Galectin-1 Promotes Gastric Carcinoma Progression and Cisplatin Resistance Through the NRP-1/c-JUN/Wee1 Pathway.

PURPOSE: Gastric cancer (GC) is among the deadliest malignancies and the third leading cause of cancer-related deaths worldwide. Galectin-1 (Gal-1) is a primary protein secreted by cancer-associated fibroblasts (CAFs); however, its role and mechanisms of action of Gal-1 in GC remain unclear. In this study, we stimulated GC cells with exogenous human recombinant galectin-1 protein (rhGal-1) to investigate its effects on the proliferation, migration, and resistance to cisplatin. MATERIALS AND METHODS: We used simulated rhGal-1 protein as a paracrine factor produced by CAFs to induce GC cells and investigated its promotional effects and mechanisms in GC progression and cisplatin resistance. Immunohistochemical (IHC) assay confirmed that Gal-1 expression was associated with clinicopathological parameters and correlated with the expression of neuropilin-1 (NRP-1), c-JUN, and Wee1. RESULTS: Our study reveals Gal-1 expression was significantly associated with poor outcomes. Gal-1 boosts the proliferation and metastasis of GC cells by activating the NRP-1/C-JUN/Wee1 pathway. Gal-1 notably increases GC cell resistance to cisplatin The NRP-1 inhibitor, EG00229, effectively counteracts these effects. CONCLUSIONS: These findings revealed a potential mechanism by which Gal-1 promotes GC growth and contributes to chemoresistance, offering new therapeutic targets for the treatment of GC.

Inhibiting caspase-3/GSDME-mediated pyroptosis ameliorates septic lung injury in mice model.

Acute lung injury is one of the most serious complications of sepsis, which is a common critical illness in clinic. This study aims to investigate the role of caspase-3/ gasdermin-E (GSDME)-mediated pyroptosis in sepsis-induced lung injury in mice model. Cecal ligation (CLP) operation was used to establish mice sepsis-induced lung injury model. Lung coefficient, hematoxylin and eosin staining and transmission electron microscopy were used to observe the lung injury degree. In addition, caspase-3-specific inhibitor Z-DEVD-FMK and GSDME-derived inhibitor AC-DMLD-CMK were used in CLP model, caspase-3 activity, GSDME immunofluorescence, serum lactate dehydrogenase (LDH) and interleukin-6 (IL-6) levels, TUNEL staining, and the expression levels of GSDME related proteins were detected. The mice in CLP group showed the increased expressions of cleaved-caspase-3 and GSDME-N terminal, destruction of lung structure, and the increases of LDH, IL-6, IL-18 and IL-1ß levels, which were improved in mice treated with Z-DEVD-FMK or AC-DMLD-CMK. In conclusion, caspase-3/GSDME mediated pyroptosis is involved in the occurrence of sepsis-induced lung injury in mice model, inhibiting caspase-3 or GSDME can both alleviate lung injury.

Damage Monitoring of Regularly Arrayed Short-Fiber-Reinforced Composite Laminates under Tensile Load Based on Acoustic Emission Technology.

Carbon-fiber-reinforced polymer (CFRP) composites are widely used in lightweight structures because of their high specific strength, specific modulus, and low coefficient of thermal expansion. Additionally, the unidirectionally arrayed chopped strand (UACS) laminates have excellent mechanical properties and flowability, making them suitable for fabricating structures with complex geometry. In this paper, the damage process of UACS quasi-isotropic laminates under tensile load was tested using acoustic emission detection technology. The mechanical properties and damage failure mechanism of UACS laminates were studied combined with finite element calculation. By comparing and analyzing the characteristic parameters of acoustic emission signals such as amplitude, relative energy, and impact event, it is found that acoustic emission behavior can accurately describe the damage evolution of specimens during loading. The results show that the high-amplitude signals representing fiber fracture in continuous fiber laminates are concentrated in the last 41%, while in UACS laminates they are concentrated in the last 30%. In UACS laminates, more of the damage is caused by matrix cracks and delamination with medium- and low-amplitude signals, which indicates that UACS laminates have a good suppression effect on damage propagation. The stress-strain curves obtained from finite element analysis agree well with the experiment results, showing the same damage sequence, which confirms that the model described in this research is reliable.

