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Molecular Mechanisms and Biomarkers in Drug-Induced Organ Injury

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 December 2020) | Viewed by 49091

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Special Issue Editor

Prof. Dr. Satohiro Masuda

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Division of Clinical Pharmaceutics, Department of Pharmaceutical Health Care, Faculty of Pharmaceutical Sciences, Himeji Dokkyo University, Himeji 670-0896, Japan
Interests: biomarker; nephrology; pharmacogenomics; immunosuppressive drugs; drug transporter; liver transplantation; kidney transplantation; inflammatory bowel disease; antiinfective agent; therapeutic drug monitoring
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Dear Colleagues,

Biomarkers reflecting, predicting, and associating pharmacological effects and/or toxicological disorders have been widely examined. Candidate molecules that act as potential biomarkers for drug-induced organ toxicity have been discovered. Endogenous compounds are well-applied in the clinical setting, such as creatinine, Na⁺, blood urea nitrogen, aminotransferase, bilirubin, and so on. Despite these classical markers, some peptides and miRNAs have been examined as new types of biomarkers.

In the field of nephrotoxicity, serum creatinine is usually examined for use as a conventional marker for renal damage in clinical treatment. However, this biochemical parameter is acknowledged to be non-specific to cover drug-induced kidney injury. Similar to kidney injury, drug-induced liver, lung, and bone marrow injury are often observed in pharmacotherapy and chemotherapy. Therefore, some organ-specific and/or drug-specific biological markers including functional proteins, peptides, nucleic acids, fatty acids, miRNAs, and so on are required to make accurate diagnosis.

Recently, the research area of biomarkers in pharmacology and toxicology has been expanded to find the physiological and pathophysiological significance in molecular-biological processes. With these exciting findings, this Special issue focuses on “Molecular Mechanisms and Biomarkers in Drug-Induced Organ Injury”.

Prof. Dr. Satohiro Masuda
Guest Editor

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Keywords

molecular mechanisms and biomarkers in drug-induced kidney injury
molecular mechanisms and biomarkers in drug-induced liver injury
molecular mechanisms and biomarkers in drug-induced lung injury
molecular mechanisms and biomarkers in drug-induced neuropathy
molecular mechanisms and biomarkers in drug-induced bone marrow injury
cancer chemotherapy
anti-infectious treatment
immunosuppressive drugs
anti-diabetic drugs
cardiovascular treatment
anti-inflammatory bowel disease
treatment against autoimmune disease

Related Special Issues

Biomarkers in Drug-Induced Organ Injury in International Journal of Molecular Sciences (10 articles)
Molecular Mechanisms and Biomarkers in Drug-Associated Organ Injury in International Journal of Molecular Sciences (1 article)

Published Papers (14 papers)

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14 pages, 1689 KiB

Open AccessArticle

Urinary Exosomes Identify Inflammatory Pathways in Vancomycin Associated Acute Kidney Injury

by Linda Awdishu, Amy Le, Jordan Amato, Vidhyut Jani, Soma Bal, Robert H. Mills, Marvic Carrillo-Terrazas, David J. Gonzalez, Ashita Tolwani, Anjali Acharya, Jorge Cerda, Melanie S. Joy, Paola Nicoletti, Etienne Macedo, Sucheta Vaingankar, Ravindra Mehta, Satish P. RamachandraRao and on behalf of the Direct Investigators

Int. J. Mol. Sci. 2021, 22(6), 2784; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22062784 - 10 Mar 2021

Cited by 17 | Viewed by 2769

Abstract

Background: Vancomycin is commonly used as a first line therapy for gram positive organisms such as methicillin resistant Staphylococcusaureus. Vancomycin-induced acute kidney injury (V-AKI) has been reported in up to 43% of patients, especially in those with higher targeted trough concentrations. The precise mechanism of injury in humans remains elusive, with recent evidence directed towards proximal tubule cell apoptosis. In this study, we investigated the protein contents of urinary exosomes in patients with V-AKI to further elucidate biomarkers of mechanisms of injury and potential responses. Methods: Urine samples from patients with V-AKI who were enrolled in the DIRECT study and matched healthy controls from the UAB-UCSD O’Brien Center Biorepository were included in the analysis. Exosomes were extracted using solvent exclusion principle and polyethylene glycol induced precipitation. Protein identity and quantification was determined by label-free liquid chromatography mass spectrometry (LC/MS). The mean peak serum creatinine was 3.7 ± 1.4 mg/dL and time to kidney injury was 4.0 ± 3.0 days. At discharge, 90% of patients demonstrated partial recovery; 33% experienced full recovery by day 28. Proteomic analyses on five V-AKI and 7 control samples revealed 2009 proteins in all samples and 251 proteins significantly associated with V-AKI (Pi-score > 1). The top discriminatory proteins were complement C3, complement C4, galectin-3-binding protein, fibrinogen, alpha-2 macroglobulin, immunoglobulin heavy constant mu and serotransferrin. Conclusion: Urinary exosomes reveal up-regulation of inflammatory proteins after nephrotoxic injury in V-AKI. Further studies are necessary in a large patient sample to confirm these findings for elucidation of pathophysiologic mechanisms and validation of potential injury biomarkers. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Biomarkers in Drug-Induced Organ Injury)

