The impact of obstructive sleep apnea on nonalcoholic fatty liver disease.

Obstructive sleep apnea (OSA) is characterized by episodic sleep state-dependent collapse of the upper airway, with consequent hypoxia, hypercapnia, and arousal from sleep. OSA contributes to multisystem damage; in severe cases, sudden cardiac death might occur. In addition to causing respiratory, cardiovascular and endocrine metabolic diseases, OSA is also closely associated with nonalcoholic fatty liver disease (NAFLD). As the prevalence of OSA and NAFLD increases rapidly, they significantly exert adverse effects on the health of human beings. The authors retrieved relevant documents on OSA and NAFLD from PubMed and Medline. This narrative review elaborates on the current knowledge of OSA and NAFLD, demonstrates the impact of OSA on NAFLD, and clarifies the underlying mechanisms of OSA in the progression of NAFLD. Although there is a lack of sufficient high-quality clinical studies to prove the causal or concomitant relationship between OSA and NAFLD, existing evidence has confirmed the effect of OSA on NAFLD. Elucidating the underlying mechanisms through which OSA impacts NAFLD would hold considerable importance in terms of both prevention and the identification of potential therapeutic targets for NAFLD.

Programmed Cell Death in Liver Fibrosis.

Programmed cell death (PCD) is a comprehensive term that encompasses various forms of cell death, such as apoptosis, necroptosis, pyroptosis, ferroptosis, and autophagy, which play a crucial role in the pathogenesis of liver fibrosis. PCD facilitates the elimination of aberrant cells, particularly activated hepatic stellate cells (HSCs), which are the primary producers of extracellular matrix (ECM). The removal of HSCs may impede ECM synthesis, thereby mitigating liver fibrosis. As such, PCD has emerged as a promising therapeutic target for the development of novel drugs to treat liver fibrosis. Numerous studies have been conducted to investigate the underlying mechanisms of PCD in the elimination of activated HSCs and other aberrant liver cells in fibrotic liver tissue, including hepatocytes, hepatic sinusoid endothelial cells (LSECs), and Kupffer cells (KCs). The induction of PCD, the interplay between different forms of PCD, and the potential harm or benefit of PCD in liver fibrosis are topics of ongoing research. Evidences suggest that PCD is a complex process with dual effects on liver fibrosis. The purpose of this review is to summarize the most recent advances in PCD and liver fibrosis research.

The impact and role of identified long noncoding RNAs in nonalcoholic fatty liver disease: A narrative review.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide, but its mechanism and pathophysiology remain unclear. Long noncoding RNAs (lncRNAs) may exert a vital influence on regulating various biological functions in NAFLD. METHODS: The databases such as Google Scholar, PubMed, and Medline were searched using the following keywords: nonalcoholic fatty liver disease, nonalcoholic fatty liver disease, NAFLD, nonalcoholic steatohepatitis, nonalcoholic steatohepatitis, NASH, long noncoding RNAs, and lncRNAs. Considering the titles and abstracts, unrelated studies were excluded. The authors evaluated the full texts of the remaining studies. RESULTS: We summarized the current knowledge of lncRNAs and the main signaling pathways of lncRNAs involved in NAFLD explored in recent years. As a heterogeneous group of noncoding RNAs (ncRNAs), lncRNAs play crucial roles in biological processes underlying the pathophysiology of NAFLD. The mechanisms, particularly those associated with the regulation of the expression and activities of lncRNAs, play important roles in NAFLD. CONCLUSION: A better comprehension of the mechanism controlled by lncRNAs in NAFLD is necessary for the identification of novel therapeutic targets for drug development and improved, noninvasive methods for diagnosis.

Water-soluble Yb3+, Er3+ codoped NaYF4 nanoparticles induced SGC-7901 cell apoptosis through mitochondrial dysfunction and ROS-mediated ER stress.

