The deregulation of microRNAs (miRNAs) plays an important role in human hepatocarcinogenesis. In this study, we highlight exosomes as mediators involved in modulating miRNA profiles in hepatocellular carcinoma (HCC) cells. First, we examined the different miRNA expression profiles in HCC cells and HCC cell–derived exosomes. Next, coculture experiments indicated that HCC cell–derived exosomes promoted the cell growth, migration, and invasion of HCC cells and had the ability to shuttle miRNAs to recipient cells. Further, our data showed that Vps4A, a key regulator of exosome biogenesis, was frequently down‐regulated in HCC tissues. The reduction of Vps4A in HCC tissues was associated with tumor progression and metastasis. In vitro studies revealed that Vps4A repressed the growth, colony formation, migration, and invasion of HCC cells. We further investigated the role and involvement of Vps4A in suppressing the bioactivity of exosomes and characterized its ability to weaken the cell response to exosomes. By small RNA sequencing, we demonstrated that Vps4A facilitated the secretion of oncogenic miRNAs in exosomes as well as accumulation and uptake of tumor suppressor miRNAs in cells. A subset of Vps4A‐associated miRNAs was identified. Kyoto Encyclopedia of Genes and Genomes pathway analysis indicated that the phosphatidylinositol‐3‐kinase/Akt signaling pathway was the most likely candidate pathway for modulation by these miRNAs. Indeed, we proved that the phosphatidylinositol‐3‐kinase/Akt pathway was inactivated by Vps4A overexpression. Conclusion: Exosome‐mediated miRNA transfer is an important mechanism of self‐modulation of the miRNA expression profiles in HCC cells, and Vps4A may function as a tumor suppressor, which utilizes exosomes as mediators to regulate the secretion and uptake of miRNAs in hepatoma cells; these observations provide new insights into the development of HCC. (Hepatology 2015;61:1284–1294)
Abdominal aortic aneurysm (AAA) is a progressive degenerative vascular disease characterized by structural weakening and pathological dilatation of the abdominal aortic wall. Currently, no effective pharmacological therapies are available, and treatment remains largely limited to surgical intervention. This underscores the urgent need to better understand the mechanisms driving disease development and progression. Among the cellular mediators implicated in AAA, neutrophils have emerged as key contributors to vascular inflammation and tissue destruction. We performed a comprehensive literature review of original research articles and relevant reviews addressing the role of neutrophils in AAA pathogenesis. Studies were identified through systematic searches of major databases, including PubMed and Google Scholar, using the keywords “abdominal aortic aneurysm”, “neutrophils”, “vascular inflammation”, “oxidative stress”, “proteases”, and “extracellular matrix degradation”. Both experimental and clinical studies were included to provide an integrated overview of current knowledge in the field. Accumulating evidence indicates that neutrophils actively infiltrate the aortic wall during AAA development, where they release a diverse array of effector molecules, including reactive oxygen species, proteolytic enzymes, pro-inflammatory cytokines, chemotactic mediators, and granule proteins. Collectively, these mediators sustain chronic vascular inflammation, promote extracellular matrix degradation, and contribute to progressive structural weakening of the arterial wall. This review summarizes both established and emerging roles of neutrophils in AAA pathogenesis, with a particular focus on their contribution to vascular inflammation, thereby providing a conceptual framework for future diagnostic and therapeutic development. Neutrophils are central regulators of AAA pathogenesis through their multifaceted roles in vascular inflammation and extracellular matrix remodeling. Targeting neutrophil activation and downstream inflammatory pathways may represent a promising therapeutic strategy. A deeper mechanistic understanding of neutrophil-driven processes may facilitate the development of novel biomarkers and pharmacological approaches aimed at limiting AAA progression and preventing rupture.
