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Life Science Alliance Aug 2024A lack of social relationships is increasingly recognized as a type 2 diabetes (T2D) risk. To investigate the underlying mechanism, we used male KK mice, an inbred...
A lack of social relationships is increasingly recognized as a type 2 diabetes (T2D) risk. To investigate the underlying mechanism, we used male KK mice, an inbred strain with spontaneous diabetes. Given the association between living alone and T2D risk in humans, we divided the non-diabetic mice into singly housed (KK-SH) and group-housed control mice. Around the onset of diabetes in KK-SH mice, we compared H3K27ac ChIP-Seq with RNA-Seq using pancreatic islets derived from each experimental group, revealing a positive correlation between single-housing-induced changes in H3K27ac and gene expression levels. In particular, single-housing-induced H3K27ac decreases revealed a significant association with islet cell functions and GWAS loci for T2D and related diseases, with significant enrichment of binding motifs for transcription factors representative of human diabetes. Although these H3K27ac regions were preferentially localized to a polymorphic genomic background, SNVs and indels did not cause sequence disruption of enriched transcription factor motifs in most of these elements. These results suggest alternative roles of genetic variants in environment-dependent epigenomic changes and provide insights into the complex mode of disease inheritance.
Topics: Animals; Mice; Diabetes Mellitus, Type 2; Islets of Langerhans; Male; Epigenomics; Histones; Polymorphism, Single Nucleotide; Epigenesis, Genetic; Diabetes Mellitus, Experimental; Genome-Wide Association Study; Disease Models, Animal; Mice, Inbred C57BL
PubMed: 38876803
DOI: 10.26508/lsa.202302099 -
Life Science Alliance Sep 2024Calcium is critical for regulating the waveform of motile cilia and flagella. Calaxin is currently the only known molecule involved in the calcium-dependent regulation...
Calcium is critical for regulating the waveform of motile cilia and flagella. Calaxin is currently the only known molecule involved in the calcium-dependent regulation in ascidians. We have recently shown that Calaxin stabilizes outer arm dynein (OAD), and the knockout of Calaxin results in primary ciliary dyskinesia phenotypes in vertebrates. However, from the knockout experiments, it was not clear which functions depend on calcium and how Calaxin regulates the waveform. To address this question, here, we generated transgenic zebrafish expressing a mutant E130A-Calaxin deficient in calcium binding. E130A-Calaxin restored the OAD reduction of sperm and the abnormal movement of left-right organizer cilia, showing that Calaxin's stabilization of OADs is calcium-independent. In contrast, our quantitative analysis of E130A-Calaxin sperms showed that the calcium-induced asymmetric beating was not restored, linking Calaxin's calcium-binding ability with an asymmetric flagellar beating for the first time. Our data show that Calaxin is a calcium-dependent regulator of the ciliary beating and a calcium-independent OAD stabilizer.
Topics: Animals; Zebrafish; Male; Calcium; Spermatozoa; Animals, Genetically Modified; Zebrafish Proteins; Dyneins; Cilia; Flagella; Sperm Motility; Calcium-Binding Proteins
PubMed: 38876797
DOI: 10.26508/lsa.202402632 -
Life Science Alliance Sep 2024Innate lymphoid cells (ILCs) are critical for intestinal adaptation to microenvironmental challenges, and the gut mucosa is characterized by low oxygen. Adaptation to...
Innate lymphoid cells (ILCs) are critical for intestinal adaptation to microenvironmental challenges, and the gut mucosa is characterized by low oxygen. Adaptation to low oxygen is mediated by hypoxia-inducible transcription factors (HIFs), and the HIF-1α subunit shapes an ILC phenotype upon acute colitis that contributes to intestinal damage. However, the impact of HIF signaling in NKp46 ILCs in the context of repetitive mucosal damage and chronic inflammation, as it typically occurs during inflammatory bowel disease, is unknown. In chronic colitis, mice lacking the HIF-1α isoform in NKp46+ ILCs show a decrease in NKp46 ILC1s but a concomitant rise in neutrophils and Ly6C macrophages. Single-nucleus RNA sequencing suggests enhanced interaction of mesenchymal cells with other cell compartments in the colon of HIF-1α KO mice and a loss of mucus-producing enterocytes and intestinal stem cells. This was, furthermore, associated with increased bone morphogenetic pathway-integrin signaling, expansion of fibroblast subsets, and intestinal fibrosis. In summary, this suggests that HIF-1α-mediated ILC1 activation, although detrimental upon acute colitis, protects against excessive inflammation and fibrosis during chronic intestinal damage.
