Combined obeticholic acid and apoptosis inhibitor treatment alleviates liver fibrosis
Open accessAbstract
Obeticholic acid (OCA), the first FXR-targeting drug, has been claimed effective in the therapy of liver fibrosis. However, recent clinical trials indicated that OCA might not be effective against liver fibrosis, possibly due to the lower dosage to reduce the incidence of the side-effect of pruritus. Here we propose a combinatory therapeutic strategy of OCA and apoptosis inhibitor for combating against liver fibrosis. CCl 4 -injured mice, d-galactosamine/LPS (GalN/LPS)-treated mice and cycloheximide/TNF α (CHX/TNF α )-treated HepG2 cells were employed to assess the effects of OCA, or together with IDN-6556, an apoptosis inhibitor. OCA treatment significantly inhibited hepatic stellate cell (HSC) activation/proliferation and prevented fibrosis. Elevated bile acid (BA) levels and hepatocyte apoptosis triggered the activation and proliferation of HSCs. OCA treatment reduced BA levels but could not inhibit hepatocellular apoptosis. An enhanced anti-fibrotic effect was observed when OCA was co-administrated with IDN-6556. Our study demonstrated that OCA inhibits HSCs activation/proliferation partially by regulating BA homeostasis and thereby inhibiting activation of HSCs. The findings in this study suggest that combined use of apoptosis inhibitor and OCA at lower dosage represents a novel therapeutic strategy for liver fibrosis.
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Written from the paper’s full text.
TL;DR
Obeticholic acid (OCA) reduces bile acid levels and hepatic stellate cell activation but does not inhibit hepatocyte apoptosis, limiting its anti-fibrotic efficacy. Combining OCA with the apoptosis inhibitor IDN-6556 produced enhanced protection against CCl4-induced liver fibrosis in mice.
Key findings
- OCA activated hepatic FXR signaling, reduced serum total bile acids, and decreased CDCA and CA in healthy and CCl4-treated mice; in CCl4-treated mice, multiple bile acids were elevated and almost all were reduced by OCA.
- OCA reduced CCl4-induced fibrosis markers: CCl4 increased Acta2, Col1a1, Col1a2, Timp-1, and Timp-2 mRNAs by 5- to 20-fold, and OCA significantly reduced these levels; OCA also reduced α-SMA-positive cells and fibrotic area but reduced ALT with little effect on AST.
- OCA did not prevent hepatocyte apoptosis: TUNEL-positive cells and caspase-3, -8, and -9 activities were unchanged by OCA in CCl4 mice, GalN/LPS-treated mice, and CHX/TNFα-treated HepG2 cells.
- Co-administration of OCA (10 mg/kg/day) and IDN-6556 (10 mg/kg/day) enhanced reductions in ALT, fibrosis histology, α-SMA, and fibrosis-related genes; IDN-6556 but not OCA alone reduced TUNEL staining and caspase activities, while OCA rescued bile acid dyshomeostasis. In patients, serum bile acids and CDCA were higher in fibrosis/cirrhosis than healthy controls, and apoptosis markers (TUNEL, serum CK-18) were elevated.
Methods
- Mouse models: C57BL/6 male mice (8-week-old, 20 g) received CCl4 (20% CCl4/mineral oil; 5 mL/kg i.p.) twice weekly for 6 weeks, GalN (800 μg/g i.p.) plus LPS (100 ng/g i.p.) for 6 h, or vehicle; OCA was given at 10 or 30 mg/kg/day, and IDN-6556 at 10 mg/kg/day in combination experiments.
- Cell models: HepG2 and HSC-T6 cells were used, including a Transwell co-culture in which HepG2 cells were treated with CHX (40 μmol/L) then TNFα (20 ng/mL) for 12 h to induce apoptosis before transfer onto HSC-T6 cells; HSC proliferation was measured by BrdU.
- Human samples: 50 patients with liver fibrosis/cirrhosis were recruited (later analyzed as 20 fibrosis and 30 cirrhosis biopsies) plus 20 healthy age-matched controls; serum bile acids, CK-18 (M30), TUNEL, and biochemical/histological markers were assessed. Statistical analysis used mean ± SD, one-way ANOVA, and Tukey’s multiple comparison test, with P < 0.05 significant.
Limitations
- The paper does not state a dedicated limitations section.
- Evident from the text: the mechanistic and combination findings rely mainly on CCl4, GalN/LPS, and CHX/TNFα models and HepG2/HSC-T6 cells; the human data are cross-sectional/retrospective with 20 fibrosis, 30 cirrhosis, and 20 healthy controls and no interventional validation.
- Evident from the text: the OCA plus IDN-6556 combination was tested only in CCl4-injured mice, with no clinical trial, long-term safety, or pruritus data; the combination used OCA at 10 mg/kg/day in mice, not a tested human low-dose regimen.
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Claims the paper makes
0 of 27 cited sources checked · 0 supported · 0 flagged
- Findingown data
OCA treatment significantly inhibited hepatic stellate cell (HSC) activation/proliferation.
“OCA treatment significantly inhibited hepatic stellate cell (HSC) activation/proliferation and prevented fibrosis.”
Quote in the paperSubstantial claim - Findingown data
OCA treatment prevented fibrosis.
“OCA treatment significantly inhibited hepatic stellate cell (HSC) activation/proliferation and prevented fibrosis.”
Quote in the paperSubstantial claim - Findingown data
An enhanced anti-fibrotic effect was observed when OCA was co-administered with IDN-6556.
“An enhanced anti-fibrotic effect was observed when OCA was co-administrated with IDN-6556.”
Quote in the paperSubstantial claim - Findingown data
OCA treatment could not inhibit hepatocellular apoptosis.
“OCA treatment reduced BA levels but could not inhibit hepatocellular apoptosis.”
Quote in the paperSubstantial claim - Findingown data
OCA treatment reduced BA levels.
“OCA treatment reduced BA levels but could not inhibit hepatocellular apoptosis.”
Quote in the paperSubstantial claim
- Findingown data
Masson and Sirius Red staining revealed a significant increase in fibrotic surface in CCl4-treated mice compared with control.
“Masson and Sirius Red staining of liver sections (Fig. 2C and D) revealed a significant increase in the fibrotic surface compared with control ones.”
Quote in the paperSubstantial claim - Findingown data
Combination had much stronger effect in reducing liver expression of Acta2, Col1a1, Col1a2, Timp-1, Timp-2.
“Consistently, the combination exhibited better effect in inhibiting HSCs activation, as indicated by α-SMA staining (Fig. 5E), and much stronger effect in reducing liver expression of a number of genes involved in liver fibrosis development, including Acta2, Col1a1, Col1a2, Timp-1 and Timp-2 (Fig. 5G).”
