Cholestane-3ß,5α,6ß-triol Induces Multiple Cell Death in A549 Cells via ER Stress and Autophagy Activation.

Cholestane-3ß,5α,6ß-triol (CT) and its analogues are abundant in natural sources and are reported to demonstrate cytotoxicity toward different kinds of tumor cells without a deep probe into their mechanism of action. CT is also one of the major metabolic oxysterols of cholesterol in mammals and is found to accumulate in various diseases. An extensive exploration of the biological roles of CT over the past few decades has established its identity as an apoptosis inducer. In this study, the effects of CT on A549 cell death were investigated through cell viability assays. RNA-sequencing analysis and western blot of CT-treated A549 cells revealed the role of CT in inducing endoplasmic reticulum (ER) stress response and enhancing autophagy flux, suggesting a putative mechanism of CT-induced cell-death activation involving reactive oxygen species (ROS)-mediated ER stress and autophagy. It is reported for the first time that the upregulation of autophagy induced by CT can serve as a cellular cytotoxicity response in accelerating CT-induced cell death in A549 cells. This research provides evidence for the effect of CT as an oxysterol in cell response to oxidative damage and allows for a deep understanding of cholesterol in its response in an oxidative stress environment that commonly occurs in the progression of various diseases.

SUMOylation of GMFB regulates its stability and function in retinal pigment epithelial cells under hyperglycemia.

BACKGROUND: Glia maturation factor beta (GMFB) is a growth and differentiation factor that acts as an intracellular regulator of signal transduction pathways. The small ubiquitin-related modifier (SUMO) modification, SUMOylation, is a posttranslational modification (PTM) that plays a key role in protein subcellular localization, stability, transcription, and enzymatic activity. Recent studies have highlighted the importance of SUMOylation in the inflammation and progression of numerous diseases. However, the relationship between GMFB and SUMOylation is unclear. RESULTS: Here, we report for the first time that GMFB and SUMO1 are markedly increased in retinal pigment epithelial (RPE) cells at the early stage of diabetes mellitus (DM) under hyperglycemia. The GMFΒ protein could be mono-SUMOylated by SUMO1 at the K20, K35, K58 or K97 sites. SUMOylation of GMFB led to its increased protein stability and subcellular translocation. Furthermore, deSUMOylation of GMFΒ downregulates multiple signaling pathways, including the Jak-STAT signaling pathway, p38 pathway and NF-kappa B signaling pathway. CONCLUSIONS: This work provides novel insight into the role of SUMOylated GMFB in RPE cells and provides a novel therapeutic target for diabetic retinopathy (DR).

NSUN2 promotes colorectal cancer progression by enhancing SKIL mRNA stabilization.

BACKGROUND: NOP2/Sun domain 2 (NSUN2) is one of the important RNA methyltransferases catalyzing 5-methylcytosine (m5C) formation and participates in many critical bioprocesses. However, the roles and underlying molecular mechanisms of NSUN2-mediated m5C modification in colorectal cancer (CRC) remain unclear. METHODS: To explore the NSUN2 expression in CRC, fresh tissue samples were collected and Nsun2 knockout mouse was constructed. In vitro and in vivo functional assays were conducted to assess the role of NSUN2. RNA array and bisulfite sequencing were used to investigate the potential targets. The mechanisms of NSUN2 function on SKIL were identified by m5C-methylated-RNA immunoprecipitation and RNA stability assays. Additionally, tissue microarray analysis was conducted and patient-derived tumour xenograft mouse (PDX) models were used to define the potential therapeutic targets. RESULTS: NSUN2 was highly expressed in CRC and correlated with poor CRC patient survival. Moreover, silencing NSUN2 suppressed CRC tumourigenesis and progression in Nsun2 knockout mouse models. In vitro and in vivo studies suggested that NSUN2 promoted colorectal cancer cell growth. Mechanistically, SKI-like proto-oncogene (SKIL) is positively regulated by NSUN2, and the NSUN2-SKIL axis is clinically relevant to CRC. NSUN2 induced m5C modification of SKIL and stabilized its mRNA, which was mediated by Y-box binding protein 1 (YBX1). Elevated SKIL levels increased transcriptional coactivator with PDZ-binding motif (TAZ) activation. CONCLUSIONS: Our findings highlight the importance of NSUN2 in the initiation and progression of CRC via m5C-YBX1-dependent stabilization of the SKIL transcript, providing a promising targeted therapeutic strategy for CRC.

