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Environmental signals can be translated into chromatin changes, which alter gene expression. Here we report a novel concept that cells can signal chromatin damage from the nucleus back to the surrounding tissue through the cytokine interleukin-1alpha (IL-1α). Thus, in addition to its role as a danger signal, which occurs when the cytokine is passively released by cell necrosis, IL-1α could directly sense DNA damage and act as signal for genotoxic stress without loss of cell integrity. Here we demonstrate localization of the cytokine to DNA-damage sites and its subsequent secretion. Interestingly, its nucleo-cytosolic shuttling after DNA damage sensing is regulated by histone deacetylases (HDAC) and IL-1α acetylation. To demonstrate the physiological significance of this newly discovered mechanism, we used IL-1α knockout mice and show that IL-1α signaling after UV skin irradiation and DNA damage is important for triggering a sterile inflammatory cascade in vivo that contributes to efficient tissue repair and wound healing.

Mechanical force is known to modulate the activity of the Jun N-terminal kinase (JNK) signaling cascade. However, the effect of mechanical stresses on JNK signaling activation has previously only been analyzed by in vitro detection methods. It still remains unknown how living cells activate the JNK signaling cascade in response to mechanical stress and what its functions are in stretched cells.We assessed in real-time the activity of the JNK pathway in Drosophila cells by Fluorescence Lifetime Imaging Microscopy (FLIM), using an intramolecular phosphorylation-dependent dJun-FRET (Fluorescence Resonance Energy Transfer) biosensor. We found that quantitative FRET-FLIM analysis and confocal microscopy revealed sustained dJun-FRET biosensor activation and stable morphology changes in response to mechanical stretch for Drosophila S2R+ cells. Further, these cells plated on different substrates showed distinct levels of JNK activity that associate with differences in cell morphology, integrin expression and focal adhesion organization.These data imply that alterations in the cytoskeleton and matrix attachments may act as regulators of JNK signaling, and that JNK activity might feed back to modulate the cytoskeleton and cell adhesion. We found that this dynamic system is highly plastic; at rest, integrins at focal adhesions and talin are key factors suppressing JNK activity, while multidirectional static stretch leads to integrin-dependent, and probably talin-independent, Jun sensor activation. Further, our data suggest that JNK activity has to coordinate with other signaling elements for the regulation of the cytoskeleton and cell shape remodeling associated with stretch.

Cells display versatile responses to mechanical inputs and recent studies have identified the mitogen-activated protein kinase (MAPK) cascades mediating the biological effects observed upon mechanical stimulation. Although, MAPK pathways can act insulated from each other, several mechanisms facilitate the crosstalk between the components of these cascades. Yet, the combinatorial complexity of potential molecular interactions between these elements have prevented the understanding of their concerted functions. To analyze the plasticity of the MAPK signaling network in response to mechanical stress we performed a non-saturating epistatic screen in resting and stretched conditions employing as readout a JNK responsive dJun-FRET biosensor. By knocking down MAPKs, and JNK pathway regulators, singly or in pairs in Drosophila S2R+ cells, we have uncovered unexpected regulatory links between JNK cascade kinases, Rho GTPases, MAPKs and the JNK phosphatase Puc. These relationships have been integrated in a system network model at equilibrium accounting for all experimentally validated interactions. This model allows predicting the global reaction of the network to its modulation in response to mechanical stress. It also highlights its context-dependent sensitivity.

The expanse of human biliverdin reductase (hBVR) functions in the cells is arguably unmatched by any single protein. hBVR is a Ser/Thr/Tyr-kinase, a scaffold protein, a transcription factor, and an intracellular transporter of gene regulators. hBVR is an upstream activator of the insulin/IGF-1 signaling pathway and of protein kinase C (PKC) kinases in the two major arms of the pathway. In addition, it is the sole means for generating the antioxidant bilirubin-IXα. hBVR is essential for activation of ERK1/2 kinases by upstream MAPKK-MEK and by PKCδ, as well as the nuclear import and export of ERK1/2. Small fragments of hBVR are potent activators and inhibitors of the ERK kinases and PKCs: as such, they suggest the potential application of BVR-based technology in therapeutic settings. Presently, we have reviewed the function of hBVR in cell signaling with an emphasis on regulation of PKCδ activity.