Topics: Animals; Hypoxia-Inducible Factor 1, alpha Subunit; Natural Cytotoxicity Triggering Receptor 1; Mice; Colitis; Fibrosis; Mice, Knockout; Lymphocytes; Intestinal Mucosa; Inflammation; Mice, Inbred C57BL; Chronic Disease; Immunity, Innate; Signal Transduction; Disease Models, Animal; Male; Intestines; Antigens, Ly
PubMed: 38876796
DOI: 10.26508/lsa.202402593 -
The Journal of Biological Chemistry Jun 2024Obesity is a major risk factor for liver and cardiovascular diseases. However, obesity-driven mechanisms that contribute to the pathogenesis of multiple organ diseases...
Obesity is a major risk factor for liver and cardiovascular diseases. However, obesity-driven mechanisms that contribute to the pathogenesis of multiple organ diseases are still obscure and treatment is inadequate. We hypothesized that increased glucose-6-phosphate dehydrogenase (G6PD), the key rate-limiting enzyme in the pentose shunt, is critical in evoking metabolic reprogramming in multiple organs and is a significant contributor to the pathogenesis of liver and cardiovascular diseases. G6PD is induced by carbohydrate-rich diet and insulin. Long-term (8 months) high-fat diet (HFD) feeding increased body weight and elicited metabolic reprogramming in visceral fat, liver, and aorta, of the wild-type rats. In addition, HFD increased inflammatory chemokines in visceral fat. Interestingly, CRISPR-edited loss-of-function Mediterranean G6PD variant (G6PD) rats, which mimic human polymorphism, moderated HFD-induced weight gain and metabolic reprogramming in visceral fat, liver, and aorta. The G6PD variant prevented HFD-induced CCL7 and adipocyte hypertrophy. Furthermore, the G6PD variant increased Magel2 - a gene encoding circadian clock-related protein that suppresses obesity associated with Prader-Willi syndrome - and reduced HFD-induced non-alcoholic fatty liver. Additionally, the G6PD variant reduced aging-induced aortic stiffening. Our findings suggest G6PD is a regulator of HFD-induced obesity, adipocyte hypertrophy, and fatty liver.
PubMed: 38876306
DOI: 10.1016/j.jbc.2024.107460 -
The Journal of Biological Chemistry Jun 2024Intracellular signaling by the pleiotropic cytokine transforming growth factor-β (TGF-β) is inhibited by Smad7 in a feedback control mechanism. The activity of Smad7...
Intracellular signaling by the pleiotropic cytokine transforming growth factor-β (TGF-β) is inhibited by Smad7 in a feedback control mechanism. The activity of Smad7 is tightly regulated by multiple post-translational modifications. Using resin-assisted capture and metabolic labeling methods, we show here that Smad7 is S-palmitoylated in mammary epithelial cell models that are widely studied because of their strong responses to TGF-β and their biological relevance to mammary development and tumor progression. S-palmitoylation of Smad7 is mediated by zDHHC17, a member of a family of 23 S-acyltransferase enzymes. Moreover, we identified four cysteine residues (Cys202, Cys225, Cys415, and Cys417) in Smad7 as palmitoylation acceptor sites. S-palmitoylation of Smad7 on Cys415 and Cys417 promoted the translocation of Smad7 from the nucleus to the cytoplasm, enhanced the stability of the Smad7 protein, and enforced its inhibitory effect on TGF-β-induced Smad transcriptional response. Thus, our findings reveal a new post-translational modification of Smad7, and highlight an important role of S-palmitoylation to enhance inhibition of TGF-β/Smad signaling by Smad7.
PubMed: 38876303
DOI: 10.1016/j.jbc.2024.107462 -
International Journal of... 2024TYK2 inhibitors and traditional natural drugs as promising drugs for psoriasis therapy are receiving increasing attention. They both affect different molecules of...