X-ray Activated Nanoprodrug for Visualization of Cortical Microvascular Alterations and NIR-II Image-Guided Chemo-Radiotherapy of Glioblastoma.

The permeability of the highly selective blood-brain barrier (BBB) to anticancer drugs and the difficulties in defining deep tumor boundaries often reduce the effectiveness of glioma treatment. Thus, exploring the combination of multiple treatment modalities under the guidance of second-generation near-infrared (NIR-II) window fluorescence (FL) imaging is considered a strategic approach in glioma theranostics. Herein, a hybrid X-ray-activated nanoprodrug was developed to precisely visualize the structural features of glioma microvasculature and delineate the boundary of glioma for synergistic chemo-radiotherapy. The nanoprodrug comprised down-converted nanoparticle (DCNP) coated with X-ray sensitive poly(Se-Se/DOX-co-acrylic acid) and targeted Angiopep-2 peptide (DCNP@P(Se-DOX)@ANG). Because of its ultrasmall size and the presence of DOX, the nanoprodrug could easily cross BBB to precisely monitor and localize glioblastoma via intracranial NIR-II FL imaging and synergistically administer antiglioblastoma chemo-radiotherapy through specific X-ray-induced DOX release and radiosensitization. This study provides a novel and effective strategy for glioblastoma imaging and chemo-radiotherapy.

Multi-omic profiling reveals associations between the gut microbiome, host genome and transcriptome in patients with colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) is the leading cancer worldwide. Microbial agents have been considered to contribute to the pathogenesis of different disease. But the underlying relevance between CRC and microbiota remain unclear. METHODS: We dissected the fecal microbiome structure and genomic and transcriptomic profiles of matched tumor and normal mucosa tissues from 41 CRC patients. Of which, the relationship between CRC-associated bacterial taxa and their significantly correlated somatic mutated gene was investigated by exome sequencing technology. Differentially expressed functional genes in CRC were clustered according to their correlation with differentially abundant species, following by annotation with DAVID. The composition of immune and stromal cell types was identified by XCELL. RESULTS: We identified a set of 22 microbial gut species associated with CRC and estimate the relative abundance of KEGG ontology categories. Next, the interactions between CRC-related gut microbes and clinical phenotypes were evaluated. 4 significantly mutated gene: TP53, APC, KRAS, SMAD4 were pointed out and the associations with cancer related microbes were identified. Among them, Fusobacterium nucleatum positively corelated with different host metabolic pathways. Finally, we revealed that Fusobacterium nucleatum modified the tumor immune environment by TNFSF9 gene expression. CONCLUSION: Collectively, our multi-omics data could help identify novel biomarkers to inform clinical decision-making in the detection and diagnosis of CRC.

GMFB/AKT/TGF-ß3 in Müller cells mediated early retinal degeneration in a streptozotocin-induced rat diabetes model.

Retinal degeneration, characterized by Müller cell gliosis and photoreceptor apoptosis, is considered an early event in diabetic retinopathy (DR). Our previous study proposed that GMFB may mediate diabetic retinal degeneration. This study identified GMFB as a sensitive and functional gliosis marker for DR. Compared to the wild type (WT) group, Gmfb knockout (KO) significantly improved visual function, attenuated gliosis, reduced the apoptosis of neurons, and decreased the mRNA levels of tumor necrosis factor α (Tnf-α) and interleukin-1ß (Il-1ß) in diabetic retinas. Tgf-ß3 was enriched by hub genes using RNA sequencing in primary WT and KO Müller cells. Gmfb KO significantly upregulated the transforming growth factor (TGF)-ß3 protein level via the AKT pathway. The protective effect of TGF-ß3 in the vitreous resulted in significantly improved visual function and decreased the number of apoptotic cells in the diabetic retina. The protection of Gmfb KO in primary Müller cells against high glucose (HG)-induced photoreceptor apoptosis was partially counteracted by TGF-ß3 antibody and administration of TGFBR1/2 inhibitors. Nuclear receptor subfamily 3 group C member 1 (NR3C1) binds to the promoter region of Gmfb and regulates Gmfb mRNA at the transcriptional level. NR3C1 was increased in the retinas of early diabetic rats but decreased in the retinas of late diabetic rats. N'-[(1E)-(3-Methoxyphenyl)Methylene]-3-Methyl-1H-Pyrazole-5-Carbohydrazide (DS-5) was identified as an inhibitor of GMFB, having a protective role in DR. We demonstrated that GMFB/AKT/TGF-ß3 mediated early diabetic retinal degeneration in diabetic rats. This study provides a novel therapeutic strategy for treating retinal degeneration in patients with DR.

