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Article ; Online: Patchouli alcohol attenuates the cognitive deficits in a transgenic mouse model of Alzheimer's disease via modulating neuropathology and gut microbiota through suppressing C/EBPβ/AEP pathway.

Xu, Qing-Qing / Su, Zi-Ren / Yang, Wen / Zhong, Mei / Xian, Yan-Fang / Lin, Zhi-Xiu

2023 Volume 20, Issue 1, Page(s) 19

Abstract: Background: Alzheimer's disease (AD) is a chronic neurodegenerative disease characterized by progressive cognitive dysfunctions and behavioral impairments. Patchouli alcohol (PA), isolated from Pogostemonis Herba, exhibits multiple pharmacological ... ...

Abstract	Background: Alzheimer's disease (AD) is a chronic neurodegenerative disease characterized by progressive cognitive dysfunctions and behavioral impairments. Patchouli alcohol (PA), isolated from Pogostemonis Herba, exhibits multiple pharmacological properties, including neuroprotective effects. This study aimed to investigate the therapeutic effects of PA against AD using the TgCRND8 transgenic AD mouse model, and to explore the underlying mechanisms targeting CCAAT/enhancer-binding protein β/asparagine endopeptidase (C/EBPβ/AEP) signaling pathway. Methods: After genotyping to confirm the transgenicity, drug treatments were administered intragastrically once daily to 3-month-old TgCRND8 mice for 4 consecutive months. Several behavioral tests were applied to assess different aspects of neurological functions. Then the brain and colon tissues were harvested for in-depth mechanistic studies. To further verify whether PA exerts anti-AD effects via modulating C/EBPβ/AEP signaling pathway in TgCRND8 mice, adeno-associated virus (AAV) vectors encoding CEBP/β were bilaterally injected into the hippocampal CA1 region in TgCRND8 mice to overexpress C/EBPβ. Additionally, the fecal microbiota transplantation (FMT) experiment was performed to verify the potential role of gut microbiota on the anti-AD effects of PA. Results: Our results showed that PA treatment significantly improved activities of daily living (ADL), ameliorated the anxiety-related behavioral deficits and cognitive impairments in TgCRND8 mice. PA modulated the amyloid precursor protein (APP) processing. PA also markedly reduced the levels of beta-amyloid (Aβ) Conclusion: All these findings amply demonstrated that PA could ameliorate the cognitive deficits in TgCRND8 mice via suppressing Aβ plaques deposition, hyperphosphorylation of tau protein, neuroinflammation and gut dysbiosis through inhibiting the activation of C/EBPβ/AEP pathway, suggesting that PA is a promising naturally occurring chemical worthy of further development into the pharmaceutical treatment of AD.
MeSH term(s)	Humans ; Mice ; Animals ; Alzheimer Disease/therapy ; Alzheimer Disease/drug therapy ; Mice, Transgenic ; tau Proteins/metabolism ; Gastrointestinal Microbiome ; Neuroinflammatory Diseases ; Activities of Daily Living ; Dysbiosis ; Neurodegenerative Diseases ; Cognitive Dysfunction/metabolism ; Amyloid beta-Protein Precursor/genetics ; Amyloid beta-Protein Precursor/metabolism ; Amyloid beta-Peptides/metabolism ; Cognition ; Disease Models, Animal
Chemical Substances	tau Proteins ; patchouli alcohol (HHH8CPR1M2) ; Amyloid beta-Protein Precursor ; Amyloid beta-Peptides
Language	English
Publishing date	2023-01-30
Publishing country	England
Document type	Journal Article
ZDB-ID	2156455-3
ISSN	1742-2094 ; 1742-2094
ISSN (online)	1742-2094
ISSN	1742-2094
DOI	10.1186/s12974-023-02704-1
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Article ; Online: Patchouli alcohol ameliorates the learning and memory impairments in an animal model of Alzheimer's disease via modulating SIRT1.

Xu, Qing-Qing / Su, Zi-Ren / Hu, Zhen / Yang, Wen / Xian, Yan-Fang / Lin, Zhi-Xiu

Phytomedicine : international journal of phytotherapy and phytopharmacology

2022 Volume 106, Page(s) 154441

Abstract: Background: Alzheimer's disease (AD) is one of the most prevalent neurodegenerative diseases. Patchouli alcohol (PA), a major active ingredient isolated from Pogostemonis Herba, exhibits extensive bioactivity in the central nervous system (CNS) and ... ...

