Propofol produces preventive analgesia via GluN2B-containing NMDA Receptor/ERK1/2 Signaling Pathway in the rat model of Inflammatory Pain

Compared to other anesthetics, propofol has showed superior analgesic effect used during surgical procedures on acute post-surgical pain. Whether propofol has preventive analgesic property remain debated. The present study investigated the antinociceptive effect of propofol and underlying molecular and cellular mechanisms via pre-emptive administration in a formalin-induced inflammatory pain model in rats. Male adult Sprague-Dawley rats were randomly allocated into 4 groups: naïve (Group Naïve), formalin injection only (Group Formalin), and formalin injection at 30 min (Group P-30min) or 2 h (Group P-2h) after intravenous infusion of propofol (0.6 mg kg-1 min-1) for 1 h. Nociceptive responses were evaluated by composite pain score-weighted scores. Protein expression of phosphorylated- or pan-GluN2B, ERK1/2, p38 MAPK and JNK in the spinal dorsal horn was assessed by Western blot. Alteration of intracellular Ca2+ concentration induced by NMDA receptor agonists with or without pre-treatment of propofol was measured using fluorometry in SH-SY5Y cells. Neuronal activation was assessed by immunofluorescence. Pre-emptive propofol reduced pain with a delayed response to formalin and a reduction in hypersensitivity that lasted at least for 2 h. The formalin-induced activation of spinal GluN2B and ERK1/2 but not p38 or JNK were also diminished by propofol treatment. Preconditioning treatment with 3 µM and 10 µM of propofol inhibited Ca2+ influx mediated through NMDA receptors in SH-SY5Y cells. Propofol also reduced the neuronal expression of c-Fos and p-ERK induced by formalin. These findings indicate that pre-emptive administration of propofol produces preventive analgesic effects on inflammatory pain through regulating neuronal GluN2B-containing NMDA receptor and ERK1/2 pathway in the spinal dorsal horn.published_or_final_versio

PAK4 signaling in development and cancer

Our understanding of cancer biology has been evolving rapidly shaped by groundbreaking discoveries. We now understand that cancer is not one disease but many, and that tumors are not foreign objects in the human body but rather the result of changes in the previously normal tissues and organs. Thus, in order to ask fundamental questions and dissect the complexity of cancer it is essential to grasp how the healthy organs develop and function and the cellular and molecular mechanisms involved. The serine/threonine PAKs are signaling hubs with proven roles in development and disease. Specifically, they are important to several hallmarks of cancer. Thus, the family in general, and PAK4 in particular, is increasingly attracting the interest of the scientific community. In this thesis I have explored the role of PAK4 in normal organ development and cancer. Novel mouse models with PAK4 depletion in the mammary gland and in the pancreas have been established and characterized in Paper I and Paper II. The absence of major tissue abnormalities upon PAK4 depletion in the mammary epithelium allowed me to use this model to study the role of PAK4 in tumorigenesis in vivo, in Paper III, and a counterpart mouse model with PAK4 overexpression in the mammary epithelium was also generated. These complementary in vivo setups showed that PAK4-overexpressing mammary glands occasionally developed mammary tumors while PAK4 abrogation impaired PyMT-driven mammary tumorigenesis. Extensive in vitro experiments, using state of the art techniques, then supported a model in which PAK4 confers selective advantages to cancer cells by overcoming the senescence barrier. This, in turn, constitutes a selective vulnerability of cancer cells that become susceptible to a senescence-like response upon PAK4 inhibition. The data presented also demonstrates a crosstalk between PAK4 and NF-κB signaling, and a direct interaction and phosphorylation site within the REL-homology domain of RELB is found to be relevant for tuning RELB-mediated transcription and cancer cell proliferation via C/EBPβ. Importantly, these findings were largely supported by correlations in clinical data and validated ex vivo in patient-derived cells, thus highlighting PAK4 as an attractive therapeutic opportunity in cancer. Therefore, this thesis contributes to a better understanding of the mechanisms that govern breast tumorigenesis, with hopes that such knowledge will prove relevant in cancer prognosis and treatment

Adiponectin Potentially Contributes to the Antidepressive Effects of Baduanjin Qigong Exercise in Women With Chronic Fatigue Syndrome-Like Illness

Our recent study demonstrates that adiponectin signaling plays a significant role in mediating physical exercise-exerted effects on hippocampal neurogenesis and antidepression in mice. Whether the findings can be translated to humans remains unknown. This study aimed to investigate the effects of Baduanjin Qigong exercise on adiponectin and to evaluate whether adiponectin is involved in the antidepressive effects of Qigong exercise on chronic fatigue syndrome (CFS)-like illness. This is a randomized, waitlist-controlled trial. One hundred eight female participants were randomly assigned to either Qigong exercise or waitlist groups. Sixteen 1.5-h Qigong lessons were conducted. Outcome measures were taken at three time points. Baseline adiponectin levels were negatively associated with body weight, body mass index, waist circumference, hip circumference, and waist/hip ratio in women with CFS-like illness. Compared with the waitlist control, Qigong exercise significantly reduced anxiety and depression symptoms and significantly raised plasma adiponectin levels (median = 0.8 vs. −0.1, p < 0.05). More interestingly, increases in adiponectin levels following Qigong exercise were associated with decreases in depression scores for the Qigong group (r = −0.38, p = 0.04). Moreover, adjusted linear regression analysis further identified Qigong exercise and change in adiponectin levels as the significant factors accounting for reduction of depression symptoms. Baduanjin Qigong significantly increased adiponectin levels in females with CFS-like illness. Decreases in depression symptoms were associated with increases in adiponectin levels following Qigong exercise, indicating that the potential contribution of adiponectin to Qigong exercise elicited antidepressive effects in human subjects