MicroRNA profiling reveals age-dependent differential expression of nuclear factor κB and mitogen-activated protein kinase in adipose and bone marrow-derived human mesenchymal stem cells

Introduction: Mesenchymal stem cells (MSCs) play a central role in mediating endogenous repair of cell and tissue damage. Biologic aging is a universal process that results in changes at the cellular and molecular levels. In the present study, the role of microRNA (miRNA) in age-induced molecular changes in MSCs derived from adipose tissue (ASCs) and bone marrow (BMSCs) from young and old human donors were investigated by using an unbiased genome-wide approach. Methods: Human ASCs and BMSCs from young and old donors were cultured, and total RNA was isolated. The miRNA fraction was enriched and used to determine the expression profile of miRNA in young and old donor MSCs. Based on miRNA expression, differences in donor MSCs were further investigated by using differentiation assays, Western blot, immunocytochemistry, and bioinformatics. Results: Biologic aging demonstrated reduced osteogenic and adipogenic potential in ASCs isolated from older donors, whereas cell size, complexity, and cell-surface markers remained intact with aging. Analysis of miRNA profiles revealed that small subsets of active miRNAs changed secondary to aging. Evaluation of miRNA showed significantly decreased levels of gene expression of inhibitory kappa B kinase (I$\kappa$B), interleukin-1$\alpha$, inducible nitric oxide synthase (iNOS), mitogen-activated protein kinase/p38, ERK1/2, c-fos, and c-jun in MSCs from older donors by both bioinformatics and Western blot analysis. Nuclear factor kappa B (NF-$\kappa$B), myc, and interleukin-4 receptor mRNA levels were significantly elevated in aged cells from both the adipose and bone marrow depots. Immunocytochemistry showed nuclear localization in young donors, but a cytosolic predominance of phosphorylated NF-$\kappa$B in ASCs from older donors. Western blot demonstrated significantly elevated levels of NF-$\kappa$B subunits, p65 and p50, and AKT. Conclusions: These findings suggest that differential expression of miRNA is an integral component of biologic aging in MSCs

MicroRNA Profiling Reveals Age-Dependent Differential Expression of Nuclear Factor B and Mitogen-Activated Protein Kinase in Adipose and Bone Marrow-Derived Human Mesenchymal Stem Cells

Introduction. Mesenchymal stem cells (MSCs) play a central role in mediating endogenous repair of cell and tissue damage. Biologic aging is a universal process that results in changes at the cellular and molecular levels. In the present study, the role of microRNA (miRNA) in age-induced molecular changes in MSCs derived from adipose tissue (ASCs) and bone marrow (BMSCs) from young and old human donors were investigated by using an unbiased genome-wide approach. Methods. Human ASCs and BMSCs from young and old donors were cultured, and total RNA was isolated. The miRNA fraction was enriched and used to determine the expression profile of miRNA in young and old donor MSCs. Based on miRNA expression, differences in donor MSCs were further investigated by using differentiation assays, Western blot, immunocytochemistry, and bioinformatics. Results: Biologic aging demonstrated reduced osteogenic and adipogenic potential in ASCs isolated from older donors, whereas cell size, complexity, and cell-surface markers remained intact with aging. Analysis of miRNA profiles revealed that small subsets of active miRNAs changed secondary to aging. Evaluation of miRNA showed significantly decreased levels of gene expression of inhibitory kappa B kinase (IκB), interleukin-1α, inducible nitric oxide synthase (iNOS), mitogen-activated protein kinase/p38, ERK1/2, c-fos, and c-jun in MSCs from older donors by both bioinformatics and Western blot analysis. Nuclear factor kappa B (NF-κB), myc, and interleukin-4 receptor mRNA levels were significantly elevated in aged cells from both the adipose and bone marrow depots. Immunocytochemistry showed nuclear localization in young donors, but a cytosolic predominance of phosphorylated NF-κB in ASCs from older donors. Western blot demonstrated significantly elevated levels of NF-κB subunits, p65 and p50, and AKT. Conclusions: These findings suggest that differential expression of miRNA is an integral component of biologic aging in MSCs

2014 Bone and Muscle Risks Standing Review Panel

The 2014 Bone and Muscle Risks Standing Review Panel (from here on referred to as the SRP) met for a site visit in Houston, TX on December 17 - 18, 2014. The SRP reviewed the updated research plans for the Risk of Impaired Performance Due to Reduced Muscle Mass, Strength and Endurance (Muscle Risk) and the Risk of Reduced Physical Performance Capabilities Due to Reduced Aerobic Capacity (Aerobic Risk). The SRP also received a status update on the Risk of Bone Fracture (Bone Risk), the Risk of Early Onset Osteoporosis Due To Spaceflight (Osteo Risk), the Risk of Intervertebral Disc Damage (IVD Risk), and the Risk of Renal Stone Formation (Renal Risk)