Quote in the paperSubstantial claim - Findingown data
HSC proliferation was significantly increased upon apoptotic HepG2 cells co-culture.
“Furthermore, BrdU incorporation analysis showed that HSC proliferation was significantly increased upon BA treatment (Fig. 4C) or apoptotic HepG2 cells co-culture (Fig. 4D).”
Quote in the paperSubstantial claim - Findingown data
HSC proliferation was significantly increased upon BA treatment.
“Furthermore, BrdU incorporation analysis showed that HSC proliferation was significantly increased upon BA treatment (Fig. 4C) or apoptotic HepG2 cells co-culture (Fig. 4D).”
Quote in the paperSubstantial claim - Findingown data
HSC-T6 cells co-cultured with apoptotic HepG2 cells had elevated mRNA levels of Acta2, Col1a1, Col1a2, Timp-1, Timp-2.
“As compared with the HSC-T6 cells co-cultured with healthy HepG2 cells, HSC-T6 cells co-cultured with apoptotic HepG2 cells were characterized with elevated mRNA levels of Acta2, Col1a1, Col1a2, Timp-1 and Timp-2, indicating that apoptotic hepatocytes may trigger HSC activation (Fig. 4B).”
Quote in the paperSubstantial claim - Findingown data
IDN-6556 in combination with OCA reduced serum AST levels.
“Besides, IDN-6556, alone or in combination with OCA, reduced serum AST levels (Fig. 5A).”
Quote in the paperNot a substantial claim - Findingown data
Multiple BAs increased in CCl4-treated mice.
“Detailed BA composition analysis revealed that multiple BAs, including lithocholic acid, ursodeoxycholic acid, hyodeoxycholic acid, CDCA, deoxycholic acid, CA, β-muricholic acid, and α-muricholic acid, increased in CCl4-treated mice, and almost all these BAs levels were reduced by OCA treatment (Fig. 1F).”
Quote in the paperSubstantial claim - Findingown data
Co-administration of OCA and IDN-6556 produced an enhanced protective effect against liver fibrosis.
“OCA or IDN-6556 alone protected against liver fibrosis development as shown by histological analysis (Fig. 5B–D), while co-administration of these two agents produced an enhanced protective effect.”
Quote in the paperSubstantial claim - Findingown data
OCA alone protected against liver fibrosis development as shown by histological analysis.
“OCA or IDN-6556 alone protected against liver fibrosis development as shown by histological analysis (Fig. 5B–D), while co-administration of these two agents produced an enhanced protective effect.”
Quote in the paperSubstantial claim - Findingown data
In CCl4-treated mice, mRNA levels of Acta2, Col1a1, Col1a2, Timp-1, Timp-2 showed a 5- to 20-fold increase.
“Consistently, quantitative RT-PCT analysis of Acta2 (encoding α-SMA), collagen1a1 (Col1a1), Col1a2, tissue inhibitor of metalloprotease-1 (Timp-1) and Timp-2 mRNAs showed a 5- to 20-fold increase in CCl4-treated mice, while OCA administration significantly reduced the mRNA levels of all these fibrosis markers (Fig. 2F).”
Quote in the paperSubstantial claim - Findingown data
OCA significantly rescued the dyshomeostasis of BA caused by CCl4.
“In contrast, OCA significant rescued the dyshomeostasis of BA caused by CCl4 (Fig. 5I and J).”
Quote in the paperNot a substantial claim - Findingown data
OCA alone reduced serum ALT levels.
“OCA or IDN-6556 alone reduced serum ALT levels, and the combination exhibited an enhanced reduction.”
Quote in the paperNot a substantial claim - Findingown data
IDN-6556 alone reduced serum AST levels.
“Besides, IDN-6556, alone or in combination with OCA, reduced serum AST levels (Fig. 5A).”
Quote in the paperNot a substantial claim - Findingown data
OCA treatment failed to protect cultured cells from apoptosis induced by CHX/TNFα.
“In accordance with the results in vivo, OCA treatment fail to protect cultured cells from apoptosis induced by CHX/TNFα (Fig. 3G—I).”
Quote in the paperSubstantial claim - Findingown data
OCA significantly rescued the dyshomeostasis of bile acids caused by CCl4.
“In contrast, OCA significant rescued the dyshomeostasis of BA caused by CCl4 (Fig. 5I and J).”
Quote in the paperSubstantial claim - Findingown data
OCA treatment significantly reduced the number of α-SMA positive cells.
“As shown in Fig. 2E, OCA treatment significantly reduced the number of α-SMA positive cells, suggesting that OCA could attenuate activation of HSCs.”
Quote in the paperSubstantial claim - Findingown data
Serum bile acid levels were significantly higher in fibrotic and cirrhotic patients than in healthy controls.
“Notably, serum BA levels were significantly higher in fibrotic and cirrhotic patients than that in healthy controls (Fig. 6A).”
Quote in the paperSubstantial claim - Findingown data
OCA administration significantly reduced mRNA levels of Acta2, Col1a1, Col1a2, Timp-1, Timp-2 in CCl4-treated mice.
“Consistently, quantitative RT-PCT analysis of Acta2 (encoding α-SMA), collagen1a1 (Col1a1), Col1a2, tissue inhibitor of metalloprotease-1 (Timp-1) and Timp-2 mRNAs showed a 5- to 20-fold increase in CCl4-treated mice, while OCA administration significantly reduced the mRNA levels of all these fibrosis markers (Fig. 2F).”
Quote in the paperSubstantial claim - Findingown data
CDCA was significantly increased in fibrotic and cirrhotic patients compared with healthy controls.
“In particular, CDCA were significantly increased in fibrotic and cirrhotic patients compared with healthy controls (Fig. 6B).”
Quote in the paperSubstantial claim - Findingown data
CDCA and CA were significantly decreased upon OCA treatment.
“In particular, CDCA and CA were significantly decreased upon OCA treatment (Fig. 1C).”
Quote in the paperSubstantial claim - Findingown data
OCA alone did not attenuate the percentage of TUNEL-positive staining.
“As expected, IDN-6556, but not OCA alone, attenuated the percentage of TUNEL-positive staining (Fig. 5F) and reduced the activities of caspases (Fig. 5H).”
Quote in the paperSubstantial claim - Findingreasoning
Combination of OCA and IDN-6556 exerted an improved protective effect against CCl4-induced fibrosis.
“Taken together, combination of OCA and IDN-6556 exerted an improved protective effect against CCl4-induced fibrosis.”
