No abstract

Social isolation is a major risk factor for the development of depressive illness; yet, no practical nonhuman primate model is available for studying processes involved in this effect. In a first study, we noted that adult male rhesus monkeys housed individually indoors occasionally exhibited a hunched, depressive-like posture. Therefore, Study 2 investigated the occurrence of a hunched posture by adult males brought from outdoor social groups to indoor individual housing. We also scored two other behaviors—lying on the substrate and day time sleeping—that convey an impression of depression. During the first week of observation following individual housing, 18 of 26 adult males exhibited the hunched posture and 21 of 26 displayed at least one depressive-like behavior. Over 2 weeks, 23 of 26 males showed depressive-like behavior during a total of only 20 min observation. Further, the behavior during the first week was positively related to the level of initial response to a maternal separation procedure experienced in infancy. In Study 3, more than half of 23 adult males of a new sample displayed depressive-like behavior during 10 min of observation each of Weeks 7–14 of individual housing. The surprisingly high frequency of depressive-like behavior in Studies 2 and 3 may have been due to recording behavior via camera with no human in the room to elicit competing responses. These results suggest that a common animal husbandry procedure might provide a practical means for examining effects of social isolation on depression-related endpoints in a nonhuman primate. The findings also suggest that trait-like differences in emotional responsiveness during separation in infancy may predict differences in responsiveness during social isolation in adulthood.

Given the adverse effects of drugs used for NAFLD treatment, identifying novel and effective natural compound to prevent NAFLD is urgently needed. In the present study, the effects of phytosterol esters (PSEs) on NAFLD were explored. Adult SD rats were randomized into five groups: normal chow diet (NC), high-fat diet (HF), low-, medium- and high-dose PSE treatment plus high-fat diet groups (PSEL, PSEM, and PSEH). Our results showed that the levels of LDL-C in the PSEL group and hepatic TG, TC, and FFA in the three PSEs groups were significantly decreased. Notably, the uric acid (UA) level was significantly decreased by PSEs intervention. The hepatic inflammatory stress was ameliorated via the inhibition of the cytokines, including TGF-β, IL-6, IL-10 and CRP in the PSEs intervention groups. Further, the oxidative status was improved by PSE treatment through adjusting the enzyme activity (SOD and XOD) and decreasing the MDA level. These beneficial effects of PSE may have been partly due to its regulation on the expression of TGF-β1, TGF-β2, TNF-α, UCP-2, PPAR-α and PPAR-γ in hepatic tissue at both mRNA and protein level. The results of this study suggest that PSEs may be used as therapeutic agents for the prevention and progression of NAFLD and that hyperuricemia is induced by high-fat diet consumption.

Cryosurgical treatment of solid cancer can be greatly assisted by further translation of our finding that a cytokine adjuvant tumor necrosis factor-A (TNF-A) can achieve complete cancer destruction out to the intraoperatively imaged iceball edge (-0.5°C) over the current clinical recommendation of reaching temperatures lower than -40°C. The present study investigates the cellular and tissue level dose dependency and molecular mechanisms of TNF-A-induced enhancement in cryosurgical cancer destruction. Microvascular endothelial MVEC and human prostate cancer LNCaP Pro 5 (LNCaP) cells were frozen as monolayers in the presence of TNF-A. Normal skin and LNCaP tumor grown in a nude mouse model were also frozen at different TNF-A doses. Molecular mechanisms were investigated by using specific inhibitors to block nuclear factor-KB -mediated inflammatory or caspasemediated apoptosis pathways. The amount of cryoinjury increased in a dose-dependent manner with TNF-A both in vitro and in vivo. MVEC were found to be more cryosensitive than LNCaP cells in both the presence and the absence of TNF-A. The augmentation in vivo was significantly greater than that in vitro, with complete cell death up to the iceball edge in tumor tissue at local TNF-A doses greater than 200 ng. The inhibition assays showed contrasting results with caspase-mediated apoptosis as the dominant mechanism in MVEC in vitro and nuclear factor-KB -mediated inflammatory mechanisms within the microvasculatures the dominant mechanism in vivo. These results suggest the involvement of endothelialmediated injury and inflammation as the critical mechanisms in cryoinjury and the use of vascular-targeting molecules such as TNF-A to enhance tumor killing and achieve the clinical goal of complete cell death within an iceball.

