Metformin and GDF15: where are we now? Kincaid, John W R; Coll, Anthony P
Nature reviews. Endocrinology,
01/2023, Letnik:
19, Številka:
1
Journal Article
The hormone GDF15 is secreted in response to cellular stressors. Metformin elevates circulating levels of GDF15, an action important for the drug's beneficial effects on body weight. Metformin can ...also inhibit mammalian respiratory complex I, leading to decreases in ATP:AMP ratio, activation of AMP Kinase (AMPK), and increased GDF15 production. We undertook studies using a range of mice with tissue-specific loss of Gdf15 (namely gut, liver and global deletion) to determine the relative contributions of two classical metformin target tissues, the gut and liver, to the elevation of GDF15 seen with metformin. In addition, we performed comparative studies with another pharmacological agent, the AMP kinase pan-activator, MK-8722. Deletion of Gdf15 from the intestinal epithelium significantly reduced the circulating GDF15 response to oral metformin, whereas deletion of Gdf15 from the liver had no effect. In contrast, deletion of Gdf15 from the liver, but not the gut, markedly reduced circulating GDF15 responses to MK-8722. Further, our data show that, while GDF15 restricts high-fat diet-induced weight gain, the intestinal production of GDF15 is not necessary for this effect. These findings add to the body of evidence implicating the intestinal epithelium in key aspects of the pharmacology of metformin action.
NAD metabolism in aging and cancer Kincaid, John WR; Berger, Nathan A
Experimental biology and medicine,
11/2020, Letnik:
245, Številka:
17
Journal Article
Recenzirano
Odprti dostop
NAD+ and its derivatives NADH, NADP+, and NADPH are essential cofactors in redox reactions and electron transport pathways. NAD serves also as substrate for an extensive series of regulatory enzymes ...including cyclic ADP-ribose hydrolases, mono(ADP-ribosyl)transferases, poly(ADP-ribose) polymerases, and sirtuin deacetylases which are O-acetyl-ADP-ribosyltransferases. As a result of the numerous and diverse enzymes that utilize NAD as well as depend on its synthesis and concentration, significant interest has developed in its role in a variety of physiologic and pathologic processes, and therapeutic initiatives have focused both on augmenting its levels as well as inhibiting some of its pathways. In this article, we examine the biosynthesis of NAD, metabolic processes in which it is involved, and its role in aging, cancer, and other age-associated comorbidities including neurodegenerative, cardiovascular, and metabolic disorders. Therapeutic interventions to augment and/or inhibit these processes are also discussed.
Impact statement
NAD is a central metabolite connecting energy balance and organismal growth with genomic integrity and function. It is involved in the development of malignancy and has a regulatory role in the aging process. These processes are mediated by a diverse series of enzymes whose common focus is either NAD’s biosynthesis or its utilization as a redox cofactor or enzyme substrate. These enzymes include dehydrogenases, cyclic ADP-ribose hydrolases, mono(ADP-ribosyl)transferases, poly(ADP-ribose) polymerases, and sirtuin deacetylases. This article describes the manifold pathways that comprise NAD metabolism and promotes an increased awareness of how perturbations in these systems may be important in disease prevention and/or progression.