Morusin-Cu(II)-indocyanine green nanoassembly ignites mitochondrial dysfunction for chemo-photothermal tumor therapy.

Nanoscale drug delivery systems derived from natural bioactive materials accelerate the innovation and evolution of cancer treatment modalities. Morusin (Mor) is a prenylated flavonoid compound with high cancer chemoprevention activity, however, the poor water solubility, low active pharmaceutical ingredient (API) loading content, and instability compromise its bioavailability and therapeutic effectiveness. Herein, a full-API carrier-free nanoparticle is developed based on the self-assembly of indocyanine green (ICG), copper ions (Cu2+) and Mor, termed as IMCNs, via coordination-driven and π-π stacking for synergistic tumor therapy. The IMCNs exhibits a desirable loading content of Mor (58.7 %) and pH/glutathione (GSH)-responsive motif. Moreover, the photothermal stability and photo-heat conversion efficiency (42.8 %) of IMCNs are improved after coordination with Cu2+ and help to achieve photothermal therapy. Afterward, the released Cu2+ depletes intracellular overexpressed GSH and mediates Fenton-like reactions, and further synergizes with ICG at high temperatures to expand oxidative damage. Furthermore, the released Mor elicits cytoplasmic vacuolation, expedites mitochondrial dysfunction, and exerts chemo-photothermal therapy after being combined with ICG to suppress the migration of residual live tumor cells. In vivo experiments demonstrate that IMCNs under laser irradiation could excellently inhibit tumor growth (89.6 %) through the multi-modal therapeutic performance of self-enhanced chemotherapy/coordinated-drugs/ photothermal therapy (PTT), presenting a great potential for cancer therapy.

Inhibiting apoptosis and GSDME-mediated pyroptosis attenuates hepatic injury in septic mice.

BACKGROUND: Sepsis is characterized by severe inflammation and organ dysfunction resulting from a dysregulated organismal response to infection. Although pyroptosis has been presumably shown to be a major cause of multiple organ failure and septic death, whether gasdermin E (GSDME)-mediated pyroptosis occurs in septic liver injury and whether inhibiting apoptosis and GSDME-mediated pyroptosis can attenuate septic liver injury remain unclear. This study investigated the role of apoptosis and GSDME-mediated pyroptosis in septic liver injury. METHODS: Adult male C57BL/6 mice were randomly divided into four groups: sham, cecal ligation puncture (CLP), CLP + Z-DEVD-FMK (a caspase-3 inhibitor, 5 mg/kg), and CLP + Ac-DMLD-CMK (a GSDME inhibitor, 5 mg/kg). Sepsis severity was assessed using the murine sepsis score (MSS). Hepatic tissue damage was observed by the hematoxylin-eosin staining method, the activities of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST), the levels of malondialdehyde (MDA), the concentrations of interleukin-1ß (IL-1ß), and tumor necrosis factor-α (TNF-α) were measured according to the related kits, and the changes in the hepatic tissue reactive oxygen species (ROS) levels were detected by immunofluorescence (IF). The protein expression levels of cleaved caspase-3, GSDME-N, IL-1ß, B-cell lymphoma-2 (Bcl-2), cytochrome C (Cyt-c), and acetaldehyde dehydrogenase 2 (ALDH2) were detected using western blotting. GSDME expression was detected by immunohistochemistry. RESULTS: Compared with the Sham group, CLP mice showed high sepsis scores and obvious liver damage. However, in the CLP + Z-DEVD-FMK and CLP + Ac-DMLD-CMK groups, the sepsis scores were reduced and liver injury was alleviated. Compared with the Sham group, the serum ALT and AST activities, MDA and ROS levels, and IL-1ß and TNF-α concentrations were increased in the CLP group, as well as the protein expression of cleaved caspase-3, GSDME-N, IL-1ß, Cyt-c, and GSDME positive cells (P < 0.05). However, the expression levels of Bcl-2 and ALDH2 protein were decreased (P < 0.05). Compared with the CLP group, the CLP + Z-DEVD-FMK and CLP + Ac-DMLD-CMK groups showed low sepsis scores, ALT and AST activities, MDA and ROS levels, decreased IL-1ß and TNF-α concentrations, and decreased expression of cleaved caspase-3, GSDME-N, IL-1ß protein expression, and GSDME positive cells (P < 0.05). The expression levels of Bcl-2 and ALDH2 protein were increased (P < 0.05). CONCLUSION: Apoptosis and GSDME-mediated pyroptosis are involved in the development of sepsis-induced hepatic injury. Inhibition of apoptosis and GSDME-mediated pyroptosis attenuates injury. ALDH2 plays a protective role by inhibiting apoptosis and pyroptosis.

