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Iron oxide nanoparticles (IONPs) have the potential to be utilized in a multitude of fields, including biomedicine. Consequently, the potential health risks associated with their use must be carefully considered. Most biosafety evaluations of IONPs have focused on examining the impact of the material’s distinctive physicochemical attributes. However, the specific attributes of individual cells are frequently disregarded, particularly under the oxidative stress conditions. This may result in an underestimation of potential risk and impede the clinical translation of IONPs. The present study thus sought to evaluate the potential cytotoxicity and underlying mechanisms of IONPs in a pathological state characterized by mild oxidative stress. A cell model of mild oxidative stress was initially established in vitro. Subsequently, a series of indicators, including cell viability, live/dead ratio, mitochondrial membrane potential, and oxidative damage, were measured to assess the cytotoxicity of IONPs. Finally, a series of ferroptosis regulators were used to elucidate the involvement of ferroptosis. Preincubation with IONPs resulted in a significant reduction in cellular viability, morphological degeneration, elevated numbers of dead cells, impaired mitochondrial function, and increased oxidative damage under mild oxidative stress conditions in vitro. The cytotoxic effects of IONPs under mild oxidative stress are largely dependent on ROS and iron ions and are strongly associated with ferroptosis, which is based on the effects of ferroptosis regulators. The present in vitro study indicated that IONPs are toxic to cells under mild oxidative stress, which is linked to ferroptosis.

Amyotrophic lateral sclerosis (ALS) is the most common and most aggressive form of adult motor neuron (MN) degeneration. The cause of the disease is still unknown, but some protein mutations have been linked to the pathological process. Loss of upper and lower MNs results in progressive muscle paralysis and ultimately death due to respiratory failure. Although initially thought to derive from the selective loss of MNs, the pathogenic concept of non-cell-autonomous disease has come to the forefront for the contribution of glial cells in ALS, in particular microglia. Recent studies suggest that microglia may have a protective effect on MN in an early stage. Conversely, activated microglia contribute and enhance MN death by secreting neurotoxic factors, and impaired microglial function at the end-stage may instead accelerate disease progression. However, the nature of microglial-neuronal interactions that lead to MN degeneration remains elusive. We review the contribution of the neurodegenerative network in ALS pathology, with a special focus on each glial cell type from data obtained in the transgenic SOD1G93A rodents, the most widely used model. We further discuss the diverse roles of neuroinflammation and microglia phenotypes in the modulation of ALS pathology. We provide information on the processes associated with dysfunctional cell-cell communication and summarize findings on pathological cross-talk between neurons and astroglia, and neurons and microglia, as well as on the spread of pathogenic factors. We also highlight the relevance of neurovascular disruption and exosome trafficking to ALS pathology. The harmful and beneficial influences of NG2 cells, oligodendrocytes and Schwann cells will be discussed as well. Insights into the complex intercellular perturbations underlying ALS, including target identification, will enhance our efforts to develop effective therapeutic approaches for preventing or reversing symptomatic progression of this devastating disease.

BMP signaling is crucial for differentiation of secretory ameloblasts, the cells that secrete enamel matrix. However, whether BMP signaling is required for differentiation of maturation-stage ameloblasts (MA), which are instrumental for enamel maturation into hard tissue, is hitherto unknown. To address this, we used an in vivo genetic approach which revealed that combined deactivation of the Bmp2 and Bmp4 genes in the murine dental epithelium causes development of dysmorphic and dysfunctional MA. These fail to exhibit a ruffled apical plasma membrane and to reabsorb enamel matrix proteins, leading to enamel defects mimicking hypomaturation amelogenesis imperfecta. Furthermore, subsets of mutant MA underwent pathological single or collective cell migration away from the ameloblast layer, forming cysts and/or exuberant tumor-like and gland-like structures. Massive apoptosis in the adjacent stratum intermedium and the abnormal cell-cell contacts and cell-matrix adhesion of MA may contribute to this aberrant behavior. The mutant MA also exhibited severely diminished tissue non-specific alkaline phosphatase activity, revealing that this enzyme’s activity in MA crucially depends on BMP2 and BMP4 inputs. Our findings show that combined BMP2 and BMP4 signaling is crucial for survival of the stratum intermedium and for proper development and function of MA to ensure normal enamel maturation.

