Endothelial dysfunction in pregnancy metabolic disorders

In recent years, the vascular endothelium has gained attention as a key player in the initiation and development of pregnancy disorders. Endothelium acts as an endocrine organ that preserves the homeostatic balance by responding to changes in metabolic status. However, in metabolic disorders, endothelial cells adopt a dysfunctional function, losing their normal responsiveness. During pregnancy, several metabolic changes occur, in which endothelial function decisively participates. Similarly, when pregnancy metabolic disorders occur, endothelial dysfunction plays a key role in pathogenesis. This review outlines the main findings regarding endothelial dysfunction in three main metabolic pathological conditions observed during pregnancy: gestational diabetes, hypertensive disorders, and obesity and hyperlipidemia. Organ, histological and cellular characteristics were thoroughly described. Also, we focused in discussing the underlying molecular mechanisms involved in the cellular signaling pathways that mediate responses in these pathological conditions

Roles of corrosion products of metal hip replacements in the etiology of adverse local tissue reactions

About two million people receive hip implants annually, to relieve the pain generated by osteoarthritis. Hip implants are composed of a titanium femoral stem and a Co-Cr-Mo head that articulates with a titanium-alloy acetabular cup, covered by a polyethylene liner (MoP). Other designs directly use a metal (Co-Cr-Mo) acetabular articulating surface (MoM). Concerns have arisen due to the elevated numbers of adverse local tissue reactions (ALTRs) to hip implants that generate pain and soft-tissue destruction. Due to the high rates of ALTRs in MoM implants, the corrosion products or wear particles from the metal surfaces are thought to trigger the immunological reactions. This thesis aimed to understand the mechanisms of ALTRs development through three studies: 1) histological analyses and comparison of ALTRs in MoM and MoP implants. 2) analysis of corrosion products in synovial fluid and tissues. 3) mechanistic study based on gene expression analysis of ALTRs, and cell culture of primary synovial fibroblasts that were exposed to Cr and Co. The histological description of ALTRs showed structural similarities between MoM and MoP, with common elements such as tissue necrosis and the presence of perivascular lymphocyte aggregates. Significantly higher levels of metal ions were found in the synovial fluid of ALTR patients, but no differences in the particles present in tissues were found in ALTRs compared to non-ALTRs. The gene expression analysis of lymphocytes aggregates found an identical and non-specific Th1/Th2 reaction in ALTRs in both MoM and MoP, with no evidence of Th17 reaction. Finally, primary synovial fibroblasts responded to concentrations of metal ions observed in the synovial fluid of patients, by releasing pro-inflammatory cytokines. After 24 hours of exposure the secreted cytokines were demonstrated to be chemotactic for human monocytes which is a key processes during inflammation. These results support the hypothesis that metal ions from the hip implants trigger cytokine secretion by synovial fibroblasts, which initiate the immune reaction to hip replacements, providing evidence to reject the hypothesis of hypersensitivity as an etiologic factor of ALTRs.Applied Science, Faculty ofBiomedical Engineering, School ofGraduat

Inelastic Deformation and Microcracking Process in Human Dentin

Dentin is a mineralized collagen tissue with robust mechanical performance. Understanding the mechanical behaviour of dentin and its relations to the dentinal structure can provide insight into the design strategies to achieve tooth functions. This study focuses on the inelastic deformation of human dentin and its underlying mechanisms. By combining four-point bending tests with fluorescent staining and laser scanning confocal microscopy, it was found that human dentin, especially root dentin, exhibited significant inelastic deformation and developed extensive microdamage in the form of microcracks prior to fracture. Similar to bone, dense and wavy microcracks spread uniformly across the tensile surface of root dentin, while compressive microcracks formed cross-hatched patterns. The presence of peritubular dentin in coronal dentin dramatically decreased the extent of microcracking, reducing inelasticity. Dentinal tubules were found to be initiation sites of both tensile and compressive microcracks. A unique crack propagation process was observed in root dentin under tension: numerous ring-shaped cracks formed at each dentinal tubule ahead of a growing crack tip. The advance of the tensile microcrack occured by the merging of those ring-shaped cracks. The current findings on the microcracking process associated with inelastic deformation helps to understand the nature of strength and toughness in dentin, as well as the mechanical significance for structural variations across the whole tooth.Applied Science, Faculty ofOther UBCNon UBCMaterials Engineering, Department ofReviewedFacultyGraduat

Expression Suppression and Activity Inhibition of TRPM7 Regulate Cytokine Production and Multiple Organ Dysfunction Syndrome During Endotoxemia: A New Target for Sepsis

Background: Main pathological features detected during sepsis and endotoxemia include over-secretion of pro-inflammatory cytokines and multiorgan dysfunction syndrome (MODS). Unfortunately, current clinical efforts to treat sepsis are unsatisfactory, and mortality remains high. Interestingly, transient receptor potential (TRP) melastatin 7 (TRPM7) ion channel controlling Ca2+ and Mg2+ permeability is involved in cytokine production and inflammatory response. Furthermore, TRPM7 downregulation has been shown to alleviate local symptoms in some models of sepsis, but its effects at a systemic level remain to be explored. Objective: To test whether TRPM7 mediates cytokine production and MODS during endotoxemia. Methods: Endotoxemic and sham-endotoxemic rats were subjected to pharmacological inhibition of TRPM7 using carvacrol, or to expression suppression by adenovirus delivery of shRNA (AdV(shTRPM7)). Then, cytokine and MODS levels in the blood were measured. Results: Inhibition of TRPM7 with carvacrol and suppression with AdV(shTRPM7 )were both efficient in inhibiting the over-secretion of pro-inflammatory cytokines TNF-alpha, IL-1 beta, IL-6, and IL-12 in endotoxemic rats, without inducing downregulation in blood levels of anti-inflammatory cytokines IL-10 and IL-4. Additionally, the use of carvacrol and AdV(shTRPM7) significantly prevented liver and pancreas dysfunction, altered metabolic function, and hypoglycemia, induced by endotoxemia. Furthermore, muscle mass wasting and cardiac muscle damage were also significantly reduced by the use of carvacrol and AdV(shTRPM7) in endotoxemic rats. Conclusion: Our results indicate TRPM7 ion channel as a key protein regulating inflammatory responses and MODS during sepsis. Moreover, TRPM7 appears as a novel molecular target for the management of sepsis