Etiological overlap between obsessive‐compulsive disorder and anorexia nervosa: a longitudinal cohort,multigenerational family and twin study

Obsessive‐compulsive disorder (OCD) often co‐occurs with anorexia nervosa (AN), a comorbid profile that complicates the clinical management of both conditions. This population‐based study aimed to examine patterns of comorbidity, longitudinal risks, shared familial risks and shared genetic factors between OCD and AN at the population level. Participants were individuals with a diagnosis of OCD (N=19,814) or AN (N=8,462) in the Swedish National Patient Register between January 1992 and December 2009; their first‐, second‐ and third‐degree relatives; and population‐matched (1:10 ratio) unaffected comparison individuals and their relatives. Female twins from the population‐based Swedish Twin Register (N=8,550) were also included. Females with OCD had a 16‐fold increased risk of having a comorbid diagnosis of AN, whereas males with OCD had a 37‐fold increased risk. Longitudinal analyses showed that individuals first diagnosed with OCD had an increased risk for a later diagnosis of AN (risk ratio, RR=3.6), whereas individuals first diagnosed with AN had an even greater risk for a later diagnosis of OCD (RR=9.6). These longitudinal risks were about twice as high for males than for females. First‐ and second‐degree relatives of probands with OCD had an increased risk for AN, and the magnitude of this risk tended to increase with the degree of genetic relatedness. Bivariate twin models revealed a moderate but significant degree of genetic overlap between self‐reported OCD and AN diagnoses (r_a=0.52, 95% CI: 0.26‐0.81), but most of the genetic variance was disorder‐specific. The moderately high genetic correlation supports the idea that this frequently observed comorbid pattern is at least in part due to shared genetic factors, though disorder‐specific factors are more important. These results have implications for current gene‐searching efforts and for clinical practice.     

Structure-guided development of dual β2 adrenergic/dopamine D2 receptor agonists

Aiming to discover dual-acting β₂ adrenergic/dopamine D₂ receptor ligands, a structure-guided approach for the evolution of GPCR agonists that address multiple targets was elaborated. Starting from GPCR crystal structures, we describe the design, synthesis and biological investigation of a defined set of compounds leading to the identification of the benzoxazinone (R)-3, which shows agonist properties at the adrenergic β₂ receptor and substantial G protein-promoted activation at the D₂ receptor. This directed approach yielded molecular probes with tuned dual activity. The congener desOH-3 devoid of the benzylic hydroxyl function was shown to be a β₂ adrenergic antagonist/D₂ receptor agonist with K_i values in the low nanomolar range. The compounds may serve as a promising starting point for the investigation and treatment of neurological disorders.     

Telomere length and metabolic syndrome traits: A Mendelian randomisation study

Observational studies have revealed associations between short leucocyte telomere length (LTL), a TL marker in somatic tissues and multiple Metabolic Syndrome (MetS) traits. Animal studies have supported these findings by showing that increased telomere attrition leads to adipose tissue dysfunction and insulin resistance. We investigated the associations between genetically instrumented LTL and MetS traits using Mendelian Randomisation (MR). Fifty‐two independent variants identified at FDR<0.05 from a genome‐wide association study (GWAS) including 78,592 Europeans and collectively accounting for 2.93% of LTL variance were selected as genetic instruments for LTL. Summary‐level data for MetS traits and for the MetS as a binary phenotype were obtained from the largest publicly available GWAS and two‐sample MR analyses were used to estimate the associations of LTL with these traits. The combined effect of the genetic instruments was modelled using inverse variance weighted regression and sensitivity analyses with MR‐Egger, weighted‐median and MR‐PRESSO were performed to test for and correct horizonal pleiotropy. Genetically instrumented longer LTL was associated with higher waist‐to‐hip ratio adjusted for body mass index (β = 0.045 SD, SE = 0.018, p = 0.01), raised systolic (β = 1.529 mmHg, SE = 0.332, p = 4x10⁻⁶) and diastolic (β = 0.633 mmHg, SE = 0.222, p = 0.004) blood pressure, and increased MetS risk (OR = 1.133, 95% CI 1.057–1.215). Consistent results were obtained in sensitivity analyses, which provided no evidence of unbalanced horizontal pleiotropy. Telomere shortening might not be a major driver of cellular senescence and dysfunction in human adipose tissue. Future experimental studies should examine the mechanistic bases for the links between longer LTL and increased upper‐body fat distribution and raised blood pressure.     