The biological activity of chondroitin sulfate (CS) and glucosamine (GlcN) food supplements (FS), sold in USA against osteoarthritis, might depend on the effective CS and GlcN contents and on the CS structural characteristics. In this paper three USA FS were compared to two pharmaceutical products (Ph). Analyses performed by HPAE-PAD, by HPCE and by SEC-TDA revealed that the CS and GlcN titers were up to −68.8% lower than the contents declared on the labels and that CS of mixed animal origin and variable molecular weights was present together with undesired keratan sulfate. Simulated gastric and intestinal digestions were performed in vitro to evaluate the real CS amount that may reach the gut as biopolymer. Chondrocytes and synoviocytes primary cells derived from human pathological joints were used to assess: cell viability, modulation of the NF-κB, quantification of cartilage oligomeric matrix protein (COMP-2), hyaluronate synthase enzyme (HAS-1), pentraxin (PTX-3) and the secreted IL-6 and IL-8 to assess inflammation. Of the three FS tested only one (US FS1) enhanced chondrocytes viability, while all of them supported synoviocytes growth. Although US FS1 proved to be less effective than Ph as it reduced NF-kB, it could not down-regulate COMP-2; HAS-1 was up-regulated but with a lower efficacy. Inflammatory cytokines were markedly reduced by Ph while a slight decrease was only found for US-FS1.

Background The majority of previous studies of the clinical outcome of video‐assisted thoracoscopic surgery (VATS) versus open lobectomy for pathological N2 non‐small cell lung cancer (pN2 NSCLC) have been single‐center experiences with small patient numbers. The aim of this study was therefore to investigate these procedures but in a large cohort of Chinese patients with pathological N2 NSCLC in real‐world conditions. Methods Patients who underwent lobectomy for pN2 NSCLC by either VATS or thoracotomy were retrospectively reviewed from 10 tertiary hospitals between January 2014 and September 2017. Perioperative outcomes and overall survival of the patients were analyzed. Cox regression analysis was performed to identify potential prognostic factors. Propensity‐score analysis was performed to reduce cofounding biases and compare the clinical outcomes between both groups. Results Among 2144 pN2 NSCLC, 1244 patients were managed by VATS and 900 by open procedure. A total of 305 (24.5%) and 344 patients died during VATS and the thoracotomy group during a median follow‐up of 16.7 and 15.6 months, respectively. VATS lobectomy patients had better overall survival when compared with those undergoing the open procedure (P < 0.0001). Multivariate COX regression analysis showed VATS lobectomy independently favored overall survival (HR = 0.75, 95% CI: 0.621–0.896, P = 0.0017). Better perioperative outcomes, including less blood loss, shorter drainage time and hospital stay, were also observed in patients undergoing VATS lobectomy (P < 0.05). After propensity‐score matching, 169 patients in each group were analyzed, and no survival difference were found between the two groups. Less blood loss was observed in the VATS group, but there was a longer operation time. Conclusions VATS lobectomy might be a feasible alternative to conventional open surgery for resectable pN2 NSCLC. Key points Significant findings of the study: VATS lobectomy has comparative OS in pN2 NSCLC versus open procedure in resectable patients. What this study adds: VATS lobectomy might be feasible for pN2 NSCLC. The present study aimed to investigate the clinical outcome of video‐assisted thoracoscopic surgery (VATS) versus open lobectomy for pathological N2 non‐small cell lung cancer (pN2 NSCLC) using a large cohort of Chinese patients in real world conditions. VATS lobectomy might be a feasible alternative for pN2 NSCLC.

