LincRNA-EPS inhibits caspase-11 and NLRP3 inflammasomes in gingival fibroblasts to alleviate periodontal inflammation.

To investigate the effects of long intergenic noncoding RNA-erythroid prosurvival (lincRNA-EPS) on periodontal inflammation mediated by inflammasomes and to explore its mechanism. Experimental periodontitis was induced in KO (lincRNA-EPS-/- ) and WT (lincRNA-EPS+/+ ) mice to compare the periodontal bone loss and inflammation by using micro-computed tomography, immunofluorescence staining and haematoxylin and eosin staining. The expression and activation of cysteinyl aspartate-specific proteinase-11 (caspase-11) and NOD-like receptor protein 3 (NLRP3) inflammasomes, as well as nuclear factor-kappa B (NF-κB) activation in mouse gingival fibroblasts (MGFs), were measured by real-time quantitative polymerase chain reaction, Western blotting, enzyme-linked immunosorbent and lactate dehydrogenase assays. MGFs were transfected with overexpression plasmids to assess the biological functions of lincRNA-EPS. RNA pull-down and immunoprecipitation experiments were performed to identify the interacting protein of lincRNA-EPS. LincRNA-EPS-expressing lentivirus was locally administered to inflamed periodontal tissues to evaluate its salvage function in periodontitis. The absence of lincRNA-EPS increased bone loss and expression of myeloperoxidase, interleukin-1α (IL-1α) and IL-1ß in the inflammatory periodontium. LincRNA-EPS KO MGFs exhibited increased expression and activation of caspase-11/NLRP3 inflammasome components than WT MGFs under lipopolysaccharide (LPS) stimulation. The expression and activation of these molecules were inhibited in lincRNA-EPS overexpressed MGFs. Mechanistically, lincRNA-EPS directly bound to transactive response DNA-binding protein 43 (TDP43) in the nucleus of MGFs, and TDP43 knockdown exerted a similar inhibitory effect on NF-κB activation and the inflammasomes as lincRNA-EPS overexpression. Locally injecting lincRNA-EPS-expressing lentivirus weakened the periodontal damage. LincRNA-EPS inhibits the LPS-induced production and activation of caspase-11 and NLRP3 inflammasomes by suppressing the activation of the NF-κB signalling pathway via interacting with TDP43, thereby alleviating periodontitis.

A novel CPT1A covalent inhibitor modulates fatty acid oxidation and CPT1A-VDAC1 axis with therapeutic potential for colorectal cancer.

Colorectal cancer (CRC) is a common and deadly disease of the digestive system, but its targeted therapy is hampered by the lack of reliable and specific biomarkers. Hence, discovering new therapeutic targets and agents for CRC is an urgent and challenging task. Here we report that carnitine palmitoyltransferase 1A (CPT1A), a mitochondrial enzyme that catalyzes fatty acid oxidation (FAO), is a potential target for CRC treatment. We show that CPT1A is overexpressed in CRC cells and that its inhibition by a secolignan-type compound, 2,6-dihydroxypeperomin B (DHP-B), isolated from the plant Peperomia dindygulensis, suppresses tumor cell growth and induces apoptosis. We demonstrate that DHP-B covalently binds to Cys96 of CPT1A, blocks FAO, and disrupts the mitochondrial CPT1A-VDAC1 interaction, leading to increased mitochondrial permeability and reduced oxygen consumption and energy metabolism in CRC cells. We also reveal that CPT1A expression correlates with the survival of tumor-bearing animals and that DHP-B exhibits anti-CRC activity in vitro and in vivo. Our study uncovers the molecular mechanism of DHP-B as a novel CPT1A inhibitor and provides a rationale for its preclinical development as well as a new strategy for CRC targeted therapy.

HECT, UBA and WWE domain containing 1 represses cholesterol efflux during CD4+ T cell activation in Sjögren's syndrome.

