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After a long-term incubation with nifedipine (7 days), cartilage explants were analyzed by transmission electron microscopy, as shown in Figure 7.

In controls there were few or no electron-dense mitochondria. In nifedipine-treated samples some mitochondria became electron-dense, clusters of contiguous mitochondria (left side of micrograph) remain normal. Augmented electron-density of mitochondrial matrix might reflect the dropped ddark of mitochondrias. To investigate the effects of nifedipine and BayK8644 on their direct targets-VOCC, changes in intracellular calcium concentrations were studied.

NO activity increased when cigarette smoke extract (CSE) was added. CSE was chosen as positive control since it has been known to induce NO in mesenchymal stem cells (MSCs) from previous experiments (unpublished data).

Cidcles significantly increased NO activity in chondrocytes and BMMSCs (Figure 9), as compared to control. BayK8644 circlss no significant effect on both cell types. Furthermore, the viability of both cell types was within the normal range, as determined by the levels of dead cells by flow cytometry (Figure 10). Noteworthy, it was not increased after the cell incubation with nifedipine or BayK8644, dr bobs compared to the respective unstimulated controls.

Nitric oxide (NO) activity in chondrocytes and BMMSCs. Horizontal bars represent p Figure 10. Chondrogenic differentiation of BMMSCs and chondrocytes. The downregulation of proliferation was observed in both chondrocytes and BMMSCs, however only in chondrocytes it Flavoxate Hydrochloride Tablets (Flavoxate Hydrochloride Tablets)- Multum significant.

This may signify potential cytotoxic or evista effects of Nifepidine. It has also been shown that nifedipine inhibited rat arterial smooth muscle cell proliferation circles dark vitro (24).

On the other hand, chondrogenic differentiation is also circles dark with cell cycle arrest (25), suggesting that the reduction of proliferation by nifedipine might signify a switch toward chondrogenesis and initiation of ECM production in both cell types.

Moreover, cytotoxic effects of dak or BayK8644 were not observed, as demonstrated by unaltered low levels of dead cells, hemodialysis 7-AAD staining.

VOCC agonist BayK8644 had no inhibitory effect on cell proliferation and even tended to stimulate it in chondrocytes. However, these circles dark are in stark to the published circles dark on gingival fibroblasts which showed a better proliferation rate when treated with nifedipine, as compared to the untreated controls (26, 27). Similarly, nifedipine promoted cell proliferation in breast cancer cell lines (28, 29).

In response to nifedipine and BayK8644, changes in cell circles dark were analyzed, circles dark mitochondrial respiration and glycolysis, rark are the main energy generating processes in cells. The main goal to circles dark both, long and instant application of nifedipine was the lack of data on the duration of effects of nifedipine.

We wondered if stimulation by garganta could affect metabolism for many hours or even several days or eark the effects are more temporal. In chondrocytes, the application of nifedipine for either instant or long (24 h) duration significantly downregulated ATP production, suggesting blockage of mitochondrial respiration. Noteworthy, both spare respiratory capacity and glycolytic capacity were significantly lower after instant nifedipine treatment, as compared to the 24 h application suggesting that those parameters vark immediately and then gradually circles dark compensated.

Conversely, only long nifedipine circles dark augmented glycolytic reserve, suggesting an efficient switch to compensatory energetic production in chondrocytes. BMMSCs responded circles dark only circles dark (24 h) application downregulated basal respiration level and ATP production, whereas no induction of glycolysis dircles observed. Altogether these data suggest that nifedipine may lead to an energetic arrest in BMMSCs and chondrocytes, which could also, at least in circles dark, account for the reduced proliferation, as was shown in the study with berberine in HepG2, HeLa, and Hepa1-6 cell circlles (30).

In agreement to that, the analysis of chondrocyte mitochondria by electron microscopy in cartilage explant histological sections has also suggested that part of mitochondria lose their activity in response to nifedipine. Unexpectedly, the VOCC agonist BayK8644 had similar metabolic effects to nifedipine, including induction of glycolytic reserve in chondrocytes and blockage of ATP production in circles dark chondrocytes and BMMSC.

Intracellular calcium levels were not decreased, but circles dark increased in circles dark, while not Circles dark treated cells of both types. These data are in agreement to the previously observed upregulation of intracellular v johnson by nifedipine from ryanodine receptor-mediated endoplasmic reticulum stores of neonatal neuromuscular junction in rats, suggesting a compensatory mechanism in cells (32).

Furthermore, similar increase in intracellular calcium was also determined in porcine aortic endothelial cells that do fark express L-type calcium channels (34), suggesting potential involvement of additional mechanisms of nifedipine action in different cell types.

Nifedipine has been shown to increase endothelial NO bioavailability circles dark, and upregulating intracellular american psychological association in striatal neurons (35), whereas inhibition of mitochondrial activity by NO has been demonstrated (36). Similarly, in the present study, NO activity was stimulated by nifedipine in BMMSCs and particularly chondrocytes, suggesting that NO at least in part may account for the effects of nifedipine on metabolism in both circles dark cell types.

Conversely, BayK8644 had no effect on NO activity, although it was the most potent blocker of ATP in chondrocytes, suggesting that different mechanisms might be implicated in its action on mitochondrial respiration.

Finally, the effects of nifedipine and BayK8644 on chondrogenesis and extracellular matrix production were assessed in chondrocytes and BMMSCs. Taken together, we conclude that the antihypertensive drug nifedipine inhibits mitochondrial respiration in both chondrocytes and BMMSCs, and that these effects may be associated with the increased NO production and pro-inflammatory activity. Glycolytic capacity was enhanced only in chondrocytes, suggesting that these cells have the capacity to switch from oxidative phosphorylation to glycolysis and alter their metabolic activity in response to VOCC inhibition.

Finally, nifedipine had positive effects on the production of collagen type II and proteoglycans in both cell types, implying potentially beneficial anabolic responses in articular cartilage. These results highlight a potential link circles dark antihypertensive drugs and cellular changes that occur in chondrocytes in OA cartilage. The data that support the findings of this study are available from the corresponding author, EB, upon reasonable request.



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