Nearly all human complex traits and disease phenotypes exhibit some degree of sex differences, including differences in prevalence, age of onset, severity or disease progression. Until recently, the ...underlying genetic mechanisms of such sex differences have been largely unexplored. Advances in genomic technologies and analytical approaches are now enabling a deeper investigation into the effect of sex on human health traits. In this Review, we discuss recent insights into the genetic models and mechanisms that lead to sex differences in complex traits. This knowledge is critical for developing deeper insight into the fundamental biology of sex differences and disease processes, thus facilitating precision medicine.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Background & Aims Tight junction dysregulation and epithelial damage contribute to barrier loss in patients with inflammatory bowel disease. However, the mechanisms that regulate these processes and ...their relative contributions to disease pathogenesis are not completely understood. We investigated these processes using colitis models in mice. Methods We induced colitis by adoptive transfer of CD4+ CD45RBhi cells or administration of dextran sulfate sodium to mice, including those deficient in tumor necrosis factor receptor (TNFR) 1, TNFR2, or the long isoform of myosin light chain kinase (MLCK). Intestinal tissues and isolated epithelial cells were analyzed by immunoblot, immunofluorescence, enzyme-linked immunosorbent assay, and real-time polymerase chain reaction assays. Results Induction of immune-mediated colitis by CD4+ CD45RBhi adoptive transfer increased intestinal permeability, epithelial expression of claudin-2, the long isoform of MLCK, and TNFR2 (but not TNFR1) and phosphorylation of the myosin II light chain. Long MLCK upregulation, myosin II light chain phosphorylation, barrier loss, and weight loss were attenuated in TNFR2 −/− , but not TNFR1 −/− , recipients of wild-type CD4+ CD45RBhi cells. Similarly, long MLCK −/− mice had limited increases in myosin II light chain phosphorylation, claudin-2 expression, and intestinal permeability and delayed onset of adoptive transfer−induced colitis. However, coincident with onset of epithelial apoptosis, long MLCK −/− mice ultimately developed colitis. This indicates that disease progresses via apoptosis in the absence of MLCK-dependent tight junction regulation. In support of this conclusion, long MLCK −/− mice were not protected from epithelial apoptosis-mediated, damage-dependent dextran sulfate sodium colitis. Conclusions In immune-mediated inflammatory bowel disease models, TNFR2 signaling increases long MLCK expression, resulting in tight junction dysregulation, barrier loss, and induction of colitis. At advanced stages, colitis progresses by apoptosis and mucosal damage that result in tight junction- and MLCK-independent barrier loss. Therefore, barrier loss in immune-mediated colitis occurs via two temporally and morphologically distinct mechanisms. Differential targeting of these mechanisms can lead to improved inflammatory bowel disease therapies.
1
-Pyrrole-2,3-diones, fused at
-side with a heterocycle, are suitable platforms for the synthesis of various angular polycyclic alkaloid-like spiroheterocycles. Recently discovered ...sulfur-containing
-fused 1
-pyrrole-2,3-diones (aroylpyrrolobenzothiazinetriones) tend to exhibit unusual reactivity. Based on these peculiar representatives of
-fused 1
-pyrrole-2,3-diones, we have developed an approach to an unprecedented 6/5/5/5-tetracyclic alkaloid-like spiroheterocyclic system of benzo
pyrrolo3',4':2,3pyrrolo2,1-
thiazole via their reaction with Schiff bases and carbodiimides. The experimental results have been supplemented with DFT computational studies. The synthesized alkaloid-like 6/5/5/5-tetracyclic compounds have been tested for their biotechnological potential as growth stimulants in the green algae
.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Acyl(imidoyl)ketenes are highly reactive heterocumulenes that enable diversity-oriented synthesis of various drug-like heterocycles. Such ketenes, bearing heterocyclic substituents, afford angularly ...fused pyridin-2(1
)-ones in their 4+2-cyclodimerization reactions. We have utilized this property for the development of a new synthetic approach to pharmaceutically interesting pyrido2,1-
1,3benzothiazol-1-ones via the 4+2-cyclodimerization of acyl(1,3-benzothiazol-2-yl)ketenes generated in situ. The thermal behaviors of 3-aroylpyrrolo2,1-
1,4benzothiazine-1,2,4-triones and 3-benzoylpyrrolo2,1-
1,3benzothiazole-1,2-dione (two new types of
-fused 1
-pyrrole-2,3-diones reported by us recently) have been studied by thermal analysis and HPLC to elucidate their capability to be a source of acyl(1,3-benzothiazol-2-yl)ketenes. As a result, we have found that only 3-aroylpyrrolo2,1-
1,4benzothiazine-1,2,4-triones are suitable for this. The experimental results are supplemented with computational studies that demonstrate that thermolysis of 3-aroylpyrrolo2,1-
1,4benzothiazine-1,2,4-triones proceeds through an unprecedented cascade of two thermal decarbonylations. Based on these studies, we discovered a novel mode of thermal transformation of
-fused 1
-pyrrole-2,3-diones and developed a new pot, atom, and step economic synthetic approach to pyrido2,1-
1,3benzothiazol-1-ones. The synthesized drug-like pyrido2,1-b1,3benzothiazol-1-ones are of interest to pharmaceutics, since their close analogs show significant antiviral activity.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
The reaction of 3-benzoylpyrrolo2,1-c1,4benzothiazine-1,2,4-trione with 2,3-dimethylquinoxaline afforded ...3-benzoyl-2-hydroxy-3a-(3-methylquinoxalin-2-yl)methyl-1H-pyrrolo2,1-c1,4benzothiazine-1,4(3aH)-dione in a moderate yield. The compound was fully characterized.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Pyrrolo2,1-
1,3benzothiazoles are an important class of fused sulfur and nitrogen-containing heterocycles intensively studied in medicinal chemistry and pharmacology. In the present paper, a new ...synthetic approach to pyrrolobenzothiazoles is developed based on 1,4-thiazine ring contraction in 3-aroylpyrrolo2,1-
1,4benzothiazine-1,2,4-triones under the action of nucleophiles. The proposed approach works well with alkanols, benzylamine, and arylamines. The scope and limitations of the developed approach are studied. The synthesized pyrrolobenzothiazole derivatives represent an interest to pharmaceutics, since their close analogs show CENP-E inhibitory activity, interesting for the targeted cancer therapy development.