Environmental signals can be translated into chromatin changes, which alter gene expression. Here we report a novel concept that cells can signal chromatin damage from the nucleus back to the surrounding tissue through the cytokine interleukin-1alpha (IL-1α). Thus, in addition to its role as a danger signal, which occurs when the cytokine is passively released by cell necrosis, IL-1α could directly sense DNA damage and act as signal for genotoxic stress without loss of cell integrity. Here we demonstrate localization of the cytokine to DNA-damage sites and its subsequent secretion. Interestingly, its nucleo-cytosolic shuttling after DNA damage sensing is regulated by histone deacetylases (HDAC) and IL-1α acetylation. To demonstrate the physiological significance of this newly discovered mechanism, we used IL-1α knockout mice and show that IL-1α signaling after UV skin irradiation and DNA damage is important for triggering a sterile inflammatory cascade in vivo that contributes to efficient tissue repair and wound healing.

Environmental signals can be translated into chromatin changes, which alter gene expression. Here we report a novel concept that cells can signal chromatin damage from the nucleus back to the surrounding tissue through the cytokine interleukin-1alpha (IL-1α). Thus, in addition to its role as a danger signal, which occurs when the cytokine is passively released by cell necrosis, IL-1α could directly sense DNA damage and act as signal for genotoxic stress without loss of cell integrity. Here we demonstrate localization of the cytokine to DNA-damage sites and its subsequent secretion. Interestingly, its nucleo-cytosolic shuttling after DNA damage sensing is regulated by histone deacetylases (HDAC) and IL-1α acetylation. To demonstrate the physiological significance of this newly discovered mechanism, we used IL-1α knockout mice and show that IL-1α signaling after UV skin irradiation and DNA damage is important for triggering a sterile inflammatory cascade in vivo that contributes to efficient tissue repair and wound healing.

Background and Objectives: Systemic inflammatory indices have been largely investigated for their potential predictive value in multiple inflammatory, infectious, and oncological diseases; however, their value in colorectal cancer is still a subject of research. This study investigates the dynamics of pre- and postoperative values of NLR, PLR, SII, and MLR in patients with colorectal cancer and their predictive value for early postoperative outcomes. Materials and Methods: A 2-year retrospective cohort study was performed on 200 patients operated for colorectal adenocarcinoma. Systemic inflammatory indices were calculated based on complete blood count preoperatively and on the first and sixth postoperative days. The patients were divided into two groups based on their emergency or elective presentation. The pre- and postoperative values of serum inflammatory biomarkers and their correlations with postoperative outcomes were separately analyzed for the two study subgroups. Results: There were no significant differences in sex distribution, addressability, associated comorbidities, or types of surgery between the two groups. Patients in the emergency group presented higher preoperative and postoperative values of WBC, neutrophils, NLR, and SII compared to elective patients. The postsurgery hospital stays correlated well with pre- and postoperative day one and day six values of NLR (p = 0.001; 0.02; and <0.001), PLR (p < 0.001), SII (p = 0.037; <0.001; <0.001), and MLR (p = 0.002; p = 0.002; <0.001). In a multivariate analysis, reintervention risk was higher for emergency presentation and anemia, and lower in right colon cancer. In the emergency group, a multivariate model including age, MLR PO1, and pTNM stage was predictive for severe postoperative complications (AUC ROC 0.818). First-day postoperative inflammatory indices correlated well with sepsis, with the best predictive value being observed for the first postoperative day NLR (AUC 0.836; sensibility 88.8%; specificity 66.7%) and SII (AUC 0.796; sensitivity 66.6%; specificity 90%). For elective patients, the first postoperative day PLR and anemia were included in a multivariate model to predict Clavien–Dindo complications graded 3 or more (AUC ROC 0.818) and reintervention (AUC ROC 0.796). Conclusions: Easy-to-calculate and inexpensive systemic inflammatory biomarkers could be useful in predicting early postoperative outcomes in colorectal cancer for both elective and emergency surgery.

Adult intussusception is a rare cause of intestinal obstruction that differs markedly from the pediatric form in etiology, clinical presentation, and management. In contrast to predominantly idiopathic pediatric cases, adult intussusception is usually associated with an underlying structural lesion, particularly malignancy in colonic involvement. This narrative review summarizes current evidence regarding the epidemiology, etiologic spectrum, clinical features, diagnostic evaluation, and management of adult colo-colic and sigmoido-rectal intussusception. Clinical presentation is often nonspecific, and distal variants may mimic rectal prolapse or large bowel obstruction, contributing to delayed diagnosis. Contrast-enhanced computed tomography represents the diagnostic modality of choice, enabling the identification of lead points and associated complications. Surgical resection remains the cornerstone of treatment due to the high risk of malignancy, while nonoperative management is reserved for carefully selected cases. Improved recognition of atypical presentations and individualized, imaging-guided management are essential to optimize outcomes in this uncommon but clinically significant condition.