Background:The effects of dietary garcinol on diarrhea and intestinal barrier function associated with its modulation of gut microbiota in weaned piglets were investigated.Method:One hundred forty four weaned piglets(...Background:The effects of dietary garcinol on diarrhea and intestinal barrier function associated with its modulation of gut microbiota in weaned piglets were investigated.Method:One hundred forty four weaned piglets(Duroc×Yorkshire×Landrace)from 16 pens(9 piglets per pen)were randomly divided into four treatment groups:controls(CON)or those supplemented with 200 mg/kg(LOW),400 mg/kg(MID),or 600 mg/kg(HIGH)diet garcinol.After 14-day trial,three piglets per pen were chosen to collect plasma,intestinal tissue and colonic digesta samples.Results:We demonstrated for the first time that garcinol promoted growth performance,as increased average daily feed intake(ADFI)and decreased feed/gain ratio(F/G);and reduced diarrhea incidence(P<0.05);and strengthened antioxidant capacity,as an increased antioxidative index(P<0.05).Additionally,garcinol ameliorated intestinal barrier dysfunction,as an increased villus height to crypt depth ratio,increased zonula occludens protein 1(ZO-1),occludin and claudin-1 expression in the jejunum and ileum(P<0.05),and decreased intestinal permeability(P<0.05);and reduced inflammation,as decreased cytokine interleukin(IL)-6,IL-10,IL-1βand tumor necrosis factor-α(TNF-α)levels in the mucosa of the jejunum and ileum,and NF-κB p65 translocation(P<0.05).Moreover,garcinol inhibited the growth of most harmful bacteria in the gut,especially Escherichia coli,and increased the growth of the beneficial bacteria Lactobacillus.Conclusion:This work provides a fundamental basis for the future development of garcinol-functional food use for improving diarrhea and intestinal barrier function in weaned piglets and for understanding the biological effects of garcinol and its potential as a functional feed additive.展开更多
OBJECTIVE Platinum compounds such as cisplatin and carboplatin are frequently used as the first-line chemotherapy for the treatment of the head and neck squamous cell carcinoma(HNSCC).In the present study,we investiga...OBJECTIVE Platinum compounds such as cisplatin and carboplatin are frequently used as the first-line chemotherapy for the treatment of the head and neck squamous cell carcinoma(HNSCC).In the present study,we investigated whether garcinol,apolyisoprenylated benzophenone can chemosensitize HNSCC to cisplatin.METHODS The effect of garcinol and cisplatin on HNSCC was assessed by MTT,Western blotting,real time PCR,FACS,immunohistochemistry,DNA binding assay and xenograft mouse model.RESULTS We found that garcinol inhibited the viability of a panel of diverse HNSCC cell lines,enhanced the apoptotic effect of cisplatin,suppressed constitutive as well as cisplatin-induced NF-κB activation,and downregulated the expression of various oncogenic gene products(cyclin D1,Bcl-2,survivin and VEGF).In vivo study showed that administration of garcinol alone(0.5 mg·kg-1,ip five times/week)significantly suppressed the growth of the tumor,and this effect was further increased by cisplatin.Both the markers of proliferation index(Ki-67)and microvessel density(CD31)were downregulated in tumor tissues by the combination of cisplatin and garcinol.The pharmacokinetic results of garcinol indicated that good systemic exposure was achievable after ip administration of garcinol at 0.5and 2mg·kg-1 with mean peak concentration(cmax)of 1825.4 and 6635.7nmol·L-1 in the mouse serum,respectively.CONCLUSION Overall,our results suggest that garcinol can indeed potentiate the effects of cisplatin by negative regulation of various inflammatory and proliferative biomarkers.展开更多
