Alcohol-associated liver disease (ALD) is a devastating complication of alcohol use disorder (AUD). Once it develops, ALD is exceedingly difficult to treat; it therefore is critical to identify ways ...to prevent ALD. By treating the causes of increased alcohol consumption, psychotherapy may offer prophylactic benefit against the development of ALD for patients with AUD.
In this retrospective cohort study, we used International Classification of Diseases, 9th and 10th revision, codes to identify 9635 patients with AUD in the Mass General Brigham Biobank. The mean follow-up period from AUD diagnosis was 9.2 years. We used Cox regression models to generate hazard ratios (HR) for the development of ALD given the receipt or nonreceipt of psychotherapy, adjusting for a range of other contributors including the receipt of medication-assisted treatment.
In our cohort, 60.4% of patients were men, 83.5% of patients were white, the median age was 57.0 years, and 3544 patients (36.8%) received psychotherapy. ALD developed in 1135 patients (11.8%). In multivariable analysis, psychotherapy was associated with a reduced rate of ALD (HR, 0.59; 95% CI, 0.50-0.71; P < .001). This association held for both individual psychotherapy (HR, 0.70; 95% CI, 0.56-0.86; P < .001) and group psychotherapy (HR, 0.76; 95% CI, 0.61-0.94; P = .01). Among patients with cirrhosis, psychotherapy was associated with a lower rate of hepatic decompensation (HR, 0.68; 95% CI, 0.48-0.95; P = .03).
The receipt of psychotherapy in the setting of AUD is associated with reduced incidence and progression of ALD. Given the safety and potential benefit of psychotherapy, clinicians should consider using it to prevent the development of ALD.
DNA nanotechnology makes use of the exquisite self-recognition of DNA in order to build on a molecular scale. Although static structures may find applications in structural biology and computer ...science, many applications in nanomedicine and nanorobotics require the additional capacity for controlled three-dimensional movement. DNA architectures can span three dimensions and DNA devices are capable of movement, but active control of well-defined three-dimensional structures has not been achieved. We demonstrate the operation of reconfigurable DNA tetrahedra whose shapes change precisely and reversibly in response to specific molecular signals. Shape changes are confirmed by gel electrophoresis and by bulk and single-molecule Förster resonance energy transfer measurements. DNA tetrahedra are natural building blocks for three-dimensional construction; they may be synthesized rapidly with high yield of a single stereoisomer, and their triangulated architecture conveys structural stability. The introduction of shape-changing structural modules opens new avenues for the manipulation of matter on the nanometre scale.
A Self-Assembled DNA Bipyramid Erben, Christoph M; Goodman, Russell P; Turberfield, Andrew J
Journal of the American Chemical Society,
06/2007, Letnik:
129, Številka:
22
Journal Article
Recenzirano
Nanometer-scale DNA polyhedra, consisting of 3- or 4-arm branch junctions connected by rigid double-helical edges, can be created by self-assembly protocols that exploit the specificity of ...base-pairing interactions. The DNA tetrahedron was the first such structure to be made rapidly and in high yield from multiple strands in a single assembly step. Facile and efficient synthesis is a necessary enabling step toward the application of these controllable three-dimensional scaffolds as building blocks for nanofabrication or as functional molecular cages. Herein we demonstrate the single-step assembly of a DNA trigonal bipyramid, demonstrating that more complex, less symmetric polyhedra can also be created by one-step assembly.