Halogen-Modulated 2D Coordination Polymers for Efficient Hydrogen Peroxide Photosynthesis under Air and Pure Water Conditions.

H2 O2 is a widely used eco-friendly oxidant and a potential energy carrier. Photocatalytic H2 O2 production from water and O2 is an ideal approach with the potential to address the current energy crisis and environmental issues. Three zig-zag two-dimensional coordination polymers (2D CPs), named CuX-dptz, were synthesized by a rapid and facile method at room temperature, showing preeminent H2 O2 photoproduction performance under pure water and open air without any additives. CuBr-dptz exhibits a H2 O2 production rate high up to 1874 µmol g-1 h-1 , exceeding most reported photocatalysts under this condition, even comparable to those supported by sacrificial agents and O2 . The coordination environment of Cu can be modulated by halogen atoms (X=Cl, Br, I), which in turn affects the electron transfer process and finally determines the reaction activity. This is the first time that 2D CPs have been used for photocatalytic H2 O2 production in such challenging conditions, which provides a new pathway for the development of portable in situ H2 O2 photosynthesis devices.

Anti-Inflammatory Ergosteroid Derivatives from the Coral-Associated Fungi Penicillium oxalicum HL-44.

To obtain the optimal fermentation condition for more abundant secondary metabolites, Potato Dextrose Agar (PDA) medium was chosen for the scale-up fermentation of the fungus Penicillium oxalicum HL-44 associated with the soft coral Sinularia gaweli. The EtOAc extract of the fungi HL-44 was subjected to repeated column chromatography (CC) on silica gel and Sephadex LH-20 and semipreparative RP-HPLC to afford a new ergostane-type sterol ester (1) together with fifteen derivatives (2-16). Their structures were determined with spectroscopic analyses and comparisons with reported data. The anti-inflammatory activity of the tested isolates was assessed by evaluating the expression of pro-inflammatory factors Tnfα and Ifnb1 in Raw264.7 cells stimulated with LPS or DMXAA. Compounds 2, 9, and 14 exhibited significant inhibition of Ifnb1 expression, while compounds 2, 4, and 5 showed strong inhibition of Tnfα expression in LPS-stimulated cells. In DMXAA-stimulated cells, compounds 1, 5, and 7 effectively suppressed Ifnb1 expression, whereas compounds 7, 8, and 11 demonstrated the most potent inhibition of Tnfα expression. These findings suggest that the tested compounds may exert their anti-inflammatory effects by modulating the cGAS-STING pathway. This study provides valuable insight into the chemical diversity of ergosteroid derivatives and their potential as anti-inflammatory agents.

Dendrobium mixture ameliorates hepatic injury induced by insulin resistance in vitro and in vivo through the downregulation of AGE/RAGE/Akt signaling pathway.

Dendrobium mixture (DM) is a patented Chinese herbal medicine which has been shown to ameliorate type 2 diabetes mellitus (T2DM) with non-alcoholic fatty liver disease (NAFLD) in vivo and in vitro. We aimed to investigate the underlying mechanism of DM as a therapeutic agent in attenuating liver steatosis in relation to type 2 diabetes mellitus (T2DM). DM (16.2 g/kg/d) was administered to db/db mice for 4 weeks. The db/m mice and db/db mice in the control and model groups were given normal saline. Additionally, DM (11.25 g/kg/d) was administered to Sprague-Dawley (SD) rats, and the serum was collected and used in an experiment involving palmitic acid (PA)-induced human liver HepG2 cells with abnormal lipid and glucose metabolism. In db/db mice, the administration of DM significantly alleviated liver steatosis, including histological damage and cell apoptosis. DM was found to prevent the upregulation of the RAGE and AKT1 proteins in liver tissues. The underlying mechanism of DM was further studied in PA-induced HepG2 cells. Post-DM administration serum from SD rats reduced lipid accumulation and regulated glucose metabolism in HepG2 cells. Consequently, it inhibited RAGE/AKT signaling and restored autophagy activity. The upregulated autophagy was associated with the mTOR-AMPK signaling pathway. Furthermore, post-DM administration serum reduced apoptosis of hepatocytes in PA-induced HepG2 cells. Our study supports the potential use of DM as a therapeutic agent for the treatment of NAFLD in T2DM. The mechanism underlying this therapeutic potential is associated with the downregulation of the AGE/RAGE/Akt signaling pathway.

