Human Ageing Genomic Resources: updates on key databases in ageing research.

Ageing is a complex and multifactorial process. For two decades, the Human Ageing Genomic Resources (HAGR) have aided researchers in the study of various aspects of ageing and its manipulation. Here, we present the key features and recent enhancements of these resources, focusing on its six main databases. One database, GenAge, focuses on genes related to ageing, featuring 307 genes linked to human ageing and 2205 genes associated with longevity and ageing in model organisms. AnAge focuses on ageing, longevity, and life-history across animal species, containing data on 4645 species. DrugAge includes information about 1097 longevity drugs and compounds in model organisms such as mice, rats, flies, worms and yeast. GenDR provides a list of 214 genes associated with the life-extending benefits of dietary restriction in model organisms. CellAge contains a catalogue of 866 genes associated with cellular senescence. The LongevityMap serves as a repository for genetic variants associated with human longevity, encompassing 3144 variants pertaining to 884 genes. Additionally, HAGR provides various tools as well as gene expression signatures of ageing, dietary restriction, and replicative senescence based on meta-analyses. Our databases are integrated, regularly updated, and manually curated by experts. HAGR is freely available online (https://genomics.senescence.info/).

Developing a national research agenda to reduce consumption of sugar-sweetened beverages and increase safe water access and consumption among 0- to 5-year-olds: a mixed methods approach.

OBJECTIVE: Sugar-sweetened beverage (SSB) consumption in early childhood is a public health concern. Adequate hydration in early childhood is also important. We developed a national research agenda to improve beverage consumption patterns among 0-5-year-olds. This article focuses on the process used to develop this research agenda. DESIGN: A mixed methods, multi-step process was used to develop the research agenda, including: (i) a scientific advisory committee; (ii) systematic reviews on strategies to reduce SSB consumption and increase water access and consumption; (iii) two stakeholder surveys to first identify and then rank strategies to reduce SSB consumption and increase water access and consumption; (iv) key informant interviews to better understand determinants of beverage consumption and strategies to improve beverage consumption patterns among high-risk groups; (v) an in-person convening with experts; and (vi) developing the final research agenda. SETTING: This process included research and stakeholders from across the United States. PARTICIPANTS: A total of 276 participants completed survey 1 and 182 participants completed survey 2. Key informant interviews were conducted with 12 stakeholders. Thirty experts attended the convening, representing academia, government, and non-profit sectors. RESULTS: Thirteen key issue areas and 59 research questions were developed. Priority topics were beverage consumption recommendations, fruit-flavoured drink consumption, interventions tailored to high-risk groups, and family engagement in childcare. CONCLUSIONS: This research agenda lays the groundwork for research efforts to improve beverage patterns of young children. The methods used can be a template to develop research agendas for other public health issues.

Sodium-Glucose Cotransporter 2 Inhibition and Diabetic Kidney Disease.

Diabetic kidney disease (DKD) is now the principal cause of chronic kidney disease leading to end-stage kidney disease worldwide. As a primary contributor to the excess risk of all-cause and cardiovascular death in diabetes, DKD is a major contributor to the progressively expanding global burden of diabetes-associated morbidity and mortality. Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a newer class of antihyperglycemic agents that exert glucose-lowering effects via glycosuric actions. Preclinical studies and clinical trials of SGLT2 inhibitors have consistently demonstrated reduction of albuminuria and preservation of kidney function. In particular, SGLT2 inhibitors lower risk of congestive heart failure, a major cardiovascular complication in DKD. This Perspective summarizes proposed mechanisms of action for SGLT2 inhibitors, integrates these data with results of recent cardiovascular outcomes trials, and discusses clinical applications for patients with DKD. The American Diabetes Association/European Association for the Study of Diabetes Consensus Report published online in October 2018 recommends SGLT inhibitors as preferred add-on therapy for patients with type 2 diabetes and established cardiovascular disease or chronic kidney disease, if kidney function is adequate. Results of the ongoing and just completed clinical trials conducted in patients with established DKD will facilitate further refinement of current guidelines.

SGLT2 Inhibition for the Prevention and Treatment of Diabetic Kidney Disease: A Review.