OBJECTIVE Hepatocellular carcinoma(HCC)is the fifth most common malignancy worldwide and the third cause of global cancer mortality.Activation of signal transducer and activator of transcription 3(STAT3)is commonly ob...OBJECTIVE Hepatocellular carcinoma(HCC)is the fifth most common malignancy worldwide and the third cause of global cancer mortality.Activation of signal transducer and activator of transcription 3(STAT3)is commonly observed in tumor cells and is a critical mediator of on cogenic signaling in HCC and controls the expression of several genes involved in proliferation,survival,metastasis and angiogenesis.Current drug-targeted therapies,besides being expensive,are associated with serious side effects and morbidity.Thus,novel agents that can suppress STAT3 activation have potential for both prevention and treatment of HCC.In the present report,we investigated whether the potent HAT/KAT inhibitor,garcinol,(apolyisoprenylatedbenzophenone),could suppress STAT3 activation in HCC cells and in nude mice model.METHODS The effect of garcinol on HCC cell lines wasdetermined by MTT assay,immunoblotting,DNA binding assays,immuno-fluorescenceand immune-histochemical analysis.The effect of garcinolon the inhibition of tumor growth in vivo was also investigated using HCCxenograft tumor modelin athymic nu/nu mice.RESULTS We found that garcinol could inhibit constitutive STAT3 activation in a dose-and time-dependent manner both by inhibiting STAT3 phosphorylation and acetylation in HCC cells.When investigated for molecular mechanism(s),we found that garcinol interferes with the dimer formation of STAT3 thereby inhibits its nuclear localization.Computational modeling showed that garcinol could bind to the SH2 domain of STAT3 and suppresses its dimerization in vitro.To understand the cellular mechanism(s)of inhibition of STAT3 function by garcinol,we observed that upon inhibition of STAT3 dimerization bygarcinol,STAT3 DNA binding ability gets repressed.The inhibition of STAT3 activation by garcinol led to the suppression of various gene products involved in proliferation,survival,and angiogenesis.Finally,when administered i.p.,garcinol inhibited the growth of human HCC xenograft tumors in athymic nu/nu mice.CONCLUSION Results frominvitroand in vivo studies suggest that garcinol exerts its anti-proliferative and pro-apoptotic effects through suppression of STAT3 signaling cascade in HCC by inhibiting its phosphorylation,acetylation and ultimately dimerization.展开更多
基金This study was partly supported by National Key Research and Development Program(grant no.2018YFD0500600)National Natural Science Foundation of China(grant no.31572409)Hubei Provincial Natural Science Foundation of China(grant no.2018CFA071).
文摘Background:The effects of dietary garcinol on diarrhea and intestinal barrier function associated with its modulation of gut microbiota in weaned piglets were investigated.Method:One hundred forty four weaned piglets(Duroc×Yorkshire×Landrace)from 16 pens(9 piglets per pen)were randomly divided into four treatment groups:controls(CON)or those supplemented with 200 mg/kg(LOW),400 mg/kg(MID),or 600 mg/kg(HIGH)diet garcinol.After 14-day trial,three piglets per pen were chosen to collect plasma,intestinal tissue and colonic digesta samples.Results:We demonstrated for the first time that garcinol promoted growth performance,as increased average daily feed intake(ADFI)and decreased feed/gain ratio(F/G);and reduced diarrhea incidence(P<0.05);and strengthened antioxidant capacity,as an increased antioxidative index(P<0.05).Additionally,garcinol ameliorated intestinal barrier dysfunction,as an increased villus height to crypt depth ratio,increased zonula occludens protein 1(ZO-1),occludin and claudin-1 expression in the jejunum and ileum(P<0.05),and decreased intestinal permeability(P<0.05);and reduced inflammation,as decreased cytokine interleukin(IL)-6,IL-10,IL-1βand tumor necrosis factor-α(TNF-α)levels in the mucosa of the jejunum and ileum,and NF-κB p65 translocation(P<0.05).Moreover,garcinol inhibited the growth of most harmful bacteria in the gut,especially Escherichia coli,and increased the growth of the beneficial bacteria Lactobacillus.Conclusion:This work provides a fundamental basis for the future development of garcinol-functional food use for improving diarrhea and intestinal barrier function in weaned piglets and for understanding the biological effects of garcinol and its potential as a functional feed additive.
