Correlations between genetically predicted lipid-lowering drug targets and inflammatory bowel disease

Abstract Background Millions of individuals globally suffer from Inflammatory bowel diseases (IBDs). There is a dearth of large population-based investigations on lipid metabolism and IBDs, and it is unclear whether lipid-lowering drugs target IBDs causally. Consequently, the aim of this study was to investigate the effects of lipid-lowering medication targets on the occurrence and progression of IBDs. Methods Among the more than 400,000 participants in the UK Biobank cohort and the more than 170,000 participants in the Global Lipids Genetics Consortium, a total of nine genes linked to lipid-lowering drug targets were obtained (ABCG5/ABCG8, APOB, APOC3, LDLR, LPL, HMGCR, NPC1L1, PCSK9, and PPARA). IBD data were acquired from de Lange et al. (patients/sample size of IBDs: 25042/59957; ulcerative colitis (UC): 12366/45,975; Crohn's disease (CD): 12194/40,266) and the FinnGen cohort (patients/total sample size of IBDs: 4420/176,899; CD: 1520/171,906; UC: 3325/173,711). All four datasets were cross-combined for validation via Mendelian randomization analysis, and potential mediating factors were explored via mediation analysis. Results Genetically proxied APOC3 inhibition was related to increased IBD risk (odds ratio (95% confidence interval): 0.87 (0.80–0.95); P < 0.01) and UC risk (0.83 (0.73–0.94); P < 0.01). IBD and CD risk were reduced by genetic mimicry of LDLR and LPL enhancements, respectively (odds ratioLDLR: 1.18 (1.03–1.36); P = 0.018; odds ratioCD: 1.26 (1.11–1.43); P = 2.60E-04). Genetically proxied HMGCR inhibition was associated with increased CD risk (0.68 (0.50–0.94); P = 0.018). These findings were confirmed through Mendelian analysis of the cross-combination of four separate datasets. APOC3-mediated triglyceride levels may contribute to IBDs partly through mediated triglycerides, Clostridium sensu stricto 1, Clostridiaceae 1, or the Lachnospiraceae FCS020 group. LDLR enhancement may contribute to IBDs partly through increasing Lactobacillaceae. Conclusion Vigilance is required to prevent adverse effects on IBDs (UC) for patients receiving volanesorsen (an antisense oligonucleotide targeting ApoC3 mRNA) and adverse effects on CD for statin users. LPL and LDLR show promise as candidate drug targets for CD and IBD, respectively, with mechanisms that are potentially independent of their lipid-lowering effects

Low-temperature wetting of sapphire using Sn–Ti active solder alloys

Monocrystalline alumina, known as sapphire, is one of the most commonly used ceramics in electronic devices. Understanding its wettability is thus of great importance for its engineering applications. In this work, the low-temperature wetting mechanisms of Sn–Ti active solder alloy on C-plane sapphire was comprehensively studied using the sessile drop method. The addition of 0.1 wt % Ti was found to effectively improve the wettability of Sn–Ti alloys, and the lowest contact angle on the sapphire substrate was achieved at 950 °C when Ti content was increased to 3 wt%. Thermal dynamics analysis and experimental results indicated that the isothermal spreading of Sn–3Ti alloy is controlled by the Ti adsorption in the vicinity of wetting triple line. Moreover, sapphire was successfully brazed using Sn–3Ti alloy at 500, 550, and 600 °C, and the maximum shear strength was measured as 30.3 MPa. Our understanding of the wettability of sapphire provides the fundamental theory for developing new bonding technique for this important crystal

Surface Chelation Enabled by Polymer-Doping for Self-Healable Perovskite Solar Cells

Polymer doping is an efficient approach to achieve self-healing perovskite solar cells. However, achieving high self-healing efficiency under moderate conditions remains challenging. Herein, an innovative self-healable polysiloxane (PAT) containing plenty of thiourea hydrogen bonds was designed and introduced into perovskite films. Abundant thiourea hydrogen bonds in PAT facilitated the self-healing of cracks at grain boundaries for damaged SPSCs. Importantly, the doped SPSCs demonstrated a champion efficiency of 19.58% with little hysteresis, almost rivalling those achieved in control atmosphere. Additionally, owing to the effective chelation by PAT and good level of thiourea hydrogen bonds, after 800 cycles of stretching, releasing and self-healing, the doped SPSCs retained 85% of their original IPCE. The self-healing characteristics were demonstrated in situ after stretching at 20% strain for 200 cycles. This strategy of pyridine-based supramolecular doping in SPSCs paves a promising way for achieving efficient and self-healable crystalline semiconductors

Elevated expression of HIGD1A drives hepatocellular carcinoma progression by regulating polyamine metabolism through c-Myc–ODC1 nexus