Subconjunctival injection of human umbilical cord mesenchymal stem cells alleviates experimental allergic conjunctivitis via regulating T cell response.

BACKGROUND: T helper 2 (Th2) cells are thought to play critical roles in allergic conjunctivitis (AC). They release inflammatory cytokines to promote an allergic response in AC. Due to individual heterogeneity and long-term chronic management, current therapies do not always effectively control AC. Mesenchymal stem cells (MSCs) have been shown to be effective in treating allergy-related disorders, but it is unclear how exactly the Th2-mediated allergic response is attenuated. This study aims to elucidate the therapeutic effect and mechanism of the human umbilical cord MSCs (hUCMSCs) in a mouse model of experimental AC (EAC). METHODS: A mouse EAC model was established by inoculating short ragweed (SRW) pollen. After the SRW pollen challenge, the mice received a single subconjunctival or tail vein injection of 2 × 106 hUCMSCs, or subconjunctival injection of hUCMSCs conditioned medium (hUCMSC-CM), and dexamethasone eye drops was used as positive control; subsequent scratching behavior and clinical symptoms were assessed. Immunostaining and flow cytometry were carried out to show allergic reactions and the activation of CD4 + T cell subsets in the conjunctiva and cervical lymph nodes (CLNs). Gene expression was determined by RNA-seq and further verified by qRT-PCR and Western blot. Co-culture assays were performed to explore the regulatory role of hUCMSCs in the differentiation of CD4 + naive T cells (Th0) into Th2 cells. RESULTS: Subconjunctival administration of hUCMSCs resulted in fewer instances of scratching and lower inflammation scores in EAC mice compared to the tail vein delivery, hUCMSC-CM and control groups. Subconjunctival administration of hUCMSCs reduced the number of activated mast cells and infiltrated eosinophils in the conjunctiva, as well as decreased the number of Th2 cells in CLNs. After pretreatment with EAC mouse serum in vitro to mimic the in vivo milieu, hUCMSCs were able to inhibit the differentiation of Th0 into Th2 cells. Further evidence demonstrated that repression of Th2 cell differentiation by hUCMSCs is mediated by CRISPLD2 through downregulation of STAT6 phosphorylation. Additionally, hUMCSCs were able to promote the differentiation of Th0 cells into regulatory T cells in CLNs of EAC mice. CONCLUSIONS: Subconjunctival injection of hUCMSCs suppressed the Th2-allergic response and alleviated clinical symptoms. This study provides not only a potential therapeutic target for the treatment of AC but also other T cell-mediated diseases.

eIF3f Mediates SGOC Pathway Reprogramming by Enhancing Deubiquitinating Activity in Colorectal Cancer.

Numerous studies have demonstrated that individual proteins can moonlight. Eukaryotic Initiation translation factor 3, f subunit (eIF3f) is involved in critical biological functions; however, its role independent of protein translation in regulating colorectal cancer (CRC) is not characterized. Here, it is demonstrated that eIF3f is upregulated in CRC tumor tissues and that both Wnt and EGF signaling pathways are participating in eIF3f's oncogenic impact on targeting phosphoglycerate dehydrogenase (PHGDH) during CRC development. Mechanistically, EGF blocks FBXW7ß-mediated PHGDH ubiquitination through GSK3ß deactivation, and eIF3f antagonizes FBXW7ß-mediated PHGDH ubiquitination through its deubiquitinating activity. Additionally, Wnt signals transcriptionally activate the expression of eIF3f, which also exerts its deubiquitinating activity toward MYC, thereby increasing MYC-mediated PHGDH transcription. Thereby, both impacts allow eIF3f to elevate the expression of PHGDH, enhancing Serine-Glycine-One-Carbon (SGOC) signaling pathway to facilitate CRC development. In summary, the study uncovers the intrinsic role and underlying molecular mechanism of eIF3f in SGOC signaling, providing novel insight into the strategies to target eIF3f-PHGDH axis in CRC.