Quote in the paperSubstantial claim - Findingcitation
Liver fibrosis is characterized by accumulation of bile acids.
“In accordance with previous studies18., 19., we have uncovered that liver fibrosis is characterized with accumulation of BAs.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites 18., 19.
Not checked in the free run.
- Findingown data
Combination of OCA and IDN-6556 exhibited enhanced reduction in serum ALT levels.
“OCA or IDN-6556 alone reduced serum ALT levels, and the combination exhibited an enhanced reduction.”
Quote in the paperSubstantial claim - Findingown data
Serum total BAs were significantly elevated in CCl4-treated mice.
“As expected, serum total levels of BAs were significantly elevated in CCl4-treated mice, which were significantly reduced by OCA treatment (Fig. 1E).”
Quote in the paperSubstantial claim - Findingown data
Serum total BAs were significantly reduced by OCA treatment in CCl4-treated mice.
“As expected, serum total levels of BAs were significantly elevated in CCl4-treated mice, which were significantly reduced by OCA treatment (Fig. 1E).”
Quote in the paperSubstantial claim - Findingown data
Pretreatment with OCA did not significantly impact apoptotic/necrotic cell death in GalN/LPS-treated mice.
“Pretreatment with OCA did not significantly impact serum transferases levels (Fig. 3C) and apoptotic/necrotic cell death as indicated by caspase activities (Fig. 3D) and histological analysis (Fig. 3E and F).”
Quote in the paperSubstantial claim - Findingown data
IDN-6556 attenuated the percentage of TUNEL-positive staining.
“As expected, IDN-6556, but not OCA alone, attenuated the percentage of TUNEL-positive staining (Fig. 5F) and reduced the activities of caspases (Fig. 5H).”
Quote in the paperSubstantial claim - Findingown data
IDN-6556 reduced the activities of caspases.
“As expected, IDN-6556, but not OCA alone, attenuated the percentage of TUNEL-positive staining (Fig. 5F) and reduced the activities of caspases (Fig. 5H).”
Quote in the paperSubstantial claim - Findingown data
Almost all these BAs levels were reduced by OCA treatment.
“Detailed BA composition analysis revealed that multiple BAs, including lithocholic acid, ursodeoxycholic acid, hyodeoxycholic acid, CDCA, deoxycholic acid, CA, β-muricholic acid, and α-muricholic acid, increased in CCl4-treated mice, and almost all these BAs levels were reduced by OCA treatment (Fig. 1F).”
Quote in the paperSubstantial claim - Findingown data
OCA treatment had little influence on AST in CCl4-treated mice.
“OCA treatment significant reduced ALT levels but had little influence on AST, indicating that OCA might have limited effects on restoring liver function (Fig. 2A).”
Quote in the paperNot a substantial claim - Findingown data
OCA treatment significantly reduced ALT levels in CCl4-treated mice.
“OCA treatment significant reduced ALT levels but had little influence on AST, indicating that OCA might have limited effects on restoring liver function (Fig. 2A).”
Quote in the paperSubstantial claim - Findingown data
The area of liver parenchyma occupied with fibrotic tissues was reduced by OCA treatment.
“The area of liver parenchyma occupied with fibrotic tissues was reduced by OCA treatment.”
Quote in the paperSubstantial claim - Findingown data
HSCs express FXR at relatively low levels compared to hepatocytes.
“The principal cell type responsible for liver fibrosis is HSCs26., 28., which express FXR at a relative low levels compared to hepatocytes (Supporting Information Fig. S1A).”
Quote in the paperNot a substantial claim - Findingown data
IDN-6556 alone reduced serum ALT levels.
“OCA or IDN-6556 alone reduced serum ALT levels, and the combination exhibited an enhanced reduction.”
Quote in the paperNot a substantial claim - Findingown data
OCA treatment had little effect on hepatocyte apoptosis in the CCl4-induced liver fibrosis model.
“In the CCl4-induced model of liver fibrosis, TUNEL-positive apoptotic hepatocytes were witnessed, and surprisingly OCA treatment had little effect in hepatocytes apoptosis (Fig. 3A).”
Quote in the paperSubstantial claim - Findingown data
Serum total BA levels were significantly reduced upon OCA treatment in healthy mice.
“Besides, serum total levels of BAs were significantly reduced upon OCA treatment (Fig. 1B).”
Quote in the paperSubstantial claim - Findingnone given
OCA is not effective against hepatocellular apoptosis.
“As a FXR agonist, OCA may inhibit HSCs activation via regulating BAs homeostasis; however, OCA is not effective against hepatocellular apoptosis and thus may limiting its clinical efficacy against liver fibrosis.”
Quote in the paperSubstantial claim - Findingown data
CDCA significantly up-regulated mRNA levels of Tgf-β, Col1a1, Col1a2, Timp-1 in HSC-T6 cells.
“As shown in Fig. 4A, CDCA significantly up-regulated the mRNA levels of Tgf-β, Col1a1, Col1a2, and Timp-1, indicating that BAs indeed could stimulate HSC activation.”
Quote in the paperSubstantial claim - Findingown data
IDN-6556 alone protected against liver fibrosis development as shown by histological analysis.
“OCA or IDN-6556 alone protected against liver fibrosis development as shown by histological analysis (Fig. 5B–D), while co-administration of these two agents produced an enhanced protective effect.”
Quote in the paperSubstantial claim - Findingown data
No difference was observed in activities of caspase-3, -8, -9 in mice treated with CCl4 alone or in combination with OCA.
“As a support, no difference was observed in the activities of caspase-3, -8, and -9, in mice treated with CCl4 alone or in combination with OCA (Fig. 3B).”
Quote in the paperSubstantial claim - Findingown data
Pretreatment with OCA did not significantly impact serum transferases levels in GalN/LPS-treated mice.
“Pretreatment with OCA did not significantly impact serum transferases levels (Fig. 3C) and apoptotic/necrotic cell death as indicated by caspase activities (Fig. 3D) and histological analysis (Fig. 3E and F).”
Quote in the paperSubstantial claim - Findingown data
Combination exhibited better effect in inhibiting HSCs activation, as indicated by α-SMA staining.
“Consistently, the combination exhibited better effect in inhibiting HSCs activation, as indicated by α-SMA staining (Fig. 5E), and much stronger effect in reducing liver expression of a number of genes involved in liver fibrosis development, including Acta2, Col1a1, Col1a2, Timp-1 and Timp-2 (Fig. 5G).”
Quote in the paperSubstantial claim - Findingown data
Serum CK-18 was significantly higher in fibrosis and cirrhosis patients.