Abstract	Background: Alzheimer's disease (AD) is one of the most prevalent neurodegenerative diseases. Patchouli alcohol (PA), a major active ingredient isolated from Pogostemonis Herba, exhibits extensive bioactivity in the central nervous system (CNS) and exerts neuroprotective effects. Purpose: This study aimed to investigate the anti-AD effects of PA in an animal model of AD and to elucidate the underlying molecular mechanisms. Methods: The gas chromatography (GC) was used to determine the ability of PA to pass the blood-brain barrier (BBB) in rats after oral administration. The sporadic AD rat model was established by intracerebroventricularly (ICV) injection with streptozotocin (STZ). PA (25 and 50 mg/kg) was given to rat orally once daily for 42 consecutive days. Morris water maze (MWM) test was performed to determine the learning and memory functions of the STZ-induced AD rats. EX527, a silent information regulator 1 (SIRT1) selective inhibitor, was used to investigate the involvement of SIRT1 in the anti-AD effects of PA in rats. Results: PA could penetrate the BBB. MWM test results showed that PA could significantly ameliorate the learning and memory deficits induced by STZ in rats. Meanwhile, PA enhanced the expression of SIRT1, and markedly alleviated the tau pathology by inhibiting the hyperacetylation (at the site of Lys174) and hyperphosphorylation (at the sites of Thr181, Thr205, Ser396 and Ser404) of tau protein. PA also efficiently suppressed the activation of microglia and astrocytes, and the beta-amyloid (Aβ) expression and the deacetylation of nuclear factor-kappa B (NF-κB) at Lys 310 (K310) in the STZ-treated AD rats. EX527, a SIRT1 selective inhibitor, could partially abolish the cognitive deficits improving effect of PA and inhibit the down-regulation of acetylated tau and acetylated NF-κB p65, suggesting that PA exhibited neuroprotective effects against AD via upregulating SIRT1. Conclusion: This study reported for the first time that PA could penetrate the BBB to exert its protective effects on the brain after a single-dose oral administration. The current experimental findings also amply demonstrated that PA could improve the cognitive and memory impairments in the STZ-induced AD rat model. The underlying mechanisms involve the alleviations of neuroinflammation, tau pathology and Aβ deposition via modulating of SIRT1 and NF-κB pathways. All these findings strongly suggest that PA is a promising naturally occurring compound worthy of further development into an anti-AD pharmaceutical.
MeSH term(s)	Alzheimer Disease/metabolism ; Animals ; Disease Models, Animal ; Hippocampus ; Maze Learning ; Memory Disorders/metabolism ; NF-kappa B/metabolism ; Neuroprotective Agents/pharmacology ; Neuroprotective Agents/therapeutic use ; Pharmaceutical Preparations/metabolism ; Rats ; Sesquiterpenes ; Sirtuin 1/metabolism ; Streptozocin/adverse effects ; tau Proteins/metabolism
Chemical Substances	NF-kappa B ; Neuroprotective Agents ; Pharmaceutical Preparations ; Sesquiterpenes ; tau Proteins ; Streptozocin (5W494URQ81) ; Sirt1 protein, rat (EC 3.5.1.-) ; Sirtuin 1 (EC 3.5.1.-) ; patchouli alcohol (HHH8CPR1M2)
Language	English
Publishing date	2022-09-06
Publishing country	Germany
Document type	Journal Article
ZDB-ID	1205240-1
ISSN	1618-095X ; 0944-7113
ISSN (online)	1618-095X
ISSN	0944-7113
DOI	10.1016/j.phymed.2022.154441
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Article ; Online: Stereoisomers of octahydrocurcumin, the hydrogenated metabolites of curcumin, display stereoselective activity on the CYP2E1 enzyme in L-02 cells.

Luo, Dandan / Lin, Yinsi / Chen, Jiannan / Huang, Xiaoqi / Xie, Youliang / Liu, Yuhong / Ni, Suiqin / Su, Ziren / Li, Yucui / Zhang, Zhenbiao

Food & function

2023 Volume 14, Issue 6, Page(s) 2822–2835

Abstract: As the final hydrogenated metabolite of curcumin, octahydrocurcumin (OHC) exhibits increased powerful bioactivities. The chiral and symmetric chemical structure indicated that there were two OHC stereoisomers, ( ... ...