ACTL6A protects gastric cancer cells against ferroptosis through induction of glutathione synthesis.

Gastric cancer (GC), one of the most common malignant tumors in the world, exhibits a rapid metastasis rate and causes high mortality. Diagnostic markers and potential therapeutic targets for GCs are urgently needed. Here we show that Actin-like protein 6 A (ACTL6A), encoding an SWI/SNF subunit, is highly expressed in GCs. ACTL6A is found to be critical for regulating the glutathione (GSH) metabolism pathway because it upregulates γ-glutamyl-cysteine ligase catalytic subunit (GCLC) expression, thereby reducing reactive oxygen species (ROS) levels and inhibiting ferroptosis, a regulated form of cell death driven by the accumulation of lipid-based ROS. Mechanistic studies show that ACTL6A upregulates GCLC as a cotranscription factor with Nuclear factor (erythroid-derived 2)-like 2 (NRF2) and that the hydrophobic region of ACTL6A plays an important role. Our data highlight the oncogenic role of ACTL6A in GCs and indicate that inhibition of ACTL6A or GCLC could be a potential treatment strategy for GCs.

Glia maturation factor beta deficiency protects against diabetic osteoporosis by suppressing osteoclast hyperactivity.

Excessive osteoclast activation, which depends on dramatic changes in actin dynamics, causes osteoporosis (OP). The molecular mechanism of osteoclast activation in OP related to type 1 diabetes (T1D) remains unclear. Glia maturation factor beta (GMFB) is considered a growth and differentiation factor for both glia and neurons. Here, we demonstrated that Gmfb deficiency effectively ameliorated the phenotype of T1D-OP in rats by inhibiting osteoclast hyperactivity. In vitro assays showed that GMFB participated in osteoclast activation rather than proliferation. Gmfb deficiency did not affect osteoclast sealing zone (SZ) formation but effectively decreased the SZ area by decreasing actin depolymerization. When GMFB was overexpressed in Gmfb-deficient osteoclasts, the size of the SZ area was enlarged in a dose-dependent manner. Moreover, decreased actin depolymerization led to a decrease in nuclear G-actin, which activated MKL1/SRF-dependent gene transcription. We found that pro-osteoclastogenic factors (Mmp9 and Mmp14) were downregulated, while anti-osteoclastogenic factors (Cftr and Fhl2) were upregulated in Gmfb KO osteoclasts. A GMFB inhibitor, DS-30, targeting the binding site of GMFB and Arp2/3, was obtained. Biocore analysis revealed a high affinity between DS-30 and GMFB in a dose-dependent manner. As expected, DS-30 strongly suppressed osteoclast hyperactivity in vivo and in vitro. In conclusion, our work identified a new therapeutic strategy for T1D-OP treatment. The discovery of GMFB inhibitors will contribute to translational research on T1D-OP.

Dendrobium mixture ameliorates type 2 diabetes mellitus with non-alcoholic fatty liver disease through PPAR gamma: An integrated study of bioinformatics analysis and experimental verification.

Dendrobium mixture (DM) is a patented Chinese herbal medicine indicated which has anti-inflammatory and improved glycolipid metabolism. However, its active ingredients, targets of action, and potential mechanisms are still uncertain. Here, we investigate the role of DM as a prospective modulator of protection against non-alcoholic fatty liver disease (NAFLD) induced by type 2 diabetes mellitus (T2DM) and illustrate the molecular mechanisms potentially involved. The network pharmacology and TMT-based quantitative protomics analysis were conducted to identify potential gene targets of the active ingredients in DM against NAFLD and T2DM. DM was administered to the mice of DM group for 4 weeks, and db/m mice (control group) and db/db mice (model group) were gavaged by normal saline. DM was also given to Sprague-Dawley (SD) rats, and the serum was subjected to the palmitic acid-induced HepG2 cells with abnormal lipid metabolism. The mechanism of DM protection against T2DM-NAFLD is to improve liver function and pathological morphology by promoting peroxisome proliferator-activated receptor γ (PPARγ) activation, lowering blood glucose, improving insulin resistance (IR), and reducing inflammatory factors. In db/db mice, DM reduced RBG, body weight, and serum lipids levels, and significantly alleviated histological damage of liver steatosis and inflammation. It upregulated the PPARγ corresponding to the prediction from the bioinformatics analysis. DM significantly reduced inflammation by activating PPARγ in both db/db mice and palmitic acid-induced HepG2 cells.

