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TGF-beta is a therapeutic target for renal fibrosis. Scientists have long sought ways to antagonize TGF-beta to ameliorate diabetic nephropathy. Bone morphogenetic protein (BMP-2) is a member of the TGF-beta superfamily and is highly regulated in the kidney. Thus, the role of BMP-2 was investigated in NRK-49F cells (rat fibroblasts). We showed that TGF-beta1 induces an increase in fibronectin. Treatment with exogenous BMP-2 or pCMV-BMP-2 significantly reversed the TGF-beta1-induced increase in fibronectin concomitant with a significant decrease in type I TGF-beta receptors (TGF-beta RI). Moreover, BMP-2 significantly shortened the half-life of TGF-beta RI. These results are related to proteosomal activation because MG132, a proteasome inhibitor, abolished BMP-2-mediated degradation of TGF-beta RI. This was confirmed because BMP-2 time course dependently enhanced the ubiquitination level of TGF-beta RI. In addition, Smads would seem to be involved in the interaction of BMP-2 and TGF-beta. We demonstrated that BMP-2 significantly reversed the TGF-beta1-induced increase in pSmad2/3 and reversed the TGF-beta1-induced decrease in inhibitory Smad7. Most importantly, Smad7 small interfering RNA abolished the BMP-2-induced decrease in TGF-beta RI. We evaluated the clinical efficacy of BMP-2 using unilateral ureteral obstruction rats. BMP-2 was administered ip for 7 d. In the unilateral ureteral obstruction kidneys, interstitial fibrosis was prominent. However, treatment with BMP-2 dramatically reduced Masson's trichrome staining (collagen) in the interstitial and tubular areas of the kidneys concomitantly with a reduction in TGF-beta RI. These results suggest that BMP-2 acts as a novel fibrosis antagonizing cytokine partly by down-regulating TGF-beta RI and Smads.

Metal-organic frameworks (MOFs), as drug delivery carriers, with high loading capacity and controllable release behavior can provide a more efficacious therapy in cancer treatments. In our work, a novel biocompatible zinc MOF Zn-cpon-1 with the (3,6)-connected rtl 3D topological network was designed and synthesized via employing ClO anion as template. The optically and chemically stable Zn-cpon-1 could be verified as a pH-responsive dual-emission platform and excellent drug delivery carrier with higher 5-fluorouracil (5-FU) (44.75 wt %) loading behavior than 6-mercaptopurine (6-MP) (4.79 wt %) ascribed to the influence of size and shape matching. The multiple interactions between Zn-cpon-1 and 5-FU drug molecules have been discussed and evidenced, which could be quantitatively estimated via the rate constant related to the topological structure. Specially, the gust release behavior of 5-FU@Zn-cpon-1 microcrystal was described and programmed via the Weibull distribution model and could be dual-triggered by the temperature and pH stimulus. This study illustrates that the Zn-cpon-1 without any postmodification performs a favorable potential of being used as biomedical drug delivery alternative carriers in effective drug payload, flexible release administration, and superior dual-stimuli responsiveness.

Mitochondrial dysfunction has been implicated in the pathogenesis of Parkinson’s disease (PD) for several decades, and disturbed mitochondrial biogenesis (mitobiogenesis) was recently found to be a common phenomenon in PD. Baicalein, a major bioactive flavone of Scutellaria baicalensis Georgi, exerted neuroprotective effects in several experimental PD models. However, the effects of baicalein in rotenone-induced PD rats and the possible mechanisms remain poorly understood. In this study, we evaluated the therapeutic effects of baicalein and explored its mechanism of action in rotenone-induced PD models. The results indicated that behavioural impairments and the depletion of dopaminergic neurons induced by rotenone were attenuated by baicalein. Furthermore, in rotenone-induced parkinsonian rats, baicalein treatment effectively restored mitochondrial function and improved mitobiogenesis, as determined by measuring the mitochondrial density and key regulators involved in mitobiogenesis. Additionally, we confirmed that baicalein enhanced mitobiogenesis through the cAMP-responsive element binding protein (CREB) and glycogen synthase kinase-3β (GSK-3β) pathways in rotenone-treated SH-SY5Y cells. Moreover, we demonstrated that the cytoprotective effects of baicalein could be attenuated by the mitobiogenesis inhibitor chloramphenicol as well as CREB siRNA transfection. Overall, our results suggested that baicalein partially enhanced mitobiogenesis to restore mitochondrial function, thus exerting therapeutic effects in rotenone-induced PD models.

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Dysregulation of epithelial-to-mesenchymal transition (EMT) may contribute to renal fibrogenesis. Our previous study indicated that bone morphogenetic protein-2 (BMP-2) significantly reversed transforming growth factor (TGF)-β1-induced renal interstitial fibrosis. In this study, we examined the underlying mechanism and elucidate the regulation of EMT process under BMP-2 treatment. Cultured renal interstitial fibroblast (NRK-49F) was treated with TGF-β1 (10 ng/ml) with or without BMP-2 (10-250 ng/ml) for 24 h. The expression of α-smooth muscle actin (α-SMA), E-cadherin, fibronectin, or Snail transcriptional factors was analyzed by immunofluorescence staining or Western blotting. Cell migration was analyzed by wound-healing assay. NRK-49F treated with TGF-β1 induced significant EMT including upregulatioin of α-SMA, fibronectin, and snail proteins and down-regulation of E-cadherin. Interestingly, co-treatment with BMP-2 dose-dependently reversed TGF-β1-induced cellular fibrosis, cell migration, and above EMT change. The above effect was closely correlated with Snail since BMP-2 dose- and time-course dependently induced a significant decrease in the level of Snail. Moreover, Snail siRNA significantly reversed TGF-β1-induced increases in the level of α-SMA and fibronectin (intracellular and extracellular). We suppose that BMP-2 have the potential to attenuate TGF-β1-induced renal interstitial fibrosis by attenuating Snail expression and reversing EMT process.