Non-invasive visualization of liver fibrosis with [68Ga]Ga-DOTA-FAPI-04 PET from preclinical insights to clinical translation.

PURPOSE: The reversibility of early liver fibrosis highlights the need for improved early detection and monitoring techniques. Fibroblast activation protein (FAP) is a promising theranostics target significantly upregulated during fibrosis. This preclinical and preliminary clinical study investigated a FAP-targeted probe, gallium-68-labeled FAP inhibitor 04 ([68Ga]Ga-DOTA-FAPI-04), for its capability to visualize liver fibrosis. METHODS: The preclinical study employed [68Ga]Ga-DOTA-FAPI-04 micro-positron emission tomography (PET)/computed tomography (CT) on carbon tetrachloride-induced mice model (n = 34) and olive oil-treated control group (n = 26), followed by validation of the probe's biodistribution. Hepatic uptake was correlated with fibrosis and inflammation levels, quantified through histology and serum assays. FAP and α-smooth muscle actin expression were determined by immunohistochemistry, as well as immunofluorescence. The subsequent clinical trial enrolled 26 patients with suspected or confirmed liver fibrosis to undergo [68Ga]Ga-DOTA-FAPI-04 PET/magnetic resonance imaging or PET/CT. Key endpoints included correlating [68Ga]Ga-DOTA-FAPI-04 uptake with histological inflammation grades and fibrosis stages, and evaluating its diagnostic and differential efficacy compared to established serum markers and liver stiffness measurement (LSM). RESULTS: [68Ga]Ga-DOTA-FAPI-04 mean uptake in mice livers was notably higher than in control mice, increasing from week 6 [0.70 ± 0.11 percentage injected dose per cubic centimeter (%ID/cc)], peaking at week 10 (0.97 ± 0.15%ID/cc) and slightly reducing at week 12 (0.89 ± 0.28%ID/cc). The hepatic biodistribution and FAP expression showed a consistent trend. In the patient cohort, hepatic [68Ga]Ga-DOTA-FAPI-04 uptake presented moderate correlations with inflammation grades (r = 0.517 to 0.584, all P < 0.05) and fibrosis stages (r = 0.653 to 0.698, all P < 0.01). The average SUVmax to background ratio in the liver showed superior discriminative ability, especially between stage 0 and stage 1, outperforming LSM (area under curve 0.984 vs. 0.865). CONCLUSION: [68Ga]Ga-DOTA-FAPI-04 PET shows significant potential for non-invasive visualization and dynamic monitoring of liver fibrosis in both preclinical experiment and preliminary clinical trial, especially outperforming other common clinical indicators in the early stage. TRIAL REGISTRATION: NCT04605939. Registered October 25, 2020, https://clinicaltrials.gov/study/NCT04605939.

Wh-Words: Existential or Universal Quantifiers in Child Mandarin?

