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Background: Alzheimer's disease (AD) is the most common neurodegenerative disease in the older adult population and is often associated with reduced physical activity. Reduced activity and mechanical loading subsequently reduce bone mineral density and increase risk of osteoporosis. Bisphosphonates (BPs) offer preventative effects on osteoporotic fractures in the general population, but their effects on patients with AD are less known. This study aimed to assess the impact of BPs on osteoporotic fractures and survival in patients with AD. Methods: In this nationwide retrospective cohort study, 43,469 patients from the Korea National Health Insurance Service database between 2004 and 2018 were included. All patients were diagnosed with AD and subsequently diagnosed with osteoporosis. Continuous use of BPs was defined as having prescriptions for BP medications one year after the diagnosis of osteoporosis. Propensity score matching paired 12,519 BP users with 12,518 non-users for post-fracture survival analysis. Results: Continuous use of BPs showed a significant preventative effect on the Cox regression model [hazard ratio (HR), 0.890–0.895; p < 0.001] but not on the logistic regression model. The occurrence of osteoporotic fractures in the hip or spine significantly increased the risk of death [hip, HR, 2.036; 95% confidence interval (CI), 1.789–2.316; p < 0.001; spine, HR, 1.465; CI, 1.305–1.644; p < 0.001]. Conclusions: Continuous use of BPs was associated with reduced occurrence of osteoporotic fractures in patients with AD. Patients with AD showed significantly higher mortality rates after the occurrence of osteoporotic fractures. Further studies with detailed patient characteristics and compliance are warranted. [ABSTRACT FROM AUTHOR]

Green nanotechnology is an emerging field of research in recent decades with rapidly growing interest. This integrates green chemistry with green engineering to avoid using toxic chemicals in the synthesis of organic nanomaterials. Green nanotechnology would create a huge potential for the use of nanoparticles for more sustainable utilization in improving animal health. Nanoparticles can be synthesised by physical, chemical and biological processes. Traditional methods for physical and chemical synthesis of nanoparticles are toxic to humans, animals and environmental health, which limits their usefulness. Green synthesis of nanoparticles via biological processes and their application in animal health could maximize the benefits of nanotechnology in terms of enhancing food animal health and production as well as minimize the undesirable impacts on Planetary Health. Recent advances in nanotechnology have meant different nanomaterials, especially those from metal sources, are now available for use in nanomedicine. Metal nanoparticles are one of the most widely researched in green nanotechnology, and the number of articles on this subject in food animal production is growing. Therefore, research on metal nanoparticles using green technologies have utmost importance. In this review, we report the recent advancement of green synthesized metal nanoparticles in terms of their utilization in monogastric animal health, elucidate the research gap in this field and provide recommendations for future prospects. [ABSTRACT FROM AUTHOR]

Background: Total ankle arthroplasty (TAA) has higher complication and failure rates compared to other surgical joint replacement procedures despite technological advances. This study aimed to find the long-term survivability of the TAA procedure and identify the patient risk factors for failure with one of the largest cohorts of patients in the literature. Methods: This retrospective cohort study involving cases between 2007 and 2018 analyzed patients who received an index primary TAA procedure in Korea. A total of 5619 cases were included in the final analysis. The TAA failure was defined as either a case with revision arthroplasty or a case with TAA implant removal and arthrodesis performed after primary TAA. Results: During the study period, the 5-year survival rate was 95.4% (95% CI, 94.7–96.1%), and the 10-year survival rate was 91.1% (95% CI, 89.1–93.1%). A younger age (<55 years, adjusted hazard ratio [AHR], 1.725; 55–64 years, AHR, 1.812; p < 0.001 for both), chronic pulmonary disease (AHR, 1.476; p = 0.013), diabetes (AHR, 1.443; p = 0.014), and alcohol abuse (AHR, 1.524; p = 0.032) showed a significantly high odds ratio for primary TAA failure in Cox regression analysis. Conclusion: The 10-year TAA survivorship rate was 91.1%. A younger age, chronic pulmonary disease, diabetes, and heavy alcohol consumption are risk factors for TAA. [ABSTRACT FROM AUTHOR]

Introduction Cyclic GMP (cGMP) and its principal effector PKG transduce NO and natriuretic peptide signaling to regulate cardiac and vascular function (1). In the heart, PKG activation suppresses adverse responses [...], The cGMP-dependent protein kinase-1[alpha] (PKG1[alpha]) transduces NO and natriuretic peptide signaling; therefore, PKG1[alpha] activation can benefit the failing heart. Disease modifiers such as oxidative stress may depress the efficacy of PKG1[alpha] pathway activation and underlie variable clinical results. PKG1[alpha] can also be directly oxidized, forming a disulfide bond between homodimer subunits at cysteine 42 to enhance oxidant-stimulated vasorelaxation; however, the impact of PKG1[alpha] oxidation on myocardial regulation is unknown. Here, we demonstrated that PKG1[alpha] is oxidized in both patients with heart disease and in rodent disease models. Moreover, this oxidation contributed to adverse heart remodeling following sustained pressure overload or Gq agonist stimulation. Compared with control hearts and myocytes, those expressing a redox-dead protein ([PKG1[alpha].sup.C42S]) better adapted to cardiac stresses at functional, histological, and molecular levels. Redox-dependent changes in PKG1[alpha] altered intracellular translocation, with the activated, oxidized form solely located in the cytosol, whereas reduced [PKG1[alpha].sup.C42S] translocated to and remained at the outer plasma membrane. This altered PKG1[alpha] localization enhanced suppression of transient receptor potential channel 6 (TRPC6), thereby potentiating antihypertrophic signaling. Together, these results demonstrate that myocardial PKG1[alpha] oxidation prevents a beneficial response to pathological stress, may explain variable responses to PKG1[alpha] pathway stimulation in heart disease, and indicate that maintaining PKG1[alpha] in its reduced form may optimize its intrinsic cardioprotective properties.