Metabolic reprogramming in colorectal cancer: regulatory networks and therapy.

With high prevalence and mortality, together with metabolic reprogramming, colorectal cancer is a leading cause of cancer-related death. Metabolic reprogramming gives tumors the capacity for long-term cell proliferation, making it a distinguishing feature of cancer. Energy and intermediate metabolites produced by metabolic reprogramming fuel the rapid growth of cancer cells. Aberrant metabolic enzyme-mediated tumor metabolism is regulated at multiple levels. Notably, tumor metabolism is affected by nutrient levels, cell interactions, and transcriptional and posttranscriptional regulation. Understanding the crosstalk between metabolic enzymes and colorectal carcinogenesis factors is particularly important to advance research for targeted cancer therapy strategies via the investigation into the aberrant regulation of metabolic pathways. Hence, the abnormal roles and regulation of metabolic enzymes in recent years are reviewed in this paper, which provides an overview of targeted inhibitors for targeting metabolic enzymes in colorectal cancer that have been identified through tumor research or clinical trials.

CSN6 Mediates Nucleotide Metabolism to Promote Tumor Development and Chemoresistance in Colorectal Cancer.

Metabolic reprogramming can contribute to colorectal cancer progression and therapy resistance. Identification of key regulators of colorectal cancer metabolism could provide new approaches to improve treatment and reduce recurrence. Here, we demonstrate a critical role for the COP9 signalosome subunit CSN6 in rewiring nucleotide metabolism in colorectal cancer. Transcriptomic analysis of colorectal cancer patient samples revealed a correlation between CSN6 expression and purine and pyrimidine metabolism. A colitis-associated colorectal cancer model established that Csn6 intestinal conditional deletion decreased tumor development and altered nucleotide metabolism. CSN6 knockdown increased the chemosensitivity of colorectal cancer cells in vitro and in vivo, which could be partially reversed with nucleoside supplementation. Isotope metabolite tracing showed that CSN6 loss reduced de novo nucleotide synthesis. Mechanistically, CSN6 upregulated purine and pyrimidine biosynthesis by increasing expression of PHGDH, a key enzyme in the serine synthesis pathway. CSN6 inhibited ß-Trcp-mediated DDX5 polyubiquitination and degradation, which in turn promoted DDX5-mediated PHGDH mRNA stabilization, leading to metabolic reprogramming and colorectal cancer progression. Butyrate treatment decreased CSN6 expression and improved chemotherapy efficacy. These findings unravel the oncogenic role of CSN6 in regulating nucleotide metabolism and chemosensitivity in colorectal cancer. SIGNIFICANCE: CSN6 deficiency inhibits colorectal cancer development and chemoresistance by downregulating PHGDH to block nucleotide biosynthesis, providing potential therapeutic targets to improve colorectal cancer treatment.

New Lactobacillus plantarum membrane proteins (LpMPs) towards oral anti-inflammatory agents against dextran sulfate sodium-induced colitis.

Inflammatory bowel disease (IBD), a progressive and unpredictable colorectal inflammatory disease, is a global health problem. Currently, therapeutic strategies for the management of the disease are limited. Results from our previous studies indicated that probiotic Lactobacillus plantarum exhibits therapeutic effects against IBD, and through screening, we obtained an active 61-amino-acid long protein, L. plantarum membrane protein 1 (LpMP-1). Based on druggability-guided strategies, the search for LpMPs with lower molecular weights and better bioactivities contributes to the development of new anti-inflammatory agents to overcome the limitations of existing therapies against IBD. We used amino-acid-truncation strategies to obtain modified LpMPs (LpMP-2 - LpMP-9) using LpMP-1 as the parent template. Furthermore, we systematically evaluated the anti-colitis pharmacodynamics of these LpMPs in terms of symptomatology, histopathology, and cytokine levels in DSS-induced ulcerative colitis mice. Their possible targets of action against IBD was investigated under an iTRAQ-based pharmacoproteomic system and a docking-guided receptor-ligand relationship frame. We found a new active protein, LpMP-8, which had a lower molecular weight than LpMP-1. LpMP-8 was found to exhibit anti-colitis activity following oral administration in vivo (50 µg/kg) by improving symptoms of colitis, colonic ulcerations, and cytokine disorders. TLRs and TGF-ß were found to be involved in the action of LpMP-8 against colitis; LpMP-8 was to compete with TLR4-MD2-bound LPS and reverse TGF-ß and Smad2/7 disorders. Our probiotic-derived LpMP-8 was shown to elicit oral anti-colitis activity, and its significant efficacy is probably associated with TLR4 and TGF-ß.