Wh-words have been analysed as existential quantifiers (Chierchia in Logic in grammar: polarity, free choice, and intervention. Oxford University Press, Oxford, 2013; Fox, in Sauerland U, Stateva P (eds) Presupposition and implicature in compositional semantics (Palgrave studies in pragmatics, language and cognition). Palgrave MacMillan, Houndmills, pp 71-120, 2007; Liao in Alternative and exhaustification: non-interrogative uses of Chinese wh-words. Harvard University, 2010) or universal quantifiers (Nishigauchi, in: Theoretical and applied linguistics at Kobe Shoin 2, Kobe Shoin Institute for Linguistic Sciences, 1999). These two accounts have distinct predictions on how children initially interpret wh-words. The universal account predicts that children should initially interpret wh-words as universal quantifiers, whereas the existential account anticipates that children should start out with the existential interpretation. To adjudicate between the two accounts, the present study was designed to explore pre-schoolers' semantic knowledge of wh-quantification. Specifically, it investigated the interpretation of the wh-word shenme 'what' with 4-and 5-year-old Mandarin-speaking children and a control group of adults. Using a Truth Value Judgment Task (Crain and Thornton in Investigations in universal grammar: a guide to experiments on the acquisition of syntax and semantics. MIT Press, Cambridge, 1998), Experiment 1 evaluated whether children interpret the wh-word shenme 'what' as closer in meaning to the polarity sensitive item renhe 'any' or the universal quantifier suoyou 'all' in the antecedent of ruguo 'if' conditionals. Using a Question-Answer Task, Experiments 2 & 3 respectively investigated whether children interpret shenme 'what' as closer in meaning to renhe 'any' or suoyou 'all' in two types of questions: yes-no questions with the particle ma and A-not-A questions. It was found that both children and adults interpret shenme 'what' as closer in meaning to renhe 'any' than suoyou 'all'. The findings suggest that Mandarin-speaking pre-schoolers already have adult-like semantic knowledge of wh-quantification: wh-words are existential quantifiers rather than universal quantifiers. Due to the paucity of primary linguistic input, children's early mastery of the non-interrogative wh-words appear to support the biolinguistic approach to language acquisition (Chomsky in Aspects of the theory of syntax. MIT Press, Cambridge, 1965; Pinker in Language learnability and language development. Harvard University Press, Cambridge, 1984; Crain et al. in Language acquisition from a biolinguistic perspective. Neurosci Biobehav Rev, 2016. https://doi.org/10.1016/j.neubiorev.2016.09.004 ).

Bile acid and nonalcoholic steatohepatitis: Molecular insights and therapeutic targets.

BACKGROUND: Nonalcoholic steatohepatitis (NASH) has been the second most common cause of liver transplantation in the United States. To date, NASH pathogenesis has not been fully elucidated but is multifactorial, involving insulin resistance, obesity, metabolic disorders, diet, dysbiosis, and gene polymorphism. An effective and approved therapy for NASH has also not been established. Bile acid is long known to have physiological detergent function in emulsifying and absorbing lipids and lipid-soluble molecules within the intestinal lumen. With more and more in-depth understandings of bile acid, it has been deemed to be a pivotal signaling molecule, which is capable of regulating lipid and glucose metabolism, liver inflammation, and fibrosis. In recent years, a plethora of studies have delineated that disrupted bile acid homeostasis is intimately correlated with NASH disease severity. AIMS: The review aims to clarify the role of bile acid in hepatic lipid and glucose metabolism, liver inflammation, as well as liver fibrosis, and discusses the safety and efficacy of some pharmacological agents targeting bile acid and its associated pathways for NASH. KEY SCIENTIFIC CONCEPTS OF REVIEW: Bile acid has a salutary effect on hepatic metabolic disorders, which can ameliorate liver fat accumulation and insulin resistance mainly through activating Takeda G-protein coupled receptor 5 and farnesoid X receptor. Moreover, bile acid also exerts anti-inflammation and anti-fibrosis properties. Furthermore, bile acid has great potential in nonalcoholic liver disease stratification and treatment of NASH.

Generating and Weighting Semantically Consistent Sample Pairs for Ultrasound Contrastive Learning.

Well-annotated medical datasets enable deep neural networks (DNNs) to gain strong power in extracting lesion-related features. Building such large and well-designed medical datasets is costly due to the need for high-level expertise. Model pre-training based on ImageNet is a common practice to gain better generalization when the data amount is limited. However, it suffers from the domain gap between natural and medical images. In this work, we pre-train DNNs on ultrasound (US) domains instead of ImageNet to reduce the domain gap in medical US applications. To learn US image representations based on unlabeled US videos, we propose a novel meta-learning-based contrastive learning method, namely Meta Ultrasound Contrastive Learning (Meta-USCL). To tackle the key challenge of obtaining semantically consistent sample pairs for contrastive learning, we present a positive pair generation module along with an automatic sample weighting module based on meta-learning. Experimental results on multiple computer-aided diagnosis (CAD) problems, including pneumonia detection, breast cancer classification, and breast tumor segmentation, show that the proposed self-supervised method reaches state-of-the-art (SOTA). The codes are available at https://github.com/Schuture/Meta-USCL.

