Free-living organisms must procure adequate nutrition by negotiating an environment in which both the quality and quantity of food vary markedly. Recent decades have seen marked progress in our understanding of neural regulation of feeding behavior. However, this progress has occurred largely in the context of energy intake, despite the fact that food intake is influenced by more than just the energy content of the diet. A large number of behavioral studies indicate that both the quantity and quality of dietary protein can markedly influence food intake. High-protein diets tend to reduce intake, low-protein diets tend to increase intake, and rodent models seem to self-select between diets in order to meet protein requirements and avoid diets that are imbalanced in amino acids. Recent work suggests that the amino acid leucine regulates food intake by altering mTOR and AMPK signaling in the hypothalamus, while activation of GCN2 within the anterior piriform cortex contributes to the detection and avoidance of amino acid-imbalanced diets. This review focuses on the role that these and other signaling systems may play in mediating the homeostatic regulation of protein balance, and in doing so, highlights our lack of knowledge regarding the physiological and neurobiological mechanisms that might underpin such a regulatory phenomenon.

Objective and BackgroundTo assess renoprotective effects of a blueberry-enriched diet in a rat model of hypertension. Oxidative stress (OS) appears to be involved in the development of hypertension and related renal injury. Pharmacological antioxidants can attenuate hypertension and hypertension-induced renal injury; however, attention has shifted recently to the therapeutic potential of natural products as antioxidants. Blueberries (BB) have among the highest antioxidant capacities of fruits and vegetables.Methods and ResultsMale spontaneously hypertensive rats received a BB-enriched diet (2% w/w) or an isocaloric control diet for 6 or 12 weeks or 2 days. Compared to controls, rats fed BB-enriched diet for 6 or 12 weeks exhibited lower blood pressure, improved glomerular filtration rate, and decreased renovascular resistance. As measured by electron paramagnetic resonance spectroscopy, significant decreases in total reactive oxygen species (ROS), peroxynitrite, and superoxide production rates were observed in kidney tissues in rats on long-term dietary treatment, consistent with reduced pathology and improved function. Additionally, measures of antioxidant status improved; specifically, renal glutathione and catalase activities increased markedly. Contrasted to these observations indicating reduced OS in the BB group after long-term feeding, similar measurements made in rats fed the same diet for only 2 days yielded evidence of increased OS; specifically, significant increases in total ROS, peroxynitrite, and superoxide production rates in all tissues (kidney, brain, and liver) assayed in BB-fed rats. These results were evidence of “hormesis” during brief exposure, which dissipated with time as indicated by enhanced levels of catalase in heart and liver of BB group.ConclusionLong-term feeding of BB-enriched diet lowered blood pressure, preserved renal hemodynamics, and improved redox status in kidneys of hypertensive rats and concomitantly demonstrated the potential to delay or attenuate development of hypertension-induced renal injury, and these effects appear to be mediated by a short-term hormetic response.

Chronic ExT preserves renal hemodynamics and structure in SHR; these effects are partially mediated by improved redox status and decreased inflammation.

ular injections of leucine are sufficient to suppress food intake, but it remains unclear whether brain leucine signaling represents a physiological signal of protein balance. We tested whether variations in dietary and circulating levels of leucine, or all three branched-chain amino acids (BCAAs), contribute to the detection of reduced dietary protein. Of the essential amino acids (EAAs) tested, only intracerebroventricular injection of leucine (10 g) was sufficient to suppress food intake. Isocaloric low-(9% protein energy; LP) or normal-(18% protein energy) protein diets induced a divergence in food intake, with an increased consumption of LP beginning on day 2 and persisting throughout the study (P Ͻ 0.05). Circulating BCAA levels were reduced the day after LP diet exposure, but levels subsequently increased and normalized by day 4, despite persistent hyperphagia. Brain BCAA levels as measured by microdialysis on day 2 of diet exposure were reduced in LP rats, but this effect was most prominent postprandially. Despite these diet-induced changes in BCAA levels, reducing dietary leucine or total BCAAs independently from total protein was neither necessary nor sufficient to induce hyperphagia, while chronic infusion of EAAs into the brain of LP rats failed to consistently block LP-induced hyperphagia. Collectively, these data suggest that circulating BCAAs are transiently reduced by dietary protein restriction, but variations in dietary or brain BCAAs alone do not explain the hyperphagia induced by a low-protein diet.branched-chain amino acids; protein restriction; hypothalamus; macronutrient; food intake ALTHOUGH THE STUDY OF ingestive behavior historically has focused largely on the regulation of energy homeostasis, the consumption of adequate amounts of protein, specifically essential amino acids (EAAs), is also central to health and survival. Therefore, it seems likely that physiological systems exist to ensure sufficient protein intake. Alterations in dietary protein content can have profound effects on food intake, with diets high in protein suppressing food intake and diets moderately low in protein increasing food intake (2,11,18,23,38,39). Furthermore, when given the choice between diets that differ in protein content, many species will self-select between diets to ensure adequate consumption of protein (16,24,27), often at the expense of carbohydrate and fat (9,19,31).Despite these behavioral observations, the mechanism regulating protein intake is largely unknown (21). Recent work has focused on the branched-chain amino acid (BCAA) leucine as a potential protein signal. Intracerebroventricular injections of leucine suppress food intake and regulate key signaling systems (mTOR/AMPK) within hypothalamic neurons, while increased dietary leucine content reproduces the anorectic effects of a high-protein diet (3,5,23,29). While these data demonstrate that administration of excess leucine either to the diet or the brain is sufficient to suppress food intake, it remains unclear whether physiological fluctua...

