American Journal of Pathology最新文献

The donor shortage increases liver transplantation (LT) waiting lists, making it crucial to consider extended criteria donors (ECDs), such as steatotic donors after brain death (DBDs) or cardiocirculatory death (DCDs). Nevertheless, steatosis, brain death, and cardiocirculatory death are key risk factors for poor LT outcomes. We investigated the role and therapeutical usefulness of several adipocytokines to protect such grafts from ECD. Sprague rats with nutritionally-induced steatosis were used in an experimental LT model with grafts from DBD or DCD. Adiponectin, resistin, and visfatin were measured, pharmacologically modulated, and effects on liver injury were assessed. Visfatin played no role under conditions of neither DBD nor DCD LT. Brain death increased adiponectin and reduced resistin. Adiponectin harmed steatotic and nonsteatotic DBD grafts, via a resistin-dependent mechanism; restraining adiponectin increased resistin, reducing damage. Resistin treatment protected both types of DBD grafts, whereas suppressing it increased damage. This adiponectin-resistin pathway was dependent on PKC. In DCD LT, adiponectin and resistin were not modified in nonsteatotic grafts, but reduced in steatotic ones. Adiponectin or resistin treatments protected steatotic grafts: hepatic adiponectin activated AMPK; hepatic resistin increased PI3k-Akt. Concomitant administration of both adipocytokines increased both signaling pathways, intensifying protection. Therefore, pharmacological modulation of adiponectin and resistin resulted in therapies that potentially might be translated to clinical studies to improve surgical outcomes for LT from ECD.

Liver fibrosis is characterized by excessive deposition of extracellular-matrix (ECM) due to chronic inflammation of the liver. HSCs become activated and produce excessive amounts of ECM. Previously, we showed that loss of HIF-prolyl-hydroxylase 1 (PHD1) attenuates HSC activation and fibrotic tissue remodeling in a murine model of biliary liver fibrosis. We thus validated the protective effect of PHD1 deficiency (PHD1^-/-) in an additional (toxic) model of liver fibrosis and evaluated the effect of dimethyloxalylglycine (DMOG), a pan-HIF-prolyl-hydroxylase inhibitor, on the development of liver fibrosis. Liver fibrosis was induced utilizing carbon tetrachloride (CCl₄) in WT, PHD1^-/-, vehicle-, and DMOG-treated mice. Livers were further analyzed by Sirius red staining and gene expression analysis of pro-fibrotic genes to assess fibrosis development. When compared to WT mice, PHD1^-/- mice developed less severe liver fibrosis. In contrast, DMOG treatment did not prevent liver fibrosis. PHD1^-/- mice showed a lower number of α SMA⁺ cells and less macrophage infiltration when compared to WT mice. Gene expression of profibrogenic and proinflammatory genes was reduced in livers from CCl₄-exposed PHD1^-/- mice. In vitro analyses of in PHD1-deficient human HSCs revealed attenuated mRNA-levels of profibrotic genes as well as impaired migration and invasion. While PHD1 deficiency attenuates activation of HSCs, pharmacological PHD inhibition does not ameliorate fibrosis development. Selective PHD1 inhibitors could prove effective in preventing and treating liver fibrosis.

Bidirectional communication between the brain and gastrointestinal tract, called the gut-brain axis is linked with our emotions. Intestinal lipids, hormones, and molecules such as bile acids (BAs) have been known to impact our mood, motivation, and emotions via the gut-brain axis. BAs are synthesized from cholesterol in the liver and serve as a regulator of lipid metabolism and hormonal secretion in the intestine. Human studies have indicated that the alteration of plasma BA levels is associated with depression and anxiety. Several possible mechanisms, such as BA receptor-dependent and independent mechanisms, have been reported for emotional control. Animal studies have indicated that the deletion of BA receptors shows behavioral abnormalities. BAs regulate gut hormones, GLP-1 secretion, bioactive lipids, oleoyl ethanolamide (OEA), and the immune system function, which influences neural activities. Thus, BAs are considered to act as an emotional regulator. This review aims to summarize 1) clinical evidence of BA concentration linked to mental disorders, including depression and anxiety, and 2) animal studies of BA-related signaling correlated with its neurobehavioral effect supporting its mechanism. In this review, we will discuss future research required for further neurobehavioral treatment.

Retinal detachment (RD) is the separation of the neural retina from the retinal pigment epithelial（RPE）, with photoreceptor degeneration being a major cause of irreversible vision loss. Ischemia and hypoxia after RD decreased the level of miR-7a-5p (miR-7) and promoted the expression of its main target, α-synuclein (α-syn), which activated the parthanatos pathway and led to photoreceptor damage. Circular RNA CDR1as, which is an antisense transcript of cerebellar degeneration-related protein 1, functions as a "sponge" for miR-7, thereby regulating its abundance and activity. In this study, we first reported that CDR1as expression is elevated after RD. AAV9 vector containing the shRNA-CDR1as sequence was used to inhibit CDR1as expression via subretinal injection. Hematoxylin and eosin staining and transmission electron microscopy (TEM) revealed that the morphology and outer nuclear layer (ONL) thickness of the retina were preserved, and photoreceptor cell death was decreased after experimental RD mice. Mechanistically, CDR1as deficiency significantly increased the expression of miR-7, then decreased the expression of α-syn, PARP-1, AIF, and MIF. Furthermore, visual function was improved as demonstrated by Morris water maze experiments in the mouse model of RD. In conclusion, our findings suggest a surprisingly neuroprotective role for CDR1as deficiency, which is probably mediated by enhancing miR-7 activity and inhibiting α-syn/PARP-1/AIF pathway, thereby preventing photoreceptor degeneration.