“Additionally, serum CK-18, an apoptotic marker, was significantly higher in fibrosis and cirrhosis patients (Fig. 6D).”
Quote in the paperSubstantial claim - Findingown data
TUNEL staining of liver biopsy indicated apparent apoptotic cell death in liver sections from both fibrosis and cirrhosis patients.
“TUNEL staining of liver biopsy indicated apparent apoptotic cell death in liver sections from both fibrosis and cirrhosis patients (Fig. 6C).”
Quote in the paperSubstantial claim - Findingnone given
Hepatocytes express abundant FXR compared to HSCs.
“More importantly, hepatocytes are highly expressed with abundant FXR compared to HSCs.”
Quote in the paperNot a substantial claim - Findingown data
OCA inhibits HSC activation/proliferation partially by regulating bile acid homeostasis.
“In this study, we demonstrated that OCA inhibits HSCs activation/proliferation partially by regulating BA homeostasis and thereby inhibiting activation of HSCs.”
Quote in the paperSubstantial claim- Rests on an assumption: HSC activation and proliferation are key events in the development of liver fibrosis.
- Rests on an assumption: Bile acids are biosynthesized from cholesterol in hepatocytes, which is precisely regulated by FXR-CYP7A1 signal.
- Findingown data
OCA has no significant effect against death receptor-engaged apoptosis of hepatocytes.
“However, we have not observed a significant effect of OCA against death receptors engaged apoptosis of hepatocytes, which is a dominant mechanism in promoting liver fibrosis.”
Quote in the paperSubstantial claim - Findingown data
OCA treatment inhibits Kupffer cell activation and cytokine transcription caused by CCl4 injection.
“In line with these findings, we further confirmed that OCA treatment could inhibit KC activation and cytokines transcription caused by CCl4 injection (Supporting Information Fig. S2).”
Quote in the paperSubstantial claim - Findingown data
In combination with IDN-6556, OCA exerts enhanced beneficial effect against fibrosis even at low dosage.
“In this study, we demonstrated that in combination with IDN-6556, another drug candidate for liver fibrosis, OCA could exert enhanced beneficial effect against fibrosis even at low dosage, providing a promising strategy for the therapy of liver fibrosis, and in the combination, OCA can be effective at low dosage with minimized side-effect.”
Quote in the paperSubstantial claim - Interpretationnone given
Hepatocyte apoptosis triggered the activation and proliferation of HSCs.
“Elevated bile acid (BA) levels and hepatocyte apoptosis triggered the activation and proliferation of HSCs.”
Quote in the paperSubstantial claim - Interpretationreasoning
OCA inhibits HSC activation/proliferation partially by regulating BA homeostasis.
“Our study demonstrated that OCA inhibits HSCs activation/proliferation partially by regulating BA homeostasis and thereby inhibiting activation of HSCs.”
Quote in the paperSubstantial claim - Interpretationown data
Combined use of apoptosis inhibitor and OCA at lower dosage represents a novel therapeutic strategy for liver fibrosis.
“The findings in this study suggest that combined use of apoptosis inhibitor and OCA at lower dosage represents a novel therapeutic strategy for liver fibrosis.”
- Also stated in: § Conclusions · hedged
“The findings in this study suggest that combined use of apoptosis inhibitor and OCA at lower dosage represents a novel therapeutic strategy for liver fibrosis.”
Quote in the paperSubstantial claim- Rests on an assumption: Anti-apoptosis is a valid strategy for the therapy of liver fibrosis.
- Rests on an assumption: HSC activation and proliferation are key events in the development of liver fibrosis.
- Rests on an assumption: Liver fibrosis and cirrhosis are generally regarded to be irreversible.
- Rests on an assumption: Inhibition of apoptosis is generally accepted as a promising therapeutic strategy to prevent liver fibrosis.
- Also stated in: § Conclusions · hedged
- Premisecitation
The high incidence side-effect of pruritus seen in clinical trials especially at 25 or 50 mg limited OCA's wide use in patients.
“However, the high incidence side-effect of pruritus seen in clinical trials especially at 25 or 50 mg10 limited its wide use in patients.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [10] Hirschfield, 2015, Efficacy of obeticholic acid in patients with primary biliary cirrhosis and inadequate response to ursodeoxycholic acid, Gastroenterology source
Not checked in the free run.
- Interpretationnone given
Elevated bile acid (BA) levels triggered the activation and proliferation of HSCs.
“Elevated bile acid (BA) levels and hepatocyte apoptosis triggered the activation and proliferation of HSCs.”
Quote in the paperSubstantial claim - Interpretationown data
BA accumulation is a key event in the pathological development of liver fibrosis/cirrhosis.
“Together, these results support that BA accumulation and apoptotic cell death are key events in the pathological development of liver fibrosis/cirrhosis.”
Quote in the paperSubstantial claim- Rests on an assumption: HSC activation and proliferation are key events in the development of liver fibrosis.
- Interpretationown data
Apoptotic cell death is a key event in the pathological development of liver fibrosis/cirrhosis.
“Together, these results support that BA accumulation and apoptotic cell death are key events in the pathological development of liver fibrosis/cirrhosis.”
Quote in the paperSubstantial claim- Rests on an assumption: HSC activation and proliferation are key events in the development of liver fibrosis.
- Interpretationreasoning
OCA's ineffectiveness against hepatocellular apoptosis may limit its clinical efficacy against liver fibrosis.
“As a FXR agonist, OCA may inhibit HSCs activation via regulating BAs homeostasis; however, OCA is not effective against hepatocellular apoptosis and thus may limiting its clinical efficacy against liver fibrosis.”
Quote in the paperSubstantial claim - Premisecitation
Hepatocyte apoptotic body may serve as a danger signal for activation of HSCs and thereby contributing to development of liver fibrosis.
“Hepatocyte apoptotic body may serve as a danger signal for the activation of HSCs and thereby contributing to the ultimate development of liver fibrosis20.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [20] Wang, 2018, Noncanonical farnesoid X receptor signaling inhibits apoptosis and impedes liver fibrosis, EBioMedicine source
Not checked in the free run.
- Premisecitation
Compared to hepatocytes, HSCs express very low levels of FXR.
“However, subsequent studies indicated that compared to hepatocytes, HSCs expressed very low levels of FXR14”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [14] Fickert, 2009, Farnesoid X receptor critically determines the fibrotic response in mice but is expressed to a low extent in human hepatic stellate cells and periductal myofibroblasts, Am J Pathol source
Not checked in the free run.
- Interpretationown data
Apoptotic hepatocytes may trigger HSC activation.
