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Article ; Online: Acetaminophen overdose causes a breach of the blood-bile barrier in mice but not in rats.

Hassan, Reham / Hobloss, Zaynab / Myllys, Maiju / González, Daniela / Begher-Tibbe, Brigitte / Reinders, Joerg / Friebel, Adrian / Hoehme, Stefan / Abdelmageed, Noha / Abbas, Aya A / Seddek, Abdel-Latief / Morad, Samy A F / Hengstler, Jan G / Ghallab, Ahmed

Archives of toxicology

2024 Volume 98, Issue 5, Page(s) 1533–1542

Abstract: Acetaminophen (APAP) is known to cause a breach of the blood-bile barrier in mice that, via a mechanism called futile bile acid (BA) cycling, increases BA concentrations in hepatocytes above cytotoxic thresholds. Here, we compared this mechanism in mice ... ...

Abstract	Acetaminophen (APAP) is known to cause a breach of the blood-bile barrier in mice that, via a mechanism called futile bile acid (BA) cycling, increases BA concentrations in hepatocytes above cytotoxic thresholds. Here, we compared this mechanism in mice and rats, because both species differ massively in their susceptibility to APAP and compared the results to available human data. Dose and time-dependent APAP experiments were performed in male C57BL6/N mice and Wistar rats. The time course of BA concentrations in liver tissue and in blood was analyzed by MALDI-MSI and LC-MS/MS. APAP and its derivatives were measured in the blood by LC-MS. APAP-induced liver damage was analyzed by histopathology, immunohistochemistry, and by clinical chemistry. In mice, a transient increase of BA in blood and in peri-central hepatocytes preceded hepatocyte death. The BA increase coincided with oxidative stress in liver tissue and a compromised morphology of bile canaliculi and immunohistochemically visualized tight junction proteins. Rats showed a reduced metabolic activation of APAP compared to mice. However, even at very high doses that caused cell death of hepatocytes, no increase of BA concentrations was observed neither in liver tissue nor in the blood. Correspondingly, no oxidative stress was detectable, and the morphology of bile canaliculi and tight junction proteins remained unaltered. In conclusion, different mechanisms cause cell death in rats and mice, whereby oxidative stress and a breach of the blood-bile barrier are seen only in mice. Since transient cholestasis also occurs in human patients with APAP overdose, mice are a clinically relevant species to study APAP hepatotoxicity but not rats.
MeSH term(s)	Mice ; Rats ; Humans ; Male ; Animals ; Acetaminophen/toxicity ; Acetaminophen/metabolism ; Bile/metabolism ; Chromatography, Liquid ; Chemical and Drug Induced Liver Injury/pathology ; Rats, Wistar ; Tandem Mass Spectrometry ; Liver/metabolism ; Hepatocytes/metabolism ; Mice, Inbred C57BL ; Tight Junction Proteins/metabolism
Chemical Substances	Acetaminophen (362O9ITL9D) ; Tight Junction Proteins
Language	English
Publishing date	2024-03-11
Publishing country	Germany
Document type	Journal Article
ZDB-ID	124992-7
ISSN	1432-0738 ; 0340-5761
ISSN (online)	1432-0738
ISSN	0340-5761
DOI	10.1007/s00204-024-03705-6
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Article ; Online: Arglabin, an EGFR receptor tyrosine kinase inhibitor, suppresses proliferation and induces apoptosis in prostate cancer cells.

El Gaafary, Menna / Morad, Samy A F / Schmiech, Michael / Syrovets, Tatiana / Simmet, Thomas

Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie

2022 Volume 156, Page(s) 113873

Abstract: Evidence for clinical efficacy of a semisynthetic derivative of arglabin in anticancer treatment prompted us to examine molecular mechanisms and cellular targets of arglabin. Arglabin, a sesquiterpene lactone isolated from Artemisia glabella was ... ...

