Faculty Bibliography

Although degenerative disc disease (DDD) and related low back pain (LBP) are growing public health problems, the underlying disease mechanisms remain unclear. An increase in the vascular endothelial growth factor (VEGF) levels in DDD has been reported. This study aimed to examine the role of VEGF receptors (VEGFRs) in DDD, using a mouse model of DDD. Progressive DDD was induced by anterior stabbing of lumbar intervertebral discs in wild type (WT) and VEGFR-1 tyrosine-kinase deficient mice (vegfr-1^TK-/- ). Pain assessments were performed weekly for 12 weeks. Histological and immunohistochemical assessments were made for discs, dorsal root ganglions, and spinal cord. Both vegfr-1^TK-/- and WT mice presented with similar pathological changes in discs with an increased expression of inflammatory cytokines and matrix-degrading enzymes. Despite the similar pathological patterns, vegfr-1^TK-/- mice showed insensitivity to pain compared with WT mice. This insensitivity to discogenic pain was related to lower levels of pain factors in the discs and peripheral sensory neurons and lower spinal glial activation in the vegfr-1^TK- /^- mice than in the WT mice. Exogenous stimulation of bovine disc cells with VEGF increased inflammatory and cartilage degrading enzyme. Silencing vegfr-1 by small-interfering-RNA decreased VEGF-induced expression of pain markers, while silencing vegfr-2 decreased VEGF-induced expression of inflammatory and metabolic markers without changing pain markers. This suggests the involvement of VEGFR-1 signaling specifically in pain transmission. Collectively, our results indicate that the VEGF signaling is involved in DDD. Particularly, VEGFR-1 is critical for discogenic LBP transmission independent of the degree of disc pathology.

Since the identification of succinate's receptor in 2004, studies supporting the involvement of succinate signaling through its receptor in various diseases have accumulated and most of these investigations have highlighted succinate's pro-inflammatory role. Taken with the fact that succinate is an intermediate metabolite in the center of mitochondrial activity, and considering its potential regulation of protein succinylation through succinyl-coenzyme A, a review on the overall multifaceted actions of succinate to discuss whether and how these actions relate to the cellular locations of succinate is much warranted. Mechanistically, it is important to consider the sources of succinate, which include somatic cellular released succinate and those produced by the microbiome, especially the gut microbiota, which is an equivalent, if not greater contributor of succinate levels in the body. Continue learning the critical roles of succinate signaling, known and unknown, in many pathophysiological conditions is important. Furthermore, studies to delineate the regulation of succinate levels and to determine how succinate elicits various types of signaling in a temporal and spatial manner are also required.

The trend of e-cigarette use among teens is ever increasing. Here we show the dysbiotic oral microbial ecology in e-cigarette users influencing the local host immune environment compared with non-smoker controls and cigarette smokers. Using 16S rRNA high-throughput sequencing, we evaluated 119 human participants, 40 in each of the three cohorts, and found significantly altered beta-diversity in e-cigarette users (p = 0.006) when compared with never smokers or tobacco cigarette smokers. The abundance of Porphyromonas and Veillonella (p = 0.008) was higher among vapers. Interleukin (IL)-6 and IL-1β were highly elevated in e-cigarette users when compared with non-users. Epithelial cell-exposed e-cigarette aerosols were more susceptible for infection. In vitro infection model of premalignant Leuk-1 and malignant cell lines exposed to e-cigarette aerosol and challenged by Porphyromonas gingivalis and Fusobacterium nucleatum resulted in elevated inflammatory response. Our findings for the first time demonstrate that e-cigarette users are more prone to infection.

Type 1 diabetes mellitus (T1DM) is an autoimmune disease characterized by insulin deficiency, and patients with diabetes have an increased risk of bone fracture and significantly impaired fracture healing. Proinflammatory cytokine tumor necrosis factor-alpha is significantly upregulated in diabetic fractures and is believed to underlie delayed fracture healing commonly observed in diabetes. Our previous genetic screen for the binding partners of progranulin (PGRN), a growth factor-like molecule that induces chondrogenesis, led to the identification of tumor necrosis factor receptors (TNFRs) as the PGRN-binding receptors. In this study, we employed several in vivo models to ascertain whether PGRN has therapeutic effects in diabetic fracture healing. Here, we report that deletion of PGRN significantly delayed bone fracture healing and aggravated inflammation in the fracture models of mice with T1DM. In contrast, recombinant PGRN effectively promoted diabetic fracture healing by inhibiting inflammation and enhancing chondrogenesis. In addition, both TNFR1 proinflammatory and TNFR2 anti-inflammatory signaling pathways are involved in PGRN-stimulated diabetic fracture healing. Collectively, these findings illuminate a novel understanding concerning the role of PGRN in diabetic fracture healing and may have an application in the development of novel therapeutic intervention strategies for diabetic and other types of impaired fracture healing.

Introduction/UNASSIGNED:standardized hydro alcoholic extract in vitro cytoprotective activity data on epithelial and osteoblastic cells exposed to zoledronic acid (ZA). Methods/UNASSIGNED:extract for 24h and 48 h. At both times, cells were submitted to viability assay and caspase 3/7 activation evaluation. Statistical analysis used one-way ANOVA and p=0.05. Results/UNASSIGNED:extract, cells showed higher viability values: 74.1%-82.3% for fibroblasts and 66% for pre-osteoblasts. Furthermore, the combined treatment presented lower caspase 3/7 activation in fibroblasts and pre-osteoblasts. Conclusion/UNASSIGNED:extract showed promising cytoprotective effects against ZA-induced damage actions; however, further in vitro and in vivo studies are required to establish the mechanism of action.

