A prospective study was carried out to determine the aetiology of cerebral abscess in relation to the primary source of infections. Seventy-five patients with cerebral abscess were included in the study in the period January 1985 to December 1988. More than half of the patients studied had single lesions and the overall most common sites were in the frontal and parietal regions. Chronic suppurative otitis media, cyanotic congenital heart diseases and meningitis were among the important predisposing conditions in these patients. Approximately 25% of the patients with cerebral abscesses had no documented antecedent infections. Pure cultures were found to be predominant (66.7%) and sterile cultures were obtained from 10 (13.3%) patients. Streptococci were isolated from 23 (30.7%) patients, the commonest species being Streptococcus milleri. Proteus sp, Pseudomonas aeruginosa, Pseudomonas putrifaciens and Bacteroides sp were almost exclusively found in cerebral abscesses secondary to chronic suppurative otitis media; these organisms were found in mixed cultures. Streptococcus milleri, Bacteroides sp and Eikenella corrodens were found in pure cultures in patients with cyanotic congenital heart disease. In patients with ventriculoperitoneal shunts in-situ, Staphylococcus aureus, Staphylococcus epidermidis and diphtheroids were common. Anaerobes were found in 15 (20.0%) patients, the majority in mixed cultures. Culture, as well as gas-liquid chromatographic analysis of volatile fatty acids of cerebral pus, was carried out to enhance the detection of the anaerobes. Based on these findings, an antibiotic regimen consisting of penicillin, chloramphenicol and metronidazole is recommended as an initial therapy while awaiting culture and sensitivity results.
Forty cases of cerebral abscesses were studied prospectively to establish the microbial agents implicated in these cases. Chronic otitis media (14 patients, 35%), congenital heart disease (five patients, 12.5%),a and meningitis (five patients, 12.5%) were among the important predisposing factors. Streptococcus (14 patients, 35%) was the most common causative pre-isolated, the predominant species being Streptococcus milleri (11 patients, 27.5%). Other organisms isolated included Proteus mirabilis in six patients (15%) and Staphylococcus aureus in five patients (12.5%). Anaerobes (12 patients, 30%), predominantly Bacteroides sp. (eight patients, 20%), played an important role in these cases, the majority of which were isolated in mixed cultures. Gas-liquid chromatographic analysis of pus detected the presence of anaerobes in another 11 cases of cerebral abscess, in which cultures of anaerobes were negative. Therefore, gas-liquid chromotography is useful as an adjunct to conventional bacteriological methods in providing a rapid and sensitive means of detecting anaerobes in pus obtained especially from patients who had received antibiotic therapy prior to hospitalization.
Resveratrol, a naturally occurring polyphenolic antioxidant, is a potential chemoprophylactic agent for various cancers, including colorectal cancer. Although emerging evidence continually suggests that a number of resveratrol derivatives may be better cancer chemopreventive candidates than resveratrol, studies on the mechanism of action of these derivatives are limited. This is the first study which investigates the mechanism underlying the cytotoxic effect of a synthesized resveratrol analogue, (E)-N-(2-(4-methoxystyryl) phenyl) furan-2-carboxamide (CS) on colorectal cancer. Previously, our group reported a series of synthesized resveratrol analogues, which showed cytotoxicity against a panel of cancer cell lines, in particular on colon cancer cells. In this study, we further discovered that CS also exerts a potent suppressive effect on HCT116 colorectal cancer cells. In contrast, normal colon cells (CCD-112 Con) were not sensitive to CS up to 72 h post treatment. CS caused cytotoxicity in HCT116 cells through several apoptotic events including activation of the Fas death receptor, FADD, caspase 8, caspase 3, caspase 9, and cleaved PARP, which occurred alongside cell cycle arrest from the up-regulation of p53 and p21. The results show that CS causes apoptosis via the activation of an extrinsic pathway leading to caspase activation and cell cycle arrest from activated p53. These findings suggest that CS may be a potential candidate for development as an anti-tumor agent in the future.
The crude extract of the bark of Dehaasia longipedicellata exhibited antiplasmodial activity against the growth of Plasmodium falciparum K1 isolate (resistant strain). Phytochemical studies of the extract led to the isolation of six alkaloids: two morphinandienones, (+)-sebiferine (1) and (-)-milonine (2); two aporphines, (-)-boldine (3) and (-)-norboldine (4); one benzlyisoquinoline, (-)-reticuline (5); and one bisbenzylisoquinoline, (-)-O-O-dimethylgrisabine (6). Their structures were determined on the basis of 1D and 2D NMR, IR, UV, and LCMS spectroscopic techniques and upon comparison with literature values. Antiplasmodial activity was determined for all of the isolated compounds. They showed potent to moderate activity with IC50 values ranging from 0.031 to 30.40 µM. (-)-O-O-dimethylgrisabine (6) and (-)-milonine (2) were the two most potent compounds, with IC50 values of 0.031 and 0.097 µM, respectively, that were comparable to the standard, chloroquine (0.090 µM). The compounds were also assessed for their antioxidant activities with di(phenyl)-(2,4,6-trinitrophenyl)iminoazanium (IC50 = 18.40-107.31 µg/mL), reducing power (27.40-87.40 %), and metal chelating (IC50 = 64.30 to 257.22 µg/mL) having good to low activity. (-)-O-O-dimethylgrisabine (6) exhibited a potent antioxidant activity of 44.3 % reducing power, while di(phenyl)-(2,4,6-trinitrophenyl)iminoazanium and metal chelating activities had IC50 values of 18.38 and 64.30 µg/mL, respectively. Thus it may be considered as a good reductant with the ability to chelate metal and prevent pro-oxidant activity. In addition to the antiplasmodial and antioxidant activities, the isolated compounds were also tested for their cytotoxicity against a few cancer and normal cell lines. (-)-Norboldine (4) exhibited potent cytotoxicity towards pancreatic cancer cell line BxPC-3 with an IC50 value of 27.060 ± 1.037 µM, and all alkaloids showed no toxicity towards the normal pancreatic cell line (hTERT-HPNE).