Abstract	Evidence for clinical efficacy of a semisynthetic derivative of arglabin in anticancer treatment prompted us to examine molecular mechanisms and cellular targets of arglabin. Arglabin, a sesquiterpene lactone isolated from Artemisia glabella was cytotoxic to different human cancer cell lines including those derived from advanced triple-negative breast, lung, androgen-dependent and androgen-independent prostate carcinomas. Noteworthy, arglabin was less toxic to non-neoplastic prostate epithelial cells indicating selectivity for cancer cells. At the molecular level, prior to any biochemical signs of cellular toxicity, arglabin reduced levels of cell-surface sulphanyl groups and inhibited phosphorylation of the redox-sensitive receptor tyrosine kinase EGFR, the only active RTK in PC-3 prostate cancer cells among 49 TRKs analyzed by the assay. Henceforth, arglabin inhibited the EGFR downstream signaling pathways mTORC1 and mTORC2. Accordingly, arglabin induced autophagosome formation and autophagic flux, inhibited phosphorylation of ribosomal protein S6 kinase beta-1 (S6K1) and eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1), and impeded cell cycle progression and proliferation of PC-3 cells. In agreement with inhibition of the mTORC2 pathway, arglabin induced sustained actin polymerization, inhibited cell migration, and triggered apoptosis in vitro in 2D cell culture and colony formation assay and in vivo in prostate cancer xenografts grown on chick chorioallantoic membranes. Under physiological conditions, arglabin rapidly formed adducts with reduced glutathione (GSH). Moreover, thiol-based antioxidants GSH and β-mercaptoethanol abolished arglabin-induced cancer cell toxicity, whereas the non-thiol antioxidant trolox was ineffective pointing to a crucial role of interaction with cell-surface sulphanyl groups for arglabin cytotoxic activity against cancer cells.
MeSH term(s)	Humans ; Male ; Prostate/pathology ; Androgens/metabolism ; Apoptosis ; Prostatic Neoplasms/pathology ; Phosphorylation ; Mechanistic Target of Rapamycin Complex 2/metabolism ; Cell Proliferation ; Protein Kinase Inhibitors/pharmacology ; ErbB Receptors/metabolism ; Cell Line, Tumor
Chemical Substances	arglabin (84692-91-1) ; Androgens ; Mechanistic Target of Rapamycin Complex 2 (EC 2.7.11.1) ; Protein Kinase Inhibitors ; ErbB Receptors (EC 2.7.10.1) ; EGFR protein, human (EC 2.7.10.1)
Language	English
Publishing date	2022-10-19
Publishing country	France
Document type	Journal Article
ZDB-ID	392415-4
ISSN	1950-6007 ; 0753-3322 ; 0300-0893
ISSN (online)	1950-6007
ISSN	0753-3322 ; 0300-0893
DOI	10.1016/j.biopha.2022.113873
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Article ; Online: The Onus of Sphingolipid Enzymes in Cancer Drug Resistance.

Morad, Samy A F / Cabot, Myles C

Advances in cancer research

2018 Volume 140, Page(s) 235–263

Abstract: Chemotherapy resistance, inherent or acquired, represents a serious barrier to the successful treatment of cancer. Although drug efflux, conducted by plasma membrane-resident proteins, detoxification enzymes, cell death inhibition, and DNA damage repair ... ...