Aldo-keto Reductase 1B10 Restrains Cell Migration, Invasion, and Adhesion of Gastric Cancer via Regulating Integrin Subunit Alpha 5.

BACKGROUND/AIMS: Gastric cancer is a prevalent malignancy with unfavorable prognosis partially resulting from its high metastasis rate. Clarifying the molecular mechanism of gastric cancer occurrence and progression for improvement of therapeutic efficacy and prognosis is needed. The study tended to delineate the role and regulatory mechanism of aldo-keto reductase 1B10 (AKR1B10) in gastric cancer progression. MATERIALS AND METHODS: The relationship of AKR1B10 expression with survival rate in gastric cancer was analyzed through Kaplan-Meier analysis. The mRNA levels of AKR1B10 and integrin subunit alpha 5 (ITGA5) in gastric cancer tissues and cell lines were measured by real-time quantitative polymerase chain reaction. Protein levels of AKR1B10 and integrin subunit alpha 5 were assayed via western blot. The molecular relationship between AKR1B10 and ITGA5 was analyzed by co-immunoprecipitation assay. Cell viability was assayed through Cell Counting Kit-8, invasion and migration of tumor cells was assessed through wound healing and transwell assays. Transwell assay was utilized to detect invasion. The adhesion of gastric cancer cells was detected using cell adhesion assays. RESULTS: The results unveiled that integrin subunit alpha 5 was upregulated, while AKR1B10 was downregulated in gastric cancer tissues and cells. Overexpressing AKR1B10 hindered gastric cancer cell proliferation, migration, invasion and adhesion. It was striking that we certified the inhibitory effect of AKR1B10 on integrin subunit alpha 5 expression and their (AKR1B10 and ITGA5)) negative relationship via bioinformatics method, real-time quantitative polymerase chain reaction, and co-immunoprecipitation assays. Via rescue experiments, it was concluded that AKR1B10 served as tumor suppressor potentially by ITGA5 expression in gastric cancer. CONCLUSION: Our results indicated that AKR1B10 inhibited migration, invasion, and adhesion of gastric cancer cells via modulation of ITGA5.

Atmosphere-inspired multilayered nanoarmor with modulable protection and delivery of Interleukin-4 for inflammatory microenvironment modulation.

Inflammatory bowel disease (IBD) has been closely associated with immune disorders and excessive M1 macrophage activation, which can be reversed by the M2-polarizing effect of interleukin-4 (IL-4). However, maintaining native IL-4 activity with its specific release in the inflammatory microenvironment and efficient biological performance remain a challenge. Inspired by the multilayered defense mechanism of the earth's atmosphere, we constructed a multilayered protective nanoarmor (NA) for IL-4 delivery (termed as IL-4@PEGRA NAs) into an intricate inflammatory microenvironment. The poly(ethylene glycol) (PEG)-ylated phenolic rosmarinic acid (RA)-grafted copolymer contains two protective layers-the intermediate polyphenol (RA molecules) and outermost shield (PEG) layers-to protect the biological activity of IL-4 and prolong its circulation in blood. Moreover, IL-4@PEGRA NAs scavenge reactive oxygen species with the specific release of IL-4 and maximize its biofunction at the site of inflammation, leading to M2 macrophage polarization and downregulation of inflammatory mediators. Simultaneously, gut microbiota dysbiosis can improve to amplify the M2-polarizing effect and inhibit the phosphatidylinositol 3 kinase/Akt signaling pathway, thereby attenuating inflammation and promoting colitis tissue repair. It provides a nature-inspired strategy for constructing an advanced multilayered NA delivery system with protective characteristics and potential for IBD management.