The PDE super-family contains 11 sub-genes conferring different cyclic nucleotide and tissue selectivity (9). PDE5A was the first cGMP-selective enzyme discovered, and has a major role in erectile and pulmonary [...], Cyclic guanosine monophosphate (cGMP) is a second messenger molecule that transduces nitric-oxide- and natriuretic-peptide-coupled signalling, stimulating phosphorylation changes by protein kinase G. Enhancing cGMP synthesis or blocking its degradation by phosphodiesterase type 5A (PDE5A) protects against cardiovascular disease (1,2). However, cGMP stimulation alone is limited by counter-adaptions including PDE upregulation (3). Furthermore, although PDE5A regulates nitric-oxide-generated cGMP (4,5), nitric oxide signalling is often depressed by heart disease (6). PDEs controlling natriuretic-peptide-coupled cGMP remain uncertain. Here we show that cGMP-selective PDE9A (refs 7,8) is expressed in the mammalian heart, including humans, and is upregulated by hypertrophy and cardiac failure. PDE9A regulates natriuretic-peptide- rather than nitric-oxide-stimulated cGMP in heart myocytes and muscle, and its genetic or selective pharmacological inhibition protects against pathological responses to neurohormones, and sustained pressure-overload stress. PDE9A inhibition reverses pre-established heart disease independent of nitric oxide synthase (NOS) activity, whereas PDE5A inhibition requires active NOS. Transcription factor activation and phosphoproteome analyses of myocytes with each PDE selectively inhibited reveals substantial differential targeting, with phosphorylation changes from PDE5A inhibition being more sensitive to nOs activation. Thus, unlike PDE5A, PDE9A can regulate cGMP signalling independent of the nitric oxide pathway, and its role in stress-induced heart disease suggests potential as a therapeutic target.

Introduction Heart disease is the major cause of death in women as well as in men in developed countries. However, there are sex-specific clinical characteristics, some of which may be [...], Inhibition of cGMP-specific phosphodiesterase 5 (PDE5) ameliorates pathological cardiac remodeling and has been gaining attention as a potential therapy for heart failure. Despite promising results in males, the efficacy of the PDE5 inhibitor sildenafil in female cardiac pathologies has not been determined and might be affected by estrogen levels, given the hormone's involvement in cGMP synthesis. Here, we determined that the heart-protective effect of sildenafil in female mice depends on the presence of estrogen via a mechanism that involves myocyte eNOS-dependent cGMP synthesis and the cGMP-dependent protein kinase Ia (PKGIα). Sildenafil treatment failed to exert antiremodeling properties in female pathological hearts from Gαq- overexpressing or pressure-overloaded mice after ovary removal; however, estrogen replacement restored the effectiveness of sildenafil in these animals. In females, sildenafil-elicited myocardial PKG activity required estrogen, which stimulated tonic cardiomyocyte cGMP synthesis via an eNOS/ soluble guanylate cyclase pathway. In contrast, eNOS activation, cGMP synthesis, and sildenafil efficacy were not estrogen dependent in male hearts. Estrogen and sildenafil had no impact on pressure-overloaded hearts from animals expressing dysfunctional PKGIα, indicating that PKGIα mediates antiremodeling effects. These results support the importance of sex differences in the use of PDE5 inhibitors for treating heart disease and the critical role of estrogen status when these agents are used in females.

On pathological stress, Wnt signaling is reactivated and induces genes associated with cardiac remodeling and fibrosis. We have previously shown that a cell surface receptor Cdon (cell-adhesion associated, oncogene regulated) suppresses Wnt signaling to promote neuronal differentiation however its role in heart is unknown. Here, we demonstrate a critical role of Cdon in cardiac function and remodeling. Cdon is expressed and predominantly localized at intercalated disk in both mouse and human hearts. Cdon-deficient mice develop cardiac dysfunction including reduced ejection fraction and ECG abnormalities. Cdon-/- hearts exhibit increased fibrosis and up-regulation of genes associated with cardiac remodeling and fibrosis. Electrical remodeling was demonstrated by up-regulation and mislocalization of the gap junction protein, Connexin 43 (Cx43) in Cdon-/- hearts. In agreement with altered Cx43 expression, functional analysis both using Cdon-/- cardiomyocytes and shRNA-mediated knockdown in rat cardiomyocytes shows aberrant gap junction activities. Analysis of the underlying mechanism reveals that Cdon-/- hearts exhibit hyperactive Wnt signaling as evident by ß-catenin accumulation and Axin2 up-regulation. On the other hand, the treatment of rat cardiomyocytes with a Wnt activator TWS119 reduces Cdon levels and aberrant Cx43 activities, similarly to Cdon-deficient cardiomyocytes, suggesting a negative feedback between Cdon and Wnt signaling. Finally, inhibition of Wnt/ß-catenin signaling by XAV939, IWP2 or dickkopf (DKK)1 prevented Cdon depletion-induced up-regulation of collagen 1a and Cx43. Taken together, these results demonstrate that Cdon deficiency causes hyperactive Wnt signaling leading to aberrant intercellular coupling and cardiac fibrosis. Cdon exhibits great potential as a target for the treatment of cardiac fibrosis and cardiomyopathy. [ABSTRACT FROM AUTHOR]

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