Abstract	As the final hydrogenated metabolite of curcumin, octahydrocurcumin (OHC) exhibits increased powerful bioactivities. The chiral and symmetric chemical structure indicated that there were two OHC stereoisomers, (3
MeSH term(s)	Rats ; Animals ; Cytochrome P-450 CYP2E1/genetics ; Cytochrome P-450 CYP2E1/metabolism ; Curcumin/chemistry ; Stereoisomerism ; Cytochrome P-450 Enzyme System/genetics ; Cytochrome P-450 Enzyme System/metabolism ; Liver/metabolism ; Microsomes, Liver/metabolism
Chemical Substances	Cytochrome P-450 CYP2E1 (EC 1.14.13.-) ; Curcumin (IT942ZTH98) ; Cytochrome P-450 Enzyme System (9035-51-2)
Language	English
Publishing date	2023-03-20
Publishing country	England
Document type	Journal Article
ZDB-ID	2612033-1
ISSN	2042-650X ; 2042-6496
ISSN (online)	2042-650X
ISSN	2042-6496
DOI	10.1039/d2fo03892g
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Article ; Online: Intestines-erythrocytes-mediated bio-disposition deciphers the hypolipidemic effect of berberine from Rhizoma Coptidis: A neglected insight.

Huang, Ziwei / Li, Minhua / Qin, Zehui / Ma, Xingdong / Huang, Ronglei / Liu, Yuhong / Xie, Jianhui / Zeng, Huifang / Zhan, Ruoting / Su, Ziren

Journal of ethnopharmacology

2023 Volume 314, Page(s) 116600

Abstract: Ethnopharmacological relevance: Rhizoma Coptidis (RC), the dried rhizome of Coptis Chinensis Franch., can dispel dampness and heat within the body and has been traditionally used for the treatment of cardiovascular disease (CVD)-associated problems ... ...

Abstract	Ethnopharmacological relevance: Rhizoma Coptidis (RC), the dried rhizome of Coptis Chinensis Franch., can dispel dampness and heat within the body and has been traditionally used for the treatment of cardiovascular disease (CVD)-associated problems including hyperlipidemia in China. Berberine (BBR) is the main active component of RC, which has been shown to possess significant therapeutic potential. However, only 0.14% of BBR is metabolized in the liver, and the extremely low bioavailability (<1%) and blood concentration of BBR in experimental and clinical settings is insufficient to achieve the effects as observed under in vitro conditions, which imposes challenges to explain its excellent pharmacological actions. Intense efforts are currently being devoted to defining its specific pharmacological molecular targets, while the exploration from the perspective of its pharmacokinetic disposition has rarely been reported to date, which could hardly make a comprehensive understanding of its hypolipidemic enigma. Aim of the study: This study made a pioneering endeavor to unveil the hypolipidemic mechanism of BBR from RC focusing on its unique intestines-erythrocytes-mediated bio-disposition. Materials and methods: The fate of BBR in intestines and erythrocytes was probed by a rapid and sensitive LC/MS-IT-TOF method. To analyze the disposition of BBR, a reliable HPLC method was subsequently developed and validated for simultaneous determination of BBR and its key active metabolite oxyberberine (OBB) in whole blood, tissues, and excreta. Meanwhile, the enterohepatic circulation (BDC) of BBR and OBB was verified by bile duct catheterization rats. Finally, lipid overloading models of L02 and HepG2 cells were employed to probe the lipid-lowering activity of BBR and OBB at in vivo concentration. Results: The results showed that BBR underwent biotransformation in both intestines and erythrocytes, and converted into the major metabolite oxyberberine (OBB). The AUC Conclusions: Cumulatively, BBR underwent unique extrahepatic metabolism and disposition into OBB by virtue of intestines and erythrocytes. BBR and OBB were mainly presented and transported in the protein-bound form within the circulating erythrocytes, potentially resulting in hepatocyte targeting accompanied by obvious enterohepatic circulation. The unique extrahepatic disposition of BBR via intestines and erythrocytes conceivably contributed enormously to its hypolipidemic effect. OBB was the important material basis for the hypolipidemic effect of BBR and RC.
MeSH term(s)	Rats ; Animals ; Berberine/pharmacology ; Berberine/therapeutic use ; Plant Extracts/pharmacology ; Triglycerides/metabolism ; Intestines ; Erythrocytes/metabolism
Chemical Substances	Berberine (0I8Y3P32UF) ; Plant Extracts ; Triglycerides
Language	English
Publishing date	2023-05-15
Publishing country	Ireland
Document type	Journal Article
ZDB-ID	134511-4
ISSN	1872-7573 ; 0378-8741
ISSN (online)	1872-7573
ISSN	0378-8741
DOI	10.1016/j.jep.2023.116600
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Article ; Online: Tetrahydroberberine alleviates high-fat diet-induced hyperlipidemia in mice via augmenting lipoprotein assembly-induced clearance of low-density lipoprotein and intermediate-density lipoprotein.

