Role of PACAP and VIP Signalling in Regulation of Chondrogenesis and Osteogenesis

Pituitary adenylate cyclase activating polypeptide (PACAP) and vasoactive intestinal peptide (VIP) are multifunctional proteins that can regulate diverse physiological processes. These are also regarded as neurotrophic and anti-inflammatory substances in the CNS, and PACAP is reported to prevent harmful effects of oxidative stress. In the last decade more and more data accumulated on the similar function of PACAP in various tissues, but its cartilage- and bone-related presence and functions have not been widely investigated yet. In this summary we plan to verify the presence and function of PACAP and VIP signalling tool kit during cartilage differentiation and bone formation. We give evidence about the protective function of PACAP in cartilage regeneration with oxidative or mechanically stress and also with the modulation of PACAP signalling in vitro in osteogenic cells. Our observations imply the therapeutic perspective that PACAP might be applicable as a natural agent exerting protecting effect during joint inflammation and/or may promote cartilage regeneration during degenerative diseases of articular cartilage

Pituitary adenylyl cyclase activating polypeptide inhibits <it>gli1 </it>gene expression and proliferation in primary medulloblastoma derived tumorsphere cultures

<p>Abstract</p> <p>Background</p> <p>Hedgehog (HH) signaling is critical for the expansion of granule neuron precursors (GNPs) within the external granular layer (EGL) during cerebellar development. Aberrant HH signaling within GNPs is thought to give rise to medulloblastoma (MB) - the most commonly-observed form of malignant pediatric brain tumor. Evidence in both invertebrates and vertebrates indicates that cyclic AMP-dependent protein kinase A (PKA) antagonizes HH signalling. Receptors specific for the neuropeptide pituitary adenylyl cyclase activating polypeptide (PACAP, gene name ADCYAP1) are expressed in GNPs. PACAP has been shown to protect GNPs from apoptosis <it>in vitro</it>, and to interact with HH signaling to regulate GNP proliferation. PACAP/<it>ptch1 </it>double mutant mice exhibit an increased incidence of MB compared to <it>ptch1 </it>mice, indicating that PACAP may regulate HH pathway-mediated MB pathogenesis.</p> <p>Methods</p> <p>Primary MB tumorsphere cultures were prepared from thirteen <it>ptch1^+/-/p53^+/-</it>double mutant mice and treated with the smoothened (SMO) agonist purmorphamine, the SMO antagonist SANT-1, the neuropeptide PACAP, the PKA activator forskolin, and the PKA inhibitor H89. Gene expression of <it>gli1 </it>and [³H]-thymidine incorporation were assessed to determine drug effects on HH pathway activity and proliferation, respectively. PKA activity was determined in cell extracts by Western blotting using a phospho-PKA substrate antibody.</p> <p>Results</p> <p>Primary tumor cells cultured for 1-week under serum-free conditions grew as tumorspheres and were found to express PAC1 receptor transcripts. <it>Gli1 </it>gene expression was significantly reduced by SANT-1, PACAP and forskolin, but was unaffected by purmorphamine. The attenuation of <it>gli1 </it>gene expression by PACAP was reversed by the PKA inhibitor H89, which also blocked PKA activation. Treatment of tumorsphere cultures with PACAP, forskolin, and SANT-1 for 24 or 48 hours reduced proliferation.</p> <p>Conclusions</p> <p>Primary tumorspheres derived from <it>ptch1^+/-/p53^+/-</it>mice exhibit constitutive HH pathway activity. PACAP antagonizes HH signalling in these cells in a manner blocked by the PKA antagonist H89. PACAP and pharmacological activation of PKA also inhibited proliferation. Our data suggests that regulation of HH signaling by PACAP/PKA signaling may provide an alternative to SMO inhibition for the treatment of MB.</p

Which Strength Training?

Key Points \u2022 Resistance training is a key element in the treatment of obesity. \u2022 High-intensity resistance training should be used with caution; low-intensity resistance training should be preferred because of reduced mechanical stress on the joints. \u2022 In particular, low-intensity, low-velocity resistance training is well tolerated and appears to provide evidence-based benefits in the obese population. \u2022 The combination of low-intensity, low-velocity strength training with aerobic training and a supervised dietary plan lead to weight loss, improved function, postural control and independence in daily life activities. \u2022 Low-velocity resistance training modalities need to be investigated for the obese population

Cardiac parasympathetic reactivation following exercise: implications for training prescription

The objective of exercise training is to initiate desirable physiological adaptations that ultimately enhance physical work capacity. Optimal training prescription requires an individualized approach, with an appropriate balance of training stimulus and recovery and optimal periodization. Recovery from exercise involves integrated physiological responses. The cardiovascular system plays a fundamental role in facilitating many of these responses, including thermoregulation and delivery/removal of nutrients and waste products. As a marker of cardiovascular recovery, cardiac parasympathetic reactivation following a training session is highly individualized. It appears to parallel the acute/intermediate recovery of the thermoregulatory and vascular systems, as described by the supercompensation theory. The physiological mechanisms underlying cardiac parasympathetic reactivation are not completely understood. However, changes in cardiac autonomic activity may provide a proxy measure of the changes in autonomic input into organs and (by default) the blood flow requirements to restore homeostasis. Metaboreflex stimulation (e.g. muscle and blood acidosis) is likely a key determinant of parasympathetic reactivation in the short term (0–90 min post-exercise), whereas baroreflex stimulation (e.g. exercise-induced changes in plasma volume) probably mediates parasympathetic reactivation in the intermediate term (1–48 h post-exercise). Cardiac parasympathetic reactivation does not appear to coincide with the recovery of all physiological systems (e.g. energy stores or the neuromuscular system). However, this may reflect the limited data currently available on parasympathetic reactivation following strength/resistance-based exercise of variable intensity. In this review, we quantitatively analyse post-exercise cardiac parasympathetic reactivation in athletes and healthy individuals following aerobic exercise, with respect to exercise intensity and duration, and fitness/training status. Our results demonstrate that the time required for complete cardiac autonomic recovery after a single aerobic-based training session is up to 24 h following low-intensity exercise, 24–48 h following threshold-intensity exercise and at least 48 h following high-intensity exercise. Based on limited data, exercise duration is unlikely to be the greatest determinant of cardiac parasympathetic reactivation. Cardiac autonomic recovery occurs more rapidly in individuals with greater aerobic fitness. Our data lend support to the concept that in conjunction with daily training logs, data on cardiac parasympathetic activity are useful for individualizing training programmes. In the final sections of this review, we provide recommendations for structuring training microcycles with reference to cardiac parasympathetic recovery kinetics. Ultimately, coaches should structure training programmes tailored to the unique recovery kinetics of each individual