Corneal scars originate from keratocyte-derived fibroblasts and myofibroblasts that are ultimately cleared through apoptosis or revert to keratocytes. A mouse model expressing a keratocyte lineage-specific reporter KeraRT/tetO-Cre/mTmG (I-Kera mTmG) was interrogated to elucidate cell phenotype dynamics during scar maturation. This mouse model expresses tdTomato (red) in all keratocan-negative cells while eGFP (green) is expressed only by keratocytes. A 1mm full-thickness keratotomy was created in adult I-KeramTmG mice. The presence or absence of keratocytes was examined at 3-, 6- and 10-months post injury. At 3- and 6-months post-injury, few green cells were visualized at the scar borders while few or no green cells were seen in the central (core) scar. At 10-months post-injury, green cells can be seen throughout the scar, but most cells were red. Proliferation of stromal cells after injury was studied by EdU labeling and Ki-67 staining and both assays showed proliferation only during the first 2 weeks after injury. Second harmonic generation (SHG) microscopy showed thickened and irregularly arranged collagen fibers in scars suggesting that neither extracellular matrix organization nor cell phenotype had changed significantly 10-months post injury. In vivo experiments suggest that in old corneal scars, a non-keratocyte phenotype persists in an abnormal matrix with unique characteristics that probably prevent regression of fibroblasts and myofibroblasts to keratocytes or invasion of surrounding keratocytes.

Gastrointestinal motility disturbances are a hallmark of inflammatory bowel disease (IBD); however, their mechanisms remain unclear. This study utilized a dextran sulfate sodium (DSS)-induced colitis mouse model, deficient in mature B and T lymphocytes, to assess intestinal motility and the role of the adaptive immune system in health and IBD. In healthy mice, the absence of adaptive lymphocytes reduced acetylcholine (ACh) sensitivity in the ileum. During colitis, it decreases motility by reducing the intensity and frequency of spontaneous contractions while increasing cholinergic responsiveness. In the proximal colon, adaptive immunity deficiency led to increased contractility and reduced ACh sensitivity in homeostasis, while colitis reduced contractile capacity. In the mid-colon, immune-deficient mice have reduced ACh sensitivity in homeostasis and exacerbated contractile responses during colitis. In the distal colon, adaptive immunity loss reduced contractility in health and cholinergic responsiveness during colitis. These motility alterations were associated with altered acetylcholinesterase and M2/M3 muscarinic receptor expression. Notably, adaptive lymphocyte deficiency resulted in reduced tissue damage and lower TNF-α expression in the colon during colitis paralleling intestinal motility changes. Overall, the adaptive immune system critically regulates motility and inflammation across different intestinal segments in IBD.

The amyloid cascade hypothesis as the etiological underpinning of Alzheimer's disease (AD) is supported by a large body of literature, the most influential of which are genetic studies of the 1980's and 1990's. Other evidence includes the neuropathology of Down syndrome, apparent toxicity of oligomeric amyloid-β (Aβ), interactions with apolipoprotein E (APOE), and the analogy of cardiac amyloidosis. On the other hand, there is considerable phenotypic heterogeneity among the rare familial AD kindreds, which tempers extrapolation to sporadic AD. Oligomer biology is still in the theoretical realm, with no clinical validation. APOE support for the amyloid cascade and other inferences from the literature are somewhat circular in their logic. Analogy with amyloidoses might also consider secondary amyloidosis, driven by systemic inflammation and treated by treating the underlying etiology. Much of the remaining literature supporting the amyloid cascade is dominated by hypothesis-generating studies. Importantly, we now have a developing evidence base from controlled clinical trials that can potentially inform the issue of Aβ as a cause or driver of disease in sporadic AD. Emerging data provide clear evidence of target engagement. Clinical outcome, however, has been either marginally positive or similar to placebo. Assuming these findings hold, it appears that Aβ neither drives nor mitigates the disease process.

Cholangiocarcinoma (CCA) is an aggressive and heterogeneous malignancy of the biliary tree that carries a poor prognosis. Multiple features at the genetic, epigenetic, and microenvironmental levels have been identified to better characterize CCA carcinogenesis. Genetic alterations, such as mutations in IDH1/2, BAP1, ARID1A, and FGFR2, play significant roles in CCA pathogenesis, with variations across different subtypes, races/ethnicities, and causes. Epigenetic dysregulation, characterized by DNA methylation and histone modifications, further contributes to the complexity of CCA, influencing gene expression and tumor behavior. Furthermore, CCA cells exchange autocrine and paracrine signals with other cancer cells and the infiltrating cell types that populate the microenvironment, including cancer-associated fibroblasts and tumor-associated macrophages, further contributing to an immunosuppressive niche that supports tumorigenesis. This review explores the multifaceted genetic, epigenetic, and microenvironmental drivers of CCA. Understanding these diverse mechanisms is essential for characterizing the complex pathways of CCA carcinogenesis and developing targeted therapies to improve patient outcomes.