A Calibration Method for the Resolution of 2D TPP Laser Direct Writing.

To improve the fabrication efficiency of the two-photon polymerization (TPP) laser direct writing, the TPP exposure process was set to complete by a single-line scan, which was named 2D TPP. The voxel of the 2D TPP should be large enough to cross the photoresist and the underlayer. To explore the resolution limit of the 2D TPP considering the thickness of the photoresist, a new method named the 45° scanning method was proposed. Meanwhile, a two-photon micro-nano fabrication platform was developed. A group of experiments based on the orthogonal decomposition method was carried out to analyze the width and length of the voxel on the S1805 photoresist under different laser power and processing speed. To confirm whether the resolution of the micro-nano structures fabricated by 2D TPP is consistent with the width of the voxel, aluminum wire grids were fabricated through the 2D TPP and the metal lift-off process. A second-order regression equation of the machining resolution and input parameters of the 2D TPP is deduced. The correlation coefficient between the width of the voxel and the aluminum wire grids is 0.961, which means a significant positive correlation between them. Finally, the second-order regression model derived from the fabrication resolution of the 2D TPP was validated by experiments. Full 2D grids were fabricated using 2D TPP and mental lift-off process. This paper provides a convenient, low-cost, and high-efficiency method for calibrating the fabrication resolution of 2D TPP on various photoresists.

The HSP90 inhibitor 17-DMAG alleviates primary biliary cholangitis via cholangiocyte necroptosis prevention.

Cholangiocyte death accompanied by the progression of primary biliary cholangitis (PBC) has not yet been thoroughly investigated. Thus, we are aimed to explore the role of HSP90 and a potential treatment strategy in cholangiocyte necroptosis. First, we detected the expression of HSP90 and necroptotic markers in liver tissues from patients and mice with PBC by immunohistochemistry (IHC) and real-time polymerase chain reaction (PCR). Then, the HSP90 inhibitor, 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG), was administered by intraperitoneal injection to evaluate its therapeutic effect for PBC by IHC, real-time PCR, and western blotting. Human intrahepatic bile duct epithelial cells (HIBECs) were induced to necroptosis by toxic bile acid and lipopolysaccharide (LPS) treatment, and evaluated via Cell Counting Kit-8 and flow cytometry assays. Additionally, 17-DMAG, cycloheximide, and a proteasome inhibitor were used to evaluate the role of HSP90 in cholangiocyte necroptosis. We found that the expression of HSP90 was elevated in the cholangiocytes of patients and mice with PBC, along with higher expressions of receptor-interacting serine/threonine-protein kinase 1 (RIPK1), RIPK3, mixed lineage kinase domain-like protein (MLKL), and phosphorylated-MLKL (p-MLKL). Proinflammatory cytokines and antibody levels of the E2 subunit of pyruvate dehydrogenase complex decreased after treatment with 17-DMAG in PBC mice. Meanwhile, RIPK1, RIPK3, phosphorylated-RIPK3, MLKL, and p-MLKL protein expressions decreased with 17-DMAG treatment. In vitro, 17-DMAG and necrostatin-1 prevented glycochenodeoxycholic acid and LPS-induced necroptosis of HIBECs. Immunoprecipitation and high-performance liquid chromatography-mass spectrometry analysis showed that RIPK1 combined with HSP90. Additionally, the 17-DMAG treatment reduced the RIPK1 half-life. Overall, 17-DMAG might be a potential therapeutic agent for PBC via cholangiocyte necroptosis prevention by accelerating RIPK1 degradation.

Functionalized gelatin/strontium hydrogel bearing endothelial progenitor cells for accelerating angiogenesis in wound tissue regeneration.