Diabetic kidney disease (DKD) is the leading cause of end-stage kidney disease in the United States and the world alike, and there is a great unmet need for treatments to reduce DKD development and progression. Inhibition of sodium/glucose co-transporter 2 (SGLT2) in the proximal tubule of the kidney has emerged as an effective antihyperglycemic treatment, leading to regulatory approval of several first-generation SGLT2 inhibitors for the treatment of type 2 diabetes. In follow-on clinical trials for the cardiovascular safety of the SGLT2 inhibitors, secondary effects to prevent or reduce albuminuria and decline in estimated glomerular filtration rate spurred further investigation into their potential application in DKD. This review summarizes the current understanding of mechanisms by which SGLT2 inhibitors block glucose reabsorption in the proximal tubule and improve systemic glucose homeostasis, the hypothesized mechanisms for kidney-protective effects of SGLT2 inhibition, and current recommendations for use of this class of antihyperglycemic agents in diabetic patients with low estimated glomerular filtration rates. Results of ongoing clinical trials in patients with DKD are eagerly awaited to expand knowledge of how SGLT2 inhibitors might be used for prevention and treatment.

Selection of Priority Natural Products for Evaluation as Potential Precipitants of Natural Product-Drug Interactions: A NaPDI Center Recommended Approach.

Pharmacokinetic interactions between natural products (NPs) and conventional medications (prescription and nonprescription) are a longstanding but understudied problem in contemporary pharmacotherapy. Consequently, there are no established methods for selecting and prioritizing commercially available NPs to evaluate as precipitants of NP-drug interactions (NPDIs). As such, NPDI discovery remains largely a retrospective, bedside-to-bench process. This Recommended Approach, developed by the Center of Excellence for Natural Product Drug Interaction Research (NaPDI Center), describes a systematic method for selecting NPs to evaluate as precipitants of potential clinically significant pharmacokinetic NPDIs. Guided information-gathering tools were used to score, rank, and triage NPs from an initial list of 47 candidates. Triaging was based on the presence and/or absence of an NPDI identified in a clinical study (≥20% or <20% change in the object drug area under the concentration vs. time curve, respectively), as well as mechanistic and descriptive in vitro and clinical data. A qualitative decision-making tool, termed the fulcrum model, was developed and applied to 11 high-priority NPs for rigorous study of NPDI risk. Application of this approach produced a final list of five high-priority NPs, four of which are currently under investigation by the NaPDI Center.

Inflammatory Mechanisms as New Biomarkers and Therapeutic Targets for Diabetic Kidney Disease.

Diabetic kidney disease (DKD) is the leading cause of CKD and end-stage kidney disease (ESKD) worldwide. Approximately 30-40% of people with diabetes develop this microvascular complication, placing them at high risk of losing kidney function as well as of cardiovascular events, infections, and death. Current therapies are ineffective for arresting kidney disease progression and mitigating risks of comorbidities and death among patients with DKD. As the global count of people with diabetes will soon exceed 400 million, the need for effective and safe treatment options for complications such as DKD becomes ever more urgent. Recently, the understanding of DKD pathogenesis has evolved to recognize inflammation as a major underlying mechanism of kidney damage. In turn, inflammatory mediators have emerged as potential biomarkers and therapeutic targets for DKD. Phase 2 clinical trials testing inhibitors of monocyte-chemotactic protein-1 chemokine C-C motif-ligand 2 and the Janus kinase/signal transducer and activator of transcription pathway, in particular, have produced promising results.

Impact of enzymatic digestion on bacterial community composition in CF airway samples.

BACKGROUND: Previous studies have demonstrated the importance of DNA extraction methods for molecular detection of Staphylococcus, an important bacterial group in cystic fibrosis (CF). We sought to evaluate the effect of enzymatic digestion (EnzD) prior to DNA extraction on bacterial communities identified in sputum and oropharyngeal swab (OP) samples from patients with CF. METHODS: DNA from 81 samples (39 sputum and 42 OP) collected from 63 patients with CF was extracted in duplicate with and without EnzD. Bacterial communities were determined by rRNA gene sequencing, and measures of alpha and beta diversity were calculated. Principal Coordinate Analysis (PCoA) was used to assess differences at the community level and Wilcoxon Signed Rank tests were used to compare relative abundance (RA) of individual genera for paired samples with and without EnzD. RESULTS: Shannon Diversity Index (alpha-diversity) decreased in sputum and OP samples with the use of EnzD. Larger shifts in community composition were observed for OP samples (beta-diversity, measured by Morisita-Horn), whereas less change in communities was observed for sputum samples. The use of EnzD with OP swabs resulted in significant increase in RA for the genera Gemella (p < 0.01), Streptococcus (p < 0.01), and Rothia (p < 0.01). Staphylococcus (p < 0.01) was the only genus with a significant increase in RA from sputum, whereas the following genera decreased in RA with EnzD: Veillonella (p < 0.01), Granulicatella (p < 0.01), Prevotella (p < 0.01), and Gemella (p = 0.02). In OP samples, higher RA of Gram-positive taxa was associated with larger changes in microbial community composition. DISCUSSION: We show that the application of EnzD to CF airway samples, particularly OP swabs, results in differences in microbial communities detected by sequencing. Use of EnzD can result in large changes in bacterial community composition, and is particularly useful for detection of Staphylococcus in CF OP samples. The enhanced identification of Staphylococcus aureus is a strong indication to utilize EnzD in studies that use OP swabs to monitor CF airway communities.