BACKGROUND: Nanoparticles are potential luminescent probes; among them, upconversion nanoparticles (UCNP) are currently being developed as fluorescent probes for biomedical applications. However, the molecular mechanisms of UCNP in human gastric cell lines remain poorly understood. Here, we aimed to examine UCNP cytotoxicity to SGC-7901 cells and explore its underlying mechanisms. METHODS: The effects of 50-400 µg/mL UCNP on human gastric adenocarcinoma (SGC-7901) cells were investigated. Flow cytometry was used to evaluate reactive oxygen species (ROS), mitochondrial membrane potential (ΔΨm), intracellular Ca2+ levels, and apoptosis. Activated caspase-3 and nine activities were measured; meanwhile, cytochrome C (Cyt C) in the cytosol and B-cell lymphoma 2 (Bcl-2), Bcl-2 associated X protein (Bax), protein kinase B (Akt), phosphorylated-Akt (p-Akt), 78 kDa glucose-regulated protein (GRP78), 94 kDa glucose-regulated protein (GRP94), calpain-1, and calpain-2 protein levels were also detected. RESULTS: UCNP inhibited the viability of SGC-7901 cells in a concentration- and time-dependent manner and increased the proportion of cell apoptosis. Exposure to UCNP enhanced the ratio of Bax/Bcl-2, elevated the level of ROS, decreased ΔΨm, increased intracellular Ca2+ and Cyt C protein levels, decreased the levels of phosphorylated Akt, increased the activity of caspase-3 and caspase-9, and upregulated the protein expression of GRP-78, GRP-94, calpain-1 and calpain-2 in SGC-7901 cells. CONCLUSION: UCNP induced SGC-7901 cell apoptosis by promoting mitochondrial dysfunction and ROS-mediated endoplasmic reticulum (ER) stress, initiating the caspase-9/caspase-3 cascade.

Effects of Hizikia fusiforme polysaccharides on innate immunity and disease resistance of the mud crab Scylla paramamosain.

In this study, we extracted the polysaccharides from Hizikia fusiforme (HFPs) and evaluated their effects on the immune response of the mud crab Scylla paramamosain. Compositional analysis revealed that HFPs were composed mainly of mannuronic acid (49.05%) and fucose (22.29%) as sulfated polysaccharides, and the sugar chain structure was ß-type. These results indicated that HFPs have potential antioxidant and immunostimulation activity in vivo or in vitro assays. Through this research, we found that HFPs inhibited viral replication in white spot syndrome virus (WSSV)-infected crabs and promoted phagocytosis of Vibrio alginolyticus by hemocytes. Quantitative PCR results showed that HFPs up-regulated the expression levels of astakine, crustin, myosin, MCM7, STAT, TLR, JAK, CAP, and p53 in crab hemocytes. HFPs also promoted the activities of superoxide dismutase and acid phosphatase and the hemolymph antioxidant activities of crabs. HFPs maintained peroxidase activity after WSSV challenge, thereby providing protection against oxidative damage caused by the virus. HFPs also promoted apoptosis of hemocytes after WSSV infection. In addition, HFPs significantly enhanced the survival rate of WSSV-infected crabs. All results confirmed that HFPs improved the innate immunity of S. paramamosain by enhancing the expression of antimicrobial peptides, antioxidant enzyme activity, phagocytosis, and apoptosis. Therefore, HFPs have potential for use as therapeutic or preventive agents to regulate the innate immunity of mud crabs and protect them against microbial infection.

Round-comb Fe2O3@SnO2 heterostructures enable efficient light harvesting and charge extraction for high-performance all-inorganic perovskite solar cells.