Decoupling Long-and Short-Term Patterns in Spatiotemporal Inference.

Sensors are the key to environmental monitoring, which impart benefits to smart cities in many aspects, such as providing real-time air quality information to assist human decision-making. However, it is impractical to deploy massive sensors due to the expensive costs, resulting in sparse data collection. Therefore, how to get fine-grained data measurement has long been a pressing issue. In this article, we aim to infer values at nonsensor locations based on observations from available sensors (termed spatiotemporal inference), where capturing spatiotemporal relationships among the data plays a critical role. Our investigations reveal two significant insights that have not been explored by previous works. First, data exhibit distinct patterns at both long-and short-term temporal scales, which should be analyzed separately. Second, short-term patterns contain more delicate relations, including those across spatial and temporal dimensions simultaneously, while long-term patterns involve high-level temporal trends. Based on these observations, we propose to decouple the modeling of short-and long-term patterns. Specifically, we introduce a joint spatiotemporal graph attention network to learn the relations across space and time for short-term patterns. Furthermore, we propose a graph recurrent network with a time skip strategy to alleviate the gradient vanishing problem and model the long-term dependencies. Experimental results on four public real-world datasets demonstrate that our method effectively captures both long-and short-term relations, achieving state-of-the-art performance against existing methods.

Driving Factors of Carbon Emissions in G20 Countries: A Weighted Average Structural Decomposition Approach.

As a major part of global development governance, G20 countries account for 80% of global carbon emissions. In order to achieve the goal of "carbon neutrality" proposed by the United Nations, it is important to compare and analyze the drivers of carbon emissions in G20 countries and provide recommendations for their carbon emission reduction. Based on the data of 17 G20 countries in the EORA database, this paper compares the drivers of carbon emissions of each country from 1990-2021 using weighted average structural decomposition and K-mean model. This paper focuses on four drivers, including carbon emission intensity, final demand structure, export structure, and production structure. Carbon emission intensity and final demand structure are the main factors of carbon emission reduction, and the other two factors have little influence. Among the G20 countries, the UK is in the first category because it does the best job on the four factors of carbon emissions, yet Italy is in the last category because it does not take full advantage of the four factors. Therefore, improving supply energy efficiency and adjusting demand, export, and industrial structure have become important tools for countries to transform and achieve carbon neutrality.

Dual-stimulus phototherapeutic nanogel for triggering pyroptosis to promote cancer immunotherapy.

Pyroptosis is a highly inflammatory programmed cell death that activates inflammatory response, reverses immunosuppression and promotes systemic immune response for solid tumors treatment. However, the uncontrollable and imprecise process of pyroptosis stimulation leads to a scanty therapeutic effect. Here, we report a GSH/ROS dual response nanogel system (IMs) that can actively target the overexpressed mannose receptor (MR) of cancer cells, serve ultra-stable photothermal capacity of indocyanine green (ICG), induce cell pyroptosis and achieve enhanced tumor immune response. Photo-triggered IMs induce cytoplasmic Ca2+ introgression and activate caspase-3 through photo-activated ICG. The disconnect of SeSe bonds can break the oxidation and reduction balance of tumor cells, causing oxidative stress and synergistically enhancing caspase-3 cleavage, and regulating cell pyroptosis ultimately. Combined with anti-programmed death receptor 1 (anti-PD-1), the nanogel system not only effectivly suppress both primary tumor and distance tumor but also prolong the survival period of mice. This work introduces a strategy to optimize the photothermal performance of ICG and enhances tumor immune response mediated by triggering pyroptosis, which provides an impressive option for immune checkpoint blockade therapy.

Moderate white light exposure enhanced spatial memory retrieval by activating a central amygdala-involved circuit in mice.