Neuropathy is often a major manifestation of systemic amyloidosis. It is most frequently seen in patients with hereditary transthyretin (TTR) amyloidosis, but is also present in 20% of patients with ...systemic immunoglobulin light chain (primary) amyloidosis. Familial amyloid polyneuropathy (FAP) is the most common form of inherited amyloidotic polyneuropathy, with clinical and electrophysiologic findings similar to neuropathies with differing etiologies (e.g., diabetes mellitus). Hereditary amyloidosis is an adult‐onset autosomal‐dominant disease with varying degrees of penetrance. It is caused by specific gene mutations, but demonstration that a patient has one such mutation does not confirm the diagnosis of amyloidosis. Diagnosis requires tissue biopsy with demonstration of amyloid deposits either by special histochemical stains or electron microscopy. Transthyretin amyloidosis is treated by liver transplantation, which eliminates the mutated transthyretin from the blood, but for some patients continued amyloid deposition can occur from wild‐type (normal) transthyretin. Presently, a study is ongoing to determine whether amyloid deposition can be inhibited by small organic molecules that are hypothesized to affect the fibril‐forming ability of transthyretin. Proposed gene therapy with antisense oligonucleotides (ASOs) to suppress hepatic transthyretin synthesis is effective in a transgenic mouse model but has not yet been tested in humans. Muscle Nerve, 2007
Courts are key players in the dynamics of federal countries since their rulings have a direct impact on the ability of governments to centralize and decentralize power. Courts in Federal Countries ...examines the role high courts play in thirteen countries, including Australia, Brazil, Canada, Germany, India, Nigeria, Spain, and the United States. The volume’s contributors analyse the centralizing or decentralizing forces at play following a court’s ruling on issues such as individual rights, economic affairs, social issues, and other matters. The thirteen substantive chapters have been written to facilitate comparability between the countries. Each chapter outlines a country’s federal system, explains the constitutional and institutional status of the court system, and discusses the high court’s jurisprudence in light of these features. Courts in Federal Countries offers insightful explanations of judicial behaviour in the world’s leading federations.
Background
Eculizumab is approved for atypical hemolytic uremic syndrome (aHUS). Guidelines discuss the importance of prompt treatment. We report a post hoc analysis investigating the effect of ...baseline factors, including patient characteristics and time from the latest aHUS manifestation to eculizumab initiation, on change from baseline in estimated glomerular filtration rate (eGFR) and other outcomes.
Methods
Data were pooled from four phase 2, open-label, single-arm, prospective clinical studies of eculizumab for patients with aHUS. Multivariate regressions identified predictors of eGFR change from baseline. The proportion of patients achieving sustained eGFR increase (defined: ≥15 ml/min/1.73 m
2
for ≥28 days) and platelet count normalization were evaluated 1 year post-treatment. Baseline characteristics and eGFR outcomes were summarized by time to treatment from last aHUS manifestation ≤7 days (
n
= 21) versus >7 days (
n
= 76).
Results
Baseline eGFR were similar between groups. Multivariate regression analysis demonstrated time from aHUS manifestation to eculizumab treatment, age, baseline lactate dehydrogenase (LDH) and baseline hemoglobin were independently predictive of eGFR change from baseline. Mean eGFR change from baseline at 1 year was significantly higher in patients treated in ≤7 days than >7 days (57 vs. 23 ml/min/1.73 m
2
, p = 0.0098). After 1 year, 17/21 and 36/76 patients in the ≤7 and >7 day groups, respectively, achieved a sustained increase in eGFR. Mean time to platelet count normalization was similar between groups.
Conclusions
Younger age, higher baseline LDH and lower baseline hemoglobin were associated with greater eGFR improvements. Early eculizumab initiation led to improved renal recovery, demonstrating the importance of rapid diagnosis and treatment of patients with aHUS.
Teaching Federalism presents innovative ideas for teaching a wide variety of key concepts of federalism and federal-country cases. Each chapter introduces a topic, explains its place in federalism ...research, and provides learning objectives, pedagogical tools, and questions for class discussions, student essays, and examinations. Evaluation and reading suggestions are included as well. The book covers twenty substantive facets of federalism important for understanding contemporary issues of federalism and federation, such as power distribution, second chambers, high courts, intergovernmental relations, fiscal federalism, multinational federalism, conflict resolution, indigenous peoples, gendered federalism, and secession. Also included are case-study examples for teaching about federalism in Germany, India, Nigeria, Switzerland, and the United States. Educators around the world who teach federalism or wish to do so will find this a wonderful resource for lesson plans on a wide variety of issues related to federalism. Students studying federalism will also find it invaluable as an introductory resource for important topics and readings on the subject.
Objective
Obesity has emerged as a prominent risk factor for multiple serious disease states, including a variety of cancers, and is increasingly recognized as a primary contributor to preventable ...cancer risk. However, few studies of leukemia have been conducted in animal models of obesity. This study sought to characterize the impact of obesity, diet, and sex in a murine model of acute promyelocytic leukemia (APL).