基金The project supported by National Medical Research Council of Singapore and NUS Academic Research fund
文摘OBJECTIVE Platinum compounds such as cisplatin and carboplatin are frequently used as the first-line chemotherapy for the treatment of the head and neck squamous cell carcinoma(HNSCC).In the present study,we investigated whether garcinol,apolyisoprenylated benzophenone can chemosensitize HNSCC to cisplatin.METHODS The effect of garcinol and cisplatin on HNSCC was assessed by MTT,Western blotting,real time PCR,FACS,immunohistochemistry,DNA binding assay and xenograft mouse model.RESULTS We found that garcinol inhibited the viability of a panel of diverse HNSCC cell lines,enhanced the apoptotic effect of cisplatin,suppressed constitutive as well as cisplatin-induced NF-κB activation,and downregulated the expression of various oncogenic gene products(cyclin D1,Bcl-2,survivin and VEGF).In vivo study showed that administration of garcinol alone(0.5 mg·kg-1,ip five times/week)significantly suppressed the growth of the tumor,and this effect was further increased by cisplatin.Both the markers of proliferation index(Ki-67)and microvessel density(CD31)were downregulated in tumor tissues by the combination of cisplatin and garcinol.The pharmacokinetic results of garcinol indicated that good systemic exposure was achievable after ip administration of garcinol at 0.5and 2mg·kg-1 with mean peak concentration(cmax)of 1825.4 and 6635.7nmol·L-1 in the mouse serum,respectively.CONCLUSION Overall,our results suggest that garcinol can indeed potentiate the effects of cisplatin by negative regulation of various inflammatory and proliferative biomarkers.
基金The project supported in part by agrant from National Medical Research Council of Singapore
文摘OBJECTIVE Hepatocellular carcinoma(HCC)is the fifth most common malignancy worldwide and the third cause of global cancer mortality.Activation of signal transducer and activator of transcription 3(STAT3)is commonly observed in tumor cells and is a critical mediator of on cogenic signaling in HCC and controls the expression of several genes involved in proliferation,survival,metastasis and angiogenesis.Current drug-targeted therapies,besides being expensive,are associated with serious side effects and morbidity.Thus,novel agents that can suppress STAT3 activation have potential for both prevention and treatment of HCC.In the present report,we investigated whether the potent HAT/KAT inhibitor,garcinol,(apolyisoprenylatedbenzophenone),could suppress STAT3 activation in HCC cells and in nude mice model.METHODS The effect of garcinol on HCC cell lines wasdetermined by MTT assay,immunoblotting,DNA binding assays,immuno-fluorescenceand immune-histochemical analysis.The effect of garcinolon the inhibition of tumor growth in vivo was also investigated using HCCxenograft tumor modelin athymic nu/nu mice.RESULTS We found that garcinol could inhibit constitutive STAT3 activation in a dose-and time-dependent manner both by inhibiting STAT3 phosphorylation and acetylation in HCC cells.When investigated for molecular mechanism(s),we found that garcinol interferes with the dimer formation of STAT3 thereby inhibits its nuclear localization.Computational modeling showed that garcinol could bind to the SH2 domain of STAT3 and suppresses its dimerization in vitro.To understand the cellular mechanism(s)of inhibition of STAT3 function by garcinol,we observed that upon inhibition of STAT3 dimerization bygarcinol,STAT3 DNA binding ability gets repressed.The inhibition of STAT3 activation by garcinol led to the suppression of various gene products involved in proliferation,survival,and angiogenesis.Finally,when administered i.p.,garcinol inhibited the growth of human HCC xenograft tumors in athymic nu/nu mice.CONCLUSION Results frominvitroand in vivo studies suggest that garcinol exerts its anti-proliferative and pro-apoptotic effects through suppression of STAT3 signaling cascade in HCC by inhibiting its phosphorylation,acetylation and ultimately dimerization.
