Dual targeted 2-Benzylideneindanone pendant hydroxamic acid group exhibits selective HDAC6 inhibition along with tubulin stabilization effect.

Abnormal epigenetics has been recognised as an early event in tumour progression and aberrant acetylation of lysine in particular has been understood in tumorigenesis. Therefore, it has become an attractive target for anticancer drug development. However, HDAC inhibitors have limited success due to toxicity and drug resistance concerns. Present study deals with design and synthesis of bivalent indanone based HDAC6 and antitubulin ligands as anticancer agents. Two of the analogues 9 and 21 exhibited potent antiproliferative activities (IC50, 0.36-3.27 µM) and high potency against HDAC 6 enzyme. Compound 21 showed high selectivity against HDAC 6 while 9 exhibited low selectivity. Both the compounds also showed microtubule stabilization effects and moderate anti-inflammatory effect. Dual targeted anticancer agents with concomitant anti-inflammatory effects will be more attractive clinical candidates in future.

Neuroprotective role of chloroquine via modulation of autophagy and neuroinflammation in MPTP-induced Parkinson's disease.

Parkinson's disease (PD) is a neuro-motor ailment that strikes adults in their older life and results in both motor and non-motor impairments. In neuronal and glial cells, PD has recently been linked to a dysregulated autophagic system and cerebral inflammation. Chloroquine (CQ), an anti-malarial drug, has been demonstrated to suppress autophagy in a variety of diseases, including cerebral ischemia, Alzheimer's disease (AD), and Traumatic brain injury (TBI), while its involvement in PD is still unclear. BALB/c mice were randomly allocated to one of four groups: 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP), CQ treatment with or without MPTP, or control. The CQ treatment group received CQ (intraperitoneally, 8 mg/kg body weight) after 1 h of MPTP induction on day 1, and it lasted for 7 days. CQ therapy preserves dopamine levels stable, inhibits tyrosine hydroxylase (TH) positive dopaminergic cell death, and lowers oxidative stress. CQ reduces the behavioural, motor, and cognitive deficits caused by MPTP after injury. Furthermore, CQ therapy slowed aberrant neuronal autophagy (microtubule-associated protein-1 light chain 3B; LC3B & Beclin1) and lowered expression levels of the inflammatory cytokines interleukin 1 (IL-1ß) and tumour necrosis factor (TNF-α) in the mice brain. In addition, CQ's antioxidant and anti-inflammatory effects were also tested in MPTP-mediated cell death in PC12 cells, demonstrating that CQ has a neurorestorative impact by successfully rescuing MPTP-induced ROS generation and cell loss. Our findings show that CQ's can help to prevent dopaminergic degeneration and improve neurological function after MPTP intoxication by lowering the harmful effects of neuronal autophagy and cerebral inflammation.

Toxic effects of oral administration of extracts of dried calyx of Hibiscus sabdariffa Linn. (Malvaceae).

The effects of a 90-day oral administration of water and alcohol extracts of dried calyx of Hibiscus sabdariffa were evaluated in albino rats. Haematological, biochemical and histopathological changes were monitored every 30 days.The death of the animals was preceded by a severe loss in weight, accompanied with diarrhoea in animals on the 2000 mg/kg dose. There was an increase in food intake (g) per kg body weight per day in the aqueous (A) and ethanol (E) 300 mg/kg extract groups. Significant reductions in the erythrocyte count with no difference in total leucocyte count were observed. The activity of aspartate aminotransferase (AST) was enhanced by the administration of aqueous and 50% ethanol extract with a significant increase in its level at higher doses (p < 0.05). Alanine aminotransferase (ALT) and creatinine levels were significantly affected by all the extracts at the different dose levels. However, aqueous extracts exhibited a significant increase in creatinine levels (p < 0.05) at higher doses. The cholesterol levels were generally not significantly affected by the extracts. No significant histopathological changes were observed, although there was a significant reduction in the weight of the spleen of the animals administered with ethanol and water extracts when compared with the control (p < 0.01). Other organs were of the same relative weight.

Bivalent furostene carbamates as antiproliferative and antiinflammatory agents.

Breast cancer is the most prevalent cancer in women affecting about 12% of world's female population. It is a multifactorial disease, mostly invasive in nature. Diosgenin and related compounds are potent antiproliferative agents. Carbamate derivatives have been synthesized at C26 of furostene ring after opening spiroketal bond (F-ring) of diosgenin. Compound 10 possessed significant antiproliferative activity against human breast cancer cells by arresting the population at G1 phase of cell division cycle and induced apoptosis. Induction of apoptosis was observed through the caspase signalling cascade by activating caspase-3. Moreover, carbamate 10 exhibited moderate antiinflammatory activity by decreasing the expression of cytokines, TNF-α and IL-6 in LPS-induced inflammation in primary macrophage cells. Furthermore, compound 10 significantly reduced Ehrlich ascites carcinoma significantly in mice. It was well tolerated and safe in acute oral toxicity in Swiss albino mice. The concomitant anticancer and antiinflammatory properties of carbamate 10 are important and thus, can further be optimized for a better anti-breast cancer candidate.

Immunomodulatory effect of extracts of Hibiscus sabdariffa L. (Family Malvaceae) in a mouse model.