“As compared with the HSC-T6 cells co-cultured with healthy HepG2 cells, HSC-T6 cells co-cultured with apoptotic HepG2 cells were characterized with elevated mRNA levels of Acta2, Col1a1, Col1a2, Timp-1 and Timp-2, indicating that apoptotic hepatocytes may trigger HSC activation (Fig. 4B).”
Quote in the paperSubstantial claim - Interpretationreasoning
Combination of OCA and an apoptosis inhibitor might be a promising strategy for combating liver fibrosis.
“We thereby propose and validate that the combination of OCA and an apoptosis inhibitor might be a promising strategy for combating liver fibrosis.”
Quote in the paperSubstantial claim- Rests on an assumption: HSC activation and proliferation are key events in the development of liver fibrosis.
- Rests on an assumption: Liver fibrosis and cirrhosis are generally regarded to be irreversible.
- Rests on an assumption: Inhibition of apoptosis is generally accepted as a promising therapeutic strategy to prevent liver fibrosis.
- Interpretationown data
Accumulated BAs and apoptotic hepatocytes may serve as potential profibrogenic factors that stimulate activation and proliferation of HSCs and ultimately promote development of liver fibrosis.
“Taken together, these results indicated that the accumulated BAs and apoptotic hepatocytes may serve as potential profibrogenic factors that stimulate activation and proliferation of HSCs and ultimately promote the development of liver fibrosis.”
Quote in the paperSubstantial claim - Interpretationown data
Hepatocellular apoptotic bodies are danger signals for HSC activation and proliferation.
“In the current study, we have identified that elevated BAs and hepatocellular apoptotic bodies are danger signals for HSC activation and proliferation.”
Quote in the paperSubstantial claim- Rests on an assumption: HSC activation and proliferation are key events in the development of liver fibrosis.
- Interpretationown data
OCA may restore bile acid homeostasis via targeting FXR.
“OCA via targeting FXR may restore the homeostasis of BAs and IDN-6556 functions via inhibiting apoptotic cell death of hepatocytes and thereby additively alleviates liver fibrosis.”
Quote in the paperSubstantial claim- Rests on an assumption: Bile acids are biosynthesized from cholesterol in hepatocytes, which is precisely regulated by FXR-CYP7A1 signal.
- Interpretationreasoning
OCA and IDN-6556 additively alleviate liver fibrosis.
“OCA via targeting FXR may restore the homeostasis of BAs and IDN-6556 functions via inhibiting apoptotic cell death of hepatocytes and thereby additively alleviates liver fibrosis.”
Quote in the paperSubstantial claim- Rests on an assumption: HSC activation and proliferation are key events in the development of liver fibrosis.
- Interpretationreasoning
OCA may inhibit HSC activation via regulating bile acid homeostasis.
“As a FXR agonist, OCA may inhibit HSCs activation via regulating BAs homeostasis; however, OCA is not effective against hepatocellular apoptosis and thus may limiting its clinical efficacy against liver fibrosis.”
Quote in the paperSubstantial claim- Rests on an assumption: HSC activation and proliferation are key events in the development of liver fibrosis.
- Rests on an assumption: Bile acids are biosynthesized from cholesterol in hepatocytes, which is precisely regulated by FXR-CYP7A1 signal.
- Interpretationown data
BAs could stimulate HSC activation.
“As shown in Fig. 4A, CDCA significantly up-regulated the mRNA levels of Tgf-β, Col1a1, Col1a2, and Timp-1, indicating that BAs indeed could stimulate HSC activation.”
Quote in the paperSubstantial claim - Interpretationreasoning
IDN-6556 functions via inhibiting apoptotic cell death of hepatocytes.
“OCA via targeting FXR may restore the homeostasis of BAs and IDN-6556 functions via inhibiting apoptotic cell death of hepatocytes and thereby additively alleviates liver fibrosis.”
Quote in the paperSubstantial claim - Premisecitation
The principal cell type responsible for liver fibrosis is HSCs.
“The principal cell type responsible for liver fibrosis is HSCs26., 28., which express FXR at a relative low levels compared to hepatocytes (Supporting Information Fig. S1A).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites 26., 28.
Not checked in the free run.
- Premisecitation
Enhanced hepatocyte apoptosis is a common feature of liver fibrosis.
“Moreover, enhanced hepatocyte apoptosis is the common feature of liver fibrosis20.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [20] Wang, 2018, Noncanonical farnesoid X receptor signaling inhibits apoptosis and impedes liver fibrosis, EBioMedicine source
Not checked in the free run.
- Interpretationown data
CDCA-induced Tgf-β and Smad2/3 phosphorylation triggers transcription of several pro-fibrotic genes.
“We demonstrated that CDCA but not CA could induce the expression of Tgf-β and promote the phosphorylation of Smad2/3 (Fig. S1B), then triggering the transcription of several pro-fibrotic genes.”
Quote in the paperSubstantial claim - Interpretationown data
Elevated bile acids are danger signals for HSC activation and proliferation.
“In the current study, we have identified that elevated BAs and hepatocellular apoptotic bodies are danger signals for HSC activation and proliferation.”
Quote in the paperSubstantial claim- Rests on an assumption: HSC activation and proliferation are key events in the development of liver fibrosis.
- Interpretationown data
OCA treatment might alleviate liver fibrosis partially via inhibiting HSCs activation.
“These results indicated that OCA treatment might alleviate liver fibrosis partially via inhibiting HSCs activation.”
Quote in the paperSubstantial claim - Interpretationown data
The combination of OCA and IDN-6556 provides a promising strategy for therapy of liver fibrosis.
“In this study, we demonstrated that in combination with IDN-6556, another drug candidate for liver fibrosis, OCA could exert enhanced beneficial effect against fibrosis even at low dosage, providing a promising strategy for the therapy of liver fibrosis, and in the combination, OCA can be effective at low dosage with minimized side-effect.”
Quote in the paperSubstantial claim- Rests on an assumption: HSC activation and proliferation are key events in the development of liver fibrosis.
- Rests on an assumption: Liver fibrosis and cirrhosis are generally regarded to be irreversible.
- Rests on an assumption: Inhibition of apoptosis is generally accepted as a promising therapeutic strategy to prevent liver fibrosis.
- Premisecitation
CCl4 intoxication for up to 12 weeks results in more severe liver injury in FXR knockout mice compared with wild-type controls.
“Besides, CCl4-intoxication for up to 12 weeks resulted in more severe liver injury in FXR knock-out mice compared with wild-type controls14.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [14] Fickert, 2009, Farnesoid X receptor critically determines the fibrotic response in mice but is expressed to a low extent in human hepatic stellate cells and periductal myofibroblasts, Am J Pathol source
Not checked in the free run.
