Bioinformatics analysis revealed the potential crosstalk genes and molecular mechanisms between intracranial aneurysms and periodontitis.

OBJECTIVES: The risk of intracranial aneurysms (IAs) development and rupture is significantly higher in patients with periodontitis (PD), suggesting an association between the two. However, the specific mechanisms of association between these two diseases have not been fully investigated. MATERIALS AND METHODS: In this study, we downloaded IAs and PD data from the Gene Expression Omnibus. Differentially expressed genes (DEGs) were identified, and functional enrichment analysis was performed. The protein-protein interaction (PPI) network and weighted gene co-expression network analysis (WGCNA) was performed to identified key modules and key crosstalk genes. In addition, the immune cell landscape was assessed and the correlation of key crosstalk genes with each immune cell was calculated. Finally, transcription factors (TFs) regulating key crosstalk genes were explored. RESULTS: 127 overlapping DEGs were identified and functional enrichment analysis highlighted the important role of immune reflection in the pathogenesis of IAs and PD. We identified ITGAX and COL4A2 as key crosstalk genes. In addition, the expression of multiple immune cells was significantly elevated in PDs and IAs compared to controls, and both key crosstalk genes were significantly negatively associated with Macrophages M2. Finally, GATA2 was identified as a potential key transcription factor (TF), which regulates two key crosstalk gene. CONCLUSIONS: The present study identifies key crosstalk genes and TF in PD and IAs, providing new insights for further study of the co-pathogenesis of PD and IAs from an immune and inflammatory perspective. Also, this is the first study to report the above findings.

Insufficient TRPM5 Mediates Lipotoxicity-induced Pancreatic ß-cell Dysfunction.

OBJECTIVE: While the reduction of transient receptor potential channel subfamily M member 5 (TRPM5) has been reported in islet cells from type 2 diabetic (T2D) mouse models, its role in lipotoxicity-induced pancreatic ß-cell dysfunction remains unclear. This study aims to study its role. METHODS: Pancreas slices were prepared from mice subjected to a high-fat-diet (HFD) at different time points, and TRPM5 expression in the pancreatic ß cells was examined using immunofluorescence staining. Glucose-stimulated insulin secretion (GSIS) defects caused by lipotoxicity were mimicked by saturated fatty acid palmitate (Palm). Primary mouse islets and mouse insulinoma MIN6 cells were treated with Palm, and the TRPM5 expression was detected using qRT-PCR and Western blotting. Palm-induced GSIS defects were measured following siRNA-based Trpm5 knockdown. The detrimental effects of Palm on primary mouse islets were also assessed after overexpressing Trpm5 via an adenovirus-derived Trpm5 (Ad-Trpm5). RESULTS: HFD feeding decreased the mRNA levels and protein expression of TRPM5 in mouse pancreatic islets. Palm reduced TRPM5 protein expression in a time- and dose-dependent manner in MIN6 cells. Palm also inhibited TRPM5 expression in primary mouse islets. Knockdown of Trpm5 inhibited insulin secretion upon high glucose stimulation but had little effect on insulin biosynthesis. Overexpression of Trpm5 reversed Palm-induced GSIS defects and the production of functional maturation molecules unique to ß cells. CONCLUSION: Our findings suggest that lipotoxicity inhibits TRPM5 expression in pancreatic ß cells both in vivo and in vitro and, in turn, drives ß-cell dysfunction.

Transient stimulated Raman scattering spectroscopy and imaging.

Stimulated Raman scattering (SRS) has been developed as an essential quantitative contrast for chemical imaging in recent years. However, while spectral lines near the natural linewidth limit can be routinely achieved by state-of-the-art spontaneous Raman microscopes, spectral broadening is inevitable for current mainstream SRS imaging methods. This is because those SRS signals are all measured in the frequency domain. There is a compromise between sensitivity and spectral resolution: as the nonlinear process benefits from pulsed excitations, the fundamental time-energy uncertainty limits the spectral resolution. Besides, the spectral range and acquisition speed are mutually restricted. Here we report transient stimulated Raman scattering (T-SRS), an alternative time-domain strategy that bypasses all these fundamental conjugations. T-SRS is achieved by quantum coherence manipulation: we encode the vibrational oscillations in the stimulated Raman loss (SRL) signal by femtosecond pulse-pair sequence excited vibrational wave packet interference. The Raman spectrum was then achieved by Fourier transform of the time-domain SRL signal. Since all Raman modes are impulsively and simultaneously excited, T-SRS features the natural-linewidth-limit spectral line shapes, laser-bandwidth-determined spectral range, and improved sensitivity. With ~150-fs laser pulses, we boost the sensitivity of typical Raman modes to the sub-mM level. With all-plane-mirror high-speed time-delay scanning, we further demonstrated hyperspectral SRS imaging of live-cell metabolism and high-density multiplexed imaging with the natural-linewidth-limit spectral resolution. T-SRS shall find valuable applications for advanced Raman imaging.

The potential crosstalk genes and molecular mechanisms between glioblastoma and periodontitis.