To examine the roles of mitochondrial calcium Ca2+ (Ca2+mt) and cytosolic Ca2+ (Ca2+cyt) in the regulation of hepatic mitochondrial fat oxidation, we studied a liver-specific mitochondrial calcium ...uniporter knockout (MCU KO) mouse model with reduced Ca2+mt and increased Ca2+cyt content. Despite decreased Ca2+mt, deletion of hepatic MCU increased rates of isocitrate dehydrogenase flux, α-ketoglutarate dehydrogenase flux, and succinate dehydrogenase flux in vivo. Rates of 14C16palmitate oxidation and intrahepatic lipolysis were increased in MCU KO liver slices, which led to decreased hepatic triacylglycerol content. These effects were recapitulated with activation of CAMKII and abrogated with CAMKII knockdown, demonstrating that Ca2+cyt activation of CAMKII may be the primary mechanism by which MCU deletion promotes increased hepatic mitochondrial oxidation. Together, these data demonstrate that hepatic mitochondrial oxidation can be dissociated from Ca2+mt and reveal a key role for Ca2+cyt in the regulation of hepatic fat mitochondrial oxidation, intrahepatic lipolysis, gluconeogenesis, and lipid accumulation.To examine the roles of mitochondrial calcium Ca2+ (Ca2+mt) and cytosolic Ca2+ (Ca2+cyt) in the regulation of hepatic mitochondrial fat oxidation, we studied a liver-specific mitochondrial calcium uniporter knockout (MCU KO) mouse model with reduced Ca2+mt and increased Ca2+cyt content. Despite decreased Ca2+mt, deletion of hepatic MCU increased rates of isocitrate dehydrogenase flux, α-ketoglutarate dehydrogenase flux, and succinate dehydrogenase flux in vivo. Rates of 14C16palmitate oxidation and intrahepatic lipolysis were increased in MCU KO liver slices, which led to decreased hepatic triacylglycerol content. These effects were recapitulated with activation of CAMKII and abrogated with CAMKII knockdown, demonstrating that Ca2+cyt activation of CAMKII may be the primary mechanism by which MCU deletion promotes increased hepatic mitochondrial oxidation. Together, these data demonstrate that hepatic mitochondrial oxidation can be dissociated from Ca2+mt and reveal a key role for Ca2+cyt in the regulation of hepatic fat mitochondrial oxidation, intrahepatic lipolysis, gluconeogenesis, and lipid accumulation.
Abstract
Background: Therapies to prevent alcohol-associated liver disease (ALD) in high-risk patients are needed. Aims: In this retrospective association study, we examined whether patients with ...alcohol use disorder (AUD) who reported greater exercise were less likely to develop liver disease. Methods: In this retrospective cohort study, we used the Mass General Brigham Biobank to investigate the impact of both moderate-high and light-intensity exercise on the development of ALD in patients with AUD, using clinician-provided diagnostic International Classification of Diseases 10 codes. Exercise was evaluated using a questionnaire completed after an AUD diagnosis, and before evidence of liver disease. Cox regressions were used to generate hazard ratios (HRs) for the development of ALD. Results: 1987 patients met inclusion criteria. These patients were followed for an average of 10.7 years. In multivariable analyses, we found that patients that reported at least 2.5 h of moderate-high intensity exercise/week (confidence interval recommendation for exercise) were less likely to develop ALD compared to patients that did not exercise (HR: 0.26, 95%CI: 0.085–0.64, P = 0.007). Indeed, each hour of moderate-high intensity exercise was associated with progressively decreasing odds of developing ALD (HR: 0.76, 95%CI: 0.58–0.91, P = 0.02). Conversely, patients who did not engage in any moderate-high intensity exercise were more likely to develop ALD (HR: 2.76, 95%CI: 1.44–5.40, P = 0.003). Conclusions: In our cohort, patients with AUD who reported moderate-high intensity exercise showed a lower association with incidence of ALD development than patients who did not exercise.
Short Summary: In this retrospective cohort study, we investigated the impact of moderate-high intensity exercise on the development of alcohol-associated liver disease in patients with alcohol use disorder, using International Classification of Diseases 10 codes. For each hour of reported moderate-high intensity exercise patients had progressively decreasing odds of developing alcohol-associated liver disease.
The family
Totiviridae
includes a number of viruses with monosegmented dsRNA genomes and isometric virions that infect either fungi or a number of medically important protozoan parasites such as
...Leishmania
and
Giardia
. A new genus,
Trichomonasvirus
, was recently approved for this family. Its name is based on the genus of its host organism,
Trichomonas vaginalis
, a protozoan parasite that colonizes the human genitourinary mucosa and is the most common non-viral sexually transmitted infection in the world. The type species of this new genus is
Trichomonas vaginalis virus 1
. Distinguishing characteristics of the new genus include infection of a human sexually transmitted parasite, stable mixed infection with more than one distinct
Trichomonasvirus
species, and sequence-based phylogenetic divergence that distinguishes it from all other family members.