Wei, Guilan / Huang, Ning / Li, Mengyao / Guan, Fengkun / Chen, Liping / Liao, Yingyi / Xie, Xingyu / Li, Yucui / Su, Ziren / Chen, Jiannan / Liu, Yuhong

European journal of pharmacology

2024 Volume 968, Page(s) 176433

Abstract: The promotion of excess low-density lipoprotein (LDL) clearance stands as an effective clinical approach for treating hyperlipidemia. Tetrahydroberberine, a metabolite of berberine, exhibits superior bioavailability compared to berberine and demonstrates ...

Abstract	The promotion of excess low-density lipoprotein (LDL) clearance stands as an effective clinical approach for treating hyperlipidemia. Tetrahydroberberine, a metabolite of berberine, exhibits superior bioavailability compared to berberine and demonstrates a pronounced hypolipidemic effect. Despite these characteristics, the impact of tetrahydroberberine on improving excessive LDL clearance in hyperlipidemia has remained unexplored. Thus, this study investigates the potential effects of tetrahydroberberine on high-fat diet-induced hyperlipidemia in mice. The findings reveal that tetrahydroberberine exerts a more potent lipid-lowering effect than berberine, particularly concerning LDL-cholesterol in hyperlipidemic mice. Notably, tetrahydroberberine significantly reduces serum levels of upstream lipoproteins, including intermediate-density lipoprotein (IDL) and very low-density lipoprotein, by promoting their conversion to LDL. This reduction is further facilitated by the upregulation of hepatic LDL receptor expression induced by tetrahydroberberine. Intriguingly, tetrahydroberberine enhances the apolipoprotein E (ApoE)/apolipoprotein B100 (ApoB100) ratio, influencing lipoprotein assembly in the serum. This effect is achieved through the activation of the efflux of ApoE-containing cholesterol in the liver. The ApoE/ApoB100 ratio exhibits a robust negative correlation with serum levels of LDL and IDL, indicating its potential as a diagnostic indicator for hyperlipidemia. Moreover, tetrahydroberberine enhances hepatic lipid clearance without inducing lipid accumulation in the liver and alleviates existing liver lipid content. Importantly, no apparent hepatorenal toxicity is observed following tetrahydroberberine treatment for hyperlipidemia. In summary, tetrahydroberberine demonstrates a positive impact against hyperlipidemia by modulating lipoprotein assembly-induced clearance of LDL and IDL. The ApoE/ApoB100 ratio emerges as a promising diagnostic indicator for hyperlipidemia, showcasing the potential clinical significance of tetrahydroberberine in lipid management.
MeSH term(s)	Mice ; Animals ; Lipoproteins, IDL/metabolism ; Hyperlipidemias ; Berberine/pharmacology ; Berberine/therapeutic use ; Berberine/analogs & derivatives ; Diet, High-Fat/adverse effects ; Triglycerides ; Cholesterol/metabolism ; Apolipoproteins E/genetics ; Cholesterol, LDL ; Liver/metabolism
Chemical Substances	Lipoproteins, IDL ; canadine (V2SSH085X8) ; Berberine (0I8Y3P32UF) ; Triglycerides ; Cholesterol (97C5T2UQ7J) ; Apolipoproteins E ; Cholesterol, LDL
Language	English
Publishing date	2024-02-16
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	80121-5
ISSN	1879-0712 ; 0014-2999
ISSN (online)	1879-0712
ISSN	0014-2999
DOI	10.1016/j.ejphar.2024.176433
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Article ; Online: Discovery of 2,8-dihydroxyadenine in HUA patients with uroliths and biomarkers for its associated nephropathy.

Zheng, Xiaohong / Lu, Xiaowei / Li, Qiuxian / Gong, Shiting / Chen, Baoyi / Xie, Qingfeng / Yan, Fang / Li, Jincan / Su, Ziren / Liu, Yuhong / Guo, Zhonghui / Chen, Jiannan / Li, Yucui

Biochimica et biophysica acta. Molecular basis of disease

2024 Volume 1870, Issue 4, Page(s) 167051

Abstract: Currently, it is acknowledged that gout is caused by uric acid (UA). However, some studies have revealed no correlation between gout and UA levels, and growing evidence suggests that 2,8-dihydroxyadenine (2,8-DHA), whose structural formula is similar to ... ...