Despite clinical and epidemiological evidence suggestive of a link between glioblastoma (GBM) and periodontitis (PD), the shared mechanisms of gene regulation remain elusive. In this study, we identify differentially expressed genes (DEGs) that overlap between the GEO datasets GSE4290 [GBM] and GSE10334 [PD]. Functional enrichment analysis was conducted, and key modules were identified using protein-protein interaction (PPI) network and weighted gene co-expression network analysis (WGCNA). The expression levels of CXCR4, LY96, and C3 were found to be significantly elevated in both the test dataset and external validation dataset, making them key crosstalk genes. Additionally, immune cell landscape analysis revealed elevated expression levels of multiple immune cells in GBM and PD compared to controls, with the key crosstalk genes negatively associated with Macrophages M2. FLI1 was identified as a potential key transcription factor (TF) regulating the three key crosstalk genes, with increased expression in the full dataset. These findings contribute to our understanding of the immune and inflammatory aspects of the comorbidity mechanism between GBM and PD.

ß-Cell miRNA-503-5p Induced by Hypomethylation and Inflammation Promotes Insulin Resistance and ß-Cell Decompensation.

Chronic inflammation promotes pancreatic ß-cell decompensation to insulin resistance because of local accumulation of supraphysiologic interleukin 1ß (IL-1ß) levels. However, the underlying molecular mechanisms remain elusive. We show that miR-503-5p is exclusively upregulated in islets from humans with type 2 diabetes and diabetic rodents because of its promoter hypomethylation and increased local IL-1ß levels. ß-Cell-specific miR-503 transgenic mice display mild or severe diabetes in a time- and expression-dependent manner. By contrast, deletion of the miR-503 cluster protects mice from high-fat diet-induced insulin resistance and glucose intolerance. Mechanistically, miR-503-5p represses c-Jun N-terminal kinase-interacting protein 2 (JIP2) translation to activate mitogen-activated protein kinase signaling cascades, thus inhibiting glucose-stimulated insulin secretion (GSIS) and compensatory ß-cell proliferation. In addition, ß-cell miR-503-5p is packaged in nanovesicles to dampen insulin signaling transduction in liver and adipose tissues by targeting insulin receptors. Notably, specifically blocking the miR-503 cluster in ß-cells effectively remits aging-associated diabetes through recovery of GSIS capacity and insulin sensitivity. Our findings demonstrate that ß-cell miR-503-5p is required for the development of insulin resistance and ß-cell decompensation, providing a potential therapeutic target against diabetes. ARTICLE HIGHLIGHTS: Promoter hypomethylation during natural aging permits miR-503-5p overexpression in islets under inflammation conditions, conserving from rodents to humans. Impaired ß-cells release nanovesicular miR-503-5p to accumulate in liver and adipose tissue, leading to their insulin resistance via the miR-503-5p/insulin receptor/phosphorylated AKT axis. Accumulated miR-503-5p in ß-cells impairs glucose-stimulated insulin secretion via the JIP2-coordinated mitogen-activated protein kinase signaling cascades. Specific blockage of ß-cell miR-503-5p improves ß-cell function and glucose tolerance in aging mice.

BRSK2 in pancreatic ß cells promotes hyperinsulinemia-coupled insulin resistance and its genetic variants are associated with human type 2 diabetes.

Brain-specific serine/threonine-protein kinase 2 (BRSK2) plays critical roles in insulin secretion and ß-cell biology. However, whether BRSK2 is associated with human type 2 diabetes mellitus (T2DM) has not been determined. Here, we report that BRSK2 genetic variants are closely related to worsening glucose metabolism due to hyperinsulinemia and insulin resistance in the Chinese population. BRSK2 protein levels are significantly elevated in ß cells from T2DM patients and high-fat diet (HFD)-fed mice due to enhanced protein stability. Mice with inducible ß-cell-specific Brsk2 knockout (ßKO) exhibit normal metabolism with a high potential for insulin secretion under chow-diet conditions. Moreover, ßKO mice are protected from HFD-induced hyperinsulinemia, obesity, insulin resistance, and glucose intolerance. Conversely, gain-of-function BRSK2 in mature ß cells reversibly triggers hyperglycemia due to ß-cell hypersecretion-coupled insulin resistance. Mechanistically, BRSK2 senses lipid signals and induces basal insulin secretion in a kinase-dependent manner. The enhanced basal insulin secretion drives insulin resistance and ß-cell exhaustion and thus the onset of T2DM in mice fed an HFD or with gain-of-function BRSK2 in ß cells. These findings reveal that BRSK2 links hyperinsulinemia to systematic insulin resistance via interplay between ß cells and insulin-sensitive tissues in the populations carrying human genetic variants or under nutrient-overload conditions.

Transient Stimulated Raman Excited Fluorescence Spectroscopy.

The pursuit of better sensitivity has always been one of the central themes in Raman spectroscopy. Recently, all-far-field single-molecule Raman spectroscopy has been demonstrated by a novel hybrid spectroscopy that couples Raman scattering with fluorescence emission. However, such frequency-domain spectroscopy lacks efficient hyperspectral excitation methods and encounters intrinsic strong fluorescence backgrounds from electronic transitions, hindering its applications in advanced Raman spectroscopy and microscopy. Here we report the ultrafast time-domain spectroscopy counterpart named transient stimulated Raman excited fluorescence (T-SREF): excited by two successive broadband femtosecond pulse pairs (i.e., the pump and Stokes pulses) with time-delay scanning, strong vibrational wave packet interference is revealed on the time-domain fluorescence trace, resulting in background-free spectra of the corresponding Raman modes after the Fourier transform. T-SREF achieves background-free Raman spectra of electronic-coupled vibrational modes with sensitivity up to the level of a few molecules, which paves the way for supermultiplexed fluorescence detection and molecular dynamics sensing.