Introduction: Sjögren's syndrome (SS) is a chronic autoimmune disorder characterized by exocrine gland dysfunction, leading to loss of salivary function. Histological analysis of salivary glands from SS patients reveals a high infiltration of immune cells, particularly activated CD4+ T cells. Thus, interventions targeting abnormal activation of CD4+ T cells may provide promising therapeutic strategies for SS. Here, we demonstrate that Hect, uba, and wwe domain containing 1 (HUWE1), a member of the eukaryotic Hect E3 ubiquitin ligase family, plays a critical role in CD4+ T-cell activation and SS pathophysiology. Methods: In the context of HUWE1 inhibition, we investigated the impact of the HUWE1 inhibitor BI8626 and sh-Huwe1 on CD4+ T cells in mice, focusing on the assessment of activation levels, proliferation capacity, and cholesterol abundance. Furthermore, we examined the therapeutic potential of BI8626 in NOD/ShiLtj mice and evaluated its efficacy as a treatment strategy. Results: Inhibition of HUWE1 reduces ABCA1 ubiquitination and promotes cholesterol efflux, decreasing intracellular cholesterol and reducing the expression of phosphorylated ZAP-70, CD25, and other activation markers, culminating in the suppressed proliferation of CD4+ T cells. Moreover, pharmacological inhibition of HUWE1 significantly reduces CD4+ T-cell infiltration in the submandibular glands and improves salivary flow rate in NOD/ShiLtj mice. Conclusion: These findings suggest that HUWE1 may regulate CD4+ T-cell activation and SS development by modulating ABCA1-mediated cholesterol efflux and presents a promising target for SS treatment.

Heliangin acts as a covalent ligand of RPS2 that disrupts pre-rRNA metabolic processes in NPM1-mutated acute myeloid leukemia.

Although NPM1 mutations are frequently found in acute myeloid leukemia patients, therapeutic strategies are scarce and unsuitable for those who cannot tolerate intensive chemotherapy. Here we demonstrated that heliangin, a natural sesquiterpene lactone, exerts favorable therapeutic responses in NPM1 mutant acute myeloid leukemia cells, with no apparent toxicity to normal hematogenous cells, by inhibiting their proliferation, inducing apoptosis, causing cell cycle arrest, and promoting differentiation. In-depth studies on its mode of action using quantitative thiol reactivity platform screening and subsequent molecular biology validation showed that the ribosomal protein S2 (RPS2) is the main target of heliangin in treating NPM1 mutant AML. Upon covalent binding to the C222 site of RPS2, the electrophilic moieties of heliangin disrupt pre-rRNA metabolic processes, leading to nucleolar stress, which in turn regulates the ribosomal proteins-MDM2-p53 pathway and stabilizes p53. Clinical data shows that the pre-rRNA metabolic pathway is dysregulated in acute myeloid leukemia patients with the NPM1 mutation, leading to a poor prognosis. We found that RPS2 plays a critical role in regulating this pathway and may be a novel treatment target. Our findings suggest a novel treatment strategy and lead compound for acute myeloid leukemia patients, especially those with NPM1 mutations.

Covalent targeting the LAS1-NOL9 axis for selective treatment in NPM1 mutant acute myeloid leukemia.

Patients with NPM1 gene mutation-associated acute myeloid leukemia (AML), particularly those over the age of 60, have no viable targeted therapeutic choices. In this study, we identified HEN-463, a sesquiterpene lactone derivative specific targets AML with this gene mutation. This compound inhibits the interaction of LAS1-NOL9 by covalently binding to the C264 site of the ribosomal biogenesis-related protein LAS1, which translocates the LAS1 to the cytoplasm, thereby inhibiting the maturation of 28 S rRNA. This has a profound effect on the NPM1-MDM2-p53 pathway and ultimately results in the stabilization of p53. Combining this treatment with the XPO1 inhibitor Selinexor (Sel) can ideally preserve the stabilized p53 in the nucleus, considerably enhancing the efficacy of HEN-463 and addressing Sel's drug resistance. Patients with AML over the age of 60 who possess the NPM1 mutation have an unusually elevated level of LAS1, which has a significant impact on their prognosis. In NPM1-mutant AML cells, decreased LAS1 expression promotes proliferation inhibition, apoptosis, cell differentiation, and cell cycle arrest. This suggests that it may be a therapeutic target for this kind of blood cancer, especially in patients over the age of 60.

Correlation analysis of body image level and female sexual dysfunction in young patients with postoperative breast cancer.

