Comparison of coronal discoloration induced by White MTA and CEM Cement

Coronal discoloration of endodontically treated teeth is a challenge in clinical dentistry. This study aimed to compare coronal discoloration induced by White Mineral Trioxide Aggregate and Calcium-enriched mixture cement. Fifty single-rooted, unrestored premolar teeth extracted for orthodontic reasons were selected. After access cavity preparation, all the root canals were instrumented with MTWO rotary files up to #40.6%. The specimens were randomly assigned to two experimental groups, White Mineral Trioxide Aggregate and Calcium-enriched mixture cement groups (n = 20), and two control groups (n = 5). In the White Mineral Trioxide Aggregate and Calcium-enriched mixture cement groups, the material was condensed via the access cavity 3 mm below the cementoenamel junction to a thickness of 3 mm. Tooth color was assessed using computer analysis of digital images. Tooth color measurements were recorded at eight time intervals: before material placement (but after tooth preparation), at 24 h, 48 h, one week, two weeks, four weeks, eight weeks, and sixteen weeks after material placement. Data were analyzed using t-test, ANOVA, repeated measure ANOVA, and Tukey HSD tests. The significance level was set at 5% for all the tests. Cervical discoloration of teeth in both experimental groups significantly increased over time (p < 0.05). However, samples in the White Mineral Trioxide Aggregate group showed more discoloration in cervical regions than Calcium-enriched mixture cement specimens after two, four, eight, and sixteen weeks (p < 0.05). Applying both White Mineral Trioxide Aggregate and Calcium-enriched mixture cement induced coronal discoloration; however, White Mineral Trioxide Aggregate samples exhibited greater cervical discoloration than Calcium-enriched mixture cement specimens after two, four, eight, and sixteen weeks

Nitric Oxide-cGMP Signaling in Hypertension:Current and Future Options for Pharmacotherapy

For the treatment of systemic hypertension, pharmacological intervention in nitric oxide-cyclic guanosine monophosphate signaling is a well-explored but unexploited option. In this review, we present the identified drug targets, including oxidases, mitochondria, soluble guanylyl cyclase, phosphodiesterase 1 and 5, and protein kinase G, important compounds that modulate them, and the current status of (pre)clinical development. The mode of action of these compounds is discussed, and based upon this, the clinical opportunities. We conclude that drugs that directly target the enzymes of the nitric oxide-cyclic guanosine monophosphate cascade are currently the most promising compounds, but that none of these compounds is under investigation as a treatment option for systemic hypertension

The Effects of Acute and Chronic Selective Phosphodiesterase 1 Inhibition on Smooth Muscle Cell-Associated Aging Features

Age-related cardiovascular diseases (CVDs) remain among the leading global causes of death, and vascular smooth muscle cell (VSMC) remodeling plays an essential role in its pathology. Reduced NO-cGMP pathway signaling is a major feature and pathogenic mechanism underlying vasodilator dysfunction. Recently, we identified phosphodiesterase (PDE) 1, an enzyme that hydrolyzes and inactivates the cyclic nucleotides cAMP and cGMP, and thereby provides a potential treatment target for restoring age-related vascular dysfunction due to aging of VSMC. Based on this hypothesis, we here tested the effects of PDE1 inhibition in a model of SMC-specific accelerated aging mice. SMC-KO and their WT littermates received either vehicle or the PDE1 inhibitor lenrispodun for 8 weeks. Vascular function was measured both in vivo (Laser Doppler technique) and ex vivo (organ bath). Moreover, we deployed UV irradiation in cell culture experiments to model accelerated aging in an in vitro situation. SMC-KO mice display a pronounced loss of vasodilator function in the isolated aorta, the cutaneous microvasculature, and mesenteric arteries. Ex vivo, in isolated vascular tissue, we found that PDE1 inhibition with lenrispodun improves vasodilation, while no improvement was observed in isolated aorta taken from mice after chronic treatment in vivo. However, during lenrispodun treatment in vivo, an enhanced microvascular response in association with upregulated cGMP levels was seen. Further, chronic lenrispodun treatment decreased TNF-α and IL-10 plasma levels while the elevated level of IL-6 in SMC-KO mice remained unchanged after treatment. PDE1 and senescence markers, p16 and p21, were increased in both SMC-KO aorta and cultured human VSMC in which DNA was damaged by ultraviolet irradiation. This increase was lowered by chronic lenrispodun. In contrast, lenrispodun increased the level of PDE1A in both situations. In conclusion, we demonstrated that PDE1 inhibition may be therapeutically useful in reversing aspects of age-related VSMC dysfunction by potentiating NO-cGMP signaling, preserving microvascular function, and decreasing senescence. Yet, after chronic treatment, the effects of PDE1 inhibition might be counteracted by the interplay between differential PDE1A and C expression. These results warrant further pharmacodynamic profiling of PDE enzyme regulation during chronic PDE1 inhibitor treatment

Selective phosphodiesterase 1 inhibition ameliorates vascular function, reduces inflammatory response, and lowers blood pressure in aging animals

Diminished nitric oxide-cGMP-mediated relaxation plays a crucial role in cardiovascular aging, leading to decreased vasodilation, vascular hypertrophy and stiffening, and ultimately, cardiovascular dysfunction. Aging is the time-related worsening of physiologic function due to complex cellular and molecular interactions, and it is at least partly driven by DNA damage. Genetic deletion of the DNA repair enzyme ERCC1 endonuclease in Ercc1D/- mice provides us an efficient tool to accelerate vascular aging, explore mechanisms, and test potential treatments. Previously, we identified the cGMP-degrading enzyme phosphodiesterase 1 as a potential treatment target in vascular aging. In the present study, we studied the effect of acute and chronic treatment with ITI-214, a selective phosphodiesterase 1 inhibitor on vascular aging features in Ercc1D/- mice. Compared with wild-type mice, Ercc1D/- mice at the age of 14 weeks showed decreased reactive hyperemia, diminished endothelium-dependent and -independent responses of arteries in organ baths, carotid wall hypertrophy, and elevated circulating levels of inflammatory cytokines. Acute ITI-214 treatment in organ baths restored the arterial endothelium-independent vasodilation in Ercc1D/- mice. An 8-week treatment with 100 mg/kg per day ITI-214 improved endothelium-independent relaxation in both aorta and coronary arteries, at least partly restored the diminished reactive hyperemia, lowered the systolic and diastolic blood pressure, normalized the carotid hypertrophy, and ameliorated inflammatory responses exclusively in Ercc1D/- mice. These findings suggest phosphodiesterase 1 inhibition would provide a powerful tool for nitric oxide-cGMP augmentation and have significant therapeutic potential to battle arteriopathy related to aging