While polymer hydrogels are frequently utilized as wound dressings, they lack the sufficient bioactivity necessary to promote re-epithelialization and angiogenesis. In this work, a therapeutic angiogenesis complex is developed using a mixture of dopamine-modified polyhedral oligomeric silsesquioxane (Dopa-POSS), strontium ions (Sr2+ ions) photocrosslinked gelatin methacryloyl (GelMA) hydrogel and endothelial progenitor cells (EPCs) for full-thickness burn wound healing. Dopa-POSS is used to reinforce the hydrogel, and Sr2+ ions stabilizer is densely incorporated inside the network of GelMA hydrogels by ultraviolet cross-linking, thus effectively enhancing the hydrogel mechanical strength. The multifunctional GelMA hydrogels comprised gelatin's arginine-glycine-aspartate (RGD) patterns and active Sr2+ ions that promote EPC biological activity and proliferation. Notably, the Sr2+ ions in the functional hydrogels substantially enhanced EPC proliferation in a three-dimensional environment, migration, and angiogenesis-related protein expression. After 14 days, the Gel/Sr2+@POSS/EPCs composite hydrogel substantially accelerates and enhances the new blood vessel development process, collagen deposition, and re-epithelialization with the almost closed wounds and newly created tissue. Thus, UV-crosslinked Gel/Sr2+@POSS hydrogels functionalized with EPCs can be a potentially beneficial therapeutic system for full-thickness burn wound healing.

RA Fibroblast-Like Synoviocytes Derived Extracellular Vesicles Promote Angiogenesis by miRNA-1972 Targeting p53/mTOR Signaling in Vascular Endotheliocyte.

Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammatory in joints. Invasive pannus is a characteristic pathological feature of RA. RA fibroblast-like synoviocytes (FLSs) are showed tumor-like biological characters that facilitate pannus generation. Importantly, it has been documented that extracellular vesicle (EVs) derived microRNAs have a vital role of angiogenesis in various immune inflammatory diseases. However, whether RA FLSs derived EVs can facilitate angiogenesis and the underlying mechanism is undefined. Herein, we aim to investigate the key role of RA FLSs derived EVs on angiogenesis in endothelial cells (ECs). We indicate that RA FLSs derived EVs promote ECs angiogenesis by enhancing migration and tube formation of ECs in vitro. Also, we confirm that RA FLSs derived EVs can significantly facilitate ECs angiogenesis with a matrigel angiogenesis mice model. In terms of the mechanisms, both RNAs and proteins in EVs play roles in promoting ECs angiogenesis, but the RNA parts are more fundamental in this process. By combining microRNA sequencing and qPCR results, miR-1972 is identified to facilitate ECs angiogenesis. The blockage of miR-1972 significantly abrogated the angiogenesis stimulative ability of RA FLSs derived EVs in ECs, while the overexpression of miR-1972 reversed the effect in ECs. Specifically, the p53 level is decreased, and the phosphorylated mTOR is upregulated in miR-1972 overexpressed ECs, indicating that miR-1972 expedites angiogenesis through p53/mTOR pathway. Collectively, RA FLSs derived EVs can promote ECs angiogenesis via miR-1972 targeted p53/mTOR signaling, targeting on RA FLSs derived EVs or miR-1972 provides a promising strategy for the treatment of patients with RA.

LncRNA NEAT1_1 suppresses tumor-like biologic behaviors of fibroblast-like synoviocytes by targeting the miR-221-3p/uPAR axis in rheumatoid arthritis.

Fibroblast-like synoviocytes (FLSs) are the predominant effector cells in the pathological progression of rheumatoid arthritis (RA). Therefore, elucidating the underlying molecular mechanism of the biologic behaviors in RA-FLSs will be helpful in developing the potent targets for the treatment of RA. We have previously documented that the tumor-like biologic behaviors of RA-FLSs are exacerbated by urokinase-type plasminogen activator receptor (uPAR), a specifically up-regulated receptor in RA-FLSs. Here, we investigate the further mechanism of uPAR and clarify its function in RA-FLSs. We demonstrate that miR-221-3p positively correlates to uPAR and regulates uPAR level in RA-FLSs. Simultaneously, one long noncoding RNA, nuclear paraspeckle assembly transcript 1_1 (NEAT1_1) is identified, which can predictively target miR-221-3p at three sites, indicating a strong possibility of being a competing endogenous RNA in RA-FLSs. Interestingly, NEAT1_1 and miR-221-3p can colocate in the nucleus and cytoplasm in RA-FLSs. Importantly, NEAT1_1 can act as a rheostat for the miR-221-3p/uPAR axis and the downstream JAK signaling. In line with the biologic function, NEAT1_1 negatively regulates the tumor-like characters, and cytokine secretions of RA-FLSs. Collectively, our data provide new insight into the mechanisms of NEAT1_1 in modulating RA-FLSs tumor-like behaviors. The targeting of NEAT1_1 and miR-221-3p/uPAR axis may have a promising therapeutic role in patients with RA.