Objective: To determine the relationship between female body image and female sexual dysfunction (FSD) in young patients (20-40 years) with postoperative breast cancer. Methods: Using the convenient sampling method, we identified 276 young patients with postoperative breast cancer from June 2017 to 2019 in the Department of Oncology and Radiotherapy of the First Affiliated Hospital of Anhui Medical University to be included in the study. A general situation questionnaire for body image scale (BIS) and female sexual function index (FSFI) scale was used to evaluate the correlation between body image level and the prevalence of FSD in young patients with postoperative breast cancer. Results: The total score for BIS was 10.98 ± 7.19, indicating that patients were moderately dissatisfied with their body image The total prevalence of FSD was 63.41%. Pearson correlation analysis showed a negative correlation between the total score, each dimension score of BIS, total FSD, and the incidence of each dimension disorder (range, r: -0.414 to -0.717, all P values <0.05). Conclusion: There is a negative correlation between the body image level and the prevalence of FSD in young patients with postoperative breast cancer. This suggests that clinical medical workers should develop an intervention plan to improve the body image level of postoperative young breast cancer patients according to the unique physiological and psychological characteristics of these patients while also reducing the prevalence of FSD.

An Almond-Based Low Carbohydrate Diet Improves Depression and Glycometabolism in Patients with Type 2 Diabetes through Modulating Gut Microbiota and GLP-1: A Randomized Controlled Trial.

BACKGROUND: Alow carbohydrate diet (LCD) is more beneficial for the glycometabolism in type 2 diabetes (T2DM) and may be effective in reducing depression. Almond, which is a common nut, has been shown to effectively improve hyperglycemia and depression symptoms. This study aimed to determine the effect of an almond-based LCD (a-LCD) on depression and glycometabolism, as well as gut microbiota and fasting glucagon-like peptide 1 (GLP-1) in patients with T2DM. METHODS: This was a randomized controlled trial which compared an a-LCD with a low-fat diet (LFD). Forty-five participants with T2DM at a diabetes club and the Endocrine Division of the First and Second Affiliated Hospital of Soochow University between December 2018 to December 2019 completed each dietary intervention for 3 months, including 22 in the a-LCD group and 23 in the LFD group. The indicators for depression and biochemical indicators including glycosylated hemoglobin (HbA1c), gut microbiota, and GLP-1 concentration were assessed at the baseline and third month and compared between the two groups. RESULTS: A-LCD significantly improved depression and HbA1c (p <0.01). Meanwhile, a-LCD significantly increased the short chain fatty acid (SCFAs)-producing bacteria Roseburia, Ruminococcus and Eubacterium. The GLP-1 concentration in the a-LCD group was higher than that in the LFD group (p <0.05). CONCLUSIONS: A-LCD could exert a beneficial effect on depression and glycometabolism in patients with T2DM. We speculate that the role of a-LCD in improving depression in patients with T2DM may be associated with it stimulating the growth of SCFAs-producing bacteria, increasing SCFAs production and GPR43 activation, and further maintaining GLP-1 secretion. In future studies, the SCFAs and GPR43 activation should be further examined.

Association of incisal overlaps with /s/ sound and mandibular speech movement characteristics.

INTRODUCTION: Modern anterior restorations are intended to achieve esthetic and functional reconstruction and coordination. The positioning of the anterior teeth can affect pronunciation, but the effect of anatomic factors on pronunciation after anterior restoration has not been critically tested. The purpose of this study was to provide possible references for the design of the anterior overlaps in future anterior restorations. METHODS: Thirty-nine subjects with normal occlusion (NO) participated. They completed questionnaires, were examined clinically, and were recorded pronouncing the /s/ sound. Links between overlaps with spectral features of the /s/ sound and mandibular movements during speech were investigated. RESULTS: When NO subjects pronounced the /s/ sound, the average fricative length was 202.54 ± 44.57 ms; the average noise peak was 4052.89 ± 445.80 Hz, which was in the high-frequency region; the center of gravity was 2452.85 ± 623.50 Hz; and the mean intensity was 40.61 ± 4.99 dB. The mandibular speech movements showed a slightly long and narrow backward and downward oblique path. Overbite positively correlated with the /s/ sound's noise peak frequency and negatively correlated with the maximum closing speed. Overjet negatively correlated with the maximum distance in the sagittal plane. CONCLUSIONS: This is the first attempt to correlate the spectral features of the /s/ sound and speaking movements with incisal overlaps. The results suggest that significant associations exist and that these associations can offer some references for esthetic anterior restoration.