- Premisecitation
OCA's clinical application might be limited by serious adverse effects such as pruritus.
“Although various preclinical studies suggested OCA might be effective against liver fibrosis, its clinical application might be limited by the observed serious adverse effects such as pruritus10.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [10] Hirschfield, 2015, Efficacy of obeticholic acid in patients with primary biliary cirrhosis and inadequate response to ursodeoxycholic acid, Gastroenterology source
Not checked in the free run.
- Interpretationcitation
Other cells in the liver may also contribute to the anti-fibrotic effect of FXR activation.
“Since HSCs are subsequently demonstrated to express relative low level of FXR14, other cells in the liver may also contribute to the anti-fibrotic effect of FXR activation.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [14] Fickert, 2009, Farnesoid X receptor critically determines the fibrotic response in mice but is expressed to a low extent in human hepatic stellate cells and periductal myofibroblasts, Am J Pathol source
Not checked in the free run.
- Interpretationcitation
FXR agonism has a direct inhibitory role on HSC activation and proliferation.
“These studies provided evidence for the direct inhibitory role of FXR agonism on HSC activation and proliferation.”
Quote in the paperSubstantial claim- Rests on an assumption: HSC activation and proliferation are key events in the development of liver fibrosis.
- Premisecitation
FXR activation in HSCs causes SHP-dependent inhibition of pro-fibrotic gene expression.
“Besides, FXR activation in HSCs was also demonstrated to cause a SHP-dependent inhibition on pro-fibrotic gene expression13.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [13] Fiorucci, 2005, A farnesoid X receptor-small heterodimer partner regulatory cascade modulates tissue metalloproteinase inhibitor-1 and matrix metalloprotease expression in hepatic stellate cells and promotes resolution of liver fibrosis, J Pharmacol Exp Ther source
Not checked in the free run.
- Interpretationreasoning
Bile acids accumulated in the liver may serve as a potential profibrogenic factor for fibrosis development.
“These evidence indicated that BAs accumulated in the liver may serve as potential profibrogenic factor for fibrosis development.”
Quote in the paperSubstantial claim- Rests on an assumption: HSC activation and proliferation are key events in the development of liver fibrosis.
- Premisecitation
Low dose (5-10 mg) OCA exerts little beneficial effect on liver fibrosis.
“However, a more recent clinical trial indicated that low dose (5–10 mg) of OCA exert little beneficial effect on liver fibrosis11.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [11] Nevens, 2016, A placebo-controlled trial of obeticholic acid in primary biliary cholangitis, N Engl J Med source
Not checked in the free run.
- Premisecitation
Increased apoptotic cell death of hepatocytes is a hallmark of liver fibrosis.
“Another hallmark of liver fibrosis is increased apoptotic cell death of hepatocytes20.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [20] Wang, 2018, Noncanonical farnesoid X receptor signaling inhibits apoptosis and impedes liver fibrosis, EBioMedicine source
Not checked in the free run.
- Interpretationreasoning
OCA in combination with apoptosis inhibitors would be a translatable strategy for therapy of liver fibrosis.
“Therefore, it is reasonable to expect that OCA in combination with apoptosis inhibitors would be a translatable strategy for the therapy of liver fibrosis.”
Quote in the paperSubstantial claim- Rests on an assumption: Liver fibrosis and cirrhosis are generally regarded to be irreversible.
- Rests on an assumption: Inhibition of apoptosis is generally accepted as a promising therapeutic strategy to prevent liver fibrosis.
- Premisecitation
Inhibition of apoptosis by pro-apoptotic gene knockout or caspase inhibitors alleviates liver diseases.
“Furthermore, inhibition of apoptosis by pro-apoptotic gene knock-out29., 30. or caspase inhibitors31., 32. alleviate liver diseases.”
Quote in the paperSubstantial claim0 of 2 sources checked- cites 29., 30.
Not checked in the free run.
- cites 31., 32.
Not checked in the free run.
- Premisecitation
The rate of pruritus is positively correlated with OCA dosage (15% at 10 mg vs 38% at 50 mg).
“The rate of this adverse side-effect was found positively correlated with the dosage of OCA (15% in 10 mg vs. 38% in 50 mg)40.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [40] Thomas, 2016, Therapy: obeticholic acid for PBC, Nat Rev Gastroenterol Hepatol source
Not checked in the free run.
- Interpretationnone given
Hepatocyte apoptosis plays a key role in HSC activation and proliferation.
“Hepatocyte apoptosis also play a key role in HSC activation and proliferation.”
Quote in the paperNot a substantial claim- Rests on an assumption: HSC activation and proliferation are key events in the development of liver fibrosis.
- May combine two claims. 19
- Classified as probably not a substantial claim. 15
May combine two claims.
Findingown dataOCA treatment upregulated hepatic Shp and Bsep mRNA and downregulated Cyp7a1 in healthy mice.
“As expected, the mRNA levels of hepatic small heterodimer partner (Shp) and bile salt export pump (Bsep) were upregulated by OCA treatment. By contrast, hepatic Cyp7a1 (encoding cholesterol 7α-hydroxylase), a suppressive target gene of Fxr, was downregulated (Fig. 1A).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataOCA treatment up-regulated Fxr, Shp, Bsep and down-regulated Cyp7a1 in CCl4-treated mice.
“While treatment with OCA significantly up-regulated the expression of Fxr, Shp, Bsep, and down-regulated the expression of Cyp7a1 (Fig. 1D).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataCDCA but not CA induces expression of Tgf-β and promotes phosphorylation of Smad2/3.
“We demonstrated that CDCA but not CA could induce the expression of Tgf-β and promote the phosphorylation of Smad2/3 (Fig. S1B), then triggering the transcription of several pro-fibrotic genes.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataIn CCl4-treated mice, hepatic FXR signal was suppressed, with decreased Fxr, Shp, Bsep and elevated Cyp7a1.
“Upon CCl4 intoxication, hepatic FXR signal was significantly suppressed as supported by decreased expression of Fxr, Shp, Bsep and elevated expression of Cyp7a1.”
Quote in the paperSubstantial claimMay combine two claims.
Findingnone givenBoth CDCA and CA promote proliferation of HSCs.
“Besides, both CDCA and CA can promote proliferation of HSC.”
Quote in the paperNot a substantial claimMay combine two claims.
FindingreasoningOCA treatment significantly inhibited synthesis of bile acids, reducing exposure of HSCs to toxic bile acids.