No abstract

Cryosurgery is increasingly being used to treat prostate cancer; however, a major limitation is local recurrence of disease within the previously frozen tissue. We have recently demonstrated that tumor necrosis factor alpha (TNF-α), given 4 hours prior to cryosurgery can yield complete destruction of prostate cancer within a cryosurgical iceball. The present work continues the investigation of the cellular and molecular mechanisms and dynamics of TNF-α enhancement on cryosurgery. In vivo prostate tumor (LNCaP Pro 5) was grown in a dorsal skin fold chamber (DSFC) on a male nude mouse. Intravital imaging, thermography, and post-sacrifice histology and immunohistochemistry were used to assess iceball location and the ensuing biological effects after cryosurgery with and without TNF-α pre-treatment. Destruction was specifically measured by vascular stasis and by the size of histologic zones of injury (i.e. inflammatory infiltrate and necrosis). TNF-α induced vascular pre-conditioning events that peaked at 4 hours and diminished over several days. Early events (4 -24 hours) include upregulation of inflammatory markers (nuclear factor-κB (NFκB) and vascular cell adhesion molecule-1 (VCAM)) and caspase activity in the tumor prior to cryosurgery. TNF-α pre-conditioning resulted in recruitment of an augmented inflammatory infiltrate at day 3 post treatment vs. cryosurgery alone. Finally, preconditioning yielded enhanced cryosurgical destruction up to the iceball edge at days 1 and 3 vs. cryosurgery alone. Thus, TNF-α pre-conditioning enhances cryosurgical lesions by vascular mechanisms that lead to tumor cell injury via promotion of inflammation and leukocyte (esp. neutrophil) recruitment.

Irreversible electroporation (IRE) has been proposed to destroy large amounts of tumorous tissue and shows advantages over thermal therapies. Unfortunately, carefully constructed studies assessing impact in in vivo tumor systems and a direct comparison of IRE with thermal therapy are lacking. In this study, we investigate the effect of IRE in a human prostate cancer (LNCaP) grown in a thin, essentially two-dimensional, dorsal skin fold chamber system. Detailed experimental characterizations of the electrical and thermal responses of the tissue were performed yielding the first thermal response measurement in vivo of its kind that we are aware of. The interaction and coupling of electrical and thermal responses were further discussed. The threshold of the tumor injury was determined for human prostate tumor model, and the threshold value (600-1300 V cm(-1)) is dependent on the IRE parameters including pulse duration and pulse number. This dependence was explained in the context of tissue electrical conductivity change during IRE. Further, the thermal injury was found not to be a dominant factor in IRE with our system, which is in agreement with previous numerical studies. Finally, it appears that the local electrical heterogeneity of the tumor tissue reduces the effectiveness of IRE in some sections of the tumor (leading to live tumor patches).

Oleaginous fungi (including fungus-like protists) are attractive in lipid production due to their short growth cycle, large biomass and high yield of lipids. Some typical oleaginous fungi including Galactomyces geotrichum, Thraustochytrids, Mortierella isabellina, and Mucor circinelloides, have been well studied for the ability to accumulate fatty acids with commercial application. Here, we review recent progress toward fermentation, extraction, of fungal fatty acids. To reduce cost of the fatty acids, fatty acid productions from raw materials were also summarized. Then, the synthesis mechanism of fatty acids was introduced. We also review recent studies of the metabolic engineering strategies have been developed as efficient tools in oleaginous fungi to overcome the biochemical limit and to improve production efficiency of the special fatty acids. It also can be predictable that metabolic engineering can further enhance biosynthesis of fatty acids and change the storage mode of fatty acids.