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The role of glyzhirizin

in liver disease

Hery Djagat Purnomo


Sub Bagian Gastroentero-hepatologi Bagian Ilmu Penyakit Dalam
RSUP Dr Kariadi
Liver cirrhosis deaths from 1980 to 2010 by region.

Mokdad et al. BMC Medicine 2014, 12:145


Liver cirrhosis deaths by 1980 to 2010

Mokdad et al. BMC Medicine 2014, 12:145


Initiation and maintenance of fibrogenesis
The roles of herbs and phytochemicals in the progression of chronic liver disease
The role of
Glycyrrhizin in ACLF
Clinical trials using compound glycyrrhizic acid injection
Compound Pharmacological activity Mechanism of action
Regulating the expression of inflammation-
Glycyrrhizic acid Anti-inflammatory, antiviral, inhibition of hepatic related factors; inhibition replication of viral

fibrosis mRNA

Regulating the expression of inflammation-


Improving the liver dysfunction
related factors; promoting the growth of
Compound glycyrrhizin augmented the entire cytotoxic function mediated by
hepatocyte;
inhibition replication of viral
tablet hepatic lymphocytes. Inhibiting the cascade leading
mRNA
to apoptosis

Regulating the expression of inflammation-


related factors; inhibition replication of

Anti-inflammatory, Antiviral
Antiallergic , Anti viral;
inhibition of the expression of


Glycyrrhetinic acid
tumor proliferation sensitizing factors and tumor-associated
factor;

Regulating the expression of inflammation-


Mechanism of Glyzhirhizin Acid (GA) effects

Inhibition of hepatic apoptosis and necrosis

Anti-inflammation and immunity regulation

Anti-viral effect

Anti-tumor effects

Inductive effects of liver enzyme Activity


Inhibition of hepatic apoptosis and necrosis

► Glycyrrhizinameliorates ConA-induced liver inflammation


and fibrosis in mice.

► Glycyrrhizin inhibits the infiltration of CD4+T cells in


livers.

► Glycyrrhizin regulates CD4+T balance to a relative


dominance of Th1 and Treg.

► Glycyrrhizin regulates CD4+T response via JNK, ERK and


PI3K/AKT pathways
International Immunopharmacology, vol. 14, no. 4, pp. 410–421, 2012.
Glyzhirrhizin memperbaiki fibrosis Hati

Journal of ethnopharmacology 2016, August, P 83-90


Anti-inflammation and immunity regulation

Microbiol. Immunol., 44(9), 799-804, 2000

Glycyrrhizin inhibits the manifestations of anti-inflammatory responses that


appear in association with systemic inflammatory response syndrome (SIRS)-
like reactions,”

Cytokine, vol. 35, no. 5-6, pp. 295–301, 2006.


Anti-viral effects of GL

Dose dependent inhibition of GL against HCV 3a genotype.

Ashfaq et al. Journal of Translational Medicine 2011, 9:112


Synergy in the antiviral activity of GL along with interferon

Ashfaq et al. Journal of Translational Medicine 2011, 9:112


Synergy in the antiviral activity of GL along with interferon

Conclusion

This study suggest that GL inhibit HCV full length viral particles
and HCV core gene expression or function in a dose dependent
manner and had synergistic effect with interferon.

In future, GL along with interferon will be better option to treat HCV


infection

Ashfaq et al. Journal of Translational Medicine 2011, 9:112


Clinical and Translational Gastroenterology (2017) 8, e104
CONCLUSIONS:

glycyrrhizin can be safe and helpful for patie


Glyzhirrhizin in HCC
Anti-tumor effects
CYP enzymes are mainly found in the liver and
bowel wall.

They are responsible for the bulk of phase I or


oxidative metabolism of xenobiotics including
dietary toxins, carcinogens, mutagens, and drugs.

Administration of GA was able to significantly


induce CYP content, which reduces the incidence
of cancer
18b-Glycyrrhetinic acid inhibits hepatocellular carcinoma
development by reversing hepatic stellate cell-mediated
immunosuppression in mice

This study found GA could inhibit angiogenesis and Treg cells


expression in vivo, but we have no evidence to prove the anticancer effect
of GA is better than sorafenib or rapamycin.

Given the complexity of the interactions between tumor cells and their
environment, the effect of a combination therapy of GA, administered in
conjunction with sorafenib or rapamycin, is worthy for further study.

In summary, this study further supports the theory that HSCs have an
inhibitory effect on immune responses via their regulation of T cells in the
development of HCC.

This interaction identifies the therapeutic target for GA, which provides
convincing evidence for GA as an anticancer drug.

Int. J. Cancer: 132, 1831–1841 (2013)


Activated hepatic stellate cells (HSCs) are potential
therapeutic targets for hepatocellular carcinoma
(HCC), based on their role in immunosuppression
and tumor progression in mouse models.

Here, the compound 18b-glycyrrhetinic acid (GA)


was investigated for possible inhibitory effects on
HSCs. The compound was found to reduce HSC-
mediated immunosuppression in HCC tumor
microenvironment in mice. The findings indicate that
GA may be a useful adjunct for immune-based
HCC therapy.
As with CLD, HMGB1 ablation reduced the expression of progenitor and
oncofetal markers, a key determinant of HCC aggressiveness, in tumors.

In summary, HMGB1 links hepatocyte death to ductular reaction, progenitor


signature, and hepatocarcinogenesis in CLD.
Conclusions:

GL has a protective effect on ischemia-reperfusion


injury in rat brains through the inhibition of
inflammation, oxidative stress and apoptotic injury
by antagonising the cytokine activity of HMGB1.

Plos ONE , March 2014 | Volume 9 | Issue 3 | e89450


Inductive effects of liver enzyme Activity

Some studies showed that GA has an inductive effect on


CYP3A activity.

Therefore, clinicians should pay attention to other drugs


catalyzed by CYP3A, especially those substrates with a
narrow therapeutic range such as cyclosporine A, to avoid
possible clinically significant interactions with GA.

Some studies revealed that the area under concentration-


time curve and the mean retention time of methotrexate
(MTX) were significantly increased by GA, which increases
the adverse reactions of MTX
Drug metabolism Dispo 2018 ,46:1310-1319
GL’s active metabolite, GA, significantly reduces MCD-induced liver injury.

Drug metabolism Dispo 2018 ,46:1310-1319


GL significantly alleviates MCD diet- induced liver damage, improves TUNEL
staining, and reduces serum transaminases.
GL and its active metabolite GA have been demonstrated
to be hepatoprotective; however, they have not yet been
examined for their activities toward NASH.

This study shows that GL, via its activate metabolite GA,
could decrease MCD diet-induced NASH, as revealed by
improved hepatic steatosis, inflammation, and fibrosis.

Mechanistically, GL may restore NASH-induced


dysregulation of bile acids and lipids and the resultant
meta-inflammation
FIBROSIS DAN CIRRHOSIS REVERSIBLE

setelah terapi etiologi dan obat anti fibrosis


Kesimpulan
• Penyakit Hati kronis merupakan maslah kesehatan
yang penting.

• Pengobatan terbaik berbasis pada etiologi penyakit


hati kronis untuk mencapai curable disease

• Glyzhirrhizin (R/ SNMC) merupakan salah satu


/complementary alternative terapi yang potensial
bermanfaat pada beberapa penyakit hati kronis
sebagai anti inflamasi, anti-steatosis, anti viral , anti
fibrosis dan anti tumor.