Plexiform angiomyxoid myofibroblastic tumor treated by endoscopic submucosal dissection: A case report and review of the literature.

BACKGROUND: Plexiform angiomyxoid myofibroblastic tumor (PAMT) is a rare mesenchymal tumor characterized by multiple nodular plexiform growth patterns and an immunophenotype with myofibroblasts. The pathological characteristics, immunohistochemistry, diagnostic criteria, differential diagnosis, and gene-level changes of PAMT have been reported in many studies. At present, the main treatment for PAMT in the reported cases is surgery; only eight cases were treated via endoscopy (excluding 1 thoracoscopic resection), and the lesions were all smaller than 5 cm. There are no reports on the prognosis and follow-up of young patients with lesion sizes reaching 5 cm who undergo endoscopic submucosal dissection (ESD). Herein, we present the first case of a young patient with a lesion size reaching 5 cm who was diagnosed with PAMT via endoscopic submucosal dissection. CASE SUMMARY: A 15-year-old young man with upper abdominal pain for 2 years presented to the Gastroenterology Department of our hospital. Painless gastroscopy showed a semicircular bulge approximately 5 cm in size in the lesser curvature near the cardia of the fundus; the surface was eroded, and shallow ulcers had formed. The pathological manifestations of the biopsy were spindle cell proliferative lesions with interstitial mucinous changes, and the surface mucosa showed chronic inflammatory changes with active lesions; immunohistochemistry showed smooth muscle actin (SMA) (+), CD117 (-), CD34 (-), DOG-1 (-), S-100 (-), and Ki67 (LI: < 1%). We performed ESD on the patient. The lesion that we removed was 5 cm × 4 cm × 2 cm in size. Pathologically, the resected tissue displayed typical manifestations, such as fat spindle-shaped fibroblasts and myofibroblast-like cells showing irregular nodular hyperplasia. Immunohistochemistry staining of the tumor cells revealed the following: CD34 (partially +), SMA (weakly +), CD117 (-), DOG-1 (-), S-100 (-), SDHB (+), PCK (-), and Ki67 (labelling index: 2%). There was no recurrence or metastasis during the 3-mo follow-up after the operation, and the treatment effect was good. We also performed a review of the literature on the clinical manifestations, pathological features, immunohistochemistry, and differential diagnosis of PAMT. CONCLUSION: At present, the diagnostic criteria for PAMT are relatively clear, but the pathogenesis and genetic changes require further study. PAMT is benign in nature, and these patients are less likely to experience local or metastatic recurrence. The main treatment is still surgery if the lesion is in the stomach. Partial gastrectomy and distal gastrectomy are the most frequently performed surgical treatments for PAMT, followed by local resection, subtotal gastrectomy, and wedge resection. But for comprehensive evaluation of the disease, ESD can be considered a suitable method to avoid excessive treatment.

Visual adaptation selective for individual limbs reveals hierarchical human body representation.

The spatial relationships between body parts are a rich source of information for person perception, with even simple pairs of parts providing highly valuable information. Computation of these relationships would benefit from a hierarchical representation, where body parts are represented individually. We hypothesized that the human visual system makes use of such representations. To test this hypothesis, we used adaptation to determine whether observers were sensitive to changes in the length of one body part relative to another. Observers viewed forearm/upper arm pairs where the forearm had been either lengthened or shortened, judging the perceived length of the forearm. Observers then adapted to a variety of different stimuli (e.g., arms, objects, etc.) in different orientations and visual field locations. We found that following adaptation to distorted limbs, but not non-limb objects, observers experienced a shift in perceived forearm length. Furthermore, this effect partially transferred across different orientations and visual field locations. Taken together, these results suggest the effect arises in high level mechanisms specialized for specific body parts, providing evidence for a representation of bodies based on parts and their relationships.

