@article{SunBlecharzLangMałeckietal.2022, author = {Sun, Aili and Blecharz-Lang, Kinga G. and Małecki, Andrzej and Meybohm, Patrick and Nowacka-Chmielewska, Marta M. and Burek, Malgorzata}, title = {Role of microRNAs in the regulation of blood-brain barrier function in ischemic stroke and under hypoxic conditions in vitro}, series = {Frontiers in Drug Delivery}, volume = {2}, journal = {Frontiers in Drug Delivery}, issn = {2674-0850}, doi = {10.3389/fddev.2022.1027098}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-291423}, year = {2022}, abstract = {The blood-brain barrier (BBB) is a highly specialized structure that separates the brain from the blood and allows the exchange of molecules between these two compartments through selective channels. The breakdown of the BBB is implicated in the development of severe neurological diseases, especially stroke and traumatic brain injury. Oxygen-glucose deprivation is used to mimic stroke and traumatic brain injury in vitro. Pathways that trigger BBB dysfunction include an imbalance of oxidative stress, excitotoxicity, iron metabolism, cytokine release, cell injury, and cell death. MicroRNAs are small non-coding RNA molecules that regulate gene expression and are emerging as biomarkers for the diagnosis of central nervous system (CNS) injuries. In this review, the regulatory role of potential microRNA biomarkers and related therapeutic targets on the BBB is discussed. A thorough understanding of the potential role of various cellular and linker proteins, among others, in the BBB will open further therapeutic options for the treatment of neurological diseases.}, language = {en} } @article{ShityakovNagaiErguenetal.2022, author = {Shityakov, Sergey and Nagai, Michiaki and Erg{\"u}n, S{\"u}leyman and Braunger, Barbara M. and F{\"o}rster, Carola Y.}, title = {The protective effects of neurotrophins and microRNA in diabetic retinopathy, nephropathy and heart failure via regulating endothelial function}, series = {Biomolecules}, volume = {12}, journal = {Biomolecules}, number = {8}, issn = {2218-273X}, doi = {10.3390/biom12081113}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-285966}, year = {2022}, abstract = {Diabetes mellitus is a common disease affecting more than 537 million adults worldwide. The microvascular complications that occur during the course of the disease are widespread and affect a variety of organ systems in the body. Diabetic retinopathy is one of the most common long-term complications, which include, amongst others, endothelial dysfunction, and thus, alterations in the blood-retinal barrier (BRB). This particularly restrictive physiological barrier is important for maintaining the neuroretina as a privileged site in the body by controlling the inflow and outflow of fluid, nutrients, metabolic end products, ions, and proteins. In addition, people with diabetic retinopathy (DR) have been shown to be at increased risk for systemic vascular complications, including subclinical and clinical stroke, coronary heart disease, heart failure, and nephropathy. DR is, therefore, considered an independent predictor of heart failure. In the present review, the effects of diabetes on the retina, heart, and kidneys are described. In addition, a putative common microRNA signature in diabetic retinopathy, nephropathy, and heart failure is discussed, which may be used in the future as a biomarker to better monitor disease progression. Finally, the use of miRNA, targeted neurotrophin delivery, and nanoparticles as novel therapeutic strategies is highlighted.}, language = {en} } @phdthesis{Reinhold2016, author = {Reinhold, Ann-Kristin}, title = {New players in neuropathic pain? microRNA expression in dorsal root ganglia and differential transcriptional profiling in primary sensory neurons}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-140314}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2016}, abstract = {Neuropathic pain, caused by neuronal damage, is a severely impairing mostly chronic condition. Its underlying molecular mechanisms have not yet been thoroughly understood in their variety. In this doctoral thesis, I investigated the role of microRNAs (miRNAs) in a murine model of peripheral neuropathic pain. MiRNAs are small, non-coding RNAs known to play a crucial role in post-transcriptional gene regulation, mainly in cell proliferation and differentiation. Initially, expression patterns in affected dorsal root ganglia (DRG) at different time points after setting a peripheral nerve lesion were studied. DRG showed an increasingly differential expression pattern over the course of one week. Interestingly, a similar effect, albeit to a smaller extent, was observed in corresponding contralateral ganglia. Five miRNA (miR-124, miR-137, miR-183, miR-27b, and miR-505) were further analysed. qPCR, in situ hybridization, and bioinformatical analysis point towards a role for miR-137 and -183 in neuropathic pain as both were downregulated. Furthermore, miR-137 is shown to be specific for non-peptidergic non-myelinated nociceptors (C fibres) in DRG. As the ganglia consist of highly heterocellular tissue, I also developed a neuron-specific approach. Primarily damaged neurons were separated from intact adjacent neurons using fluorescence-activated cell-sorting and their gene expression pattern was analysed using a microarray. Thereby, not only were information obtained about mRNA expression in both groups but, by bioinformatical tools, also inferences on miRNA involvement. The general expression pattern was consistent with previous findings. Still, several genes were found differentially expressed that had not been described in this context before. Among