Abstract	Chemotherapy resistance, inherent or acquired, represents a serious barrier to the successful treatment of cancer. Although drug efflux, conducted by plasma membrane-resident proteins, detoxification enzymes, cell death inhibition, and DNA damage repair are ensemble players in this unwanted biology, a full understanding of the many in concert molecular mechanisms driving drug resistance is lacking. Recent discoveries in sphingolipid (SL) metabolism have provided significant insight into the role of these lipids in cancer growth; however, considerably less is known with respect to SLs and the drug-resistant phenotype. One exception here is enhanced ceramide glycosylation, a hallmark of multidrug resistance that is believed responsible, in part, for diminishing ceramides tumor-suppressor potential. This chapter will review various aspects of SL biology that relate to chemotherapy resistance and extend this topic to acknowledge the role of chemotherapy selection pressure in promoting dysregulated SL metabolism, a characteristic in cancer and an exploitable target for therapy.
MeSH term(s)	Animals ; Antineoplastic Agents/pharmacology ; Apoptosis ; Ceramides/metabolism ; Drug Resistance, Neoplasm ; Enzymes/metabolism ; Humans ; Neoplasms/drug therapy ; Neoplasms/enzymology ; Neoplasms/pathology ; Sphingolipids/metabolism
Chemical Substances	Antineoplastic Agents ; Ceramides ; Enzymes ; Sphingolipids
Language	English
Publishing date	2018-06-05
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	127-2
ISSN	2162-5557 ; 0065-230X
ISSN (online)	2162-5557
ISSN	0065-230X
DOI	10.1016/bs.acr.2018.04.013
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Article ; Online: Therapeutic effectiveness of Ocimum basilicum extract on bovine cutaneous papillomatosis

AbdulRahman A. Saied / Ashraf A. El-Ghoneimy / Abdel-latif Seddek / Sary Kh. AbdelGhafar / Samy A.F. Morad

SVU-International Journal of Veterinary Sciences, Vol 3, Iss 2, Pp 60-

2020 Volume 77

Abstract: Bovine cutaneous papillomatosis is a common cutaneous disease of cattle in the Egyptian veterinary field. Ocimum basilicum L. (Rehan) is one of the aromatic plants originating in Asia and Africa. Many studies showed that Ocimum basilicum has interesting ... ...

Abstract	Bovine cutaneous papillomatosis is a common cutaneous disease of cattle in the Egyptian veterinary field. Ocimum basilicum L. (Rehan) is one of the aromatic plants originating in Asia and Africa. Many studies showed that Ocimum basilicum has interesting antiviral and anticancer activities. However, there is no report demonstrating the clinical significance of the anti-papilloma activity of Ocimum basilicum against bovine skin papillomas. Thus, our study was designed to evaluate the therapeutic potential of Ocimum basilicum extract (OBEx) as an anti-papilloma agent against bovine papillomatosis. OBEx was prepared and undergone phytochemical analysis that revealed presence of alkaloids, phenolics, and flavonoids. Ten cutaneous papillomatosis-infected cattle were diagnosed clinically and histopathologically. Animals were treated with OBEx ointment 2% that topically applied daily and papillomas regression was recorded weekly. Clinically, papillomas started to disappear from the 7th - 21st day after the start of treatment. Histopathological analysis showed improvement in histological features of wart tissue returning to the normal skin structure with presence of lymphocytic infiltration. We concluded that the topical application of OBEx is an effective, promising alternative, cheap, and easily apply agent for treatment of skin papilloma.
Keywords	basil leaf (ocimum basilicum) ; clinicopathological ; bovine cutaneous papillomatosis ; effectiveness ; Agriculture ; S ; Veterinary medicine ; SF600-1100
Subject code	630
Language	English
Publishing date	2020-09-01T00:00:00Z
Publisher	South Valley University
Document type	Article ; Online
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Article: Tamoxifen regulation of sphingolipid metabolism--Therapeutic implications.

Morad, Samy A F / Cabot, Myles C

Biochimica et biophysica acta

2015 Volume 1851, Issue 9, Page(s) 1134–1145

Abstract: Tamoxifen, a triphenylethylene antiestrogen and one of the first-line endocrine therapies used to treat estrogen receptor-positive breast cancer, has a number of interesting, off-target effects, and among these is the inhibition of sphingolipid ... ...

