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In contrast to postmenopausal women, evidence for a favorable effect of exercise on Bone Mineral Density (BMD) is still limited for men. This might be due to the paucity of studies, but also to the great variety of participants and study characteristics that may dilute study results. The aim of the present systematic review and meta-analysis was to evaluate the effect of exercise on BMD changes with rational eligibility criteria. A comprehensive search of six electronic databases up to 15 March 2021 was conducted. Briefly, controlled trials ≥6 months that determined changes in areal BMD in men >18 years old, with no apparent diseases or pharmacological therapy that relevantly affect bone metabolism, were included. BMD changes (standardized mean differences: SMD) of the lumbar spine (LS) and femoral neck (FN) were considered as outcomes. Twelve studies with 16 exercise and 12 control groups were identified. The pooled estimate of random-effect analysis was SMD = 0.38, 95%-CI: 0.14–0.61 and SMD = 0.25, 95%-CI: 0.00–0.49, for LS and FN, respectively. Heterogeneity between the trials was low–moderate. Funnel plots and rank and regression correlation tests indicate evidence for small study publication bias for LS but not FN-BMD. Subgroup analyses that focus on study length, type of exercise and methodologic quality revealed no significant difference between each of the three categories. In summary, we provided further evidence for a low but significant effect of exercise on BMD in men. However, we are currently unable to give even rough exercise recommendations for male cohorts.
This review summarizes important information on the ectoenzyme tissue-nonspecific alkaline phosphatase (TNAP) and gives a brief insight into the symptoms, diagnostics, and treatment of the rare disease Hypophosphatasia (HPP), which is resulting from mutations in the TNAP encoding ALPL gene. We emphasize the role of TNAP beyond its well-known contribution to mineralization processes. Therefore, above all, the impact of the enzyme on central molecular processes in the nervous system and on inflammation is presented here.
Introduction: Abdominal aortic aneurysm (AAA) is a pathological saccular enlargement most often of the infrarenal aorta. Eventual rupture is fatal, making preemptive surgical therapy upon a diameter threshold of >50mm the treatment of choice. The pathophysiology, especially the initial trigger aortic remodeling is still largely unknown. However, some characteristic features involved in aneurysm growth have been established, such as medial angiogenesis, low-grade inflammation, vascular smooth muscle cell (VSMC) phenotype switch, extracellular remodeling, altered hemodynamics and an eventual humoral immune answer. Currently, no medical treatment options are available. RNA therapeutics and drug repurposing offer new possibilities to overcome this shortage. Using such to target angiogenesis in the aneurysm wall and investigate their potential mechanisms is the aim of this thesis. Material and Methods: We test our hypothesis by targeting the long non-coding RNA H19 and re-use the anti-cancer drug Lenvatinib in two murine inducible AAA models and one preclinical large animal model in the LDLR-/- pig. Furthermore, a H19-/- mouse is included to verify the results. AAA and control samples from a human biobank along with a primary human cell culture are used to verify results ex vivo by qPCR, WesternBlot, live cell imaging, histo- and immunohistochemistry along with gene array analysis, RNA knockdown, pull-down- and promotor assays. Results: H19 is significantly upregulated in AAA mice models and its knockdown limited aneurysm growth. It is well known that H19 interacts with several transcription factors. We found that cytoplasmic interaction between H19 and hypoxia-inducible factor 1-alpha (HIF1α) increased apoptosis in cultured SMCs associated with sequential p53 stabilization. In contrast, the knockdown of H19 was associated with markedly decreased apoptotic cell rates. Our data underline that HIF1α was essential in mediating the pro-apoptotic effects of H19. Secondly, Lenvatinib was applied both systemically and locally by endovascular means in mice with an established AAA. The drug significantly halted aneurysm growth and array analysis revealed myosin heavy chain 11 (MYH11) as the most differentially regulated target. This was shown to be up regulated after Lenvatinib treatment of primary AAA smooth muscle cells suggesting a salvage mechanism to obtain a contractile phenotype based on gene expression and immunohistochemistry. The same results were shown upon a local endovascular Lenvatinib-coated balloon angioplasty in the established aneurysmatic lesion of a novel atherosclerotic LDLR-/- Yucatan minipig model. Decreased phosphorylation of extracellular-signal regulated kinases 1-2 (ERK1-2) is the downstream effect of Lenvatinib-specific blockage of the vascular endothelial growth factor receptor (VEGFR2). Conclusion: Taking into account the heterogeneity of the disease, inhibition of VSMC phenotype switch, extracellular remodeling and angiogenesis seem promising targets in some if not all AAA patients. Together with surveillance and surgical therapy, these new non-invasive treatment strategies would allow for a more personalized approach to treat this disease.
Metabolic glycoengineering enables a directed modification of cell surfaces by introducing target molecules to surface proteins displaying new features. Biochemical pathways involving glycans differ in dependence on the cell type; therefore, this technique should be tailored for the best results. We characterized metabolic glycoengineering in telomerase-immortalized human mesenchymal stromal cells (hMSC-TERT) as a model for primary hMSC, to investigate its applicability in TERT-modified cell lines. The metabolic incorporation of N-azidoacetylmannosamine (Ac\(_4\)ManNAz) and N-alkyneacetylmannosamine (Ac\(_4\)ManNAl) into the glycocalyx as a first step in the glycoengineering process revealed no adverse effects on cell viability or gene expression, and the in vitro multipotency (osteogenic and adipogenic differentiation potential) was maintained under these adapted culture conditions. In the second step, glycoengineered cells were modified with fluorescent dyes using Cu-mediated click chemistry. In these analyses, the two mannose derivatives showed superior incorporation efficiencies compared to glucose and galactose isomers. In time-dependent experiments, the incorporation of Ac\(_4\)ManNAz was detectable for up to six days while Ac\(_4\)ManNAl-derived metabolites were absent after two days. Taken together, these findings demonstrate the successful metabolic glycoengineering of immortalized hMSC resulting in transient cell surface modifications, and thus present a useful model to address different scientific questions regarding glycosylation processes in skeletal precursors.