Background Tumor size is a valuable prognostic factor because it is considered a measure of tumor burden. However, it is not always correlated with the tumor burden. This study aimed to identify the prognostic role of pathological tumor proportional size using the proportion of tumor cells on the pathologic report after curative resection in pathologic stage I lung adenocarcinoma. Methods We retrospectively reviewed the medical records of 630 patients with pathologic stage I lung adenocarcinoma after lung resection for curative aims. According to the pathologic data, the proportion of tumor cells was reviewed and pathological tumor proportional size was estimated by multiplying the maximal diameter of the tumor by the proportion of tumor cells. We investigated the prognostic role of pathological tumor proportional size. Results The median tumor size was 2 cm (range: 0.3–4), and the median pathological tumor proportional size was 1.5 (range: 0.12–3.8). This value was recategorized according to the current tumor‐node‐metastasis (TNM) classification, and 184 patients showed down staging compared with the current stage. The survival curve for disease‐free survival using pathological tumor proportional size showed more distinction than the current stage classification. Multivariate analysis revealed that a down stage indicated a favorable prognostic factor. Conclusion Pathological tumor cell proportional size may be associated with prognosis in stage I lung adenocarcinoma. If the pathological tumor proportional size shows a downward stage, it may indicate a smaller tumor burden and better prognosis The entire tumor size is a valuable prognostic factor and plays a key role in determining cancer stage and treatment. It is considered tumor burden and is correlated with cancer progression. However, tumor size usually has no prognostic impact in stage I lung adenocarcinoma from many studies. In this study, we investigated the prognostic role of tumor size using tumor cell proportion.

The single amino acid mutation G26R in human apolipoprotein A-I (apoA-I Iowa ) is the first mutation that was associated with familial AApoA1 amyloidosis. The N-terminal fragments (amino acid residues 1–83) of apoA-I containing this mutation deposit as amyloid fibrils in patients’ tissues and organs, but the mechanisms of cellular degradation and cytotoxicity have not yet been clarified. In this study, we demonstrated degradation of apoA-I Iowa fibrils via the autophagy-lysosomal pathway in human embryonic kidney 293 cells. ApoA-I Iowa fibrils induced an increase in lysosomal pH and the cytosolic release of the toxic lysosomal protease cathepsin B. The mitochondrial dysfunction caused by apoA-I Iowa fibrils depended on cathepsin B and was ameliorated by increasing the degradation of apoA-I Iowa fibrils. Thus, although apoA-I Iowa fibril transport to lysosomes and fibril degradation in lysosomes may have occurred, the presence of an excess number of apoA-I Iowa fibrils, more than the lysosomes could degrade, may be detrimental to cells. Our results thus provide evidence that the target of apoA-I Iowa fibrils is lysosomes and we thereby gained a novel insight into the mechanism of AApoA1 amyloidosis.

Scars are composed of stiff collagen fibers, which contract strongly owing to the action of myofibroblasts. To explore the substances that modulate scar contracture, the fibroblast-populated collagen lattice (FPCL) model has been used. However, the molecular signature of the patient-derived FPCL model has not been verified. Here, we examined whether the patient-derived keloid FPCL model reflects scar contraction, analyzing detailed gene expression changes using comprehensive RNA sequencing and histological morphology, and revealed that these models are consistent with the changes during human scar contracture. Moreover, we examined whether conditioned media derived from adipose stem cells (ASC-CM) suppress the scar contracture of the collagen disc. Detailed time-series measurements of changes in disc area showed that the addition of ASC-CM significantly inhibited the shrinkage of collagen discs. In addition, a deep sequencing data analysis revealed that ASC-CM suppressed inflammation-related gene expression in the early phase of contraction; in the later phase, this suppression was gradually replaced by extracellular matrix (ECM)-related gene expression. These lines of data suggested the effectiveness of ASC-CM in suppressing scar contractures. Therefore, the molecular analysis of the ASC-CM actions found in this study will contribute to solving medical problems regarding pathological scarring in wound prognosis.