The precise design of an electron transport layer (ETL) to improve the light-harvesting and quality of perovskite (PVK) film plays a crucial role in the photovoltaic performance of n-i-p perovskite solar cells (PSCs). In this work, a novel three-dimensional (3D) round-comb Fe2O3@SnO2 heterostructure composites with high conductivity and electron mobility induced by its Type-II band alignment and matched lattice spacing is prepared and employed as an efficient mesoporous ETL for all-inorganic CsPbBr3 PSCs. Arising from the multiple light scattering sites provided by the 3D round-comb structure, the diffuse reflectance of Fe2O3@SnO2 composites is increased to improve the light absorption of the deposited PVK film. Besides, the mesoporous Fe2O3@SnO2 ETL affords not only more active surface for sufficient exposure to the CsPbBr3 precursor solution but also a wettable surface to reduce the barrier for heterogeneous nucleation, which realizes the regulated growth of a high-quality PVK film with less undesired defect. Hence, both the light-harvesting capability, the photoelectrons transport and extraction are improved, and the charge recombination is restrained, delivering an optimized power conversion efficiency (PCE) of 10.23 % with a high short-circuit current density of 7.88 mA cm-2 for the c-TiO2/Fe2O3@SnO2 ETL based all-inorganic CsPbBr3 PSCs. Moreover, under lasting erosion at 25 °C and 85 % RH for 30 days and light-soaking (AM 1.5G) for 480 h in air atmosphere, the unencapsulated-device shows superiorly persistent durability.

MiR-155-5p-SOCS1/JAK1/STAT1 participates in hepatic lymphangiogenesis in liver fibrosis and cirrhosis by regulating M1 macrophage polarization.

BACKGROUND: The role and underlying mechanism of liver macrophages and their derived miR-155-5p in hepatic lymphangiogenesis in liver fibrosis remain unclear. Here, we investigated the mechanism by which macrophages and miR-155-5p were involved in lymphangiogenesis during liver fibrosis and cirrhosis. METHODS: In vivo, hepatic lymphatic vessel expansion was evaluated; the liver macrophage subsets, proportion of peripherally-derived macrophages and expressions of CCL25, MCP-1, VAP-1 and MAdCAM-1 were documented; and miR-155-5p in the peripheral blood and liver was detected. In vitro, macrophages with miR-155-5p overexpression and inhibition were used to clarify the effect of miR-155-5p on regulation of macrophage polarization and the possible signalling pathway. RESULTS: Hepatic lymphangiogenesis was observed in mice with liver fibrosis and cirrhosis challenged with carbon tetrachloride (CCl4). In the liver, the number of M1 macrophages was associated with lymphangiogenesis and the degree of fibrosis. The liver recruitment of peripherally-derived macrophages occurred during liver fibrosis. The levels of miR-155-5p in the liver and peripheral blood gradually increased with aggravation of liver fibrosis. In vitro, SOCS1, a target of miR-155-5p, regulated macrophage polarization into the M1 phenotype through the JAK1/STAT1 pathway. CONCLUSION: MiR-155-5p-SOCS1/JAK1/STAT1 pathway participates in hepatic lymphangiogenesis in mice with liver fibrosis and cirrhosis induced by CCl4 by regulating the polarization of macrophages into the M1 phenotype.

Preparation and Characterization of Furosemide Solid Dispersion with Enhanced Solubility and Bioavailability.

Furosemide (FMD), as a potent circulating diuretic, is commonly used for the treatment of hypertension and edema arising from cardiac, renal, and hepatic failure. However, the low solubility of furosemide restricts its dissolution and bioavailability. In this study, Polyvinylpyrrolidone K30 (PVP-K30), mesoporous (Syloid 244FP, Syloid XDP 3050), and non-mesoporous (Aeroperl 300, Aerosil 200) silica were chosen as combined carrier to develop novel amorphous solid dispersions of furosemide, and then its dissolution and bioavailability were evaluated. Characterization study included XRD, DSC, TGA, SEM, FT-IR, and molecular docking. We found that FMD:PVP-K30:244FP achieved its best performance in terms of dissolution at the ratio of 1:1:1 when PVP-K30 and mesoporous silica Syloid 244FP (244FP) were chosen as combined carrier. SEM, DSC, and XRD studies indicated that furosemide existed in an amorphous form in the solid dispersion. FT-IR and molecular docking analysis showed that there might be an intermolecular interaction between FMD and the carrier. Moreover, the in vivo pharmacokinetics study revealed that the bioavailability of solid dispersion in rats had significant improvement. In particular, Cmax and AUClast were greatly increased by 2.69- and 2.08-fold in the solid dispersion (FMD-PVP-K30-244FP) group, respectively, and the relative bioavailability was 208.00%. In conclusion, the solid dispersion (FMD-PVP-K30-244FP) can significantly improve the solubility and oral bioavailability of furosemide. Mesoporous silica can be used as an excellent carrier material for furosemide, which can provide new ideas and methods for improving the stability of solid dispersion and further improving the dissolution of insoluble drugs. Graphical Abstract.