these are corticoliberin or cation-regulating proteins like Otopetrin1. Bioinformatical data conformed, in part, to results from whole DRG, e.g. they implied a down-regulation of miR-124, -137, and -183. However, these results were not significant. In summary, I found that a) miRNA expression in DRG is influenced by nerve lesions typical of neuropathic pain and that b) these changes develop simultaneously to over-expression of galanin, a marker for neuronal damage. Furthermore, several miRNAs (miR-183, -137) exhibit distinct expression patterns in whole-DRG as well as in neuron-specific approaches. Therefore, further investigation of their possible role in initiation and maintenance of neuropathic pain seems promising. Finally, the differential expression of genes like Corticoliberin or Otopetrin 1, previously not described in neuropathic pain, has already resulted in follow-up projects.}, subject = {Schmerzforschung}, language = {en} } @article{ReinholdKrugSalvadoretal.2022, author = {Reinhold, Ann Kristin and Krug, Susanne M. and Salvador, Ellaine and Sauer, Reine S. and Karl-Sch{\"o}ller, Franziska and Malcangio, Marzia and Sommer, Claudia and Rittner, Heike L.}, title = {MicroRNA-21-5p functions via RECK/MMP9 as a proalgesic regulator of the blood nerve barrier in nerve injury}, series = {Annals of the New York Academy of Sciences}, volume = {1515}, journal = {Annals of the New York Academy of Sciences}, number = {1}, doi = {10.1111/nyas.14816}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-318226}, pages = {184 -- 195}, year = {2022}, abstract = {Both nerve injury and complex regional pain syndrome (CRPS) can result in chronic pain. In traumatic neuropathy, the blood nerve barrier (BNB) shielding the nerve is impaired—partly due to dysregulated microRNAs (miRNAs). Upregulation of microRNA-21-5p (miR-21) has previously been documented in neuropathic pain, predominantly due to its proinflammatory features. However, little is known about other functions. Here, we characterized miR-21 in neuropathic pain and its impact on the BNB in a human-murine back translational approach. MiR-21 expression was elevated in plasma of patients with CRPS as well as in nerves of mice after transient and persistent nerve injury. Mice presented with BNB leakage, as well as loss of claudin-1 in both injured and spared nerves. Moreover, the putative miR-21 target RECK was decreased and downstream Mmp9 upregulated, as was Tgfb. In vitro experiments in human epithelial cells confirmed a downregulation of CLDN1 by miR-21 mimics via inhibition of the RECK/MMP9 pathway but not TGFB. Perineurial miR-21 mimic application in mice elicited mechanical hypersensitivity, while local inhibition of miR-21 after nerve injury reversed it. In summary, the data support a novel role for miR-21, independent of prior inflammation, in elicitation of pain and impairment of the BNB via RECK/MMP9.}, language = {en} } @article{CurtazReifschlaegerStraehleetal.2022, author = {Curtaz, Carolin J. and Reifschl{\"a}ger, Leonie and Str{\"a}hle, Linus and Feldheim, Jonas and Feldheim, Julia J. and Schmitt, Constanze and Kiesel, Matthias and Herbert, Saskia-Laureen and W{\"o}ckel, Achim and Meybohm, Patrick and Burek, Malgorzata}, title = {Analysis of microRNAs in exosomes of breast cancer patients in search of molecular prognostic factors in brain metastases}, series = {International Journal of Molecular Sciences}, volume = {23}, journal = {International Journal of Molecular Sciences}, number = {7}, issn = {1422-0067}, doi = {10.3390/ijms23073683}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-284476}, year = {2022}, abstract = {Brain metastases are the most severe tumorous spread during breast cancer disease. They are associated with a limited quality of life and a very poor overall survival. A subtype of extracellular vesicles, exosomes, are sequestered by all kinds of cells, including tumor cells, and play a role in cell-cell communication. Exosomes contain, among others, microRNAs (miRs). Exosomes can be taken up by other cells in the body, and their active molecules can affect the cellular process in target cells. Tumor-secreted exosomes can affect the integrity of the blood-brain barrier (BBB) and have an impact on brain metastases forming. Serum samples from healthy donors, breast cancer patients with primary tumors, or with brain, bone, or visceral metastases were used to isolate exosomes and exosomal miRs. Exosomes expressed exosomal markers CD63 and CD9, and their amount did not vary significantly between groups, as shown by Western blot and ELISA. The selected 48 miRs were detected using real-time PCR. Area under the receiver-operating characteristic curve (AUC) was used to evaluate the diagnostic accuracy. We identified two miRs with the potential to serve as prognostic markers for brain metastases. Hsa-miR-576-3p was significantly upregulated, and hsa-miR-130a-3p was significantly downregulated in exosomes from breast cancer patients with cerebral metastases with AUC: 0.705 and 0.699, respectively. Furthermore, correlation of miR levels with tumor markers revealed that hsa-miR-340-5p levels were significantly correlated with the percentage of Ki67-positive tumor cells, while hsa-miR-342-3p levels were inversely correlated with tumor staging. Analysis of the expression levels of miRs in serum exosomes from breast cancer patients has the potential to identify new, non-invasive, blood-borne prognostic molecular markers to predict the potential for brain metastasis in breast cancer. Additional functional analyzes and careful validation of the identified markers are required before their potential future diagnostic use.}, language = {en} }