The immunomodulatory activity of water and alcohol extracts (including its fractions) of the dried calyx of the plant was evaluated in mice. The ability of the extracts to inhibit or enhance the production of two cytokines, namely tumor necrosis factor-alpha (TNF- alpha) and interleukin-10 (IL-10), respectively, implicated as proinflammatory and antiinflammatory interleukins were also evaluated. The extracts at doses of 50 mg/kg were found to possess higher immunostimulatory activities in comparison with levamisole (positive control), with significant effects when compared with the vehicle-treated group (p < 0.01). Increased activity was observed with increase in doses of the 50% ethanol and absolute ethanol extracts. The insoluble fraction exhibited a significant dose-dependent immunostimulatory activity (p < 0.05), while the residual water-soluble fraction exhibited activity at 100 mg/kg body weight. The production of tumor necrosis factor-alpha (TNF-alpha), was low in all the extract groups tested, while the production of interleukin 10 (IL-10) was high compared with the control. The production of IL-10 was high in 300 mg/kg aqueous extract. The insoluble fraction exhibited a profound dose-dependent immunostimulatory activity higher than the positive control at 100 mg/kg. This study established the immunoenhancing properties of the extracts of this plant confirming that the immunomodulatory activity is cell mediated and humoral. The insoluble fraction could find use as an immunostimulatory agent in humans.

(22ß,25R)-3ß-Hydroxy-spirost-5-en-7-iminoxy-heptanoic acid exhibits anti-prostate cancer activity through caspase pathway.

Prostate cancer is one of the most common cancers in men. Diosgenin and related compounds are potential cytotoxic agents. Twelve diverse analogues of long chain fatty acid/ester of diosgenin-7-ketoxime have been prepared. Six of the analogues exhibited significant anticancer activity against a panel of human cancer cell lines with IC50 ranging from 12 to 35µM. Compound 16, the best representative of the series exerted S phase arrest in DU145 prostate cancer cells and induced apoptosis through caspase pathway. Additionally, these analogues inhibited lipopolysaccharide induced pro-inflammatory cytokines (TNF-α and IL-6) up to 47.7% and 23.3% respectively. Compound 16 was found to be safe in acute oral toxicity in Swiss albino mice up to 300mg/kg dose. The anticancer and antiinflammatory properties of compound 16 are important and can further be optimized for a better anti-prostate cancer candidate.

Effects of oxidizing and reducing agents on ovine pulmonary artery responses to nitric oxide donors, sodium nitroprusside and 3-morpholino-sydnonimine.

Nitrovasodilators-sodium nitroprusside (SNP; 10(-9)-10(-4) M) and 3-morpholino-sydnonimine (SIN-1; 10(-9)-10(-4) M) produced concentration-dependent relaxation of the fourth generation sheep pulmonary artery, preconstricted with 5-hydroxytryptamine (1 microM). Oxidizing agents [oxidized glutathione (GSSG, 1 mM) and CuSO4 (5 and 20 microM)] and reducing agents [dithiothreitol (DTT, 0.1 mM), ascorbic acid (1 mM) and reduced glutathione (GSH, 1 mM)] caused opposite effects on nitric oxide (NO)-induced vasodilation in the artery. Ascorbic acid and GSH potentiated the NO responses, while GSSG and CuSO4 inhibited relaxation caused by the nitrovasodilators. DTT, however, reduced the relaxant potency and efficacy of SNP and SIN-1. Pretreatment of the pulmonary artery strips with DTT (0.1 mM) inhibited SNP (10 microM)-induced Na(+)-K(+)-ATPase activity, while ascorbic acid (1 mM) and GSH (1 mM) had no effect either on basal or SNP (10 microM)-stimulated 86Rb uptake, an index of Na(+)-K(+)-ATPase activity, in ovine pulmonary artery. The results suggest that reducing agents like ascorbic acid may have beneficial effect in improving the vascular function under oxidative stress.

Synthesis and anti-inflammatory activity of derivatives of coumarino-lignoid, cleomiscosin A and its methyl ether.

Six novel cleomiscosin A (a coumarino-lignoid), derivatives have been synthesized for the first time by using electrophilic substitution reaction to give nuclear nitrated and halogenated derivatives of cleomiscosin A in good yields. Structures of these compounds were established on the basis of IR, (1)H NMR, (13)C NMR and Mass spectral data. Some of the synthesized derivatives were tested for in-vitro target based anti-inflammatory study using primary macrophages cell culture bioassay system. The results showed that the compounds 1a, 3a and 4a (1 and 10 µg/mL) exhibited potent anti-inflammatory activity.

Modulation of inflammatory mediators by coumarinolignoids from Cleome viscosa in female swiss albino mice.

The effect of coumarinolignoid cleomiscosins A, B and C isolated from the plant Cleome viscosa on inflammatory mediators were studied in female swiss albino mice. A mixture of coumarinolignoid A, B, and C at 10, 30 and 100 mg/kg body weight once a day for 14 consecutive days were administered orally to the mice. Pro-inflammatory mediators such as IL-6, TNF-alpha and nitric oxide were estimated from culture supernatant obtained from peritoneal macrophages stimulated by LPS and anti-inflammatory mediator IL-4 was estimated from culture supernatant obtained from spleenocytes stimulated by Con-A. For further confirmation, expressions of inflammatory mediators from serum and mortality rate were studied in LPS-induced toxicity model in mice. The expression of Pro-inflammatory mediators was significantly (P <0.05) decreased in coumarinolignoids treatment group in dose dependent manner, whereas the anti-inflammatory mediator expression was significantly increased in coumarinolignoids at 10 mg/kg treatment. Mortality rate was also significantly reduced in treatment group in LPS-induced toxicity model. The result of this study concluded that the oral administration of coumarinolignoids inhibited the pro-inflammatory mediators and enhances the production of anti-inflammatory mediator in dose dependent manner.