Non-alcoholic fatty liver disease and intestinal immune status: a narrative review.

Background and objectives: Non-alcoholic fatty liver disease (NAFLD) interacts with the gut immunity. However, the mechanisms underlying alternations of intestinal immune system in NAFLD remains unclear. To date, no effective medical interventions exist that completely reverse the disease. In this review, we mainly elaborates on the impact of NAFLD on intestinal immune cells and briefly summarize the new treatment methods for NAFLD targeting at intestinal immune cells.Methods: We searched MEDLINE, EMBASE and Web of Science for English-language sources. The preferred citations were meta-analyses and systematic or narrative reviews. Citation tracking was completed for all identified studies included in the refined library, using Google Scholar. No restriction was placed on the year of publication for the included reports.Results: The intestinal immune imbalance promotes liver inflammation and fibrosis in the process of NAFLD, and meanwhile, NAFLD influences disorders of immune cells in the liver and intestinal tract. Biological agents targeting at intestinal immunity has been shown in preclinical studies to be an effective method for systemic immune modulation and alleviates immune-mediated injury.Conclusions: Intestinal immune disorder plays an important role in triggering and amplifying hepatic inflammation in NAFLD. Advances in knowledge of the gut-liver axis are driving the development of diagnostic, prognostic and therapeutic tools based on intestine immunity for the management of NAFLD.

Adsorptive granulomonocytapheresis alters the gut bacterial microbiota in patients with active ulcerative colitis.

BACKGROUND: Ulcerative colitis (UC) is a refractory disease with unclear etiology. Studies have shown that UC is closely associated with gut microbiota dysbiosis. Adsorptive granulomonocytapheresis (GMA) using an Adacolumn has been found to treat UC effectively, but its underlying mechanism of treatment has not been fully elucidated. In this study, we aimed to investigate the influence of GMA on the gut microbiota in patients with active UC. METHODS: We conducted a single-center prospective analysis of patients with active UC who received GMA therapy and ultimately achieved clinical remission. Stool samples of healthy controls and patients before and after 5 or 10 sessions of GMA therapy were collected. Subsequently, high-throughput sequencing of the 16S rRNA V3 and V4 gene region of the stool was conducted and clustering of operational taxonomic units and species annotation were performed. RESULTS: Gut microbial profiles in patients with UC were characterized by low bacterial diversity. After 5 or 10 sessions of GMA therapy, the gut microbiota diversity in patients with UC increased and was similar to that of healthy controls. UC was further characterized by increased abundances of Proteobacteria and Bacteroides, as well as decreased abundances of Faecalibacterium, Roseburia, Firmicutes, and Dialister; however, after GMA therapy, the abundance of Bacteroides decreased, whereas those of Faecalibacterium, Roseburia, and Firmicutes increased. CONCLUSIONS: Active UC is associated with gut microbiota dysbiosis. GMA therapy exerts a strong regulatory effect on the gut microbiota in patients with UC.

Impaired CCR9/CCL25 signalling induced by inefficient dendritic cells contributes to intestinal immune imbalance in nonalcoholic steatohepatitis.