Abstract Background Hypoxia contributes to cancer progression through various molecular mechanisms and hepatocellular carcinoma (HCC) is one of the most hypoxic malignancies. Hypoxia-inducible gene domain protein-1a (HIGD1A) is typically induced via epigenetic regulation and promotes tumor cell survival during hypoxia. However, the role of HIGD1A in HCC remains unknown. Methods HIGD1A expression was determined in 24 pairs of human HCC samples and para-tumorous tissues. Loss-of-function experiments were conducted both in vivo and in vitro to explore the role of HIGD1A in HCC proliferation and metastasis. Results Increased HIGD1A expression was found in HCC tissues and cell lines, which was induced by hypoxia or low-glucose condition. Moreover, HIGD1A knockdown in HCC cells arrested the cell cycle at the G2/M phase and promoted hypoxia-induced cell apoptosis, resulting in great inhibition of cell proliferation, migration, and invasion, as well as tumor xenograft formation. Interestingly, these anti-tumor effects were not observed in normal hepatocyte cell line L02. Further, HIGD1A knockdown suppressed the expression of ornithine decarboxylase 1 (ODC1), a rate-limiting enzyme of polyamine metabolism under c-Myc regulation. HIGD1A was found to bind with the c-Myc promoter region, and its knockdown decreased the levels of polyamine metabolites. Consistently, the inhibitory effect on HCC phenotype by HIGD1A silencing could be reversed by overexpression of c-Myc or supplementation of polyamines. Conclusions Our results demonstrated that HIGD1A activated c-Myc–ODC1 nexus to regulate polyamine synthesis and to promote HCC survival and malignant phenotype, implying that HIGD1A might represent a novel therapeutic target for HCC

Additional file 1 of HIGD2A silencing impairs hepatocellular carcinoma growth via inhibiting mitochondrial function and the MAPK/ERK pathway

Additional file 1: Table S1. The shRNA sequences of HIGD2A and the primer sequences used in real-time PCR analysis. Figure S1. Diagnostic and prognostic value of HIGD2A expression and its correlation with clinical features. A Representative immunohistochemistry images of HIGD2A expression in normal liver tissues and liver cancer tissues from the HPA. B The protein level of HIGD2A in normal hepatocyte L02 cell line and different liver cancer cell lines. C–F HIGD2A expression in different status of T stage (C), pathologic stage (D), vascular invasion (E) and OS event (F). G–J Kaplan–Meier plots of OS for HIGD2A expression levels in subgroups including T stage: T1 (G), N stage: N0 (H), M stage: M0 (I) and pathologic stage: stage I (J). K Nomogram for OS prediction, with T stage, N stage, M stage, histologic grade and expression of HIGD2A applied as parameters. L Calibration curves of the nomogram for 1-, 3-, 5-year survival prediction. *P < 0.05, **P < 0.01. Figure S2. Knockdown of HIGD2A impedes MHCC97H cells proliferation and migration. A Western blot assay for total HIGD2A protein expression in HIGD2A-knockdown MHCC97H cells. B Left, colony formation of MHCC97H cells transfected shCtrl or shHIGD2A.1. Right, quantification of colony formation based on three independent assays. C The proliferation ability of MHCC97H cells infected with shCtrl lentivirus or shHIGD2A.1 lentivirus was measured by CCK8 assay at the indicated time points. D, E Flow cytometry analysis of Annexin V/7-AAD double stained HepG2, Huh7 and MHCC97H cells transfected shCtrl or shHIGD2A.1. Representative flow cytometric plot (D) and the proportion of apoptosis cells (E). F Annexin V/7-AAD apoptosis assay of L02 cells after HIGD2A gene silencing. Left, representative flow cytometric plot. Right, the proportion of apoptosis cells. G Left, cell migration ability of MHCC97H cells transfected shCtrl or shHIGD2A.1 was analyzed by Transwell assay. Right, quantitative data of migrated cells. Results shown are mean ± SEM. an unpaired t-test was used. *P < 0.05, **P < 0.01, ***P < 0.001, ns, not significant. Scale bar, 100 µm. Figure S3. HIGD2A knockdown inhibited the proliferation and migration of HCC cells in vitro. A, B Colony formation experiments for the effect of HIGD2A knockdown with shRNA on the proliferation of HepG2 and Huh7 cells. C, D The effect of HIGD2A knockdown on the growth of HepG2 and Huh7 cells was detected by CCK8 assays. E The effect of HIGD2A knockdown on cell apoptosis was detected by western blot. F, G Transwell chamber was used to evaluated the effect of HIGD2A knockdown on the migration of HepG2 and Huh7 cells. Results shown are mean ± SEM. an unpaired t-test was used. *P < 0.05, **P < 0.01 and ***P < 0.001. Scale bar, 100 µm. Figure S4. Depletion of HIGD2A induces mitochondrial stress in MHCC97H. A, B Intercellular ATP level in MHCC97H (A) and L02 (B) cells transfected with shCtrl or shHIGD2A.1. C Immunofluorescent (IF) images showing mitochondria morphology in MHCC97H transfected with shCtrl or shHIGD2A.1. Left, representative IF images (magenta, MitoTracker; yellow, DAPI) and 3D mitochondria reconstruction of shCtrl- and shHIGD2A-infected MHCC97H cell. Scale bar, 5 μm; Sphericity heat map, 0.326–0.915. Right, sphericity analysis of 3D reconstructed mitochondria (results are presented as mean ± SD). D Left, oxygen consumption rate (OCR) in MHCC97H transfected with shCtrl or shHIGD2A.1 was measured by seahorse analyzer. Right, basal respiration rate and maximal respiration capacity are shown. E Comparison of Basal Respiration among L02 and HCC cells. Results shown are mean ± SEM. A Mann–Whitney test was used. *P < 0.05, **P < 0.01 and ***P < 0.001; ns, not significant

Additional file 1 of Elevated expression of HIGD1A drives hepatocellular carcinoma progression by regulating polyamine metabolism through c-Myc–ODC1 nexus

Supplementary Material 1