The 3-hydroxy-1,5-dihydro-2H-pyrrol-2-one motif is a valuable scaffold in drug discovery. The replacement of the 3-oxy fragment in 3-hydroxy-1,5-dihydro-2H-pyrrol-2-ones-based compounds with a ...3-amino one (3-amino analogs of 3-hydroxy-1,5-dihydro-2H-pyrrol-2-ones, 3-amino-1,5-dihydro-2H-pyrrol-2-ones) can play a crucial role in their biological effect. Thus, approaches to 3-amino-1,5-dihydro-2H-pyrrol-2-ones are of significant interest. We developed an approach to 5-spiro-substituted 3-amino-1,5-dihydro-2H-pyrrol-2-ones that could not be obtained using previously reported approaches (reactions of 3-hydroxy-1,5-dihydro-2H-pyrrol-2-ones with amines). The developed approach is based on the thermal decomposition of 1,3-disubstituted urea derivatives of 5-spiro-substituted 3-hydroxy-1,5-dihydro-2H-pyrrol-2-ones, which were prepared via their reaction with carbodiimides.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Sterol Response Element Binding Protein 2 (SREBP2) transcription factor is a master regulator of cholesterol homeostasis. Treatment with statins, inhibitors of cholesterol synthesis, activates ...intestinal SREBP2, which may hinder their cholesterol-lowering effects. Overactivation of SREBP2 in mouse liver was shown to have no effect on plasma cholesterol. However, the influence of activating intestinal SREBP2 on plasma cholesterol is not known. We have generated a novel transgenic mouse model with intestine specific overexpression of active SREBP2 (ISR2) driven by villin promoter. ISR2 mice showed overexpression of active SREBP2 specifically in the intestine. Microarray analysis of jejunal RNA from ISR2 mice showed a significant increase in genes involved in fatty acid and cholesterol synthesis. Cholesterol and triglyceride (TG) in jejunum and liver (mg/g protein) were significantly increased in ISR2 vs wild type mice. Serum Cholesterol was significantly increased in VLDL and LDL fractions whereas the level of serum triglycerides was decreased in ISR2 vs wild type mice. In conclusion, activation of intestinal SREBP2 alone seems to be sufficient to increase plasma cholesterol, highlighting the essential role of intestine in maintaining cholesterol homeostasis in the body.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Phenotypic sex-based differences exist for many complex traits. In other cases, phenotypes may be similar, but underlying biology may vary. Thus, sex-aware genetic analyses are becoming increasingly ...important for understanding the mechanisms driving these differences. To this end, we provide a guide outlining the current best practices for testing various models of sex-dependent genetic effects in complex traits and disease conditions, noting that this is an evolving field. Insights from sex-aware analyses will not only teach us about the biology of complex traits but also aid in achieving the goals of precision medicine and health equity for all.
Sex-associated characteristics influence human health in many ways. This primer reviews best practices for testing various models of sex-related genetic effects in complex traits and diseases. Such analyses not only improve our understanding of biology but can also, when done properly, further precision medicine and health equity goals.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The origin of sex differences in prevalence and presentation of neuropsychiatric and behavioral traits is largely unknown. Given established genetic contributions and correlations, we tested for a ...sex-differentiated genetic architecture within and between traits.
Using European ancestry genome-wide association summary statistics for 20 neuropsychiatric and behavioral traits, we tested for sex differences in single nucleotide polymorphism (SNP)-based heritability and genetic correlation (rg < 1). For each trait, we computed per-SNP z scores from sex-stratified regression coefficients and identified genes with sex-differentiated effects using a gene-based approach. We calculated correlation coefficients between z scores to test for shared sex-differentiated effects. Finally, we tested for sex differences in across-trait genetic correlations.
We observed no consistent sex differences in SNP-based heritability. Between-sex, within-trait genetic correlations were high, although <1 for educational attainment and risk-taking behavior. We identified 4 genes with significant sex-differentiated effects across 3 traits. Several trait pairs shared sex-differentiated effects. The top genes with sex-differentiated effects were enriched for multiple gene sets, including neuron- and synapse-related sets. Most between-trait genetic correlation estimates were not significantly different between sexes, with exceptions (educational attainment and risk-taking behavior).
Sex differences in the common autosomal genetic architecture of neuropsychiatric and behavioral phenotypes are small and polygenic and unlikely to fully account for observed sex-differentiated attributes. Larger sample sizes are needed to identify sex-differentiated effects for most traits. For well-powered studies, we identified genes with sex-differentiated effects that were enriched for neuron-related and other biological functions. This work motivates further investigation of genetic and environmental influences on sex differences.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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