“As expected, OCA treatment significantly inhibited the synthesis of BAs, reducing the exposure of HSCs to toxic BAs.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataBoth BA accumulation and apoptotic death of hepatocytes were observed in human patients with liver fibrosis.
“To provide a translational link to the clinic, we found that both BA accumulation and apoptotic death of hepatocytes were witnessed from human patients with liver fibrosis.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataIDN-6556 treatment prevented hepatocyte apoptosis and reduced fibrosis induced by CCl4.
“Here in this study we revealed that treatment with IDN-6556, prevented hepatocyte apoptosis and reduced fibrosis induced by CCl4.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
PremisecitationFXR is beneficial for various liver diseases.
“Farnesoid X receptor (FXR, NR1H4), a bile acid (BA)-responsive transcription factor1., 2., has been demonstrated to be beneficial for various liver diseases3., 4..”
Quote in the paperSubstantial claim0 of 1 sources checked- cites 3., 4.
Not checked in the free run.
Probably not a substantial claim: may not pass S2 (checkable).
PremisecitationFXR is widely accepted as a promising therapeutic target.
“Thus FXR is widely accepted as a promising therapeutic target5”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [5] Ding, 2015, Bile acid nuclear receptor FXR and digestive system diseases, Acta Pharm Sin B source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenAnimal studies were approved by the Animal Ethics Committee of China Pharmaceutical University.
“The animal studies were approved by the Animal Ethics Committee of China Pharmaceutical University.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductown dataMice were randomly divided into treatment groups in the experiments.
“mice were randomly divided into 3 groups and treated with vehicle or OCA at 10 mg/kg/day or 30 mg/kg/day, respectively, for 5 days.”
Quote in the paperNot a substantial claimMay combine two claims.
Interpretationown dataOCA treatment has little influence on hepatocyte apoptosis, which may explain its limited effects in liver fibrosis at lower dosage.
“Collectively, these results indicate that OCA treatment has little influence on hepatocyte apoptosis, which may explain its limited effects in liver fibrosis at lower dosage11.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [11] Nevens, 2016, A placebo-controlled trial of obeticholic acid in primary biliary cholangitis, N Engl J Med source
Not checked in the free run.
Classified as probably not a substantial claim.
Study design and conductnone givenDiagnoses of liver fibrosis and cirrhosis were confirmed with liver biopsy directed by ultrasonography within 1 week after inclusion.
“Diagnoses were confirmed with liver biopsy directed by ultrasonography within 1 week after inclusion.”
Quote in the paperSubstantial claimMay combine two claims.
Study design and conductown dataThe fibrosis and cirrhosis patient groups did not differ significantly in gender or body mass index.
“A univariate analysis revealed that the two groups did not differ significantly in gender nor body mass index (Table S3).”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationSerum BAs are increased during liver fibrosis progression and may represent biomarkers for staging the severity of liver fibrosis and cirrhosis.
“More importantly, serum BAs are increased during liver fibrosis progression and may represent as biomarkers for staging the severity of liver fibrosis and cirrhosis18., 19..”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites 18., 19.
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductnone givenThe human study was approved by the ethics committee of First Affiliated Hospital of Anhui Medical University and all patients gave written informed consent.
“The study was approved by the ethics committee of First Affiliated Hospital of Anhui Medical University (PJ2016-10-11) and all patients gave written informed consent prior to participation.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
PremisecitationOCA could prevent the development of fibrosis and cirrhosis by inhibiting HSCs activation.
“Previous studies have shown that OCA could prevent the development of fibrosis and cirrhosis by inhibiting hepatic stellate cells (HSCs) activation12., 13..”
Quote in the paperSubstantial claim0 of 1 sources checked- cites 12., 13.
Not checked in the free run.
May combine two claims.
PremisecitationLower dose regimes (5-10 mg) address pruritus but clinical efficiency against fibrosis almost disappeared at this dosage.
“Although this side effect appears to be addressed by the use of lower dose regimes (5–10 mg), its clinical efficiency against fibrosis almost disappeared at this dosage11.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [11] Nevens, 2016, A placebo-controlled trial of obeticholic acid in primary biliary cholangitis, N Engl J Med source
Not checked in the free run.
May combine two claims.
PremisecitationFXR activation leads to up-regulation of microRNA-29a in HSCs, which inhibits ECM production.
“Early studies indicated that FXR activation led to up-regulation of microRNA-29a in HSCs, which plays an inhibitory role in ECM production35.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [35] Li, 2011, Roles of microRNA-29a in the antifibrotic effect of farnesoid X receptor in hepatic stellate cells, Mol Pharmacol source
Not checked in the free run.
Classified as probably not a substantial claim. May combine two claims.
PremisecitationFXR activation protects liver cells from apoptosis induced by serum deprivation in vitro and fasting in vivo.
“FXR activation was previously reported to protect liver cells from apoptosis induced by serum deprivation in vitro and fasting in vivo38.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [38] Wang, 2008, Farnesoid X receptor protects liver cells from apoptosis induced by serum deprivation in vitro and fasting in vivo, Mol Endocrinol source
Not checked in the free run.
Classified as probably not a substantial claim. May combine two claims.
PremisecitationFXR is a member of the nuclear receptor superfamily and has a crucial role in controlling bile acid homeostasis.
“FXR is a member of nuclear receptor superfamily and has crucial role in controlling BA homeostasis1., 4..”
Quote in the paperSubstantial claim0 of 1 sources checked- cites 1., 4.
Not checked in the free run.
Probably not a substantial claim: may not pass S4 (based).
InterpretationreasoningHepatocytes may regulate activation of HSCs via secretion of bile acids and apoptotic bodies.
“Since hepatocytes may regulate the activation of HSCs via secretion of BAs and apoptotic bodies, we supposed that FXR ligands may also impede HSCs activation indirectly via targeting FXR in hepatocytes.”
Quote in the paperNot a substantial claim- Rests on an assumption: HSC activation and proliferation are key events in the development of liver fibrosis.
Classified as probably not a substantial claim.
InterpretationreasoningFXR ligands may impede HSC activation indirectly via targeting FXR in hepatocytes.
“Since hepatocytes may regulate the activation of HSCs via secretion of BAs and apoptotic bodies, we supposed that FXR ligands may also impede HSCs activation indirectly via targeting FXR in hepatocytes.”
Quote in the paperSubstantial claim- Rests on an assumption: HSC activation and proliferation are key events in the development of liver fibrosis.
May combine two claims.
InterpretationreasoningIn the combination, OCA can be effective at low dosage with minimized side-effect.