18F-FDG PET/CT and MR imaging features of liver metastases in gastrointestinal stromal tumors: a cross-sectional analysis.

Background: Early detection of gastrointestinal stromal tumor (GIST) liver metastases is crucial for the management and prognosis. In our experience, GIST liver metastases can display hypermetabolism on 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) and marked enhancement on magnetic resonance imaging (MRI), which are uncommon in other tumors before treatment. Most literature focus on the imaging evaluation, prognosis after treatment and less is known about imaging features on both imaging methods before treatment. This study analyzes the imaging features of newly diagnosed GIST liver metastases on 18F-FDG PET/CT and MRI, with goal of improving diagnostic accuracy. Methods: This retrospective study included 55 patients with pathological or radiographical confirmed GIST liver metastases who underwent PET/CT (n=29), MRI (n=22), or both methods (n=4). PET/CT and MRI interpretation including lesion's morphologic features, number, density or signal intensity, hemorrhage, cystic changes or necrosis, maximum standardized uptake value (SUVmax) of liver metastases and liver background on PET imaging, degree and pattern of enhancement on MRI were obtained by two experienced nuclear medicine physicians and two radiologists respectively. Data are presented as numbers, percentages, means ± standard deviations or median (interquartile range). The correlation between diameter and SUVmax of metastases, and primary tumor SUVmax and synchronous liver metastases SUVmax were analyzed by Spearman's rank test. Results: On PET/CT visual analysis, 38.9%, 23.9%, and 37.2% of lesions showed significant hypermetabolism, slightly higher metabolism, and equal or lower metabolism than liver, respectively. There was a weak correlation between the diameter and SUVmax of liver metastases (rs =0.370, P<0.001), and a moderate correlation between SUVmax of synchronous liver metastases and the primary tumors (rs =0.492, P<0.001). On contrast-enhanced MRI, 90.8% of lesions showed heterogeneous enhancement in the arterial phase with the variable presentation, and 74.3% had different enhancement patterns between margins and intratumoral parenchyma. Conclusions: Liver lesions in GIST displaying significant, slight hypermetabolism on 18F-FDG PET/CT, marked or heterogeneous gradual enhancement within the intratumoral parenchyma with ring-like enhancement on MRI may denote the diagnosis of liver metastasis. However, GIST liver metastases may also display equal or lower metabolism than liver parenchyma on PET, making small lesions more difficult to diagnose.

Induced retinal pigment epithelial cells with anti-epithelial-to-mesenchymal transition ability delay retinal degeneration.

The hostile microenvironment of the retina in patients with age-related macular degeneration (AMD) may trigger epithelial-to-mesenchymal transition (EMT) of grafted retinal pigment epithelial (RPE) cells, thus attenuating the therapeutic outcome. Here, we transformed human dedifferentiated induced pluripotent stem cell-derived RPE (iPSC-RPE) cells into induced RPE (iRPE) cells using a cocktail of four transcription factors (TFs)-CRX, MITF-A, NR2E1, and C-MYC. These critical TFs maintained the epithelial property of iRPE cells by regulating the expression of bmp7, forkhead box f2, lin7a, and pard6b, and conferred resistance to TGF-ß-induced EMT in iRPE cells by targeting ppm1a. The iRPE cells with Tet-on system-regulated c-myc expression exhibited EMT resistance and better therapeutic function compared with iPSC-RPE cells in rat AMD model. Our study demonstrates that endowing RPE cells with anti-EMT property avoids the risk of EMT after cells are grafted into the subretinal space, and it may provide a suitable candidate for AMD treatment.