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Progressive loss of nigrostriatal dopamine (DA) neurons is the neuropathological hallmark of Parkinson's disease (PD). Symptoms of the disease can often be treated by DA D2 agonists and thus seem related to disinhibition of the indirect striatal pathway. However, there is no evidence that symptoms arise by low extracellular DA concentration or are associated with reduced D2 receptor binding. Here I provide a theoretical analysis of the pathophysiology and postsynaptic adaptation resulting from striatal DA denervation. I found that progressive denervation may alter DA signaling by three independent mechanisms depending on degree of denervation and macroscopic morphology of the lesion. As long as the remaining innervation stays anatomically coherent, denervation reduces phasic variations in extracellular DA, but the DA tone is not changed. The reduction of phasic signaling can be partially compensated by upregulating postsynaptic signaling cascades. However, changes in DA dynamics evade compensation. With 80-99% denervation, a persistent aberrant signal develops in D2-regulated pathways caused by random fluctuations in tonic DA release. Permanent low DA levels occur in regions completely void of innervation. Simulation of l-dopa therapy reduced the aberrant D2 signal. With a high degree of denervation, l-dopa enhanced another aberrant signal, this time in the D1 pathway. This analysis provides a quantitative, physiologically consistent view of the early and late stages of PD, the effect of main therapeutic medications, and potential side effects. The mechanisms described here may also provide an explanation to currently inexplicable pathological phenomena such as psycho stimulant-induced contraversive rotations in animal models.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6615501 | PMC |
http://dx.doi.org/10.1523/JNEUROSCI.1458-14.2014 | DOI Listing |
Biomed Rep
February 2025
School of Chemistry, Institute of Science, Suranaree University of Technology, Nakhon Ratchasima 30000, Thailand.
Cholangiocarcinoma (CCA) is an aggressive cancer of the bile duct epithelium. Anthocyanins are water-soluble flavonoids that contribute to the color of fruits and pigmented rice. Black rice bran is rich in anthocyanin pigments and exhibits certain health benefits, including anticancer activity; however, the effect of black rice bran-derived anthocyanins (BBR-M-10) on CCA progression remains unclear.
View Article and Find Full Text PDFChin Med J (Engl)
December 2024
Department of Organ Transplantation, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, China.
Nucleotide-binding oligomerization domain (NOD)-like receptor protein 3 (NLRP3) is a cytosolic pattern recognition receptor that recognizes multiple pathogen-associated molecular patterns and damage-associated molecular patterns. It is a cytoplasmic immune factor that responds to cellular stress signals, and it is usually activated after infection or inflammation, forming an NLRP3 inflammasome to protect the body. Aberrant NLRP3 inflammasome activation is reportedly associated with some inflammatory diseases and metabolic diseases.
View Article and Find Full Text PDFInt J Pharm
December 2024
School of Studies in Biotechnology, Pt. Ravishankar Shukla University, Raipur 492 010, India. Electronic address:
Wounds that represent one of the most critical complications can occur in individuals suffering from diabetes mellitus, and results in the need for hospitalisation and, in severe cases, require amputation. This condition is primarily characterized by infections, persistent inflammation, and delayed healing processes, which exacerbate the overall health of the patients. As per the standard mechanism, signalling pathways such as PI3K/AKT, HIF-1, TGF-β, Notch, Wnt/β-Cat, NF-κB, JAK/STAT, TLR, and Nrf2 play major roles in inflammatory, proliferative and remodelling phases of wound healing.
View Article and Find Full Text PDFJ Biol Chem
December 2024
Center for Mitochondrial Biomedicine and Department of Otolaryngology-Head and Neck Surgery, the Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu, Zhejiang, China; Institute of Genetics, Zhejiang University International School of Medicine, Hangzhou, Zhejiang, China; Center for Genetic Medicine, Zhejiang University International Institute of Medicine, Yiwu, Zhejiang, China; Joint Institute of Genetics and Genomic Medicine between Zhejiang University and University of Toronto, Hangzhou, Zhejiang, China. Electronic address:
Human mitochondrial 12S ribosomal RNA (rRNA) 1555A>G mutation has been associated with aminoglycoside-induced and nonsyndromic deafness in many families worldwide. Our previous investigation revealed that the m.1555A>G mutation impaired mitochondrial translation and oxidative phosphorylation (OXPHOS).
View Article and Find Full Text PDFCancer Cell Int
December 2024
Sezione di Farmacologia, Dipartimento di Medicina Interna, Università di Genova, Genova, Italy.
Background: Cellular prion protein (PrP) is a widely expressed membrane-anchored glycoprotein, which has been associated with the development and progression of several types of human malignancies, controlling cancer stem cell activity. However, the different molecular mechanisms regulated by PrP in normal and tumor cells have not been characterized yet.
Methods: To assess the role of PrP in patient-derived glioblastoma stem cell (GSC)-enriched cultures, we generated cell lines in which PrP was either overexpressed or down-regulated and investigated, in 2D and 3D cultures, its role in cell proliferation, migration, and invasion.
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