Traumatic brain injury (TBI) is increasingly recognized as a systemic disorder with significant effects on skeletal biology. This review summarizes current evidence describing how TBI impacts fracture healing, heterotopic ossification, and long-term bone remodeling. Clinical observations and experimental models demonstrate that TBI can accelerate early fracture callus formation and increase the risk of heterotopic ossification, suggesting a transient pro-osteogenic state following injury. Proposed mechanisms include neuroinflammatory cytokine release, sympathetic nervous system activation, neuroendocrine dysregulation, and mobilization of osteoprogenitor cells. Conversely, persistent neuroinflammation, hypothalamic–pituitary axis dysfunction, oxidative stress, and altered autonomic signaling are associated with impaired fracture remodeling, increased bone resorption, and progressive bone loss. Emerging data implicate extracellular vesicle-mediated signaling as a key pathway linking brain injury to skeletal outcomes. TBI induces a contextual, biphasic skeletal response with both osteogenic and degenerative consequences. Understanding this duality is essential for optimizing fracture care and preserving bone health after neurotrauma.
Cancer treatments can deplete the ovarian follicle reserve causing infertility and early menopause, with subsequent decline in cardiovascular, cognitive, and overall health. Medical measures to prevent this chemotherapy-induced ovarian damage are currently not available. Anti-Müllerian hormone (AMH) is important for preserving the ovarian follicle pool via downregulation of granulosa cell replication and function. Despite proven therapeutic ability to protect the ovarian follicle number in mice exposed to chemotherapy, AMH is not approved for human use. To overcome this gap, we created and patented a peptide designed to specifically bind to the AMH receptor, AMHR2 binding peptide (AMHR2BP), that could serve as an alternative therapeutic treatment. By activating the same downstream signaling and replicating the biological effects of natural AMH, we sought to investigate whether AMHR2BP could protect the follicle pool in both natural and accelerated ovarian aging mouse models. Here, we present a series of in vitro and in vivo translational studies to verify AMHR2BP’s affinity, specificity, mechanism of action, stability, and in vivo toxicity and efficacy. We performed immunofluorescence, immunoprecipitation, real-time RT-PCR, mass spectrometry, histological, and immunohistochemistry testing to validate our findings on two levels, gene activation and protein translation. We found that AMHR2BP activates the same SMAD signaling pathways as AMH and ultimately preserves the ovarian follicle pool by preventing the progression of primordial to antral follicles in naturally aging mice. Additionally, we demonstrated that AMHR2BP prevents follicle loss in an accelerated, chemotherapy-induced ovarian aging model, thereby effectively preventing identifiable ovarian damage. Importantly, AMHR2BP also portrays excellent plasma stability with no detectable toxicity. By mimicking the function of AMH, AMHR2BP represents a new medical therapeutic strategy to preserve fertility and reduce long-term reproductive and health risks from chemotherapy treatments.
This study proposed air-abrasion (AA) and additional firing techniques to improve the bond strength of resin cements to 4Y-PSZ zirconia (ZIRC). ZIRC plates (Katana STML) were obtained and submitted to six surface treatments (n = 15): Control 1: AA using Al2O3 particles (50 & micro;m) + Clearfil Ceramic Primer + Tooth Primer and Panavia V5 (Kuraray Noritake); Control 2: Al2O3 particles + Scotchbond Universal and RelyX Ultimate (Solventum); Control 3: CoJet Sand particles (30 & micro;m) (CO) + silane (SI) + bonding resin (BR) (CO-SI-BR); Control 4: CO + ultrasonic cleaning (UC) + SI + BR (CO-UC-SI-BR); Control 5: CO + additional firing (AF) at 800 degrees C + SI + BR (CO-AF-SI-BR), and Control 6: CO-AF-UC-SI-BR. For experimental groups, the RelyX/ARC resin cement (Solventum) was used. Samples for the shear bond strength (BS) test were stored in distilled water at 37 degrees C for 24 h and 1 year before testing. BS data were analyzed by two-way analysis of variance and Tukey post hoc test (alpha = 0.05). Additionally, CoJet-Sand particles and CO-treated ZIRC surfaces were characterized using energy-dispersive X-ray spectroscopy analysis. CO particles impregnated the silicon chemical element on the ZIRC surface; however, UC was able to remove it. When CO ZIRC was subjected to AF, UC did not remove silicon. CO-AF-SI-BR and CO-AF-UC-SI-BR groups increased BS (p < 0.05), which remained stable after one year. Controls showed intermediate results, and CO-SI-BR and CO-UC-SI-BR exhibited the worst BS outcomes (p < 0.05). AF of CO air-abraded ZIRC did not allow displacement of silicon from the ZIRC surface after UC and yielded higher and stable BS results.