Abnormal crosstalk between gut immune and the liver was involved in nonalcoholic steatohepatitis (NASH). Mice with methionine choline-deficient (MCD) diet-induced NASH presented an imbalance of pro-(IL-6 and IFN-γ) and anti-inflammatory cytokines (IL-10) in the intestine. We also clarified that the ratio of CD4+ T cells and found that the NASH mesenteric lymph node (MLN) presents decreased numbers of CD4+Th17 cells but increased numbers of CD4+CD8+FoxP3+ regulatory T cells (Tregs). Furthermore, the intestinal immune imbalance in NASH was attributed to impaired gut chemokine receptor 9 (CCR9)/chemokine ligand 25 (CCL25) signalling, which is a crucial pathway for immune cell homing in the gut. We also demonstrated that CD4+CCR9+ T cell homing was dependent on CCL25 and that the numbers and migration abilities of CD4+CCR9+ T cells were reduced in NASH. Interestingly, the analysis of dendritic cell (DC) subsets showed that the numbers and retinal dehydrogenase (RALDH) activity of CD103+CD11b+ DCs were decreased and that the ability of these cells to upregulate CD4+ T cell CCR9 expression was damaged in NASH. Taken together, impaired intestinal CCR9/CCL25 signalling induced by CD103+CD11b+ DC dysfunction contributes to the gut immune imbalance observed in NASH.

Efficacy and safety of adsorptive granulomonocytapheresis in Chinese patients with ulcerative colitis: A retrospective analysis of 50 cases with focus on factors impacting clinical efficacy.

BACKGROUND: Myeloid-derived leucocytes, a major source of inflammatory cytokines, play an important role in the exacerbation of ulcerative colitis (UC). Selective depletion of myeloid leucocytes by adsorptive granulomonocytapheresis (GMA) with an Adacolumn should alleviate inflammation and promote remission. However, there are discrepancies among the reported efficacy outcomes. This study aimed to evaluate the efficacy and safety of GMA in UC patients with a focus on factors affecting clinical efficacy. METHODS: This was a retrospective analysis of 50 patients with active UC who had received GMA therapy. GMA efficacy was evaluated based on the Rachmilewitz's clinical activity index (CAI) and Mayo endoscopic score for mucosal healing. Laboratory findings were analyzed to demonstrate any relationship with the GMA-responder or nonresponder feature. Adverse events were recorded during and after GMA therapy. RESULTS: The overall clinical remission rate (CAI ≤4) was 79.2%, and among these, the mucosal healing rate was 59.2%. The clinical remission rate was 69.2% in patients who received 5 GMA sessions and 82.3% in patients who received 10 sessions. Significantly higher baseline CAIs and lower albumin and hemoglobin levels were observed in nonremission cases compared with those who achieved remission. Four patients (8%) experienced transient adverse events, but none were severe. CONCLUSIONS: GMA was favored by patients because of its safety and nonpharmacological treatment options. Accordingly, UC patients were spared from pharmaceuticals after applying GMA therapy.

Selective granulocyte and monocyte apheresis in inflammatory bowel disease: Its past, present and future.

The etiology and pathogenesis of inflammatory bowel disease (IBD), including ulcerative colitis and Crohn's disease, are not fully understood so far. Therefore, IBD still remains incurable despite the fact that significant progress has been achieved in recent years in its treatment with innovative medicine. About 20 years ago, selective granulocyte and monocyte apheresis (GMA) was invented in Japan and later approved by the Japanese health authority for IBD treatment. From then on this technique was extensively used for IBD patients in Japan and later in Europe. Clinical trials from Japan and European countries have verified the effectiveness and safety of GMA therapy in patients with IBD. In 2013, GMA therapy was approved by China State Food and Drug Administration for therapeutic use for the Chinese IBD patients. However, GMA therapy has not been extensively used in China, although a few clinical studies also showed that it was effective in clinical and endoscopic induction of remission in Chinese IBD patients with a high safety profile. This article reviews past history, present clinical application as well as the future prospective of GMA therapy for patients with IBD.

SHIP-1, a target of miR-155, regulates endothelial cell responses in lung fibrosis.