Like many effective therapeutics, interleukin-12 (IL-12) therapy often causes side effects. Tumor targeted delivery may improve the efficacy and decrease the toxicity of systemic IL-12 treatments. In this study, a novel targeting approach was investigated. A secreted alkaline phosphatase (SEAP) reporter gene-based screening process was used to identify a mini-peptide which can be produced in vivo to target gene products to tumors. The coding region for the best peptide was inserted into an IL-12 gene to determine the antitumor efficacy. Affinity chromatography, mass spectrometry analysis, and binding studies were used to identify a receptor for this peptide. We discovered that the linear peptide VNTANST increased the tumor accumulation of the reporter gene products in five independent tumor models including one human xenogeneic model. The product from VNTANST-IL-12 fusion gene therapy increased accumulation of IL-12 in the tumor environment, and in three tumor models, VNTANST-IL-12 gene therapy inhibited distal tumor growth. In a spontaneous lung metastasis model, inhibition of metastatic tumor growth was improved compared to wild-type IL-12 gene therapy, and in a squamous cell carcinoma model, toxic liver lesions were reduced. The receptor for VNTANST was identified as vimentin. These results show the promise of using VNTANST to improve IL-12 treatments.

Based on superior outcomes from electrochemogene therapy (ECGT) compared to electrochemotherapy (ECT)in mice, we determined the efficacy of ECGT applied to spontaneous canine neoplasms. Intralesional bleomycin (BLM) and feline interleukin-12 DNA (fIL-12 DNA) injection combined with trans-lesional electroporation resulted in complete cure of two recurrent World Health Organization (WHO) stageT2bN0M0 oral squamous cell carcinomas (SCCs)and one T2N0M0acanthomatous ameloblastoma. Three remaining dogs, which had no other treatment options, had partial responses to ECGT; one had mandibular T3bN2bM1 melanoma with pulmonary and lymph node metastases; one had cubital T3N0M1 histiocytic sarcoma with spleen metastases; and one had soft palate T3N0M0fibrosarcoma. The melanoma dog had decrease in the size of the primary tumor before recrudescence and euthanasia. The histiocytic sarcoma dog had resolution of the primary tumor, but was euthanized because of metastases four months after the only treatment. The dog with T 3N0M0 fibrosarcoma had tumor regression with recrudescence. Treatment was associated with minimal side effects and was easy to perform; was associated with repair of bone lysis in cured dogs; improved quality of life for dogs with partial responses; and extended overall survival time. ECGT appears to be a safe and resulted in complete responses in SCC and acanthomatous ameloblastoma.

Abstract. Two quadrigeminal arachnoid cysts with different pathogenesis are described in 2 different species. A 10-week-old male Persian kitten with a progressively decreasing level of consciousness died spontaneously. At necropsy, mild internal hydrocephalus, caudal cerebellar coning, and cerebellar herniation through the foramen magnum were associated with a congenital quadrigeminal arachnoid cyst compressing the rostral cerebellum and shifting the entire cerebellum caudally. In contrast, a possibly acquired quadrigeminal cyst was observed in a 2-year-old male neutered Yorkshire Terrier in association with necrotizing encephalitis. Quadrigeminal arachnoid cysts have been rarely reported in dogs and humans.

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