Istradefylline protects from cisplatin-induced nephrotoxicity and peripheral neuropathy while preserving cisplatin antitumor effects

Cisplatin is a potent chemotherapeutic drug that is widely used in the treatment of various solid cancers. However, its clinical effectiveness is strongly limited by frequent severe adverse effects, in particular nephrotoxicity and chemotherapy-induced peripheral neuropathy. Thus, there is an urgent medical need to identify novel strategies that limit cisplatin-induced toxicity. In the present study, we show that the FDA-approved adenosine A2A receptor antagonist istradefylline (KW6002) protected from cisplatin-induced nephrotoxicity and neuropathic pain in mice with or without tumors. Moreover, we also demonstrate that the antitumoral properties of cisplatin were not altered by istradefylline in tumor-bearing mice and could even be potentiated. Altogether, our results support the use of istradefylline as a valuable preventive approach for the clinical management of patients undergoing cisplatin treatment

Parathyroid hormone and its receptor gene polymorphisms: implications in osteoporosis and in fracture healing

Abstract Parathyroid glands secrete parathyroid hormone (PTH) which plays multiple roles in calcium homeostasis and in bone remodeling. Secretion of PTH is regulated by extracellular calcium levels and other humoral factors including 1α,25(OH)2D3. PTH regulates gene expression and induces biological effects directly and indirectly. The human gene encoding PTH is located on chromosome 11. In this review, we study the diverse PTH along with its receptor gene polymorphisms and their association with osteoporosis and fracture healing. Genetic factors are associated with osteoporosis by influencing bone mineral density (BMD), bone turnover, calcium homeostasis, and susceptibility to osteoporotic fractures. Polymorphisms in genes encoding PTH may contribute to genetic regulation of BMD and thus susceptibility to fracture risk. PTH stimulates the proliferation of osteoprogenitor cells, production of alkaline phosphatise, and bone matrix proteins that contribute to hard callus formation and increases strength at the site of fractured bone. During remodeling, PTH promotes osteoclastogenesis restoring the original shape, structure, and mechanical strength of the bone. Some PTH polymorphisms have shown an association with fracture risk. Further research is needed to elucidate the relative importance of PTH genetics and the mechanisms of genetic contributions to gene-gene interactions in the pathogenesis of osteoporosis and in fracture healing

Race/ethnic differences in atherosclerotic cardiovascular disease risk factors among patients with hypertension: Analysis from 143 primary care clinics

Background: While it is known that sex and race/ethnic disparities persist for atherosclerotic cardiovascular disease (ASCVD), disparities in risk factor control have not been well-described in primary care where ASCVD can be prevented. Methods: Adult patients with a hypertension diagnosis without ASCVD were included in this analysis of electronic health records from a large US healthcare system from 2018. Patients were categorized based on risk factor control defined as blood pressure (BP) \u3c130/80 mm Hg; statin prescription among patients with indications, HbA1c of \u3c7%, and not smoking. Multivariable Poisson regressions were developed to explore associations with race/ethnicity. Results are presented as relative risk (RR), 95% confidence intervals (CIs). Results: Among 5,227 patients, 55.8% women and 60.0% men had uncontrolled BP, 47.3% women and 46.4% men with statin therapy indication did not have a prescription, 34.9% women and 40.9% men had uncontrolled HbA1c values, and 9.3% women and 13.7% men were smokers. African Americans were more likely to have uncontrolled BP (women: RR 1.18, 95% CI 1.07-1.30; men: RR 1.20, 95% CI 1.05-1.34) and more likely to lack a statin prescription (women: RR 1.23, 95% CI 1.05-1.45; men: RR 1.25, 95% CI 1.03-1.51) compared to Caucasians. Differences in HbA1c control were not statistically significant among Hispanic/Latino compared to Caucasians (women: RR 1.28, 95% CI 0.86-1.90; men: RR 1.20, 95% CI 0.72-1.97). Conclusions: Disparities in controlling ASCVD risk factors in primary care persist and were not fully explained by demographic or clinical characteristics. Monitoring changes in disparities is important to ensure equity as interventions to prevent ASCVD in primary care are developed and implemented