Src Homology 2-containing Inositol Phosphatase-1 (SHIP-1) is a target of miR-155, a pro-inflammatory factor. Deletion of the SHIP-1 gene in mice caused spontaneous lung inflammation and fibrosis. However, the role and function of endothelial miR-155 and SHIP-1 in lung fibrosis remain unknown. Using whole-body miR-155 knockout mice and endothelial cell-specific conditional miR-155 (VEC-Cre-miR-155 or VEC-miR-155) or SHIP-1 (VEC-SHIP-1) knockout mice, we assessed endothelial-mesenchymal transition (EndoMT) and fibrotic responses in bleomycin (BLM) induced lung fibrosis models. Primary mouse lung endothelial cells (MLEC) and human umbilical vein endothelial cells (HUVEC) with SHIP-1 knockdown were analyzed in TGF-ß1 or BLM, respectively, induced fibrotic responses. Fibrosis and EndoMT were significantly reduced in miR-155KO mice and changes in EndoMT markers in MLEC after TGF-ß1 stimulation confirmed the in vivo findings. Furthermore, lung fibrosis and EndoMT responses were reduced in VEC-miR-155 mice but significantly enhanced in VEC-SHIP-1 mice after BLM challenge. SHIP-1 knockdown in HUVEC cells resulted in enhanced EndoMT induced by BLM. Meanwhile, these changes involved the PI3K/AKT, JAK/STAT3, and SMAD/STAT signaling pathways. These studies demonstrate that endothelial miR-155 plays an important role in fibrotic responses in the lung through EndoMT. Endothelial SHIP-1 is essential in controlling fibrotic responses and SHIP-1 is a target of miR-155. Endothelial cells are an integral part in lung fibrosis.

PPARγ alleviated hepatocyte steatosis through reducing SOCS3 by inhibiting JAK2/STAT3 pathway.

Peroxisome proliferator-activated receptor gamma (PPARγ) participates in the process of insulin resistance (IR), a crucial pathophysiology in non-alcoholic fatty liver disease (NAFLD). Meanwhile, suppressor of cytokine signaling3 (SOCS3) also regulates IR in NAFLD. Both PPARγ and SOCS3 play a role in NAFLD through regulating IR, while it is unclear whether these two proteins interact to regulate hepatic steatosis. PPARγ, SOCS3 and its associated JAK2/STAT3 pathway were analyzed using Kuppfer cells (KCs) treatment with LPS and BRL-3A cells treatment with palmitic acid, KC-conditioned medium (KCCM), PPARγ agonist rosiglitazone (ROZ) or JAK2 inhibitor AG490 to demonstrate the role of PPARγ and SOCS3 in hepatocytes steatosis. As LPS concentration increasing, phagocytosis activity of KCs decreased; but releasing of TNF-α and IL-6 increased. After treatment with KCCM, mRNA level of SOCS3, JAK2 and STAT3 as well as protein expression of SOCS3, p-JAK2 and p-STAT3 in steatosis BRL-3A cells increased significantly, which were inhibited by AG490 or ROZ treatment. Taken together, these results indicated that KCCM attributed to KCs dysfunction facilitated hepatocyte steatosis through promoting expressing SOCS3; but PPARγ agonist ROZ alleviated steatosis through reducing SOCS3 expression by inhibiting JAK2/STAT3 in hepatocytes.

5-ASA-loaded SiO2 nanoparticles-a novel drug delivery system targeting therapy on ulcerative colitis in mice.