Abstract	Tamoxifen, a triphenylethylene antiestrogen and one of the first-line endocrine therapies used to treat estrogen receptor-positive breast cancer, has a number of interesting, off-target effects, and among these is the inhibition of sphingolipid metabolism. More specifically, tamoxifen inhibits ceramide glycosylation, and enzymatic step that can adventitiously support the influential tumor-suppressor properties of ceramide, the aliphatic backbone of sphingolipids. Additionally, tamoxifen and metabolites N-desmethyltamoxifen and 4-hydroxytamoxifen, have been shown to inhibit ceramide hydrolysis by the enzyme acid ceramidase. This particular intervention slows ceramide destruction and thereby depresses formation of sphingosine 1-phosphate, a mitogenic sphingolipid with cancer growth-promoting properties. As ceramide-centric therapies are becoming appealing clinical interventions in the treatment of cancer, agents like tamoxifen that can retard the generation of mitogenic sphingolipids and buffer ceramide clearance via inhibition of glycosylation, take on new importance. In this review, we present an abridged, lay introduction to sphingolipid metabolism, briefly chronicle tamoxifen's history in the clinic, examine studies that demonstrate the impact of triphenylethylenes on sphingolipid metabolism in cancer cells, and canvass works relevant to the use of tamoxifen as adjuvant to drive ceramide-centric therapies in cancer treatment. The objective is to inform the readership of what could be a novel, off-label indication of tamoxifen and structurally-related triphenylethylenes, an indication divorced from estrogen receptor status and one with application in drug resistance.
MeSH term(s)	Acid Ceramidase/antagonists & inhibitors ; Acid Ceramidase/metabolism ; Antineoplastic Agents, Hormonal/metabolism ; Antineoplastic Agents, Hormonal/pharmacology ; Biotransformation ; Breast Neoplasms/drug therapy ; Breast Neoplasms/metabolism ; Breast Neoplasms/pathology ; Ceramides/metabolism ; Drug Resistance, Neoplasm ; Female ; Humans ; Hydrolysis ; Lipid Metabolism/drug effects ; Lysophospholipids/antagonists & inhibitors ; Lysophospholipids/metabolism ; Sphingosine/analogs & derivatives ; Sphingosine/antagonists & inhibitors ; Sphingosine/metabolism ; Tamoxifen/analogs & derivatives ; Tamoxifen/metabolism ; Tamoxifen/pharmacology
Chemical Substances	Antineoplastic Agents, Hormonal ; Ceramides ; Lysophospholipids ; Tamoxifen (094ZI81Y45) ; afimoxifene (17197F0KYM) ; sphingosine 1-phosphate (26993-30-6) ; Acid Ceramidase (EC 3.5.1.23) ; Sphingosine (NGZ37HRE42) ; N-desmethyltamoxifen (OOJ759O35C)
Language	English
Publishing date	2015-09
Publishing country	Netherlands
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	60-7
ISSN	1879-2596 ; 1879-260X ; 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)	1879-2596 ; 1879-260X ; 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.bbalip.2015.05.001
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Article: Tamoxifen regulation of sphingolipid metabolism—Therapeutic implications

Morad, Samy A.F / Myles C. Cabot

Biochimica et biophysica acta. 2015 Sept., v. 1851, no. 9

2015

Abstract	Tamoxifen, a triphenylethylene antiestrogen and one of the first-line endocrine therapies used to treat estrogen receptor-positive breast cancer, has a number of interesting, off-target effects, and among these is the inhibition of sphingolipid metabolism. More specifically, tamoxifen inhibits ceramide glycosylation, and enzymatic step that can adventitiously support the influential tumor-suppressor properties of ceramide, the aliphatic backbone of sphingolipids. Additionally, tamoxifen and metabolites N-desmethyltamoxifen and 4-hydroxytamoxifen, have been shown to inhibit ceramide hydrolysis by the enzyme acid ceramidase. This particular intervention slows ceramide destruction and thereby depresses formation of sphingosine 1-phosphate, a mitogenic sphingolipid with cancer growth-promoting properties. As ceramide-centric therapies are becoming appealing clinical interventions in the treatment of cancer, agents like tamoxifen that can retard the generation of mitogenic sphingolipids and buffer ceramide clearance via inhibition of glycosylation, take on new importance. In this review, we present an abridged, lay introduction to sphingolipid metabolism, briefly chronicle tamoxifen's history in the clinic, examine studies that demonstrate the impact of triphenylethylenes on sphingolipid metabolism in cancer cells, and canvass works relevant to the use of tamoxifen as adjuvant to drive ceramide-centric therapies in cancer treatment. The objective is to inform the readership of what could be a novel, off-label indication of tamoxifen and structurally-related triphenylethylenes, an indication divorced from estrogen receptor status and one with application in drug resistance.
Keywords	adjuvants ; breast neoplasms ; ceramides ; drug resistance ; enzymatic hydrolysis ; estrogen receptors ; glycosylation ; metabolism ; metabolites ; neoplasm cells ; sphingosine ; tamoxifen
Language	English
Dates of publication	2015-09
Size	p. 1134-1145.
Publishing place	Elsevier B.V.
Document type	Article
ISSN	1388-1981
DOI	10.1016/j.bbalip.2015.05.001
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Wound-Healing Activity of Green and Chemical Zinc Oxide Nanoparticles (ZnO-NPs) Gels in Equine Wounds