INTRODUCTION
TYK2 inhibitors and traditional natural drugs as promising drugs for psoriasis therapy are receiving increasing attention. They both affect different molecules of JAK/STAT pathway, but it is currently unclear whether their combination will enhance the effect on psoriasis. In this study, we used imiquimod (IMQ)-induced psoriasis mouse model to investigate the therapeutic effects of the combined administration of deucravacitinib (TYK2 inhibitor) and shikonin.
METHODS
Aldara cream containing 5% IMQ was used to topically treat the dorsal skin of each mouse for a total of six consecutive days to induce psoriasis. The psoriasis area and severity index (PASI) scores were recorded every day. On the 7 day, skin tissues were taken for histopathological examination and the content of cytokines in skin were evaluated. The frequency of immune cells in peripheral blood, spleen and skin were detected through flow cytometry.
RESULTS
Compared to the vehicle control group, the psoriasis symptoms and immune disorder improved significantly in the combination therapy group and deucravacitinib treatment group on the 7th day, and the expressions of p-STAT3 and Ki67 in skin were reduced as well. Moreover, the combined treatment of deucravacitinib and shikonin for psoriasis was superior to the monotherapy group, especially in inhibiting abnormal capillaries proliferation, reducing immune cells infiltration and decreasing the concentration of IL-12p70 in skin.
CONCLUSION
The combination of deucravacitinib and shikonin is a promising clinical application.
Topics: Animals; Psoriasis; Imiquimod; Naphthoquinones; Drug Therapy, Combination; Mice; Skin; Disease Models, Animal; Cytokines; Mice, Inbred BALB C; Male; Female; Benzimidazoles; Quinolones
PubMed: 38876119
DOI: 10.1177/03946320241260262 -
Medicine Jun 2024High Immunoglobulin E(IgE) levels associated with hypersensitivity or parasitic infection were well established, but the clinical significance of ultra-low IgE was... (Observational Study)
Observational Study
High Immunoglobulin E(IgE) levels associated with hypersensitivity or parasitic infection were well established, but the clinical significance of ultra-low IgE was largely unknown. Previous studies indicated these patients have an elevated risk of cancer, but large-scale epidemiological studies on the prevalence and clinical manifestations of these ultra-low IgE patients are still lacking. A total of 62,997 patients who were admitted to the First Affiliated Hospital of Wenzhou Medical University and had IgE level tests from January 2010 to March 2020 were included. Patients with serum IgE levels < 2 IU/mL were defined to have ultra-low IgE. And the clinical characteristics of these patients were retrospectively analyzed based on electronic medical record system and follow-up. A total of 223 patients (223/62,997, 0.35%) had ultra-low IgE were documented in 62,997 patients who had IgE tests. Among the clinical manifestations of these 223 ultra-low IgE patients, infection ranked first (125/223, 56.05%), following allergic diseases (51/223, 22.87%), hematological disorders (37/223, 16.59%), tumor (27/223, 12.11%) and autoimmune diseases (23/223, 10.31%). To the best of our knowledge, we first reported that the prevalence and clinical characteristics of 223 ultra-low IgE patients in China. The most common comorbidities were infection, allergic diseases, hematological disorders, tumor and autoimmune diseases.
Topics: Humans; Male; Female; China; Immunoglobulin E; Cross-Sectional Studies; Adult; Tertiary Care Centers; Middle Aged; Retrospective Studies; Adolescent; Prevalence; Young Adult; Child; Hypersensitivity; Aged; Child, Preschool; Neoplasms; Autoimmune Diseases; Hematologic Diseases
PubMed: 38875431
DOI: 10.1097/MD.0000000000038397 -
Medicine Jun 2024To explore the value of machine learning (ML) models based on contrast-enhanced cone-beam breast computed tomography (CE-CBBCT) radiomics features for the preoperative...