The targeting of 5-aminosalicylic acid (5-ASA), a first-line therapeutic agent for mild to moderate active ulcerative colitis (UC), to the site of inflammation has remained a challenge and an unmet requirement in the treatment of UC. However, nanoscale carriers for targeted drug delivery are promising for pharmacotherapy, and nanoparticles improve the pharmacokinetics of the loaded therapeutics based on their physical properties. To design and prepare 5­ASA­loaded silicon dioxide nanoparticles (5­ASA­SiO2 NPs), a micro­emulsion method was conducted, and their respective therapeutic effects were validated in a mouse model of UC. Cytotoxicity of 5­ASA­SiO2 NPs was detected in vitro using the Cell Counting Kit­8 method. The therapeutic effect of 5­ASA­SiO2 NPs was assessed based on their disease activity index (DAI), colon histopathology, myeloperoxidase (MPO) and levels of tumor necrosis factor­α (TNF­α) and interleukin­6 (IL­6). SiO2 NPs were successfully prepared, and cytotoxicity of 5­ASA­SiO2 NPs was identified as being similar to 5­ASA and SiO2 NPs. DAI and colonic histopathology scores in the normal dosage, high dosage and the 5­ASA­SiO2 NP groups demonstrated a significant improvement when compared with the model group. DAI in the high dosage and 5­ASA­SiO2 NP groups also demonstrated a significant improvement when compared with the normal dosage group. However, MPO, serum IL­6 and TNF­α levels in normal dosage, high dosage and 5­ASA­SiO2 NPs groups were significantly lower than in the model group, and these indexes in the high dosage group and 5­ASA­SiO2 NP group were significantly lower than that in the normal dosage group. Expression of IL­6 and TNF­α mRNA in colonic mucosa in the normal dosage, high dosage and 5­ASA­SiO2 NP group was significantly lower than that in the model group. Colonic mucosal IL­6 and TNF­α mRNA expression in the high dosage and 5­ASA­SiO2 NP groups was significantly lower than that in the normal dosage group (P<0.05). In conclusion, 5­ASA­SiO2 NPs are a selective drug release system that target the inflamed colon, characteristics of UC, and can greatly increase therapeutic efficacy in UC.

Salidroside protects against bleomycin-induced pulmonary fibrosis: activation of Nrf2-antioxidant signaling, and inhibition of NF-κB and TGF-ß1/Smad-2/-3 pathways.

Pulmonary fibrosis (PF) can severely disrupt lung function, leading to fatal consequences. Salidroside is a principal active ingredient of Rhodiola rosea and has recently been reported to protect against lung injures. The present study was aimed at exploring its therapeutic effects on PF. Lung fibrotic injuries were induced in SD rats by a single intratracheal instillation of 5 mg/kg bleomycin (BLM). Then, these rats were administrated with 50, 100, or 200 mg/kg salidroside for 28 days. BLM-triggered structure distortion, collagen overproduction, excessive inflammatory infiltration, and pro-inflammatory cytokine release, and oxidative stress damages in lung tissues were attenuated by salidroside in a dose-dependent manner. Furthermore, salidroside was noted to inhibit IκBα phosphorylation and nuclear factor kappa B (NF-κB) p65 nuclear accumulation while activating Nrf2-antioxidant signaling in BLM-treated lungs. Downregulation of E-cadherin and upregulation of vimentin, fibronectin, and α-smooth muscle actin (α-SMA) indicated an epithelial-mesenchymal transition (EMT)-like shift in BLM-treated lungs. These changes were suppressed by salidroside. The expression of TGF-ß1 and the phosphorylation of its downstream targets, Smad-2/-3, were enhanced by BLM, but weakened by salidroside. Additionally, salidroside was capable of reversing the recombinant TGF-ß1-induced EMT-like changes in alveolar epithelial cells in vitro. Our study reveals that salidroside's protective effects against fibrotic lung injuries are correlated to its anti-inflammatory, antioxidative, and antifibrotic properties.

Glycyrrhizic acid alleviates bleomycin-induced pulmonary fibrosis in rats.

Idiopathic pulmonary fibrosis is a progressive and lethal form of interstitial lung disease that lacks effective therapies at present. Glycyrrhizic acid (GA), a natural compound extracted from a traditional Chinese herbal medicine Glycyrrhiza glabra, was recently reported to benefit lung injury and liver fibrosis in animal models, yet whether GA has a therapeutic effect on pulmonary fibrosis is unknown. In this study, we investigated the potential therapeutic effect of GA on pulmonary fibrosis in a rat model with bleomycin (BLM)-induced pulmonary fibrosis. The results indicated that GA treatment remarkably ameliorated BLM-induced pulmonary fibrosis and attenuated BLM-induced inflammation, oxidative stress, epithelial-mesenchymal transition, and activation of transforming growth factor-beta signaling pathway in the lungs. Further, we demonstrated that GA treatment inhibited proliferation of 3T6 fibroblast cells, induced cell cycle arrest and promoted apoptosis in vitro, implying that GA-mediated suppression of fibroproliferation may contribute to the anti-fibrotic effect against BLM-induced pulmonary fibrosis. In summary, our study suggests a therapeutic potential of GA in the treatment of pulmonary fibrosis.

