Immunomodulatory effect of DL-α-lipoic acid in aged rats

Senescence is the result of an imbalance between free radical production and antioxidant defenses, with concomitant oxidative stress and age-dependent functional decline. This process is especially evident in the immune cells, which use free radicals in their functions and suffer a senescent deterioration probably linked to oxygen stress. We hypothesize that oxidative damage and antioxidant imbalance may play a critical role in the immune dysfunction in aging. In the present study, we investigated this hypothesis in aged rats by treatment with alpha-lipoic acid (α-LA). We studied the effect of α-LA on immune function by examining immunomodulating factors in the plasma. Then we examined oxidative damage and antioxidant defense systems in the plasma. We found out that immune dysfunction in aged animals is associated with increased oxidative damage and decreased antioxidant status and treatment with α-LA effectively elevated immune function, decreased oxidative insult and enhanced antioxidant status. These results suggest that α-LA may be effective in improving immune function in aging through decreasing oxidative damage and revitalizing antioxidants in blood.     

Adenylyl cyclase type 6 overexpression selectively enhances β-adrenergic and prostacyclin receptor-mediated inhibition of cardiac fibroblast function because of colocalization in lipid rafts

Cardiac fibroblasts produce and degrade extracellular matrix and are critical in regulating cardiac remodeling and hypertrophy. Fibroblasts are activated by factors such as transforming growth factor beta and inhibited by agents that elevate 3',5'-cyclic adenosine monophosphate (cAMP) levels. cAMP signal generation and response is known to be compartmentalized in many cell types in part through the colocalization of receptors and specific adenylyl cyclase isoforms in lipid rafts and caveolae. The present study sought to define the localization of key G protein-coupled receptors with adenylyl cyclase type 6 (AC6) in lipid rafts of rat cardiac fibroblasts and to determine if this colocalization was functionally relevant. We found that cardiac fibroblasts produce cAMP in response to agonists for beta-adrenergic (isoproterenol), prostaglandin EP(2) (butaprost), adenosine (adenosine-5'-N-ethylcarboxamide, NECA), and prostacyclin (beraprost) receptors. Overexpression of AC6 increased cAMP production stimulated by isoproterenol and beraprost but not by butaprost or NECA. A key function of fibroblasts is the production of collagen. Isoproterenol- and beraprostmediated inhibition of collagen synthesis was also enhanced by AC6 overexpression, while inhibition by butaprost and NECA were unaltered. Lipid raft fractions from cardiac fibroblasts contain the preponderance of beta-adrenergic receptors and AC6 but exclude EP(2) receptors. While we could not determine the localization of native prostacyclin receptors, we were able to determine that epitope-tagged prostanoid IP receptors (IPR) expressed in COS7 cells did localize, in part, in lipid raft fractions. These findings indicate that IP receptors are expressed in lipid rafts and can activate raft-localized AC isoforms. AC6 is completely compartmentized in lipid raft domains where it is activated solely by coresident G protein-coupled receptors to regulate cardiac fibroblast function.     

Epilepsia partialis continua: A new manifestation of anti-Hu–associated paraneoplastic encephalomyelitis

We report on 3 anti-Hu–positive patients who presented with clinical and electroencephalographic (EEG) features of epilepsia partialis continua (EPC). Two of the patients had an associated small cell carcinoma. Magnetic resonance imaging (MRI) disclosed a hyperintense nonenhancing focal lesion in T2-weighted images in the sensorimotor area in 2 patients. Histopathological analysis of the lesion revealed inflammatory infiltrates and neuronal cell loss. In the patient who had a postmortem study, these neuropathological changes were not observed in other areas of the nervous system. This study emphasizes that the possibility of an anti-Hu–associated paraneoplastic disorder must be considered in patients with cortical encephalitis presenting with EPC when a brain tumor can be excluded. Ann Neurol 1999;45:255–258     

Colon cancer chemopreventive efficacy of silibinin through perturbation of xenobiotic metabolizing enzymes in experimental rats