To explore the value of machine learning (ML) models based on contrast-enhanced cone-beam breast computed tomography (CE-CBBCT) radiomics features for the preoperative prediction of human epidermal growth factor receptor 2 (HER2)-low expression breast cancer (BC). Fifty-six patients with HER2-negative invasive BC who underwent preoperative CE-CBBCT were prospectively analyzed. Patients were randomly divided into training and validation cohorts at approximately 7:3. A total of 1046 quantitative radiomic features were extracted from CE-CBBCT images and normalized using z-scores. The Pearson correlation coefficient and recursive feature elimination were used to identify the optimal features. Six ML models were constructed based on the selected features: linear discriminant analysis (LDA), random forest (RF), support vector machine (SVM), logistic regression (LR), AdaBoost (AB), and decision tree (DT). To evaluate the performance of these models, receiver operating characteristic curves and area under the curve (AUC) were used. Seven features were selected as the optimal features for constructing the ML models. In the training cohort, the AUC values for SVM, LDA, RF, LR, AB, and DT were 0.984, 0.981, 1.000, 0.970, 1.000, and 1.000, respectively. In the validation cohort, the AUC values for the SVM, LDA, RF, LR, AB, and DT were 0.859, 0.880, 0.781, 0.880, 0.750, and 0.713, respectively. Among all ML models, the LDA and LR models demonstrated the best performance. The DeLong test showed that there were no significant differences among the receiver operating characteristic curves in all ML models in the training cohort (P > .05); however, in the validation cohort, the DeLong test showed that the differences between the AUCs of LDA and RF, AB, and DT were statistically significant (P = .037, .003, .046). The AUCs of LR and RF, AB, and DT were statistically significant (P = .023, .005, .030). Nevertheless, no statistically significant differences were observed when compared to the other ML models. ML models based on CE-CBBCT radiomics features achieved excellent performance in the preoperative prediction of HER2-low BC and could potentially serve as an effective tool to assist in precise and personalized targeted therapy.
Topics: Humans; Female; Breast Neoplasms; Prospective Studies; Middle Aged; Receptor, ErbB-2; Adult; Machine Learning; Cone-Beam Computed Tomography; Contrast Media; ROC Curve; Aged; Support Vector Machine; Area Under Curve; Radiomics
PubMed: 38875420
DOI: 10.1097/MD.0000000000038513 -
Medicine Jun 2024A prospective cohort study investigated the effectiveness of platelet-rich plasma (PRP) infusion for refractory thin endometrium in 38 infertile patients. Patients...
Treating refractory thin endometrium through a novel way of activation and administration of Platelet-rich plasma in sexually active women: An interventional prospective cohort clinical study.
A prospective cohort study investigated the effectiveness of platelet-rich plasma (PRP) infusion for refractory thin endometrium in 38 infertile patients. Patients showed significant improvement in endometrial thickness post-PRP injection, leading to successful implantation and pregnancy. The study revealed a negative correlation between antimullerian hormone (AMH) levels and the need for PRP interventions, suggesting higher ovarian reserve may reduce the necessity for repeated treatments. This implies AMH levels could serve as a prognostic indicator for treatment outcomes, aiding clinicians in optimizing protocols and reducing patient burden. Further research is needed to confirm these findings in larger and more diverse populations, along with exploring long-term reproductive success rates post-PRP treatment.
Topics: Humans; Female; Platelet-Rich Plasma; Prospective Studies; Adult; Endometrium; Infertility, Female; Anti-Mullerian Hormone; Pregnancy; Ovarian Reserve; Treatment Outcome
PubMed: 38875415
DOI: 10.1097/MD.0000000000038554 -
Medicine Jun 2024As a subtype of the 5-hydroxytryptamine (5-HT) receptor, 5-HT1A receptors are involved in the pathological process of psychiatric disorders and is an important target... (Review)
Review
As a subtype of the 5-hydroxytryptamine (5-HT) receptor, 5-HT1A receptors are involved in the pathological process of psychiatric disorders and is an important target for antidepressants. The research groups focus on these area have tried to design novel compounds to alleviate depression by targeting 5-HT1A receptor. The heterocyclic structures is an important scaffold to enhance the antidepressant activity of ligands, including piperazine, piperidine, benzothiazole, and pyrrolidone. The current review highlights the function and significance of nitrogen-based heterocyclics 5-HT1AR represented by piperazine, piperidine, benzothiazole, and pyrrolidone in the development of antidepressant.
Topics: Humans; Serotonin 5-HT1 Receptor Agonists; Antidepressive Agents; Receptor, Serotonin, 5-HT1A; Piperazines; Benzothiazoles; Heterocyclic Compounds; Piperidines; Pyrrolidinones; Depression
PubMed: 38875413
DOI: 10.1097/MD.0000000000038496