Bacterial dysbiosis accompanies carcinogenesis in malignancies such as colon and liver cancer, and has recently been implicated in the pathogenesis of pancreatic ductal adenocarcinoma (PDA)¹. However, the mycobiome has not been clearly implicated in tumorigenesis. Here we show that fungi migrate from the gut lumen to the pancreas, and that this is implicated in the pathogenesis of PDA. PDA tumours in humans and mouse models of this cancer displayed an increase in fungi of about 3,000-fold compared to normal pancreatic tissue. The composition of the mycobiome of PDA tumours was distinct from that of the gut or normal pancreas on the basis of alpha- and beta-diversity indices. Specifically, the fungal community that infiltrated PDA tumours was markedly enriched for Malassezia spp. in both mice and humans. Ablation of the mycobiome was protective against tumour growth in slowly progressive and invasive models of PDA, and repopulation with a Malassezia species-but not species in the genera Candida, Saccharomyces or Aspergillus-accelerated oncogenesis. We also discovered that ligation of mannose-binding lectin (MBL), which binds to glycans of the fungal wall to activate the complement cascade, was required for oncogenic progression, whereas deletion of MBL or C3 in the extratumoral compartment-or knockdown of C3aR in tumour cells-were both protective against tumour growth. In addition, reprogramming of the mycobiome did not alter the progression of PDA in Mbl- (also known as Mbl2) or C3-deficient mice. Collectively, our work shows that pathogenic fungi promote PDA by driving the complement cascade through the activation of MBL.

High circulating insulin-like growth factor-1 (IGF-1) levels increase the risk of prostate cancer. However, whether circulating IGF-1 levels directly aggravate prostate cancer remains elusive. In this study, we crossed a transgenic prostate adenocarcinoma mouse model, Hi-Myc mice, with a liver-specific IGF-1 transgenic mouse model (HIT) to increase their circulating IGF-1 levels to investigate the impact of the elevated circulating IGF-1 on prostate cancer development in vivo. The Hi-Myc/HIT mice had increased incidence and invasiveness of prostate cancer. IGF-1 elevation led to the accumulation of FOXO3A in the cytosol of prostate tumor cells and downregulation of its target gene Bim, which resulted in the apoptosis inhibition and prostate cancer overgrowth. The differential expressions of IGF-1R, FOXO3A, and BIM in the benign versus malignant prostate tissues supported a negative association between the FOXO3A/BIM axis and IGF-1R expression in human prostate adenocarcinoma. Our findings suggest that targeting the IGF-1/FOXO3A/BIM signaling axis could be an attractive strategy for prostate cancer prevention or treatment.

Background: Acute exercise can increase motor cortical excitability and enhance motor learning in healthy individuals, an effect known as exercise priming. Whether it has the same effects in people with stroke is unclear. Objectives: The objective of this study was to investigate whether a short, clinically-feasible high-intensity exercise protocol can increase motor cortical excitability in non-exercised muscles of chronic stroke survivors. Methods: Thirteen participants with chronic, unilateral stroke participated in two sessions, at least one week apart, in a crossover design. In each session, they underwent either high-intensity lower extremity exercise or quiet rest. Motor cortical excitability of the extensor carpi radialis muscles was measured bilaterally with transcranial magnetic stimulation before and immediately after either exercise or rest. Motor cortical excitability changes (post-exercise or rest measures normalized to pre-test measures) were compared between exercise vs. rest conditions. Results: All participants were able to reach the target high-intensity exercise level. Blood lactate levels increased significantly after exercise (p < .001, d = 2.85). Resting motor evoked potentials from the lesioned hemisphere increased after exercise (mean 1.66; 95% CI: 1.19, 2.13) compared to the rest condition (mean 1.23; 95% CI: 0.64, 1.82), p = .046, d = 2.76, but this was not the case for the non-lesioned hemisphere (p = .406, d = 0.25). Conclusions: High-intensity exercise can increase lesioned hemisphere motor cortical excitability in a non-exercised muscle post-stroke. Our short and clinically-advantageous exercise protocol shows promise as a potential priming method in stroke rehabilitation.

Astragalus Polysaccharide (APS) is the main component of Astragalus membranaceus, an anti-diabetic herb being used for thousands of years in Chinese Traditional Medicine (TCM). In this study, we aimed to evaluate the impact of APS on hepatic insulin signaling, autophagy and ER stress response in high-fat-diet (HFD)-induced insulin resistance (IR) mice. APS was intra gastrically administrated and metformin was used as a control medicine. Apart from monitoring the changes in the important parameters of IR progression, the gene and protein expression of the key factors marking the state of hepatic ER stress and autophagic flux was examined. We found that, largely comparable to the metformin regime, APS treatment resulted in an overall improvement of IR, as indicated by better control of body weight and blood glucose/lipid levels, recovery of liver functions, and regained insulin sensitivity. In particular, the excessive and pro-apoptotic ER stress response and inhibition of autophagy, as a result of prolonged HFD exposure, were significantly corrected by APS administration, indicating a switch of the cellular fate in favor of cell survival. Using the HepG2/IR cell model, we demonstrated that APS modulated the insulin-initiated phosphorylation cascades in a similar manner as metformin. This study provides a rationale for exploiting the insulin-sensitizing potential of APS, which has a therapeutic performance almost equivalent to metformin, to enrich our options in the treatment of IR.