Light exposure can profoundly affect neurological functions and behaviors. Here, we show that short-term exposure to moderate (400 lux) white light during Y-maze test promoted spatial memory retrieval and induced only mild anxiety in mice. This beneficial effect involves the activation of a circuit including neurons in the central amygdala (CeA), locus coeruleus (LC), and dentate gyrus (DG). Specifically, moderate light activated corticotropin-releasing hormone (CRH) positive (+) CeA neurons and induced the release of corticotropin-releasing factor (CRF) from their axon terminals ending in the LC. CRF then activated tyrosine hydroxylase-expressing LC neurons, which send projections to DG and release norepinephrine (NE). NE activated ß-adrenergic receptors on CaMKIIα-expressing DG neurons, ultimately promoting spatial memory retrieval. Our study thus demonstrated a specific light scheme that can promote spatial memory without excessive stress, and unraveled the underlying CeA-LC-DG circuit and associated neurochemical mechanisms.

Single cell molecular alterations reveal target cells and pathways of conditioned fear memory.

OBJECTIVES: Recent evidence indicates that hippocampus is important for conditioned fear memory (CFM). Though few studies consider the roles of various cell types' contribution to such a process, as well as the accompanying transcriptome changes during this process. The purpose of this study was to explore the transcriptional regulatory genes and the targeted cells that are altered by CFM reconsolidation. METHODS: A fear conditioning experiment was established on adult male C57 mice, after day 3 tone-cued CFM reconsolidation test, hippocampus cells were dissociated. Using single cell RNA sequencing (scRNA-seq) technique, alterations of transcriptional genes expression were detected and cell cluster analysis were performed and compared with those in sham group. RESULTS: Seven non-neuronal and eight neuronal cell clusters (including four known neurons and four newly identified neuronal subtypes) has been explored. Among them, CA subtype 1 has characteristic gene markers of Ttr and Ptgds, which is speculated to be the outcome of acute stress and promotes the production of CFM. The results of KEGG pathway enrichment indicate the differences in the expression of certain molecular protein functional subunits in long-term potentiation (LTP) pathway between two types of neurons (DG and CA1) and astrocytes, thus providing a new transcriptional perspective for the role of hippocampus in the CFM reconsolidation. More importantly, the correlation between the reconsolidation of CFM and neurodegenerative diseases-linked genes is substantiated by the results from cell-cell interactions and KEGG pathway enrichment. Further analysis shows that the reconsolidation of CFM inhibits the risk-factor genes App and ApoE in Alzheimer's Disease (AD) and activates the protective gene Lrp1. CONCLUSIONS: This study reports the transcriptional genes expression changes of hippocampal cells driven by CFM, which confirm the involvement of LTP pathway and suggest the possibility of CFM-like behavior in preventing AD. However, the current research is limited to normal C57 mice, and further studies on AD model mice are needed to prove this preliminary conclusion.

Research on Low-Velocity Impact Response of Novel Short-Fiber-Reinforced Composite Laminates.

Short-fiber-reinforced polymers (SFRPs) based on unidirectionally arrayed chopped strands (UACSs) have excellent formability and outstanding mechanical response. The low-velocity impact response, such as the delamination, damage tolerance and energy absorption of UACS composites, are essential to guarantee the stability and safety of composite components in service. The current study investigates the low-velocity impact response of continuous carbon-fiber-reinforced polymer (CFRP) and UACS laminates with vertical slits under drop-weight impact with various impact energies (4, 7 and 11 J). The in-plane size of the studied samples is 100 mm × 100 mm, and the stacking sequence is [0/90]4s. The time-history curves of load and energy are examined during low-velocity impact experiments, as well as the nonvisible damages are obtained by ultrasound C-scan imaging technique. A user-defined subroutine VUMAT, including the Johnson-Cook material and failure model, which is used to simulate the elastic-plastic property of the slits filled with resin, is coded in ABAQUS/Explicit. According to C-scan inspections of the impact-damaged laminates, UACS specimens show more severe delamination as impact energy increases. The damaged area of continuous CFRP laminates under impact energy of 11 J is 311 mm2, while that of UACS laminates is 1230 mm2. The slits have a negative effect on the load-bearing capacity but increase the energy absorption of UACS laminates by approximately 80% compared to the continuous CFRP laminates at 7 J. According to the variables of different damage modes in numerical simulation, cracks appear at the slits and then expand along the direction perpendicular to the slits, leading to the fracture of fiber. Nevertheless, as the damage expands to the slits, the delamination confines the damage propagation. The existence of slits could guide the path of damage propagation.

