Targeting hepatic stellate cells to prevent or reverse liver fibrosis

Activation of stellate cells as a target for the treatment of liver fibrosisIn his thesis, Zhang introduces the crucial role of hepatic stellate cell activation in the development of liver fibrosis. Activated liver stellate cells are the main precursors of myofibroblasts. Therapy targeting hepatic stellate cells can prevent or reverse liver fibrosis.The aging ("senescence") of hepatic stellate cells is interpreted as a mechanism that protects against the progression of liver fibrosis. The biomarkers, signaling pathways and likely effects of hepatic stellate cell senescence are explained. Zhang proposes that the biomarkers P21 (cell cycle arrest), senescence-associated β-galactosidase (lysosomal galactosidase), and interleukin-6 (senescence-associated secretory phenotype) can be used to identify senescent hepatic stellate cells. Although the senescence of liver stellate cells has not yet been fully elucidated, therapy-induced senescence of hepatic stellate cells, followed by senolytics, may be an optimal strategy for combating liver fibrosis.Esculetin, a coumarin derivative, has also been shown to cause the senescence of hepatic stellate cells. It appears that in senescent hepatic stellate cells, collagen production and cell proliferation are reduced. In addition, senescent hepatic stellate cells develop resistance to a return to active proliferation

Artificial Neural Network Based Identification of Multi-Operating-Point Impedance Model

The black-box impedance model of voltage source inverters (VSIs) can be measured at their terminals without access to internal control details, which greatly facilitate the analysis of inverter-grid interactions. However, the impedance model of VSI is dependent on its operating point and can have different profiles when the operating point is changed. This letter proposes a method for identifying the impedance model of VSI under a wide range of operating points. The approach is based on the artificial neural network (ANN), where a general framework for applying the ANN to identify the VSI impedance is established. The effectiveness of the ANN-based method is validated with the analytical impedance models

Selectively fluorinated citronellol analogues support a hydrogen bonding donor interaction with the human OR1A1 olfactory receptor

Authors thank the Chinese Scholarship Council for funding a Studentship (No. 202008060063) at the University of St. Andrews, U.K.C-2 fluorinated and methylated stereoisomers of the fragrance citronellol 1 and its oxalate esters were prepared from (R)-pulegone 11 and explored as agonists of the human olfactory receptor OR1A1 and assayed also against site-specific mutants. There were clear isomer preferences and C-2 difluorination as in 18 led to the most active compound suggesting an important hydrogen bond donor role for citronellol 1. C-2 methylation and the corresponding oxalate ester analogues were less active.Publisher PDFPeer reviewe

Hepatic Stellate Cell Senescence in Liver Fibrosis:Characteristics, Mechanisms and Perspectives

Myofibroblasts play an important role in fibrogenesis. Hepatic stellate cells are the main precursors of myofibroblasts. Cellular senescence is the terminal cell fate in which proliferating cells undergo irreversible cell cycle arrest. Senescent hepatic stellate cells were identified in liver fibrosis. Senescent hepatic stellate cells display decreased collagen production and proliferation. Therefore, induction of senescence could be a protective mechanism against progression of liver fibrosis and the concept of therapy-induced senescence has been proposed to treat liver fibrosis. In this review, characteristics of senescent hepatic stellate cells and the essential signaling pathways involved in senescence are reviewed. Furthermore, the potential impact of senescent hepatic stellate cells on other liver cell types are discussed. Senescent cells are cleared by the immune system. The persistence of senescent cells can remodel the microenvironment and interact with inflammatory cells to induce aging-related dysfunction. Therefore, senolytics, a class of compounds that selectively induce death of senescent cells, were introduced as treatment to remove senescent cells and consequently decrease the disadvantageous effects of persisting senescent cells. The effects of senescent hepatic stellate cells in liver fibrosis need further investigation

Hydrogen sulfide stimulates activation of hepatic stellate cells through increased cellular bio-energetics