Abstract	Currently, it is acknowledged that gout is caused by uric acid (UA). However, some studies have revealed no correlation between gout and UA levels, and growing evidence suggests that 2,8-dihydroxyadenine (2,8-DHA), whose structural formula is similar to UA but is less soluble, may induce gout. Hence, we hypothesized that uroliths from hyperuricemia (HUA) patients, which is closely associated with gout, may contain 2,8-DHA. In this study, 2,8-DHA in uroliths and serum of HUA patients were determined using HPLC. Moreover, bioinformatics was used to investigate the pathogenic mechanisms of 2,8-DHA nephropathy. Subsequently, a mouse model of 2,8-DHA nephropathy established by the gavage administration of adenine, as well as a model of injured HK-2 cells induced by 2,8-DHA were used to explore the pathogenesis of 2,8-DHA nephropathy. Interestingly, 2,8-DHA could readily deposit in the cortex of the renal tubules, and was found in the majority of these HUA patients. Additionally, the differentially expressed genes between 2,8-DHA nephropathy mice and control mice were found to be involved in inflammatory reactions. Importantly, CCL2 and IL-1β genes had the maximum degree, closeness, and betweenness centrality scores. The expressions of CCL2 and IL-1β genes were significantly increased in the serum of 24 HUA patients with uroliths, indicating that they may be significant factors for 2,8-DHA nephropathy. Further analysis illustrated that oxidative damage and inflammation were the crucial processes of 2,8-DHA renal injury, and CCL2 and IL-1β genes were verified to be essential biomarkers for 2,8-DHA nephropathy. These findings revealed further insights into 2,8-DHA nephropathy, and provided new ideas for its diagnosis and treatment.
MeSH term(s)	Humans ; Mice ; Animals ; Hyperuricemia/metabolism ; Kidney Diseases ; Kidney/metabolism ; Gout ; Uric Acid/metabolism ; Adenine/analogs & derivatives
Chemical Substances	2,8-dihydroxyadenine (30377-37-8) ; Uric Acid (268B43MJ25) ; Adenine (JAC85A2161)
Language	English
Publishing date	2024-02-07
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	60-7
ISSN	1879-260X ; 1879-2596 ; 1872-8006 ; 1879-2642 ; 1879-2618 ; 1879-2650 ; 0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
ISSN (online)	1879-260X ; 1879-2596 ; 1872-8006 ; 1879-2642 ; 1879-2618 ; 1879-2650
ISSN	0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
DOI	10.1016/j.bbadis.2024.167051
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Article ; Online: Intestines-erythrocytes-mediated bio-disposition deciphers the hypolipidemic effect of berberine from Rhizoma Coptidis: A neglected insight

Huang, Ziwei / Li, Minhua / Qin, Zehui / Ma, Xingdong / Huang, Ronglei / Liu, Yuhong / Xie, Jianhui / Zeng, Huifang / Zhan, Ruoting / Su, Ziren

Journal of Ethnopharmacology. 2023 Oct., v. 314 p.116600-

2023

Abstract: Rhizoma Coptidis (RC), the dried rhizome of Coptis Chinensis Franch., can dispel dampness and heat within the body and has been traditionally used for the treatment of cardiovascular disease (CVD)-associated problems including hyperlipidemia in China. ... ...