Our findings reported so far demonstrate that silibinin modulates gut microbial enzymes, colonic oxidative stress and Wnt/β-catenin signaling, to exert its antiproliferative effect against 1,2 di-methylhydrazine (DMH) induced colon carcinogenesis. Since xenobiotic metabolizing enzymes play a crucial role in carcinogen activation and metabolism, we aimed to explore the effect of silibinin on xenobiotic metabolizing enzymes during DMH induced colon carcinogenesis. Male albino rats were randomly divided into six groups. Group 1 served as control and group 2 rats received 50mg/kg body weight of silibinin p.o. every day. Groups 3-6 rats were given DMH at a dose of (20mg/kg body weight subcutaneously) once a week for 15 weeks to induce colonic tumors. In addition to DMH, group 4 (initiation), group 5 (post-initiation) and group 6 (entire period) rats received silibinin (50mg/kg body weight, p.o., everyday) at different time points during the experimental period of 32 weeks. Rats exposed to DMH alone showed increased activities of phase I enzymes (cytochrome b5, cytochrome b5 reductase, cytochromeP450, cytochromeP450 reductase, cytochromP4502E1) and decreased activities of phase II enzymes (Uridine diphospho glucuronyl transferase, Glutathione-S-transferase and DT-Diaphorase) in the liver and colonic mucosa as compared to control rats. Silibinin supplementation modulates the xenobiotic metabolizing enzymes favoring carcinogen detoxification. Evaluation of lipid peroxidation and antioxidants status showed that silibinin supplementation counteracts DMH induced hepatic and circulatory oxidative stress. Tumor burden in experimental animals was assessed both macroscopically and microscopically in the colon tissues. Our findings emphasize the potential chemopreventive action of silibinin against DMH induced colon carcinogenesis.     

Causal role of the prefrontal cortex in top-down modulation of visual processing and working memory

Selective attention filters information to limit what is encoded and maintained in working memory. Although the prefrontal cortex (PFC) is central to both selective attention and working memory, the underlying neural processes that link these cognitive abilities remain elusive. Using functional magnetic resonance imaging to guide repetitive transcranial magnetic stimulation with electroencephalographic recordings in humans, we perturbed PFC function at the inferior frontal junction in participants before they performed a selective-attention, delayed-recognition task. This resulted in diminished top-down modulation of activity in posterior cortex during early encoding stages, which predicted a subsequent decrement in working memory accuracy. Participants with stronger fronto-posterior functional connectivity displayed greater disruptive effects. Our data further suggests that broad alpha-band (7-14 Hz) phase coherence subserved this long-distance top-down modulation. These results suggest that top-down modulation mediated by the prefrontal cortex is a causal link between early attentional processes and subsequent memory performance.     

Brain metastases after breast-conserving therapy and systemic therapy: incidence and characteristics by biologic subtype

The characteristics of brain metastases (BM) that develop after breast-conserving therapy (BCT) for early-stage breast cancer (BC) remain incompletely defined. We examined 1,434 consecutive patients with stage I/II invasive BC who received BCT from 1997 to 2006, 91?% of whom received adjuvant systemic therapy, according to BC subtype. Median follow-up was 85?months. Overall 5-year cumulative incidence of BM was 1.7?%; 0.1?% for luminal A, 3.3?% for luminal B, 3.2?% for luminal-HER2, 3.7?% for HER2, and 7.4?% for triple negative (TN). Women who developed BM were more likely at BC diagnosis to be younger (P?<?.0001) and have node-positive (P?<?.0001), grade 3 (P?<?.0001), hormone receptor-negative (P?=?.006), and HER2-positive (P?=?.01) tumors. Median time from BC diagnosis to BM was 51.4?months (range, 7.6?C108?months), which was longer among luminal versus non-luminal subtypes (P?=?.0002; median, 61.4 vs. 34.5?months). Thirty-four percent of patients who developed distant metastases (DM) eventually developed BM. Median time from DM to BM was 12.8?months but varied by subtype, including 7.4?months for TN, 9.6?months for luminal B, and 27.1?months for HER2. Eighty-one percent of all BM patients presented with neurologic symptoms. Median number of BM at diagnosis was two, and median BM size was 15?mm, with TN (27?mm) and luminal B (16?mm) exhibiting the largest median sizes. In conclusion, the risk of BM after BCT varies significantly by subtype. Given the large size and symptomatic presentation among luminal B and TN subtypes, earlier BM detection might improve quality of life or increase eligibility for non-invasive treatments including stereotactic radiosurgery. Women with DM from these two BC subtypes have a high incidence of BM with a short latency, suggesting an ideal target population for trials evaluating the utility of MRI screening.