Disruption of oxidative phosphorylation and synaptic Na,K-ATPase activity by pristanic acid in cerebellum of young rats

Aims

Peroxisomal biogenesis disorders (PBD) are inherited disorders clinically manifested by neurological symptoms and brain abnormalities, in which the cerebellum is usually involved. Biochemically, patients affected by these neurodegenerative diseases accumulate branched-chain fatty acids, including pristanic acid (Prist) in the brain and other tissues.

Main methods

In the present investigation we studied the in vitro influence of Prist, at doses found in PBD, on oxidative phosphorylation, by measuring the activities of the respiratory chain complexes I–IV and ATP production, as well as on creatine kinase and synaptic Na⁺, K⁺-ATPase activities in rat cerebellum.

Key findings

Prist significantly decreased complexes I–III (65%), II (40%) and especially II–III (90%) activities, without altering the activities of complex IV of the respiratory chain and creatine kinase. Furthermore, ATP formation and synaptic Na⁺, K⁺-ATPase activity were markedly inhibited (80–90%) by Prist. We also observed that this fatty acid altered mitochondrial and synaptic membrane fluidity that may have contributed to its inhibitory effects on the activities of the respiratory chain complexes and Na⁺, K⁺-ATPase.

Significance

Considering the importance of oxidative phosphorylation for mitochondrial homeostasis and of Na⁺, K⁺-ATPase for the maintenance of cell membrane potential, the present data indicate that Prist compromises brain bioenergetics and neurotransmission in cerebellum. We postulate that these pathomechanisms may contribute to the cerebellar alterations observed in patients affected by PBD in which Prist is accumulated.     

The Human Obesity Gene Map: The 2001 Update

This report constitutes the eighth update of the human obesity gene map, incorporating published results up to the end of October 2001. Evidence from the rodent and human obesity cases caused by single-gene mutations, Mendelian disorders exhibiting obesity as a clinical feature, quantitative trait loci (QTLs) uncovered in human genome-wide scans and in crossbreeding experiments in various animal models, association and linkage studies with candidate genes and other markers is reviewed. The human cases of obesity related in some way to single-gene mutations in six different genes are incorporated. Twenty-five Mendelian disorders exhibiting obesity as one of their clinical manifestations have now been mapped. The number of different QTLs reported from animal models currently reaches 165. Attempts to relate DNA sequence variation in specific genes to obesity phenotypes continue to grow, with 174 studies reporting positive associations with 58 candidate genes. Finally, 59 loci have been linked to obesity indicators in genomic scans and other linkage study designs. The obesity gene map depicted in Figure 1 reveals that putative loci affecting obesity-related phenotypes can be found on all chromosomes except chromosome Y. A total of 54 new loci have been added to the map in the past 12 months, and the number of genes, markers, and chromosomal regions that have been associated or linked with human obesity phenotypes is now above 250. Likewise, the number of negative studies, which are only partially reviewed here, is also on the rise.     

嗜黏蛋白阿克曼氏菌治疗疾病的潜力与作用机制研究进展

嗜黏蛋白阿克曼氏菌(Akkermansia muciniphila, AKK)可促进肠道黏液分泌,维持肠道黏液动态平衡,调节肠黏膜屏障功能,在机体代谢调节、免疫应答中发挥重要作用。AKK对肠道炎症、神经炎症、机体代谢紊乱和癌症等疾病具有显著改善作用,被视为极具潜力的下一代益生菌。本文分别从消化系统、神经系统、代谢性紊乱和癌症等角度入手,系统概述AKK在疾病治疗中的潜力及作用分子机制。     

Metabolic defects shared by Alzheimer's disease and diabetes: A focus on mitochondria

Type 2 diabetes (T2D) and Alzheimer's disease (AD) are two global epidemics that share several metabolic defects, such as insulin resistance, impaired glucose metabolism, and mitochondrial defects. Importantly, strong evidence demonstrates that T2D significantly increases the risk of cognitive decline and dementia, particularly AD. Here, we provide an overview of the metabolic defects that characterize and link both pathologies putting the focus on mitochondria. The biomarker potential of mitochondrial components and the therapeutic potential of some drugs that target and modulate mitochondria are also briefly discussed.     

