Nanoparticles are useful for increasing drug stability, solubility, and availability. The small molecule baicalein inhibits fibrillation, and detoxifies aggregates of α‐synuclein (αSN) associated with Parkinson's disease (PD), but it suffers from instability, low solubility and consequent low availability. Here it is demonstrated that incorporation of baicalein into zwitterionic nanoliposomes (NLP‐Ba) addresses these problems. NLP‐Ba inhibits αSN fibril initiation, elongation, secondary nucleation, and also depolymerizes mature fibrils more effectively than free baicalein and prevents soluble αSN aggregates from seeding new fibrils. Importantly, NLP‐Ba perturbs oligomers’ capacity to permeabilize the membrane. The interaction between NLP‐Ba and αSN is confirmed by different biophysical techniques. This nanosystem crosses the blood‐brain barrier in vitro and is effective against rotenone neurotoxicity in vivo. The effect of NLP‐Ba on αSN fibrillation/cytotoxicity is attributed to a combination of free baicalein and empty NLPs. The results indicate a neuroprotective role for NLP‐Ba in decreasing αSN pathogenicity in PD and highlight the use of nanoliposomes to mobilize poorly soluble hydrophobic drugs.
GSK-3β is a key molecule in several signalling pathways, including the Wnt/β-catenin signalling pathway. There is increasing evidence suggesting Wnt/β-catenin signalling is involved in the neural differentiation of embryonic, somatic and neural stem cells. However, a large body of evidence indicates that this pathway maintains stem cells in a proliferative state. To address this controversy, we have investigated whether the Wnt/β-catenin pathway is present and involved in the neural differentiation of newly introduced USSCs (unrestricted somatic stem cells). Our results indicate that the components of Wnt/β-catenin signalling are present in undifferentiated USSCs. We also show that the treatment of neurally induced USSCs with BIO (6-bromoindirubin-3'-oxime), a specific GSK-3β inhibitor and Wnt activator, for 5 and 10 days results in increased expression of a general neuronal marker (β-tubulin III). Moreover, the expression of pGSK-3β and stabilized β-catenin increased by BIO in neurally induced USSCs, indicates that the Wnt pathway is activated and functional in these cells. Thus, inhibition of GSK-3β in USSCs enhances their neural differentiation, which suggests a positive role of the Wnt/β-catenin signalling pathway towards neural fate.
In recent years, extensive studies have been performed to enhance stem cell-based therapies for bone and cartilage repair. Among various sources of stem cells, cord blood-derived unrestricted somatic stem cells (USSCs) seem to be the most appropriate option for an autologous transplantation. Among different signaling pathways, the transforming growth factor-β (TGF-β) pathway is shown as an important regulator of proliferation and osteogenic differentiation in osteoblast progenitors as well as mesenchymal stem cells. Due to its contradictory and temporally variable effects on different cell types, we sought to investigate whether and how the TGF-β signaling pathway regulates the osteogenic differentiation of the USSCs. Therefore, in the current study, we treated USSCs with the recombinant protein TGF-β1 (1 ng/mL) and showed that the expression of matrix metalloproteinase 9, a well-known effector in this pathway, was significantly induced, indicating that the TGF-β signaling pathway is active in USSCs. Then we applied a TGF-β receptor antagonist (SB431542; 10 μM) to the osteogenic media cultured USSCs for single periods of 3.5 days within the 21-day differentiation period starting at day 0, 3.5, 7, 10.5, 14, and 17.5. The expression analysis results of the of the osteogenic marker runt-related transcription factor 2 as well as the production of bone matrix showed that SB431542 induced the osteogenic differentiation of USSCs more significantly during the early stage of differentiation, suggesting that the TGF-β pathway temporally regulates the osteogenic differentiation of USSCs.
Lithium chloride (LiCl) is a drug used to treat bipolar disorder, but has side effects in the female reproductive system. Although lithium is known to decrease folliculogenesis and induce follicular atresia in rodent ovaries, its cellular and molecular effects in the ovary have not yet been addressed. To investigate these effects, 23-day-old immature female rats were injected with 10 IU pregnant mare serum gonadotropin (PMSG), followed by injections of 250 mg/kg LiCl every 12 hr for four doses. Ovaries were removed 40 and 48 hr after PMSG administration and prepared for histology, immunohistochemistry, Western blotting, and DNA laddering analysis. Our results showed that in the ovaries of LiCl-treated rats, few antral but more atretic follicles were present compared to those of the control rats. The induction of atresia by LiCl was further confirmed by the presence of DNA fragmentation, accompanied by a reduced level of 17β-estradiol in the serum. At the cellular level, lithium significantly decreased the number of proliferating cell nuclear antigen (PCNA)-positive cells and conversely increased the number of TUNEL-positive cells in the granulosa layer of the antral follicles. At the molecular level, lithium increased the level of phosphorylated glycogen synthase kinase-3β, and unexpectedly decreased the expression of active (stabilized) β-catenin. Altogether, our results indicate that lithium disrupts the balance between proliferation and apoptosis in granulosa cells, leading to follicular atresia possibly through the reduction in both the stabilized β-catenin and 17β-estradiol synthesis.
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