Hepatic fibrosis is caused by chronic inflammation and characterized as the excessive accumulation of extra cellular matrix (ECM) by activated hepatic stellate cells (HSCs). Gasotransmitters like NO and CO are known to modulate inflammation and fibrosis, however, little is known about the role of the gasotransmitter hydrogen sulfide (H2S) in liver fibrogenesis and stellate cell activation. Endogenous H2S is produced by the enzymes cystathionine beta-synthase (CBS), cystathionine gamma-lyase (CTH) and 3-mercaptopyruvate sulfur transferase (MPST) [1]. The aim of this study was to elucidate the role of endogenously produced and/or exogenously administered H2S on rat hepatic stellate cell activation and fibrogenesis. Primary rat HSCs were culture-activated for 7 days and treated with different H2S releasing donors (slow releasing donor GYY4137, fast releasing donor NaHS) or inhibitors of the H2S producing enzymes CTH and CBS (DL-PAG, AOAA). The main message of our study is that mRNA and protein expression level of H2S synthesizing enzymes are low in HSCs compared to hepatocytes and Kupffer cells. However, H2S promotes hepatic stellate cell activation. This conclusion is based on the fact that production of H2S and mRNA and protein expression of its producing enzyme CTH are increased during hepatic stellate cell activation. Furthermore, exogenous H2S increased HSC proliferation while inhibitors of endogenous H2S production reduce proliferation and fibrotic makers of HSCs. The effect of H2S on stellate cell activation correlated with increased cellular bioenergetics. Our results indicate that the H2S generation in hepatic stellate cells is a target for anti-fibrotic intervention and that systemic interventions with H2S should take into account cell-specific effects of H2S.</p

Pirfenidone Inhibits Cell Proliferation and Collagen I Production of Primary Human Intestinal Fibroblasts

Intestinal fibrosis is a common complication of inflammatory bowel disease. So far, there is no safe and effective drug for intestinal fibrosis. Pirfenidone is an anti-fibrotic compound available for the treatment of idiopathic pulmonary fibrosis. Here, we explored the anti-proliferative and anti-fibrotic properties of pirfenidone on primary human intestinal fibroblasts (p-hIFs). p-hIFs were cultured in the absence and presence of pirfenidone. Cell proliferation was measured by a real-time cell analyzer (xCELLigence) and BrdU incorporation. Cell motility was monitored by live cell imaging. Cytotoxicity and cell viability were analyzed by Sytox green, Caspase-3 and Water Soluble Tetrazolium Salt-1 (WST-1) assays. Gene expression of fibrosis markers was determined by quantitative reverse transcription PCR (RT-qPCR). The mammalian target of rapamycin (mTOR) signaling was analyzed by Western blotting and type I collagen protein expression additionally by immunofluorescence microscopy. Pirfenidone dose-dependently inhibited p-hIF proliferation and motility, without inducing cell death. Pirfenidone suppressed mRNA levels of genes that contribute to extracellular matrix production, as well as basal and TGF-beta 1-induced collagen I protein production, which was associated with inhibition of the rapamycin-sensitive mTOR/p70S6K pathway in p-hIFs. Thus, pirfenidone inhibits the proliferation of intestinal fibroblasts and suppresses collagen I production through the TGF-beta 1/mTOR/p70S6K signaling pathway, which might be a novel and safe anti-fibrotic strategy to treat intestinal fibrosis

Thalamic volume and functional connectivity are associated with nicotine dependence severity and craving

Tobacco smoking is associated with deleterious health outcomes. Most smokers want to quit smoking, yet relapse rates are high. Understanding neural differences associated with tobacco use may help generate novel treatment options. Several animal studies have recently highlighted the central role of the thalamus in substance use disorders, but this research focus has been understudied in human smokers. Here, we investigated associations between structural and functional magnetic resonance imaging measures of the thalamus and its subnuclei to distinct smoking characteristics. We acquired anatomical scans of 32 smokers as well as functional resting‐state scans before and after a cue‐reactivity task. Thalamic functional connectivity was associated with craving and dependence severity, whereas the volume of the thalamus was associated with dependence severity only. Craving, which fluctuates rapidly, was best characterized by differences in brain function, whereas the rather persistent syndrome of dependence severity was associated with both brain structural differences and function. Our study supports the notion that functional versus structural measures tend to be associated with behavioural measures that evolve at faster versus slower temporal scales, respectively. It confirms the importance of the thalamus to understand mechanisms of addiction and highlights it as a potential target for brain‐based interventions to support smoking cessation, such as brain stimulation and neurofeedback