In this study, a new apoptotic monoterpenoid indole alkaloid, subditine (1), and four known compounds were isolated from the bark of Nauclea subdita. Complete (1)H- and (13)C- NMR data of the new compound were reported. The structures of isolated compounds were elucidated with various spectroscopic methods such as 1D- and 2D- NMR, IR, UV and LCMS. All five compounds were screened for cytotoxic activities on LNCaP and PC-3 human prostate cancer cell-lines. Among the five compounds, the new alkaloid, subditine (1), demonstrated the most potent cell growth inhibition activity and selective against LNCaP with an IC50 of 12.24±0.19 µM and PC-3 with an IC50 of 13.97±0.32 µM, compared to RWPE human normal epithelial cell line (IC50 = 30.48±0.08 µM). Subditine (1) treatment induced apoptosis in LNCaP and PC-3 as evidenced by increased cell permeability, disruption of cytoskeletal structures and increased nuclear fragmentation. In addition, subditine (1) enhanced intracellular reactive oxygen species (ROS) production, as reflected by increased expression of glutathione reductase (GR) to scavenge damaging free radicals in both prostate cancer cell-lines. Excessive ROS could lead to disruption of mitochondrial membrane potential (MMP), release of cytochrome c and subsequent caspase 9, 3/7 activation. Further Western blot analyses showed subditine (1) induced down-regulation of Bcl-2 and Bcl-xl expression, whereas p53 was up-regulated in LNCaP (p53-wild-type), but not in PC-3 (p53-null). Overall, our data demonstrated that the new compound subditine (1) exerts anti-proliferative effect on LNCaP and PC-3 human prostate cancer cells through induction of apoptosis.
Centratherum anthelminticum (L.) seeds (CA) is a well known medicinal herb in Indian sub-continent. We recently reported anti-oxidant property of chloroform fraction of Centratherum anthelminticum (L.) seeds (CACF) by inhibiting tumor necrosis factor-α (TNF-α)-induced growth of human breast cancer cells. However, the active compounds in CACF have not been investigated previously.
Plants in the Meliaceae family are known to possess interesting biological activities, such as antimalaral, antihypertensive and antitumour activities. Previously, our group reported the plant-derived compound cycloart-24-ene-26-ol-3-one isolated from the hexane extracts of Aglaia exima leaves, which shows cytotoxicity towards various cancer cell lines, in particular, colon cancer cell lines. In this report, we further demonstrate that cycloart-24-ene-26-ol-3-one, from here forth known as cycloartane, reduces the viability of the colon cancer cell lines HT-29 and CaCO-2 in a dose- and time-dependent manner. Further elucidation of the compound's mechanism showed that it binds to tumour necrosis factor-receptor 1 (TNF-R1) leading to the initiation of caspase-8 and, through the activation of Bid, in the activation of caspase-9. This activity causes a reduction in mitochondrial membrane potential (MMP) and the release of cytochrome-C. The activation of caspase-8 and -9 both act to commit the cancer cells to apoptosis through downstream caspase-3/7 activation, PARP cleavage and the lack of NFkB translocation into the nucleus. A molecular docking study showed that the cycloartane binds to the receptor through a hydrophobic interaction with cysteine-96 and hydrogen bonds with lysine-75 and -132. The results show that further development of the cycloartane as an anti-cancer drug is worthwhile.
This study was set to investigate antiproliferative potential of dentatin (a natural coumarin isolated from Clausena excavata Burm. F) against prostate cancer and to delineate the underlying mechanism of action. Treatment with dentatin dose-dependently inhibited cell growth of PC-3 and LNCaP prostate cancer cell lines, whereas it showed less cytotoxic effects on normal prostate epithelial cell line (RWPE-1). The inhibitory effect of dentatin on prostate cancer cell growth was due to induction of apoptosis as evidenced by Annexin V staining and cell shrinkage. We found that dentatin-mediated accumulation of reactive oxygen species (ROS) and downregulated expression levels of antiapoptotic molecules (Bcl-2, Bcl-xL, and Survivin), leading to disruption of mitochondrial membrane potential (MMP), cell membrane permeability, and release of cytochrome c from the mitochondria into the cytosol. These effects were associated with induction of caspase-9, -3/7 activities, and subsequent DNA fragmentation. In addition, we found that dentatin inhibited TNF-α-induced nuclear translocation of p65, suggesting dentatin as a potential NF-κB inhibitor. Thus, we suggest that dentatin may have therapeutic value in prostate cancer treatment worthy of further development.