Michaelskafte1304

Review ofRosenstock J, Perkovic V, Johansen, OE, et al. Effect of linagliptin vs placebo on major cardiovascular events in adults with type 2 diabetes and high cardiovascular and renal risk the CARMELINA randomized clinical trial. JAMA. 2019;32169-79.McGuire DK, Alexander JH, Johansen OE, et al. Linagliptin effects on heart failure and related outcomes in individuals with type 2 diabetes mellitus at high cardiovascular and renal risk in CARMELINA. Circulation. 2019;139351-361.These two papers describe the findings from the CARMELINA trial (Cardiovascular and Renal Microvascular Outcome Study with Linagliptin) the first paper reported results for the primary cardiovascular composite outcome (cardiovascular [CV] death, nonfatal myocardial infarction [MI], or nonfatal stroke; 3-point major adverse cardiovascular event [3P-MACE]) and the key secondary renal composite outcome (renal death, end-stage kidney disease, or sustained ≥40% decrease in eGFR from baseline); the second paper reported secondary analyses of hngs from the CARMELINA trial reaffirm treatment guidelines for choosing additional therapies for patients with T2DM at elevated CV and/or renal risk, and provide new information on the role of linagliptin in the management of T2DM.Purpose Hesperidin has anti-inflammatory and anti-oxidant stress effects, but its functions in chronic obstructive pulmonary disease (COPD) remains unknown. This study analyzed the role of hesperidin in COPD mice, aiming to provide a basis for the hesperidin application.Materials and methods Mice were injected with cigarette smoke extract (CSE) to construct COPD models and then treated with budesonide or hesperidin. Hematoxylin-eosin (HE) and TUNEL assays were used to observe the pathological changes and cell death of lung tissue. The levels of interleukin (IL)-6, IL-8, malondialdehyde (MDA), superoxide dismutase (SOD), and catalase (CAT) in bronchoalveolar lavage fluid (BLAF), as well as myeloperoxidase (MPO) content in lung tissues were confirmed. The expression levels of SIRT1, PGC-1α, and p65 proteins were measured by western blotting (WB) analysis.Results CSE induced inflammatory cell infiltration and cell death in the lung tissues of mice, whereas budesonide and hesperidin effectively alleviated these pathological changes. C59 chemical structure The levels of IL-6, IL-8, and MDA in BLAF and pulmonary MPO content in the COPD mice were effectively increased, while the levels of SOD and CAT in BLAF were decreased, which could be reversed by budesonide and hesperidin. Moreover, the addition of budesonide or hesperidin reliably accelerated the expression levels of PGC-1α and SIRT1 but suppressed the phosphorylation of p65 in COPD mice. In general, high-dose hesperidin had a stronger regulatory effect on COPD mice.Conclusions Hesperidin alleviated inflammation and oxidative stress responses in CES-induced COPD mice, associated with SIRT1/PGC-1α/NF-κB signaling axis, which might become a new direction for COPD treatment.Human papillomavirus-related oropharyngeal squamous cell carcinoma (HPV+ OPSCC) represents a unique disease entity within head and neck cancer with rising incidence. Previous work has shown that alternative splicing events (ASEs) are prevalent in HPV+ OPSCC, but further validation is needed to understand the regulation of this process and its role in these tumours. In this study, eleven ASEs (GIT2, CTNNB1, MKNK2, MRPL33, SIPA1L3, SNHG6, SYCP2, TPRG1, ZHX2, ZNF331, and ELOVL1) were selected for validation from 109 previously published candidate ASEs to elucidate the post-transcriptional mechanisms of oncogenesis in HPV+ disease. In vitro qRT-PCR confirmed differential expression of 9 of 11 ASE candidates, and in silico analysis within the TCGA cohort confirmed 8 of 11 candidates. Six ASEs (MRPL33, SIPA1L3, SNHG6, TPRG1, ZHX2, and ELOVL1) showed significant differential expression across both methods. Further evaluation of chromatin modification revealed that ASEs strongly correlated with cancer-specific distribution of acetylated lysine 27 of histone 3 (H3K27ac). Subsequent epigenetic treatment of HPV+ HNSCC cell lines (UM-SCC-047 and UPCI-SCC-090) with JQ1 not only induced downregulation of cancer-specific ASE isoforms, but also growth inhibition in both cell lines. The UPCI-SCC-090 cell line, with greater ASE expression, also showed more significant growth inhibition after JQ1 treatment. This study confirms several novel cancer-specific ASEs in HPV+OPSCC and provides evidence for the role of chromatin modifications in regulation of alternative splicing in HPV+OPSCC. This highlights the role of epigenetic changes in the oncogenesis of HPV+OPSCC, which represents a unique, unexplored target for therapeutics that can alter the global post-transcriptional landscape.Adequate bone volume is required for osseointegrated implants to restore lost teeth and oral function. Several studies have demonstrated potential advantage of stem cells in regenerative medicine using osteoblasts. The periosteum is composed of osteoblast, fibroblast, and osteo-progenitor cells. It may be an alternative source for bone tissue engineering because of easy isolation and rapid proliferation in vivo and in vitro. Low-intensity pulsed ultrasound (LIPUS) has proven successful recoveries from non-unions, delayed unions and fracture of the bone in both animal experiments and clinical treatments. The study was to investigate the influence of LIPUS on the osteogenic differentiation in murine periosteum-derived cells (PDCs) and the underlying mechanism of LIPUS. PDCs were treated daily with LIPUS for 20 min up to 21 days with 3 MHz frequency, 30 mW/cm2 intensity and pulse repetition frequency of 1 kHz. The effects of LIPUS on cell proliferation and viability were investigated. Osteogenic differentiation l Smad-signaling pathway in an osteogenic medium, leading to mineral apposition. Therefore, LIPUS might have potential to promote osteogenesis in PDCs.Traumatic brain injury (TBI) alters stress responses, which may influence neuroinflammation and behavioral outcome. Sleep disruption (SD) is an understudied post-injury environmental stressor that directly engages stress-immune pathways. Thus, we predicted that maladaptive changes in the hypothalamic-pituitary-adrenal (HPA) axis after TBI compromise the neuroendocrine response to SD and exacerbate neuroinflammation. To test this, we induced lateral fluid percussion TBI or sham injury in female and male C57BL/6 mice aged 8-10 weeks that were then left undisturbed or exposed to 3 days of transient SD. At 3 days post-injury (DPI) plasma corticosterone (CORT) was reduced in TBI compared to Sham mice, indicating altered HPA-mediated stress response to SD. This response was associated with approach-avoid conflict behavior and exaggerated cortical neuroinflammation. Post-injury SD specifically enhanced neutrophil trafficking to the injured brain in conjunction with dysregulated AQP4 polarization. Delayed and persistent effects of post-injury SD were determined 4 days after SD concluded at 7 DPI.