Density of σ70 promoter-like sites in the intergenic regions dictates the redistribution of RNA polymerase during osmotic stress in Escherichia coli.

RNA polymerase (RNAP), the transcription machinery, shows dynamic binding across the genomic DNA under different growth conditions. The genomic features that selectively redistribute the limited RNAP molecules to dictate genome-wide transcription in response to environmental cues remain largely unknown. We chose the bacterial osmotic stress response model to determine genomic features that direct genome-wide redistribution of RNAP during the stress. Genomic mapping of RNAP and transcriptome profiles corresponding to the different temporal states after salt shock were determined. We found rapid redistribution of RNAP across the genome, primarily at σ70 promoters. Three subsets of genes exhibiting differential salt sensitivities were identified. Sequence analysis using an information-theory based σ70 model indicates that the intergenic regions of salt-responsive genes are enriched with a higher density of σ70 promoter-like sites than those of salt-sensitive genes. In addition, the density of promoter-like sites has a positive linear correlation with RNAP binding at different salt concentrations. The RNAP binding contributed by the non-initiating promoter-like sites is important for gene transcription at high salt concentration. Our study demonstrates that hyperdensity of σ70 promoter-like sites in the intergenic regions of salt-responsive genes drives the RNAP redistribution for reprograming the transcriptome to counter osmotic stress.

Nitrogen-starvation triggers cellular accumulation of triacylglycerol in Metarhizium robertsii.

Nitrogen starvation can induce cellular triacylglycerol (TAG) accumulation in different organisms with an unclear mechanism. In this study, we performed nutrient starvation and lipid droplet (LD) proteomics analyses of the filamentous fungus Metarhizium robertsii. Our results indicated that nitrogen starvation activated cell autophagic activity but inhibited the internalization of LDs into vacuoles for degradation. LD proteomic analyses identified an array of differentially accumulated proteins including autophagy-related (ATG) proteins, heat shock proteins, TAG metabolic and phospholipid biosynthetic enzymes when the fungus was grown in different nutrient conditions. In contrast to the highly activated MrATG8, the ATG proteins involved in vacuolar LD internalization were down-regulated after nitrogen starvation. Cellular TAG contents were increased in different ATG-gene null mutants of M. robertsii. In addition, TAG increase could be due to the up-regulation of TAG biogenesis along with the down-regulation of TAG catabolic enzymes in fungal cells after nitrogen deprivation. The data of this study benefit our understanding of the mechanism of nitrogen starvation induced TAG increase in different cells.

Diverse effect of phosphatidylcholine biosynthetic genes on phospholipid homeostasis, cell autophagy and fungal developments in Metarhizium robertsii.

Phosphatidylcholine (PC) plays an important role in maintaining membrane integrity and functionality. In this study, two key genes (Mrpct and Mrpem) putatively involved in the cytidine diphosphate (CDP)-choline and phosphatidylethanolamine N-methyltransferase (PEMT) pathways for PC biosynthesis were characterized in the insect pathogenic fungus Metarhizium robertsii. The results indicated that disruption of Mrpct did not lead to any reduction of total PC content but impaired fungal virulence and increased cellular accumulation of triacylglycerol. Deletion of Mrpem reduced PC content and impaired fungal conidiation and infection structure differentiation but did not result in virulence defects. Lipidomic analysis revealed that deletion of Mrpct and Mrpem resulted in dissimilar effects on increase and decrease of PC moieties and other phospholipid species accumulations. Interestingly, we found that these two genes played opposite roles in activation of cell autophagy when the fungi were grown in a nutrient-rich medium. The connection between PC metabolism and autophagy was confirmed because PC content was drastically reduced in Mratg8Δ and that the addition of PC could rescue null mutant sporulation defect. The results of this study facilitate the understanding of PC metabolism on fungal physiology.