Prioritizing pharmacokinetic drug interaction precipitants in natural products: application to OATP inhibitors in grapefruit juice.

Natural products, including botanical dietary supplements and exotic drinks, represent an ever-increasing share of the health-care market. The parallel ever-increasing popularity of self-medicating with natural products increases the likelihood of co-consumption with conventional drugs, raising concerns for unwanted natural product-drug interactions. Assessing the drug interaction liability of natural products is challenging due to the complex and variable chemical composition inherent to these products, necessitating a streamlined preclinical testing approach to prioritize precipitant individual constituents for further investigation. Such an approach was evaluated in the current work to prioritize constituents in the model natural product, grapefruit juice, as inhibitors of intestinal organic anion-transporting peptide (OATP)-mediated uptake. Using OATP2B1-expressing MDCKII cells (Madin-Darby canine kidney type II) and the probe substrate estrone 3-sulfate, IC50s were determined for constituents representative of the flavanone (naringin, naringenin, hesperidin), furanocoumarin (bergamottin, 6',7'-dihydroxybergamottin) and polymethoxyflavone (nobiletin and tangeretin) classes contained in grapefruit juice. Nobiletin was the most potent (IC50 , 3.7 µm); 6',7'-dihydroxybergamottin, naringin, naringenin and tangeretin were moderately potent (IC50 , 20-50 µm); and bergamottin and hesperidin were the least potent (IC50 , >300 µm) OATP2B1 inhibitors. Intestinal absorption simulations based on physiochemical properties were used to determine the ratios of unbound concentration to IC50 for each constituent within enterocytes and to prioritize in order of pre-defined cut-off values. This streamlined approach could be applied to other natural products that contain multiple precipitants of natural product-drug interactions. Copyright © 2016 John Wiley & Sons, Ltd.

Molecular Identification of Staphylococcus aureus in Airway Samples from Children with Cystic Fibrosis.

BACKGROUND: Staphylococcus aureus is a common and significant pathogen in cystic fibrosis. We sought to determine if quantitative PCR (qPCR) and 16S rRNA gene sequencing could provide a rapid, culture-independent approach to the identification of S. aureus airway infections. METHODS: We examined the sensitivity and specificity of two qPCR assays, targeting the femA and 16S rRNA gene, using culture as the gold standard. In addition, 16S rRNA gene sequencing to identify S. aureus directly from airway samples was evaluated. DNA extraction was performed with and without prior enzymatic digestion. RESULTS: 87 samples [42 oropharyngeal (OP) and 45 expectorated sputum (ES)] were analyzed. 59 samples (68%) cultured positive for S. aureus. Using standard extraction techniques, sequencing had the highest sensitivity for S. aureus detection (85%), followed by FemA qPCR (52%) and 16SrRNA qPCR (34%). For all assays, sensitivity was higher from ES samples compared to OP swabs. Specificity of the qPCR assays was 100%, but 21.4% for sequencing due to detection of S. aureus in low relative abundance from culture negative samples. Enzymatic digestion increased the sensitivity of qPCR assays, particularly for OP swabs. CONCLUSION: Sequencing had a high sensitivity for S. aureus, but low specificity. While femA qPCR had higher sensitivity than 16S qPCR for detection of S. aureus, neither assay was as sensitive as sequencing. The significance of S. aureus detection with low relative abundance by sequencing in culture-negative specimens is not clear.

Evidence for distinct effects of exercise in different cardiac hypertrophic disorders.

Aerobic exercise training (AET) attenuates or reverses pathological cardiac remodeling after insults such as chronic hypertension and myocardial infarction. The phenotype of the pathologically hypertrophied heart depends on the insult; therefore, it is likely that distinct types of pathological hypertrophy require different exercise regimens. However, the mechanisms by which AET improves the structure and function of the pathologically hypertrophied heart are not well understood, and exercise research uses highly inconsistent exercise regimens in diverse patient populations. There is a clear need for systematic research to identify precise exercise prescriptions for different conditions of pathological hypertrophy. Therefore, this review synthesizes existing evidence for the distinct mechanisms by which AET benefits the heart in different pathological hypertrophy conditions, suggests strategic exercise prescriptions for these conditions, and highlights areas for future research.