effects, where it inhibited the expression of BCL-2, p-38 MAPK and TGF-ß in both follicular and Burkitt's lymphoma cells and was non-toxic against normal human fibroblast cells. The in silico studies against BCL-2 revealed that the unsubstituted Sulphur group in (II) is involved in the crucial interactions with the binding site residue. CONCLUSION: The compound (II) can be a potential therapeutic candidate for B-cell non-Hodgkin lymphoma and deserves further development as a novel anti-lymphoma agent.

Characterization of Green and Yellow Papaya (Carica papaya) for Anti-Diabetic Activity in Liver and Myoblast Cells and Wound-Healing Activity in Fibroblast Cells.

Obesity and diabetes, often characterized as "metabolic syndrome", have been recognized as two of the most important public health issues worldwide. The objective of the present research was to evaluate green and yellow papaya for anti-oxidation and anti-diabetic properties. Leaves, skin, pulp, and seed samples from papayas were freeze-dried and then extracted in water or 80% methanol. The extracts were used to determine total polyphenolic content and anti-oxidation activities, and to determine biological activities, including glucose uptake, Glut-2 expression, triglyceride reduction, and wound-healing activity. Our data demonstrated that methanol and water extracts of green and yellow papaya have similar concentrations of polyphenols in skin (10-20 mg/g dry powder), leaf (25-30 mg/g dry powder), and pulp (1-3 mg/g dry powder) fractions. However, both methanol and water extracts of seeds from yellow papaya have substantially higher concentrations of polyphenols compared to green papaya. Both water and methanol extracts of yellow papaya exhibited higher anti-oxidation activity compared to green papaya in skin (50-60%), pulp (200-300%), and seeds (10-800%). Old leaves also showed greater anti-oxidation activity (30-40%) compared to new leaves. Pulp extracts from both yellow and green papaya stimulated greater glucose uptake, but only pulp from green papaya stimulated glucose uptake in muscle cells. Similarly, pulp extract stimulated glucose transporter Glut-2 expression in liver cells. The skin, pulp, and seeds of green or yellow papaya showed triglyceride-lowering activity in liver cells by 60-80%, but samples taken from yellow papaya had a more potent effect. Seeds from both green and yellow papaya significantly stimulated the migration of fibroblasts in the wounded area by 2-2.5-fold compared to the untreated control. Consistent with these data, seeds from both green and yellow papaya also significantly stimulated collagen synthesis in fibroblast cells by almost 3-fold. In conclusion, our data indicate that different parts of papaya produce stimulatory effects on glucose uptake, Glut-2 expression, TG reduction, and wound-healing activities. This study concludes that different parts of the papaya can be beneficial for preventing diabetes and diabetes-related wound healing.

Dysregulation of Type I Interferon (IFN-I) Signaling: A Potential Contributor to Racial Disparity in Hepatocellular Carcinoma (HCC).

African-American (AA)/Black hepatocellular carcinoma (HCC) patients have increased incidence and decreased survival rates compared to non-Hispanic (White) patients, the underlying molecular mechanism of which is not clear. Analysis of existing RNA-sequencing (RNA-seq) data in The Cancer Genome Atlas (TCGA) and in-house RNA-sequencing of 14 White and 18 AA/Black HCC patients revealed statistically significant activation of type I interferon (IFN-I) signaling pathway in AA/Black patients. A four-gene signature of IFN-stimulated genes (ISGs) showed increased expression in AA/Black HCC tumors versus White. HCC is a disease of chronic inflammation, and IFN-Is function as pro-inflammatory cytokines. We tested efficacy of ginger extract (GE), a dietary compound known for anti-inflammatory properties, on HCC cell lines derived from White (HepG2), AA/Black (Hep3B and O/20) and Asian (HuH-7) patients. GE exhibited a significantly lower IC50 on Hep3B and O/20 cells than on HepG2 and HuH-7 cells. The GE treatment inhibited the activation of downstream mediators of IFN-I signaling pathways and expression of ISGs in all four HCC cells. Our data suggest that ginger can potentially attenuate IFN-I-mediated signaling pathways in HCC, and cells from AA/Black HCC patients may be more sensitive to ginger. AA/Black HCC patients might benefit from a holistic diet containing ginger.

Naringenin protects AlCl3/D-galactose induced neurotoxicity in rat model of AD via attenuation of acetylcholinesterase levels and inhibition of oxidative stress.

Currently prescribed medications for the treatment of Alzheimer's disease (AD) that are based on acetylcholinesterase inhibition only offer symptomatic relief but do not provide protection against neurodegeneration. There appear to be an intense need for the development of therapeutic strategies that not only improve brain functions but also prevent neurodegeneration. The oxidative stress is one of the main causative factors of AD. Various antioxidants are being investigated to prevent neurodegeneration in AD. The objective of this study was to investigate the neuroprotective effects of naringenin (NAR) against AlCl3+D-gal induced AD-like symptoms in an animal model. Rats were orally pre-treated with NAR (50 mg/kg) for two weeks and then exposed to AlCl3+D-gal (150 mg/kg + 300 mg/kg) intraperitoneally for one week to develop AD-like symptoms. The standard drug, donepezil (DPZ) was used as a stimulator of cholinergic activity. Our results showed that NAR pre-treatment significantly protected AD-like behavioral disturbances in rats. In DPZ group, rats showed improved cognitive and cholinergic functions but the neuropsychiatric functions were not completely improved and showed marked histopathological alterations. However, NAR not only prevented AlCl3+D-gal induced AD-like symptoms but also significantly prevented neuropsychiatric dysfunctions in rats. Results of present study suggest that NAR may play a role in enhancing neuroprotective and cognition functions and it can potentially be considered as a neuroprotective compound for therapeutic management of AD in the future.

Prevention of cadmium-induced neurotoxicity in rats by essential nutrients present in nuts.

Cadmium, a heavy metal with no physiological function in the human body, is considered a bio-hazard. It is also considered to be a potent neurotoxin. The primary sources of cadmium exposure are diet and cigarette smoke. It has been postulated that nutritional deficiencies can increase the risk of cadmium toxicity. Nuts provide essential nutrients which are necessary for the maintenance of brain health in humans. The present study was designed to investigate the possible protective effects of almond and walnut supplementation on cadmium-induced neurotoxicity. Cadmium was orally administered at a dose of 50 mg/kg weekly with or without the supplementation of almond and walnut in rats. Intensities of depression­ and anxiety-related behaviors were assessed by the forced swim test and light/dark transition test, respectively. Memory function was also evaluated by the elevated plus maze, Morris water maze and novel object recognition task. After four weeks of treatment it was observed that cadmium administration significantly induced depressogenic and anxiogenic behaviors. Memory function was also impaired by cadmium administration. Cadmium-treated rats exhibited reduced noradrenalin, dopamine and serotonin levels in the brain, whereas the levels of their respective metabolites were significantly increased. The dietary supplementation of almond and walnut at a dose of 400 mg/kg/day significantly attenuated cadmium-induced depression, anxiety and memory impairments. Neurochemical aberrations also normalized following supplementation with these nuts in rats. The present study demonstrates that long-term supplementation with almond and walnut provides essential nutrients which may overcome nutritional deficiencies and thereby reduce heavy-metal intoxication.