Intestinal mucosal barrier dysfunction participates in the progress of nonalcoholic fatty liver disease.

Intestinal mucosal barrier dysfunction is closely related to liver diseases, which implies impaired gut-liver axis may play a role in the pathogenesis of NAFLD. In our study, rats were divided into three groups: normal chow diet (NCD) group, high-fat diet (HFD) group and TNBS-induced colitis with high-fat diet (C-HFD) group. Liver tissues were obtained for histological observation and TNF-α, IL-6 mRNA determination and blood samples were collected for liver enzymes and LPS analysis. Ultrastructural changes of jejuna epithelium, SIBO and amounts of CD103(+)MHCII(+)DCs and CD4(+)CD25(+)FoxP3(+)T-regs in terms of percentage in mesenteric lymph nodes (MLN) were observed by electron microscope, bacterial cultivation and flow cytometry, respectively. The results demonstrated the pathological characteristics accorded with nonalcoholic simple fatty liver (NAFL) and NASH in HFD group by week 8 and 12, respectively. Besides, the degree of hepatic steatosis and steatohepatitis was more severe in C-HFD group compared with HFD-group at the same time point. NAFLD activity score (NAS), liver enzymes, concentration of LPS and mRNA expressions of TNF-α, IL-6 were higher significantly in C-HFD group compared with HFD and NCD group at week 4, 8 and 12, respectively. In HFD group, epithelium microvilli atrophy, disruptive tight junctions and SIBO were present, and these changes were more severe in NASH compared with NAFL. The percentage of CD103+MHCII+DCs and CD4+CD25+FoxP3+T-regs decreased significantly in NAFL and NASH compared with NCD group. Our conclusion was that gut-liver axis was impaired in NAFLD, which played crucial role in the pathogenesis of NAFLD.

Tanshinone IIA ameliorates bleomycin-induced pulmonary fibrosis and inhibits transforming growth factor-beta-ß-dependent epithelial to mesenchymal transition.

BACKGROUND: Epithelial to mesenchymal transition (EMT) of alveolar epithelial cells occurs in lung fibrotic diseases. Tanshinone IIA (Tan IIA) has been reported to exert anti-inflammatory effects in pulmonary fibrosis. Nonetheless, whether Tan IIA affects lung fibrosis-related EMT remains unknown and requires for further investigations. MATERIALS AND METHODS: A single intratracheal instillation of saline containing bleomycin (BLM; 5 mg/kg body weight) was performed to induce pulmonary fibrosis in Sprague-Dawley rats. Rats receiving an instillation of equivoluminal normal saline served as controls. Then, these rats were given a daily intraperitoneal administration of Tan IIA (15 mg/kg body weight) for 28 d before sacrifice. In vitro, recombinant transforming growth factor-beta 1 (TGF-ß1; 10 ng/mL) was used to treat human alveolar epithelial A549 cells for 48 h. Tan IIA (10 µM) or control DMSO was used to pretreat cells for 2 h before TGF-ß1 stimulation. Rat lung tissue samples and A549 cells were then subjected to further assessments. RESULTS: Tan IIA was noted to alleviate BLM-induced pulmonary collagen deposition and macrophage infiltration in rats. Epithelial-cadherin expression was decreased after BLM stimulation, whereas α-smooth muscle actin, fibronectin, and vimentin were increased. These expression alterations were partially reversed by Tan IIA. Moreover, Tan IIA suppressed BLM-induced increases in TGF-ß1, phosphorylated Smad-2, and -3 in rats. Additionally, pretreatment of Tan IIA inhibited TGF-ß1-triggered EMT, reduced collagen Ⅰ production, and blocked TGF-ß signal transduction in A549 cells. CONCLUSIONS: Our research suggests that Tan IIA mitigates BLM-induced pulmonary fibrosis and suppresses TGF-ß-dependent EMT of lung alveolar epithelial cells.