Reduction-triggered polycyclodextrin supramolecular nanocage induces immunogenic cell death for improved chemotherapy.

Polycyclodextrin-based supramolecular nanoplatform crosslinked by stimuli-responsive moiety shows great promise in cancer therapy owing to its superior bio-stability and feasible modification of architectures. Here, the endogenous glutathione (GSH)-responsive polycyclodextrin supramolecular nanocages (PDOP NCs) are constructed by covalent crosslinking of multiple ß-cyclodextrin (ß-CD) molecules. The polycyclodextrin provide sites for conjugation of chemotherapeutic doxorubicin (DOX). Meanwhile, the PDOP NCs are stabilized by multiple interactions including host-guest interaction between DOX and ß-CD and hydrogen bonds between ß-CD units. The supramolecular crosslinked structure endowed the nanocage with high stability and drug loading capacity. Tons of GSH-sensitive disulfide linkages in PDOP NCs were broken at tumor cells, promoting tumor-specific DOX release. Besides, the redox equilibrium in tumor microenvironment could be disturbed due to GSH depletion, which further sensitized the DOX effects and alleviated drug resistance, facilitating inducing immunogenic cell death effect for enhanced chemotherapy, thereby achieving efficient tumor suppression and prolonged survival. Thus, the versatile polycyclodextrin-based supramolecular nanocage provides a novel and efficient drug delivery strategy for cancer treatment.

PBRM1 presents a potential prognostic marker and therapeutic target in duodenal papillary carcinoma.

BACKGROUND: Due to its rarity, duodenal papillary carcinoma (DPC) is seldom studied as a unique disease and no specific molecular features or treatment guidelines are provided. METHODS: Whole-exome sequencing was performed to gain new insights into the DPC mutation landscape and to identify potential signalling pathways and therapeutic targets. Mechanistically, immunohistochemistry (IHC), immunofluorescence, RNA-seq, ATAC-seq and in vitro cell function experiments were performed to confirm the underlying mechanisms. RESULTS: We described the mutational landscape of DPC for the first time as a group of rare tumours with a high frequency of dysregulation in the chromatin remodelling pathway, particularly PBRM1-inactivating mutations that are significantly higher than duodenal adenocarcinomas and ampullary adenocarcinoma (27% vs. 0% vs. 7%, p < .01). In vitro cell experiments showed that downregulation of PBRM1 expression could significantly promote the cancer progression and epithelial-to-mesenchymal transition via the PBRM1-c-JUN-VIM axis. The IHC data indicated that PBRM1 deficiency (p = .047) and c-JUN expression (p < .001) were significantly associated with poor prognosis. Meanwhile, the downregulation of PBRM1 expression in HUTU-80 cells was sensitive to radiation, which may be due to the suppression of c-JUN by irradiation. CONCLUSIONS: Our findings define a novel molecular subgroup of PBRM1-inactivating mutations in DPC. PBRM1 play an important role in DPC progression and may serve as a potential therapeutic target and prognostic indicator.

ROS-responsive resveratrol-loaded cyclodextrin nanomicelles reduce inflammatory osteolysis.

Bone loss in inflammatory disorders such as osteomyelitis, septic arthritis, and periodontitis is caused by excessive osteoclastic activity. Meanwhile, reactive oxygen species (ROS) have been identified as contributors to osteoclast differentiation, and the application of ROS scavengers has emerged as a promising strategy to protect against bone loss. Recently, resveratrol (RSV), a polyphenolic phytoalexin, has been demonstrated to inhibit osteoclastogenesis by scavenging ROS; however, the application of RSV as an antioxidant is limited by its low water solubility, structural instability, and short elimination half-life. In this study, we developed a PEGylated cyclodextrin (CD)-based nanoplatform (PCP) for local delivery of RSV as nanomicelles (RSV-NMs). In addition, polymer functionalization with phenylboronic acid ester in RSV-NMs successfully achieved ROS-responsive release of RSV. The RSV-NMs in a well-dispersed state possessed good biocompatibility as well as improved solubility and stability compared with RSV compound. In vitro, RSV-NMs significantly inhibited the formation of tartrate-resistant acid phosphatase (TRAP)-positive multinuclear cells and suppressed F-actin (filamentous actin) ring formation. Additionally, the mRNA expressions of osteoclastic marker genes, including matrix metalloprotein-9 (MMP-9), nuclear factor of activated T cells 1 (NFATc1), TRAP, and cathepsin K, were consequently downregulated in the presence of RSV-NMs. In vivo, RSV-NMs provided protection against LPS-induced bone destruction, as evidenced by a decreased number of osteoclasts, increased bone density, and reduced area of bone resorption. Taken together, these results indicate that our ROS-responsive RSV-NMs can be employed as a potential therapeutic agent for the treatment of inflammatory osteolysis.

