site-specific-lysine-lactylation-via-genetic-code-expansion-e-coli

Site-Specific Lysine Lactylation via Genetic Code Expansion in <em>E. coli </em>and Mammalian Cells

Lactylation is a recently discovered post-translational modification (PTM) with diverse biological functions. Since its initial identification in 2019 as ...

Nanjing University of Chinese Medicine

Accumulating evidence indicates that hepatic stellate cells (HSCs) are the central mediators and major effectors in the development of hepatic fibrosis. It is well-known that regulation of cell proliferation and apoptosis are potential strategies to block the activation of HSCs. Recently, several studies have revealed that induction of HSC senescence could prevent and cure the liver fibrosis. In our previous work, we have demonstrated that the natural product tetramethylpyrazine (TMP) could inhibit the activation of HSCs and ameliorate hepatic fibrosis. The aim of this study was to identify a new role of TMP in the regulation of activated HSC senescence and to elucidate the underlying mechanisms. In this study, our data showed that TMP could promote HSC senescence in vivo and in vitro. Moreover, TMP affected the cell cycle and telomerase activity. We further demonstrated that P53 siRNA or P53 pharmacological inhibitor PFT-α abrogated the TMP-induced HSC senescence in vitro. Meanwhile, similar results were obtained in vivo. Further studies indicated that TMP promoted the expression of P53 through a YAP inhibition-dependent mechanism. Moreover, silencing YAP enhanced TMP induction of activated HSC senescence. Collectively, our results suggested that TMP inhibited the activation of HSCs by inducing senescence and had therapeutic implication for the treatment of liver fibrosis.

Inhibition of YAP signaling contributes to senescence of hepatic stellate cells induced by tetramethylpyrazine.

Portal hypertension is a frequent pathological symptom occurring especially in hepatic fibrosis and cirrhosis. Current paradigms indicate that inhibition of hepatic stellate cell (HSC) activation and contraction is anticipated to be an attractive therapeutic strategy, because activated HSC dominantly facilitates an increase in intrahepatic vein pressure through secreting extracellular matrix and contracting. Our previous in vitro study indicated that dihydroartemisinin (DHA) inhibited contractility of cultured HSC by activating intracellular farnesoid X receptor (FXR). However, the effect of DHA on fibrosis-related portal hypertension still requires clarification. In this study, gain- and loss-of-function models of FXR in HSC were established to investigate the mechanisms underlying DHA protection against chronic CCl -caused hepatic fibrosis and portal hypertension. Immunofluorescence staining visually showed a decrease in FXR expression in CCl -administrated rat HSC but an increase in that in DHA-treated rat HSC. Serum diagnostics and morphological analyses consistently indicated that DHA exhibited hepatoprotective effects on CCl -induced liver injury. DHA also reduced CCl -caused inflammatory mediator expression and inflammatory cell infiltration. These improvements were further enhanced by INT-747 but weakened by Z-guggulsterone. Noteworthily, DHA, analogous to INT-747, significantly lowered portal vein pressure and suppressed fibrogenesis. Experiments on mice using FXR shRNA lentivirus consolidated the results above. Mechanistically, inhibition of HSC activation and contraction was found as a cellular basis for DHA to relieve portal hypertension. These findings demonstrated that DHA attenuated portal hypertension in fibrotic rodents possibly by targeting HSC contraction via a FXR activation-dependent mechanism. FXR could be a target molecule for reducing portal hypertension during hepatic fibrosis.

Dihydroartemisinin counteracts fibrotic portal hypertension via farnesoid X receptor-dependent inhibition of hepatic stellate cell contraction.

Hepatic fibrosis, a common scarring response to various forms of chronic liver injury, is a precursor to cirrhosis and liver cancer. During liver fibrosis, hepatic stellate cells (HSCs) initially activate and proliferate, which are responsible for the secretion of extracellular matrix components. However, these cells eventually senesce and are cleared by natural killer (NK) cells. Our previous researches have shown that the natural product curcumin could promote the senescence of activated HSC. In this study, we investigated how NK cells target senescent HSC and assessed the effect of this process on liver fibrosis. We found that senescent HSC induced by curcumin are susceptible to NK cells killing, due to the increased expression of NK cell activating ligand major histocompatibility complex class I chain-related genes A (MICA) and UL16-binding proteins 2 (ULBP2), but not Poliovirus Receptor (PVR). Further studies displayed that the interaction between NK cells and senescent LX2 cells stimulated granule exocytosis. Moreover, the inhibition of granule exocytosis weakened the cytotoxicity of NK cells and promoted the accumulation of senescent LX2 cells. Therefore, these aggregated data indicated that NK cells mediated clearance of senescent LX2 cells and granule exocytosis could play a protective role in the improvement of liver fibrosis.

Article	Year
Inhibition of YAP signaling contributes to senescence of hepatic stellate cells induced by tetramethylpyrazine. European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences\| PubMed ID: 27717875	2017
Dihydroartemisinin counteracts fibrotic portal hypertension via farnesoid X receptor-dependent inhibition of hepatic stellate cell contraction. The FEBS journal\| PubMed ID: 27896916	2017
Hepatic stellate cell interferes with NK cell regulation of fibrogenesis via curcumin induced senescence of hepatic stellate cell. Cellular signalling\| PubMed ID: 28188823	2017

Shunyu Yao

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