Asmaa A. Metwally / Abdel-Nasser A.A. Abdel-Hady / Khaled Ebnalwaled / Samy A.F. Morad / Ahmed A. Soliman

SVU-International Journal of Veterinary Sciences, Vol 3, Iss 1, Pp 66-

A clinical Study

2019 Volume 79

Abstract: This study was aimed to evaluate the wound healing activity of both green and chemical Zinc oxide Nanoparticles in equine. Ten animals (nine donkeys and one horse) suffered from traumatized infected or non-infected wounds were used in this study. The ... ...

Abstract	This study was aimed to evaluate the wound healing activity of both green and chemical Zinc oxide Nanoparticles in equine. Ten animals (nine donkeys and one horse) suffered from traumatized infected or non-infected wounds were used in this study. The visible signs of wound infection were evaluated in six cases, while the other four cases were admitted with fresh recent wounds. Animals were topically treated once a day in and day out and monitored for three weeks. It was observed that, the macroscopic wound contraction percents in animals treated with green Zinc oxide Nanoparticles gel in 1st, 2nd and 3rd weeks were 45%, 76%, and 93.6% respectively. While, those which treated with chemical Zinc oxide Nanoparticles gel were 40.4%, 67.2%, and 90.6% respectively. The study revealed that, green Zinc oxide Nanoparticles gel accelerated the wound healing and cleared the wound infection faster when compared to chemical Zinc oxide Nanoparticles gel. It was concluded that, topical green Zinc oxide Nanoparticles gel can significantly accelerate the process of wound healing and clear the wound infections in wounded equine from clinical field cases.
Keywords	green zno-nps ; gel ; wound healing ; lawsonia inermis extract ; clinical efficacy ; equine ; Agriculture ; S ; Veterinary medicine ; SF600-1100
Subject code	630 ; 620
Language	English
Publishing date	2019-03-01T00:00:00Z
Publisher	South Valley University
Document type	Article ; Online
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Article: Therapeutic effectiveness of Ocimum basilicum extract on bovine cutaneous papillomatosis

AbdulRahman A. Saied / Ashraf A. El-Ghoneimy / Abdel-latif Seddek / Sary Kh. AbdelGhafar / Samy A.F. Morad

