Impact of aliphatic acyl and aromatic thioamide substituents on the anticancer activity of Ru(II)-p-cymene complexes with acylthiourea ligands-in vitro and in vivo studies.

Six different acylthiourea ligands (L1-L6) and their corresponding Ru(II)-p-cymene complexes (P1-P6) were designed to explore the structure-activity relationship of the complexes upon aliphatic chain and aromatic conjugation on the C- and N-terminals, respectively. The compounds were synthesized and adequately characterized using various analytical and spectroscopic techniques. The structures of P2-P6, solved using single crystal X-ray diffraction (XRD), confirmed the neutral monodentate coordination of the S atoms of the acylthiourea ligands to Ru(II) ions. In silico studies showed an increase of lipophilicity for the ligands with an increase in alkyl chain length or aromatic conjugation at the C- or N-terminal, respectively. Subsequently, mitogen-activated protein kinases (MAPK) were predicted as one of the primary targets for the complexes, which showed good binding affinity towards extracellular signal-regulated kinases (ERK1, ERK2 and ERK5), c-Jun N-terminal kinase (JNK) and p38 of the MAPK pathway. Henceforth, the complexes were tested for their anticancer activity in lung carcinoma (A549) and cisplatin-resistant lung carcinoma (cisA549R) cells and human umbilical vein epithelial normal cells (HUVEC). Interestingly, an increase in chain length or aromatic conjugation led to an increase in the activity of the complexes, with P5 (7.73 and 13.04 µM) and P6 (6.52 and 14.45 µM) showing the highest activity in A549 and cisA549R cells, which is better than the positive control, cisplatin (8.72 and 44.28 µM). Remarkably, we report the highest activity yet observed for complexes of the type [(η6-p-cymene)RuIICl2(S-acylthiourea)] in the tested cell lines. Aqueous solution studies showed that complexes P5 and P6 are rapidly hydrolyzed to produce solely aquated species that remained stable for 24 h. Staining assays and flow cytometric analyses of P5 and P6 in A549 cells revealed that the complexes induced apoptosis and arrested the cell cycle predominantly in the S phase. In vivo studies demonstrated the higher toxicity of cisplatin and a comparatively higher survival rate of mice injected with the most active complex P6. Histological analyses revealed that treatment with P6 at high doses of up to 8 mg kg-1 did not cause any palpable damage to the tested organs.

Oral TNFα Modulation Alters Neutrophil Infiltration, Improves Cognition and Diminishes Tau and Amyloid Pathology in the 3xTgAD Mouse Model.

Cytokines such as TNFα can polarize microglia/macrophages into different neuroinflammatory types. Skewing of the phenotype towards a cytotoxic state is thought to impair phagocytosis and has been described in Alzheimer's Disease (AD). Neuroinflammation can be perpetuated by a cycle of increasing cytokine production and maintenance of a polarized activation state that contributes to AD progression. In this study, 3xTgAD mice, age 6 months, were treated orally with 3 doses of the TNFα modulating compound isoindolin-1,3 dithione (IDT) for 10 months. We demonstrate that IDT is a TNFα modulating compound both in vitro and in vivo. Following long-term IDT administration, mice were assessed for learning & memory and tissue and serum were collected for analysis. Results demonstrate that IDT is safe for long-term treatment and significantly improves learning and memory in the 3xTgAD mouse model. IDT significantly reduced paired helical filament tau and fibrillar amyloid accumulation. Flow cytometry of brain cell populations revealed that IDT increased the infiltrating neutrophil population while reducing TNFα expression in this population. IDT is a safe and effective TNFα and innate immune system modulator. Thus small molecule, orally bioavailable modulators are promising therapeutics for Alzheimer's disease.

Outcome of multi-drug resistant tuberculosis cases treated by individualized regimens at a tertiary level clinic.

AIM: To determine the clinical, radiological and drug resistance profile as well as the factors associated with treatment outcome of Multi-Drug Resistant Tuberculosis (MDR-TB). MATERIAL AND METHODS: All newly diagnosed patients with pulmonary MDR-TB from August 2002 to December 2004 enrolled at New Delhi Tuberculosis Centre, were included in the study. They were followed up clinically, radiologically and bacteriologically by sputum smear, culture and Drug Susceptibility Testing (DST) at regular intervals. According to their DST pattern and previous history of Anti-Tubercular Treatment (ATT), individualized treatment regimens were tailored for each patient. RESULTS: Out of total 27 bacteriologically proven cases of MDR-TB included in this study, 19 were males (mean age and weight 38.5 years and 52.6 kgs, respectively) and eight females (mean age and weight 34.3 years and 40.7 kgs, respectively). A majority (18) were residents of Delhi and the rest hailed from different parts of North India. All of them had a history of previous treatment ranging from six to 34 months. Cavity on chest X-rays was seen in 81%, while 44% showed extensive involvement. The patients received at least four "second line drugs" during their treatment with a mean of 6.2 anti-tubercular drugs during their intensive phase. Of the 27 patients, 13 were cured, 10 defaulted, one died, one is still on treatment and two were referred for surgery. Radiological improvement was observed in two third of cases and chest X-ray of two patients showed a complete resolution. Six predictors were identified for successful outcome of MDR-TB. They include weight gain at six months, culture conversion, radiological improvement during treatment, disease with M. tuberculosis strains exhibiting resistance to less than or up to three anti-tubercular drugs, use of less than or up to three second line drugs in treatment and no change of regimen during treatment. CONCLUSION: Default from treatment was observed to be a major challenge in the treatment of MDR-TB due to long duration and expense of ATT.