Reversal effect of Jagged1 signaling inhibition on CCl4-induced hepatic fibrosis in rats.

The role of the Notch ligand Jagged1 in hepatic fibrosis remains to be elucidated. In the current study, we investigated the role of Jagged1 in the activation of hepatic stellate cells (HSCs) and development of hepatic fibrosis in rats. In vitro, Jagged1 in HSCs was downregulated and upregulated by Jagged1 siRNA and pcDNA3.1 Jagged1, respectively. The levels of epithelial-mesenchymal transition (EMT) markers and HSC activation markers were assessed using western blot analysis. The proliferation and migration capacity of HSCs were assessed using 5-ethynyl-2'-deoxyuridine (EdU) incorporation and Transwell migration assays. In vivo, a recombinant adeno-associated virus type 1 (rAAV1) vector carrying Jagged1 shRNA (rAAV1-Jagged1-shRNA) was constructed and transferred to rat livers via the tail vein. Reversion of liver fibrosis and the effect of Jagged1 signaling on EMT were studied using pathological, immunohistochemical and immunofluorescence methods. Our findings revealed that downregulation and upregulation of Jagged1 inhibited and promoted, respectively, HSC activation. The migratory capacity of HSCs was markedly restrained by Jagged1 siRNA. Furthermore, downregulation of Jagged1 suppressed EMT in HSCs. rAAV1-Jagged1-shRNA was generated to treat CCl4-induced hepatic fibrosis in rats. Treatment with rAAV1-Jagged1-shRNA reversed hepatic fibrosis by decreasing EMT. The results of the present study suggest that inhibition of Jagged1 is a potential treatment to ameliorate liver fibrosis.

Inhibition of Notch Signaling Attenuates Schistosomiasis Hepatic Fibrosis via Blocking Macrophage M2 Polarization.

Macrophages play a key role in the pathogenesis of liver granuloma and fibrosis in schistosomiasis. However, the underlying mechanisms have not been fully characterized. This study revealed that the macrophages infiltrating the liver tissues in a murine model of Schistosoma japonica infection exhibited M2 functional polarization, and Notch1/Jagged1 signaling was significantly upregulated in the M2 polarized macrophages in vivo and in vitro. Furthermore, the blockade of Notch signaling pathway by a γ-secretase inhibitor could reverse macrophage M2 polarization in vitro and alleviate liver granuloma and fibrosis in the murine model of schistosomiasis. These results implied that the Notch1/Jagged1 signaling-dependent M2 polarization of macrophages might play an important role in liver granuloma and fibrosis in schistosomiasis, and the inhibition of Notch1/Jagged1 signaling might provide a novel therapeutic approach to administrate patients with schistosomiasis.

The Bax inhibitor MrBI-1 regulates heat tolerance, apoptotic-like cell death, and virulence in Metarhizium robertsii.

Bax inhibitor 1 (BI-1) is a highly conserved protein originally identified as a suppressor of the proapoptotic protein Bax to inhibit cell death in animals and plants. The orthologs of BI-1 are widely distributed in filamentous fungi but their functions remain largely unknown. Herein, we report the identification and characterizations of MrBI-1, an ortholog of BI-1, in the entomopathogenic fungus Metarhizium robertsii. First, we found that MrBI-1 could partially rescue mammalian Bax-induced cell death in yeast. Deletion of MrBI-1 impaired fungal development, virulence and heat tolerance in M. robertsii. We also demonstrated that inactivation of MrBI-1 reduced fungal resistance to farnesol but not to hydrogen peroxide, suggesting that MrBI-1 contributes to antiapoptotic-like cell death via the endoplasmic reticulum stress-signaling pathway rather than the classical mitochondrium-dependent pathway. In particular, we found that unlike the observations in yeasts and plants, expression of mammalian Bax did not lead to a lethal effect in M. robertsii; however, it did aggravate the fungal apoptotic effect of farnesol. The results of this study advance our understanding of BI-1-like protein functions in filamentous fungi.