Methods
Male and female C57BL/6J.mCG+/PR mice, genetically predisposed to sporadic APL development, and C57BL/6J (wild type) mice were placed on either a high‐fat diet (HFD) or a low‐fat diet (LFD) for up to 500 days.
Results
Relative to LFD‐fed mice, HFD‐fed animals displayed increased disease penetrance and shortened disease latency as indicated by accelerated disease onset. In addition, a diet‐responsive sex difference in APL penetrance and incidence was identified, with LFD‐fed male animals displaying increased penetrance and shortened latency relative to female counterparts. In contrast, both HFD‐fed male and female mice displayed 100% disease penetrance and insignificant differences in disease latency, indicating that the sexual dimorphism was reduced through HFD feeding.
Conclusions
Obesity and obesogenic diet promote the development of APL in vivo, reducing sexual dimorphisms in disease latency and penetrance.
To what extent do federal systems promote multiple identities and attachments? How do their identities affect the trust that is assigned to various orders of government and contribute to cohesion in ...federalist systems? Do cohesive federations depend on public trust and strong attachment to the national or central government? Are attachments and identification with the various orders of government in conflict or are they compatible? Identities, Trust, and Cohesion in Federal Systems offers eight comparative essays that provide key insights into identity debates in federalist countries. The findings are drawn from extensive analyses of public opinion data in Australia, Belgium, Canada, Germany, Mexico, Spain, Switzerland, and the United States. The editors seek to improve our understanding of how identity, trust, and cohesion correlate with centralized, decentralized, and asymmetrical models of federalism in order to gain insight into the diverse governance challenges that various nations encounter. Making effective use of empirical data to draw evidence-based conclusions about federalist governance, Identities, Trust, and Cohesion in Federal Systems breaks new ground in public policy studies.To what extent do federal systems promote multiple identities and attachments? How do their identities affect the trust that is assigned to various orders of government and contribute to cohesion in federalist systems? Do cohesive federations depend on public trust and strong attachment to the national or central government? Are attachments and identification with the various orders of government in conflict or are they compatible? Identities, Trust, and Cohesion in Federal Systems offers eight comparative essays that provide key insights into identity debates in federalist countries. The findings are drawn from extensive analyses of public opinion data in Australia, Belgium, Canada, Germany, Mexico, Spain, Switzerland, and the United States. The editors seek to improve our understanding of how identity, trust, and cohesion correlate with centralized, decentralized, and asymmetrical models of federalism in order to gain insight into the diverse governance challenges that various nations encounter. Making effective use of empirical data to draw evidence-based conclusions about federalist governance, Identities, Trust, and Cohesion in Federal Systems breaks new ground in public policy studies.
In a study of 406 patients with myotonic dystrophy type 1, 96 had severe electrocardiographic (ECG) abnormalities when first evaluated. During an average of 5.7 years of follow-up, there were 81 ...deaths, of which 27 were sudden. The presence of a severe ECG abnormality at baseline was an independent predictor of sudden death (relative risk, 3.3).
In a study of 406 patients with myotonic dystrophy type 1, 96 had severe electrocardiographic (ECG) abnormalities when first evaluated. The presence of a severe ECG abnormality at baseline was an independent predictor of sudden death (relative risk, 3.3).
Myotonic dystrophy is an autosomal dominant disorder that is the most common muscular dystrophy presenting in adults.
1
It is characterized by myotonia (delayed muscle relaxation after contraction), progressive weakness and atrophy of the skeletal muscles, and systemic manifestations, including cardiac involvement.
2
Myotonic dystrophy type 1, the more common and typically the more severe of the two major types, is caused by an expanded cytosine–thymine–guanine (CTG) repeat on chromosome 19 in the 3′ untranslated region of a serine–threonine protein kinase gene called
DMPK
(dystrophia myotonica protein kinase).
3
–
5
Sudden death can occur in patients with myotonic dystrophy type 1 as a . . .
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