Implication of the hepatokine,fibrinogen-like protein 1 in liver diseases,metabolic disorders and cancer: The need to harness its full potential

Fibrinogen-like protein 1 (FGL1) is a novel hepatokine that forms part of the fibrinogen superfamily. It is predominantly expressed in the liver under normal physiological conditions. When the liver is injured by external factors, such as chemical drugs and radiation, FGL1 acts as a protective factor to promote the growth of regenerated cells. However, elevated hepatic FGL1 under high fat conditions can cause lipid accumulation and inflammation, which in turn trigger the development of non-alcoholic fatty liver disease, diabetes, and obesity. FGL1 is also involved in the regulation of insulin resistance in adipose tissues and skeletal muscles as a means of communication between the liver and other tissues. In addition, the abnormally changed FGL1 levels in the plasma of cancer patients make it a potential predictor of cancer incidence in clinical practice. FGL1 was recently identified as a major functional ligand of the immune inhibitory receptor, lymphocyte-activation gene 3 (LAG3), thus making it a promising target for cancer immunotherapy except for the classical programmed cell death protein 1/programmed cell death ligand 1 (PD-1/PD-L1) axis. Despite the potential of FGL1 as a new cancer biomarker and therapeutic target, there are few related studies and much of what has been reported are superficial and lack depth and particularity. Therefore, elucidating the role and underlying mechanisms of FGL1 could be crucial for the development of promising diagnostic and therapeutic strategies for related diseases. Here, we provide a comprehensive review of the cellular mechanisms and clinical prospects of FGL1 in the prevention and treatment of liver diseases, metabolic disorders and cancer, and proffer suggestions for future studies.     

Dopamine Receptor Microdomains Involved in Molecular Recognition and the Regulation of Drug Affinity and Function

A cationic protonatable amine moiety on dopaminergic ligands forms a high affinity reinforced ionic bond with an anionic aspartic acid at position 3.32 of dopamine receptors. When present, catechol hydroxyls of the ligands form hydrogen bonds with serines at position 5.42, 5.43, and 5.46, and this network of hydrogen bonds serves to orient ligands in the binding-site crevice and increase their binding affinity. A steric clash between aromatic moieties of the ligands and aromatic amino acids of the receptor (e.g., H6.55, F6.52 or F6.51 and W6.48) is likely to be propagated in domino-like fashion along the length of TM6, which is believed to trigger activation of the receptor. Specifically, it is the change in the conformation of W6.48 from an orientation perpendicular to the plane of the lipid membrane to one that is parallel that is believed to result in activation. Molecular determinants that mediate the D4/D2-selectivity of many extremely D4-selective 1,4-DAP ligands, include a nonconserved cluster of bulky amino acids at the TM2/TM3 interface (positions 2.61, 3.28 and 3.29).     

Special issue on “AGEs and ALEs: chemistry,physiopathology and molecular strategies for their inhibition”

Methamphetamine (METH)-induced neurotoxicity is associated with mitochondrial dysfunction and enhanced oxidative stress. The aims of the present study conducted in the mouse brain repetitively treated with METH were to (1) examine the redox status using the redox-sensitive imaging probe 3-methoxycarbonyl-2,2,5,5-tetramethylpiperidine-1-oxyl (MCP) and (2) non-invasively visualize the brain redox status with electron paramagnetic resonance (EPR) imaging. The rate of reduction of MCP was measured from a series of temporal EPR images of mouse heads, and this rate was used to construct a two-dimensional map of rate constants called a “redox map.” The obtained redox map clearly illustrated the change in redox balance in the METH-treated mouse brain that is a known result of oxidative damage. Biochemical assays also showed that the level of thiobarbituric acid-reactive substance, an index of lipid peroxidation, was increased in mouse brains by METH. The enhanced reduction in MCP observed in mouse brains was remarkably suppressed by treatment with the dopamine synthase inhibitor, α-methyl-p-tyrosine, suggesting that enhancement of the reduction reaction of MCP resulted from enzymatic reduction in the mitochondrial respiratory chain. Furthermore, magnetic resonance imaging (MRI) of METH-treated mice using a blood–brain barrier (BBB)-impermeable paramagnetic contrast agent revealed BBB dysfunction after treatment with METH for 7 days. MRI also indicated that the impaired BBB recovered after withdrawal of METH. EPR imaging and MRI are useful tools not only for following changes in the redox status and BBB dysfunction in mouse brains repeatedly administered METH, but also for tracing the drug effect after withdrawal of METH.