SVU- International Journal of Veterinary Sciences. 2020 Sept., v. 3, no. 2

2020

Abstract	Bovine cutaneous papillomatosis is a common cutaneous disease of cattle in the Egyptian veterinary field. Ocimum basilicum L. (Rehan) is one of the aromatic plants originating in Asia and Africa. Many studies showed that Ocimum basilicum has interesting antiviral and anticancer activities. However, there is no report demonstrating the clinical significance of the anti-papilloma activity of Ocimum basilicum against bovine skin papillomas. Thus, our study was designed to evaluate the therapeutic potential of Ocimum basilicum extract (OBEx) as an anti-papilloma agent against bovine papillomatosis. OBEx was prepared and undergone phytochemical analysis that revealed presence of alkaloids, phenolics, and flavonoids. Ten cutaneous papillomatosis-infected cattle were diagnosed clinically and histopathologically. Animals were treated with OBEx ointment 2% that topically applied daily and papillomas regression was recorded weekly. Clinically, papillomas started to disappear from the 7th - 21st day after the start of treatment. Histopathological analysis showed improvement in histological features of wart tissue returning to the normal skin structure with presence of lymphocytic infiltration. We concluded that the topical application of OBEx is an effective, promising alternative, cheap, and easily apply agent for treatment of skin papilloma.
Keywords	Ocimum basilicum ; cattle ; flavonoids ; histology ; histopathology ; ointments ; papilloma ; phenolic compounds ; topical application ; Africa ; Asia
Language	English
Dates of publication	2020-09
Size	p. 60-77.
Publishing place	South Valley University
Document type	Article
ZDB-ID	2941832-X
ISSN	2535-1877 ; 2535-1826
ISSN (online)	2535-1877
ISSN	2535-1826
DOI	10.21608/svu.2020.35596.1067
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Article ; Online: Ceramide-orchestrated signalling in cancer cells.

Morad, Samy A F / Cabot, Myles C

Nature reviews. Cancer

2012 Volume 13, Issue 1, Page(s) 51–65

Abstract: One crucial barrier to progress in the treatment of cancer has been the inability to control the balance between cell proliferation and apoptosis: enter ceramide. Discoveries over the past 15 years have elevated this sphingolipid to the lofty position of ...

Abstract	One crucial barrier to progress in the treatment of cancer has been the inability to control the balance between cell proliferation and apoptosis: enter ceramide. Discoveries over the past 15 years have elevated this sphingolipid to the lofty position of a regulator of cell fate. Ceramide, it turns out, is a powerful tumour suppressor, potentiating signalling events that drive apoptosis, autophagic responses and cell cycle arrest. However, defects in ceramide generation and metabolism in cancer cells contribute to tumour cell survival and resistance to chemotherapy. This Review focuses on ceramide signalling and the targeting of specific metabolic junctures to amplify the tumour suppressive activities of ceramide. The potential of ceramide-based therapeutics in the treatment of cancer is also discussed.
MeSH term(s)	Animals ; Ceramides/therapeutic use ; Humans ; Neoplasms/drug therapy ; Neoplasms/pathology ; Signal Transduction/drug effects
Chemical Substances	Ceramides
Language	English
Publishing date	2012-12-13
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2062767-1
ISSN	1474-1768 ; 1474-175X
ISSN (online)	1474-1768
ISSN	1474-175X
DOI	10.1038/nrc3398
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Article ; Online: Inhibition of the renal apical sodium dependent bile acid transporter prevents cholemic nephropathy in mice with obstructive cholestasis.

Ghallab, Ahmed / González, Daniela / Strängberg, Ellen / Hofmann, Ute / Myllys, Maiju / Hassan, Reham / Hobloss, Zaynab / Brackhagen, Lisa / Begher-Tibbe, Brigitte / Duda, Julia C / Drenda, Carolin / Kappenberg, Franziska / Reinders, Joerg / Friebel, Adrian / Vucur, Mihael / Turajski, Monika / Seddek, Abdel-Latief / Abbas, Tahany / Abdelmageed, Noha /

Morad, Samy A F / Morad, Walaa / Hamdy, Amira / Albrecht, Wiebke / Kittana, Naim / Assali, Mohyeddin / Vartak, Nachiket / van Thriel, Christoph / Sous, Ansam / Nell, Patrick / Villar-Fernandez, Maria / Cadenas, Cristina / Genc, Erhan / Marchan, Rosemarie / Luedde, Tom / Åkerblad, Peter / Mattsson, Jan / Marschall, Hanns-Ulrich / Hoehme, Stefan / Stirnimann, Guido / Schwab, Matthias / Boor, Peter / Amann, Kerstin / Schmitz, Jessica / Bräsen, Jan H / Rahnenführer, Jörg / Edlund, Karolina / Karpen, Saul J / Simbrunner, Benedikt / Reiberger, Thomas / Mandorfer, Mattias / Trauner, Michael / Dawson, Paul A / Lindström, Erik / Hengstler, Jan G

Journal of hepatology

2023 Volume 80, Issue 2, Page(s) 268–281

Abstract: Background & aims: Cholemic nephropathy (CN) is a severe complication of cholestatic liver diseases for which there is no specific treatment. We revisited its pathophysiology with the aim of identifying novel therapeutic strategies.: Methods: ... ...