“In this study, we demonstrated that in combination with IDN-6556, another drug candidate for liver fibrosis, OCA could exert enhanced beneficial effect against fibrosis even at low dosage, providing a promising strategy for the therapy of liver fibrosis, and in the combination, OCA can be effective at low dosage with minimized side-effect.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationIDN-6556 is a pan-caspase inhibitor currently undergoing phase II clinical studies.
“The proof of concept of this strategy is illustrated by IDN-6556, a pan-caspase inhibitor currently undergoing phase II clinical studies39.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [39] Baskin-Bey, 2007, Clinical trial of the pan-caspase inhibitor, IDN-6556, in human liver preservation injury, Am J Transplant source
Not checked in the free run.
May combine two claims.
InterpretationreasoningFXR activation by agonists might be effective against intrinsic apoptosis but not death receptor-engaged extrinsic apoptosis.
“It seems that FXR activation by agonists might be effective against intrinsic apoptosis, as that induced by fast, but not death-receptors engaged extrinsic apoptosis.”
Quote in the paperSubstantial claim- Rests on an assumption: Death receptor-engaged apoptosis is a dominant mechanism in promoting liver fibrosis.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationFXR activation by OCA decelerates thioacetamide-induced fibrogenesis indirectly by targeting hepatic inflammation in both Kupffer cells and liver sinusoidal endothelial cells.
“Previously, FXR activation by OCA was demonstrated to decelerate thioacetamide-induced fibrogenesis indirectly by targeting hepatic inflammation in both KC and liver sinusoidal endothelial cells37.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [37] Verbeke, 2016, FXR agonist obeticholic acid reduces hepatic inflammation and fibrosis in a rat model of toxic cirrhosis, Sci Rep source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationHSCs can be activated by stimulated Kupffer cells via paracrine production of pro-inflammatory cytokines.
“HSC could be activated by stimulated Kupffer cells (KC) via paracrine production of pro-inflammatory cytokines36.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [36] Mishra, 2016, Immunotherapy in liver diseases: a balance between immunity and tolerance, Curr Drug Metab source
Not checked in the free run.
The paper relies on this without support.
Anti-apoptosis is a valid strategy for the therapy of liver fibrosis.
“Therefore, anti-apoptosis has been supposed to be a strategy for the therapy of liver fibrosis.”
The paper relies on this without support.
HSC activation and proliferation are key events in the development of liver fibrosis.
“HSCs activation and proliferation are key events in the development of liver fibrosis.”
The paper relies on this without support.
Liver fibrosis and cirrhosis are generally regarded to be irreversible.
“Since liver fibrosis and cirrhosis are generally regarded to be irreversible, one of the most effective strategies for fibrosis prevention or treatment is to inhibit the activation and proliferation of HSCs.”
The paper relies on this without support.
Death receptor-engaged apoptosis is a dominant mechanism in promoting liver fibrosis.
“However, we have not observed a significant effect of OCA against death receptors engaged apoptosis of hepatocytes, which is a dominant mechanism in promoting liver fibrosis.”
The paper relies on this without support.
Bile acids are biosynthesized from cholesterol in hepatocytes, which is precisely regulated by FXR-CYP7A1 signal.
“BAs are biosynthesized from cholesterol in hepatocytes, which is precisely regulated by FXR-CYP7A1 signal.”
The paper relies on this without support.
Inhibition of apoptosis is generally accepted as a promising therapeutic strategy to prevent liver fibrosis.
“Inhibition of apoptosis is generally accepted as a promising therapeutic strategy to prevent liver fibrosis.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Various FXR agonists have shown anti-fibrotic effects in diverse preclinical animal models.
“Although various FXR agonists have shown anti-fibrotic effects in diverse preclinical animal models, the response rate and efficacies in clinical trials were not optimum.”
From SUMOylation inhibitors synergize with FXR agonists in combating liver fibrosis (2020) · cites this paper as [39]
Activation of FXR in hepatocytes inhibits the biosynthesis of BAs, contributing in part to its anti-fibrotic activity.
“Activation of FXR in hepatocytes inhibits the biosynthesis of BAs, contributing in part to its anti-fibrotic activity39.”
From SUMOylation inhibitors synergize with FXR agonists in combating liver fibrosis (2020) · cites this paper as [39]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Patient samples are described as both plasma and serum
MinorThe methods say patients' blood samples were processed to plasma, but the results describe the patient samples used for bile-acid analysis as serum. These are different sample types.
“Blood samples were obtained from patients at the time of liver biopsy, processed to plasma and stored at –80 °C until use.”
“Serum from liver fibrotic patients (n = 20), cirrhotic patients (n = 30) as well as healthy donors (n = 20) were collected.”
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Intestinal FXR agonism synergizes with leptin to improve obesity by reducing appetite via secretin
Zhu, X., Wang, K., Hu, H., Guo, Y., Cui, S., Cui, M., Chen, A., Bai, J., Ma, Y., Gong, M., et al. (2026) · EMBO Reports · doi:10.1038/s44319-026-00938-7
Self-citation
- Authors
- Zhou, J., Huang, N., Guo, Y., Cui, S., Ge, C., He, Q., Pan, X., Wang, G., Wang, H., & Hao, H.
- Affiliations
- China Pharmaceutical University (CN)
- Corresponding author
- Wang, Guangji
- Wang, Hong
- Hao, Haiping
- ORCID
- Venue
- Acta Pharmaceutica Sinica B
- Publisher
- Elsevier BV
- Published
- 2019-05
- Volume
- 9
- Issue
- 3
- Pages
- 526-536
- ISSN
- 2211-3835 (ISSN-L)
- PMC
- PMC6542786
- OpenAlex
- W2903493113
- Cited by
- 99
- References
- 41
- Citations by year
- 2026: 6 · 2025: 14 · 2024: 22 · 2023: 21 · 2022: 19 · 2021: 7 · 2020: 10
- FWCI
- 2.66
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Acta Pharmaceutica Sinica B (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- China Postdoctoral Science Foundation (2016M600455, 2017T100423)
- State Key Laboratory of Natural Medicines (SKLNMZZCX201610, SKLNMZZCX201801)
- Overseas Expertise Introduction Project for Discipline Innovation (CPU2018GF01, CPU2018GF09, G20582017001)
- National Natural Science Foundation of China (81421005, 81430091, 81603194, 81720108032, 91429308)
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Health Sciences › Medicine › Hepatology › Liver Diseases and Immunity
- Keywords
- obeticholic acid, liver fibrosis, apoptosis inhibitor, IDN-6556, farnesoid X receptor, hepatic stellate cell activation, bile acid homeostasis, hepatocyte apoptosis, combination therapy, hepatotoxicity
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-06.
Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-06.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
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