Sustained release of chlorogenic acid-loaded nanomicelles alleviates bone loss in mouse periodontitis.

Periodontitis is a prevalent chronic inflammatory disease that destroys the periodontal supporting tissues, impinges on oral health, and is correlated with an increased risk of systemic disease. Currently, the main drug treatment is antibiotic therapy; however, systemic antibiotic therapy still has various drawbacks such as bacterial resistance, low bioavailability and burst release. It is noteworthy that the local use of non-antibiotic drugs with sustained release characteristics can effectively overcome these problems. It has been documented that chlorogenic acid (CGA) has good anti-inflammatory and antioxidant properties. To achieve the sustained release of CGA, we synthesized CGA-PLGA@PVP nanomicelles by loading CGA onto poly(D,L-lactide-co-glycolide) (PLGA) and modified them with polyvinylpyrrolidone (PVP) for better dispersion. The results demonstrated that CGA-PLGA@PVP nanomicelles could prolong the release time of CGA, and could not only effectively remove reactive oxygen species (ROS) but also downregulate the overexpression of proinflammatory cytokines in lipopolysaccharide (LPS)-treated RAW264.7 cells. Moreover, CGA-PLGA@PVP nanomicelles could remain in gingival tissue for more than 24 hours after local injection, inhibit alveolar bone resorption and prevent the progression of periodontitis in a mouse model, showing good biocompatibility. Therefore, CGA-PLGA@PVP nanomicelles have great properties and are expected to be a novel therapeutic strategy for periodontitis.

Eucalyptol prevents bleomycin-induced pulmonary fibrosis and M2 macrophage polarization.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fibrosing interstitial pneumonia with limited therapeutic options. Eucalyptol, a terpenoid oxide isolated from eucalyptus species, reportedly exhibits various biological activities such as anti-inflammatory and antioxidant effects. In the present study, we aimed to determine whether eucalyptol could alleviate bleomycin (BLM)-induced pulmonary fibrosis and inhibit interleukin (IL)-13-induced M2 macrophage polarization. Upon treatment with eucalyptol, BLM-induced pulmonary fibrosis and lung inflammation were significantly reduced. The pulmonary neutrophil accumulation and pulmonary permeability were inhibited and the expression of hydroxyproline, alpha-smooth muscle actin, and fibronectin was significantly down-regulated. Eucalyptol also markedly inhibited the expression of arginase-1, Ym-1, IL-13, and transforming growth factor (TGF)-ß1, reduced the production of IL-13, IL-6, tumor necrosis factor (TNF)-α, and attenuated the activity of TGF-ß1 in bronchoalveolar lavage fluid (BALF). Furthermore, the in vitro assay revealed that eucalyptol disturbed M2 macrophage polarization and reduced the macrophage-mediated secretion of the profibrotic factor TGF-ß1. Eucalyptol inhibited the nuclear location of signal transducer and activator of transcription 6 (STAT6) and the phosphorylation of STAT6 and p38 mitogen-activated protein kinase (p38 MAPK), and reduced the expression of their downstream transcription factors, krupple-like factor 4 (KLF4) and peroxisome proliferator-activated receptor gamma (PPAR-γ). These findings indicated that eucalyptol alleviates BLM-induced pulmonary fibrosis by regulating M2 macrophage polarization, which, in turn, inhibits the activation of signaling molecules (e.g., STAT6 and p38 MAPK) and the expression of transcription factors (e.g., KLF4 and PPAR-γ). Thus, eucalyptol might be a potential therapeutic agent for IPF.