Common genetic variants in glucokinase regulator (GCKR), which encodes GKRP, a regulator of hepatic glucokinase (GCK), influence multiple metabolic traits in genome-wide association studies (GWASs), ...making GCKR one of the most pleiotropic GWAS loci in the genome. It is unclear why. Prior work has demonstrated that GCKR influences the hepatic cytosolic NADH/NAD+ ratio, also referred to as reductive stress. Here, we demonstrate that reductive stress is sufficient to activate the transcription factor ChREBP and necessary for its activation by the GKRP-GCK interaction, glucose, and ethanol. We show that hepatic reductive stress induces GCKR GWAS traits such as increased hepatic fat, circulating FGF21, and circulating acylglycerol species, which are also influenced by ChREBP. We define the transcriptional signature of hepatic reductive stress and show its upregulation in fatty liver disease and downregulation after bariatric surgery in humans. These findings highlight how a GCKR-reductive stress-ChREBP axis influences multiple human metabolic traits.
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•Increases in hepatic cytosolic NADH/NAD+ (reductive stress) change the hepatic transcriptome•These transcriptional changes are mediated by ChREBP, which is activated by reductive stress•GCKR’s metabolic pleiotropy is explained in part by ChREBP’s activation via reductive stress•Multiple human metabolic traits may be influenced by a GCKR-NADH/NAD+-ChREBP-FGF21 axis
Singh et al. find that increased hepatic cytosolic NADH/NAD+ activates the transcription factor ChREBP. This pathway underlies some metabolic traits associated with common GCKR genetic variants, such as circulating FGF21 and triglyceride levels, and likely more generally influences certain deleterious metabolic traits in humans.
One serious side effect of statin drugs is skeletal muscle myopathy. Although the mechanism(s) responsible for statin myopathy remains to be fully determined, an increase in muscle atrophy gene ...expression and changes in mitochondrial content and/or function have been proposed to play a role. In this study, we examined the relationship between statin-induced expression of muscle atrophy genes, regulators of mitochondrial biogenesis, and markers of mitochondrial content in slow- (ST) and fast-twitch (FT) rat skeletal muscles. Male Sprague Dawley rats were treated with simvastatin (60 or 80 mg·kg(-1)·day(-1)) or vehicle control via oral gavage for 14 days. In the absence of overt muscle damage, simvastatin treatment induced an increase in atrogin-1, MuRF1 and myostatin mRNA expression; however, these were not associated with changes in peroxisome proliferator gamma co-activator 1 alpha (PGC-1α) protein or markers of mitochondrial content. Simvastatin did, however, increase neuronal nitric oxide synthase (nNOS), endothelial NOS (eNOS) and AMPK α-subunit protein expression, and tended to increase total NOS activity, in FT but not ST muscles. Furthermore, simvastatin induced a decrease in β-hydroxyacyl CoA dehydrogenase (β-HAD) activity only in FT muscles. These findings suggest that the statin-induced activation of muscle atrophy genes occurs independent of changes in PGC-1α protein and mitochondrial content. Moreover, muscle-specific increases in NOS expression and possibly NO production, and decreases in fatty acid oxidation, could contribute to the previously reported development of overt statin-induced muscle damage in FT muscles.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Growing literature highlights the need to integrate hepatology and addiction care to improve outcomes for patients with alcohol use disorder and alcohol-associated liver disease. However, prospective ...data for this approach are lacking.
We prospectively examined the efficacy of an integrated hepatology and addiction medicine approach on alcohol use and hepatology outcomes in inpatients with alcohol use disorder.
An integrated approach improved the uptake of medical alcohol therapy, hepatic fibrosis screening, and viral hepatitis vaccination compared with a historical control of patients who received addiction medicine care alone. There were no differences in the rates of early alcohol remission. The integration of hepatology and addiction care may improve outcomes in patients with alcohol use disorder.
Despite being a leading cause of advanced liver disease, alcohol-associated liver disease (ALD) has no effective medical therapies. The circulating proteome, which comprises proteins secreted by ...different cells and tissues in the context of normal physiological function or in the setting of disease and illness, represents an attractive target for uncovering novel biology related to the pathogenesis of ALD. In this work, we used the aptamer-based SomaScan proteomics platform to quantify the relative concentration of over 1300 proteins in a well-characterized cohort of patients with the spectrum of ALD. We found a distinct circulating proteomic signature that correlated with ALD severity, including over 600 proteins that differed significantly between ALD stages, many of which have not previously been associated with ALD to our knowledge. Notably, certain proteins that were markedly dysregulated in patients with alcohol-associated hepatitis were also altered, to a lesser degree, in patients with subclinical ALD and may represent early biomarkers for disease progression. Taken together, our work highlights the vast and distinct changes in the circulating proteome across the wide spectrum of ALD, identifies potentially novel biomarkers and therapeutic targets, and provides a proteomic resource atlas for ALD researchers and clinicians.
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