Abstract	Background & aims: Cholemic nephropathy (CN) is a severe complication of cholestatic liver diseases for which there is no specific treatment. We revisited its pathophysiology with the aim of identifying novel therapeutic strategies. Methods: Cholestasis was induced by bile duct ligation (BDL) in mice. Bile flux in kidneys and livers was visualized by intravital imaging, supported by MALDI mass spectrometry imaging and liquid chromatography-tandem mass spectrometry. The effect of AS0369, a systemically bioavailable apical sodium-dependent bile acid transporter (ASBT) inhibitor, was evaluated by intravital imaging, RNA-sequencing, histological, blood, and urine analyses. Translational relevance was assessed in kidney biopsies from patients with CN, mice with a humanized bile acid (BA) spectrum, and via analysis of serum BAs and KIM-1 (kidney injury molecule 1) in patients with liver disease and hyperbilirubinemia. Results: Proximal tubular epithelial cells (TECs) reabsorbed and enriched BAs, leading to oxidative stress and death of proximal TECs, casts in distal tubules and collecting ducts, peritubular capillary leakiness, and glomerular cysts. Renal ASBT inhibition by AS0369 blocked BA uptake into TECs and prevented kidney injury up to 6 weeks after BDL. Similar results were obtained in mice with humanized BA composition. In patients with advanced liver disease, serum BAs were the main determinant of KIM-1 levels. ASBT expression in TECs was preserved in biopsies from patients with CN, further highlighting the translational potential of targeting ASBT to treat CN. Conclusions: BA enrichment in proximal TECs followed by oxidative stress and cell death is a key early event in CN. Inhibiting renal ASBT and consequently BA enrichment in TECs prevents CN and systemically decreases BA concentrations. Impact and implications: Cholemic nephropathy (CN) is a severe complication of cholestasis and an unmet clinical need. We demonstrate that CN is triggered by the renal accumulation of bile acids (BAs) that are considerably increased in the systemic blood. Specifically, the proximal tubular epithelial cells of the kidney take up BAs via the apical sodium-dependent bile acid transporter (ASBT). We developed a therapeutic compound that blocks ASBT in the kidneys, prevents BA overload in tubular epithelial cells, and almost completely abolished all disease hallmarks in a CN mouse model. Renal ASBT inhibition represents a potential therapeutic strategy for patients with CN.
MeSH term(s)	Humans ; Mice ; Animals ; Cholestasis/complications ; Cholestasis/metabolism ; Kidney/metabolism ; Symporters/metabolism ; Kidney Diseases ; Bile Acids and Salts/metabolism ; Liver/metabolism ; Bile Ducts/metabolism ; Liver Diseases/metabolism ; Sodium ; Carrier Proteins ; Membrane Glycoproteins ; Organic Anion Transporters, Sodium-Dependent
Chemical Substances	bile acid binding proteins ; sodium-bile acid cotransporter (145420-23-1) ; Symporters ; Bile Acids and Salts ; Sodium (9NEZ333N27) ; Carrier Proteins ; Membrane Glycoproteins ; Organic Anion Transporters, Sodium-Dependent
Language	English
Publishing date	2023-11-07
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	605953-3
ISSN	1600-0641 ; 0168-8278
ISSN (online)	1600-0641
ISSN	0168-8278
DOI	10.1016/j.jhep.2023.10.035
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In stock of ZB MED Cologne/Königswinter

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