Abstract	Rhizoma Coptidis (RC), the dried rhizome of Coptis Chinensis Franch., can dispel dampness and heat within the body and has been traditionally used for the treatment of cardiovascular disease (CVD)-associated problems including hyperlipidemia in China. Berberine (BBR) is the main active component of RC, which has been shown to possess significant therapeutic potential. However, only 0.14% of BBR is metabolized in the liver, and the extremely low bioavailability (<1%) and blood concentration of BBR in experimental and clinical settings is insufficient to achieve the effects as observed under in vitro conditions, which imposes challenges to explain its excellent pharmacological actions. Intense efforts are currently being devoted to defining its specific pharmacological molecular targets, while the exploration from the perspective of its pharmacokinetic disposition has rarely been reported to date, which could hardly make a comprehensive understanding of its hypolipidemic enigma. This study made a pioneering endeavor to unveil the hypolipidemic mechanism of BBR from RC focusing on its unique intestines-erythrocytes-mediated bio-disposition. The fate of BBR in intestines and erythrocytes was probed by a rapid and sensitive LC/MS-IT-TOF method. To analyze the disposition of BBR, a reliable HPLC method was subsequently developed and validated for simultaneous determination of BBR and its key active metabolite oxyberberine (OBB) in whole blood, tissues, and excreta. Meanwhile, the enterohepatic circulation (BDC) of BBR and OBB was verified by bile duct catheterization rats. Finally, lipid overloading models of L02 and HepG2 cells were employed to probe the lipid-lowering activity of BBR and OBB at in vivo concentration. The results showed that BBR underwent biotransformation in both intestines and erythrocytes, and converted into the major metabolite oxyberberine (OBB). The AUC₀₋ₜ ratio of total BBR to OBB was approximately 2:1 after oral administration. Besides, the AUC₀₋ₜ ratio of bound BBR to its unbound counterpart was 4.6:1, and this ratio of OBB was 2.5:1, indicative of abundant binding-type form in the blood. Liver dominated over other organs in tissue distribution. BBR was excreted in bile, while the excretion of OBB in feces was significantly higher than that in bile. Furthermore, the bimodal phenomenon of both BBR and OBB disappeared in BDC rats and the AUC₀₋ₜ was significantly lower than that in the sham-operated control rats. Interestingly, OBB significantly decreased triglycerides and cholesterol levels in lipid overloading models of L02 and HepG2 cells at in vivo-like concentration, which was superior to the prodrug BBR. Cumulatively, BBR underwent unique extrahepatic metabolism and disposition into OBB by virtue of intestines and erythrocytes. BBR and OBB were mainly presented and transported in the protein-bound form within the circulating erythrocytes, potentially resulting in hepatocyte targeting accompanied by obvious enterohepatic circulation. The unique extrahepatic disposition of BBR via intestines and erythrocytes conceivably contributed enormously to its hypolipidemic effect. OBB was the important material basis for the hypolipidemic effect of BBR and RC.
Keywords	Coptis chinensis ; berberine ; bile ; bile ducts ; bioavailability ; biotransformation ; cardiovascular diseases ; catheters ; cholesterol ; erythrocytes ; excretion ; feces ; heat ; hyperlipidemia ; lipemic effect ; liver ; metabolites ; oral administration ; pharmacokinetics ; rhizomes ; tissue distribution ; traditional medicine ; China ; Extrahepatic metabolism ; Intestine microflora ; Erythrocyte ; Oxyberberine ; Hypolipidemic ; AST ; ALT ; BBR ; BDC ; BSA ; CD ; EHC ; FFAs ; HCl ; IS ; OA ; OBB ; PA ; TFA ; TG
Language	English
Dates of publication	2023-10
Publishing place	Elsevier B.V.
Document type	Article ; Online
ZDB-ID	134511-4
ISSN	1872-7573 ; 0378-8741
ISSN (online)	1872-7573
ISSN	0378-8741
DOI	10.1016/j.jep.2023.116600
Database	NAL-Catalogue (AGRICOLA)

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Article: Patchouli alcohol ameliorates the learning and memory impairments in an animal model of Alzheimer's disease via modulating SIRT1

Xu, Qing-Qing / Su, Zi-Ren / Hu, Zhen / Yang, Wen / Xian, Yan-Fang / Lin, Zhi-Xiu

Phytomedicine. 2022 Nov., v. 106

2022

Abstract: Alzheimer's disease (AD) is one of the most prevalent neurodegenerative diseases. Patchouli alcohol (PA), a major active ingredient isolated from Pogostemonis Herba, exhibits extensive bioactivity in the central nervous system (CNS) and exerts ... ...

Abstract	Alzheimer's disease (AD) is one of the most prevalent neurodegenerative diseases. Patchouli alcohol (PA), a major active ingredient isolated from Pogostemonis Herba, exhibits extensive bioactivity in the central nervous system (CNS) and exerts neuroprotective effects. This study aimed to investigate the anti-AD effects of PA in an animal model of AD and to elucidate the underlying molecular mechanisms. The gas chromatography (GC) was used to determine the ability of PA to pass the blood-brain barrier (BBB) in rats after oral administration. The sporadic AD rat model was established by intracerebroventricularly (ICV) injection with streptozotocin (STZ). PA (25 and 50 mg/kg) was given to rat orally once daily for 42 consecutive days. Morris water maze (MWM) test was performed to determine the learning and memory functions of the STZ-induced AD rats. EX527, a silent information regulator 1 (SIRT1) selective inhibitor, was used to investigate the involvement of SIRT1 in the anti-AD effects of PA in rats. PA could penetrate the BBB. MWM test results showed that PA could significantly ameliorate the learning and memory deficits induced by STZ in rats. Meanwhile, PA enhanced the expression of SIRT1, and markedly alleviated the tau pathology by inhibiting the hyperacetylation (at the site of Lys174) and hyperphosphorylation (at the sites of Thr181, Thr205, Ser396 and Ser404) of tau protein. PA also efficiently suppressed the activation of microglia and astrocytes, and the beta-amyloid (Aβ) expression and the deacetylation of nuclear factor-kappa B (NF-κB) at Lys 310 (K310) in the STZ-treated AD rats. EX527, a SIRT1 selective inhibitor, could partially abolish the cognitive deficits improving effect of PA and inhibit the down-regulation of acetylated tau and acetylated NF-κB p65, suggesting that PA exhibited neuroprotective effects against AD via upregulating SIRT1. This study reported for the first time that PA could penetrate the BBB to exert its protective effects on the brain after a single-dose oral administration. The current experimental findings also amply demonstrated that PA could improve the cognitive and memory impairments in the STZ-induced AD rat model. The underlying mechanisms involve the alleviations of neuroinflammation, tau pathology and Aβ deposition via modulating of SIRT1 and NF-κB pathways. All these findings strongly suggest that PA is a promising naturally occurring compound worthy of further development into an anti-AD pharmaceutical.
Keywords	Alzheimer disease ; Pogostemon cablin ; active ingredients ; alcohols ; animal models ; astrocytes ; bioactive properties ; blood-brain barrier ; brain ; cognition ; gas chromatography ; memory ; oral administration ; streptozotocin ; transcription factor NF-kappa B
Language	English
Dates of publication	2022-11
Publishing place	Elsevier GmbH
Document type	Article
ZDB-ID	1205240-1
ISSN	1618-095X ; 0944-7113
ISSN (online)	1618-095X
ISSN	0944-7113
DOI	10.1016/j.phymed.2022.154441
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: High fructose-induced skeletal muscle insulin resistance could be alleviated by berberine via AMPD1 and ADSL

Cheng, Juanjuan / Ma, Xingdong / Yan, Guangtao / Yu, Qiuxia / Huang, Zhen / Lin, Guoshu / Li, Mengyao / Guan, Fengkun / Su, Ziren / Yan, Fang / Liu, Yuhong / Xie, Qingfeng

Food and Chemical Toxicology. 2023 May, v. 175 p.113731-

2023

Abstract: AMP-activated protein kinase (AMPK) is a master regulator of energy homeostasis that is activated in response to an elevated intracellular AMP/ATP ratio. Although many studies have shown berberine is an AMPK activator widely used in metabolic syndrome, ... ...

Abstract	AMP-activated protein kinase (AMPK) is a master regulator of energy homeostasis that is activated in response to an elevated intracellular AMP/ATP ratio. Although many studies have shown berberine is an AMPK activator widely used in metabolic syndrome, how to properly control AMPK activity remains obscure. Our present study aimed to examine the protective effect of berberine against fructose-induced insulin resistance in rats and L6 cells, as well as its potential activation mechanism on AMPK. The results showed that berberine effectively reversed body weight gain, Lee's index, dyslipidemia and insulin intolerance. Moreover, berberine alleviated inflammatory response, antioxidant capacity and promoted glucose uptake in vivo and in vitro. The beneficial effect was associated with upregulation of both Nrf2 and AKT/GLUT4 pathways, which were regulated by AMPK. Notably, berberine could increase the level of AMP and the ratio of AMP/ATP, then further activate AMPK. Mechanistic experiments revealed that berberine suppressed the expression of adenosine monophosphate deaminase 1 (AMPD1) and promoted the expression of adenylosuccinate synthetase (ADSL). Taken together, berberine exerted excellent therapeutic effect on insulin resistance. And its mode of action may be related to the AMP‐AMPK pathway by regulating AMPD1 and ADSL.
Keywords	AMP deaminase ; AMP-activated protein kinase ; antioxidant activity ; berberine ; body weight changes ; energy ; glucose ; homeostasis ; hyperlipidemia ; inflammation ; insulin ; insulin resistance ; mechanism of action ; metabolic syndrome ; protective effect ; skeletal muscle ; therapeutics ; toxicology ; Fructose ; AMPD1 ; ADSL
Language	English
Dates of publication	2023-05
Publishing place	Elsevier Ltd
Document type	Article ; Online
ZDB-ID	782617-5
ISSN	1873-6351 ; 0278-6915
ISSN (online)	1873-6351
ISSN	0278-6915
DOI	10.1016/j.fct.2023.113731
Database	NAL-Catalogue (AGRICOLA)

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Article: In vitro and in vivo hypoglycemia effect of oxyberberine, a novel HO-1 agonist: A renewed evidence linking HO-1 to diabetes mellitus

Dou, Yaoxing / Ai, Gaoxiang / Huang, Ronglei / Huang, Ziwei / Li, Yucui / Liu, Yuhong / Xie, Jianhui / Chen, Jiannan / Su, Ziren

Phytomedicine. 2022 July, v. 101

2022

Abstract: Oxyberberine (OBB), an important in vivo metabolite of berberine, exerts superior hypoglycemia effect. However, the underlying mechanism remains obscure. Heme oxygenase-1 (HO-1) holds a crucial status in the pathogenesis of diabetes. Previous research ... ...

Abstract	Oxyberberine (OBB), an important in vivo metabolite of berberine, exerts superior hypoglycemia effect. However, the underlying mechanism remains obscure. Heme oxygenase-1 (HO-1) holds a crucial status in the pathogenesis of diabetes. Previous research has indicated that OBB can specifically bind to hemoglobin and significantly up-regulated the HO-1 expression in diabetic rat. Based on cellular protection features of HO-1, this work aimed to probe the anti-diabetic effect of OBB and the association with the potential induction of HO-1 expression. A type 2 diabetic mellitus rat model was established. Glucolipid metabolism and insulin sensitivity were analyzed. Immunohistochemistry, Western blotting and in silico simulations were also performed. Administration of OBB or HO-1 inducer hemin significantly reduced fasting blood glucose level, blood fat, and inflammatory cytokine levels, while increased antioxidant capacity of pancreas. Meanwhile, OBB treatment remarkably stimulated liver glycogenesis and inhibited gluconeogenesis. Besides, OBB improved the glucose utilizing of muscle. Noteworthily, OBB inhibited the islet cell apoptosis and improved pancreatic function. In addition, OBB effectively improved the consumption of glucose in insulin-resistant HepG2 cells. Moreover, OBB also reduced oxidative stress, promoted glucose-elicited insulin secretion and enhanced expression of β-cell function proteins in INS-1 cells. Nevertheless, these effects were significantly reversed by treatment with Zincprotoporphrin (ZnPP). Additionally, in silico simulations indicated that OBB exhibited superior affinity with HO-1. OBB effectively ameliorated hyperglycemia, dyslipidemia, and insulin resistance, improved oral glucose tolerance, and maintained glucose metabolism homeostasis, at least in part, by promoting HO-1-mediated activation of phosphoinositide 3-kinase / protein kinase B (PI3K/Akt) and AMP-activated protein kinase (AMPK) pathways. These data eloquently suggest that OBB, as a novel HO-1 agonist, has good potential to be a promising candidate drug for the management of diabetes, and support a therapeutic role of HO-1 induction in diabetes that potentially paves the way to translational research.
Keywords	AMP-activated protein kinase ; agonists ; antioxidant activity ; apoptosis ; berberine ; blood ; blood glucose ; computer simulation ; cytokines ; drugs ; gluconeogenesis ; glucose ; glucose tolerance ; glycemic effect ; glycogenesis ; heme oxygenase (biliverdin-producing) ; hemoglobin ; homeostasis ; hyperglycemia ; hyperlipidemia ; hypoglycemia ; immunohistochemistry ; insulin resistance ; insulin secretion ; liver ; metabolites ; muscles ; non-specific serine/threonine protein kinase ; noninsulin-dependent diabetes mellitus ; oxidative stress ; pathogenesis ; phosphatidylinositol 3-kinase ; rats ; therapeutics
Language	English
Dates of publication	2022-07
Publishing place	Elsevier GmbH
Document type	Article
ZDB-ID	1205240-1
ISSN	1618-095X ; 0944-7113
ISSN (online)	1618-095X
ISSN	0944-7113
DOI	10.1016/j.phymed.2022.154135
Database	NAL-Catalogue (AGRICOLA)

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