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13 pages, 4431 KiB

Open AccessArticle

Suppressed Hepatic Production of Indoxyl Sulfate Attenuates Cisplatin-Induced Acute Kidney Injury in Sulfotransferase 1a1-Deficient Mice

by Nozomi Yabuuchi, Huixian Hou, Nao Gunda, Yuki Narita, Hirofumi Jono and Hideyuki Saito

Int. J. Mol. Sci. 2021, 22(4), 1764; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22041764 - 10 Feb 2021

Cited by 12 | Viewed by 2508

Abstract

Endogenous factors involved in the progression of cisplatin nephropathy remain undetermined. Here, we demonstrate the toxico-pathological roles of indoxyl sulfate (IS), a sulfate-conjugated uremic toxin, and sulfotransferase 1A1 (SULT1A1), an enzyme involved in its synthesis, in cisplatin-induced acute kidney injury using Sult1a1-deficient (Sult1a1^-/- KO) mice. With cisplatin administration, severe kidney dysfunction, tissue damage, and apoptosis were attenuated in Sult1a1^-/- (KO) mice. Aryl hydrocarbon receptor (AhR) expression was increased by treatment with cisplatin in mouse kidney tissue. Moreover, the downregulation of antioxidant stress enzymes in wild-type (WT) mice was not observed in Sult1a1^-/- (KO) mice. To investigate the effect of IS on the reactive oxygen species (ROS) levels, HK-2 cells were treated with cisplatin and IS. The ROS levels were significantly increased compared to cisplatin or IS treatment alone. IS-induced increases in ROS were reversed by downregulation of AhR, xanthine oxidase (XO), and NADPH oxidase 4 (NOX4). These findings suggest that SULT1A1 plays toxico-pathological roles in the progression of cisplatin-induced acute kidney injury, while the IS/AhR/ROS axis brings about oxidative stress. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Biomarkers in Drug-Induced Organ Injury)

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17 pages, 5876 KiB

Open AccessArticle

Aesculetin Attenuates Alveolar Injury and Fibrosis Induced by Close Contact of Alveolar Epithelial Cells with Blood-Derived Macrophages via IL-8 Signaling

by Su Yeon Oh, Yun-Ho Kim, Min-Kyung Kang, Eun-Jung Lee, Dong Yeon Kim, Hyeongjoo Oh, Soo-Il Kim, Woojin Na and Young-Hee Kang

Int. J. Mol. Sci. 2020, 21(15), 5518; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21155518 - 01 Aug 2020

Cited by 10 | Viewed by 3601

Abstract

Pulmonary fibrosis is a disease in which lung tissues become fibrous and thereby causes severe respiratory disturbances. Various stimuli induce infiltration of macrophages to the respiratory tract, secreting inflammatory cytokines, which subsequently leads to the development of pulmonary fibrosis. Aesculetin, a major component of the sancho tree and chicory, is known to biologically have antioxidant and anti-inflammatory effects. Human alveolar epithelial A549 cells were cultured for 24 h in conditioned media of THP-1 monocyte-derived macrophages (mCM) with 1–20 μM aesculetin. Micromolar aesculetin attenuated the cytotoxicity of mCM containing inflammatory tumor necrosis factor-α (TNF)-α and interleukin (IL)-8 as major cytokines. Aesculetin inhibited alveolar epithelial induction of the mesenchymal markers in mCM-exposed/IL-8-loaded A549 cells (≈47–51% inhibition), while epithelial markers were induced in aesculetin-treated cells subject to mCM/IL-8 (≈1.5–2.3-fold induction). Aesculetin added to mCM-stimulated A549 cells abrogated the collagen production and alveolar epithelial CXC-chemokine receptor 2 (CXCR2) induction. The production of matrix metalloproteinase (MMP) proteins in mCM-loaded A549 cells was reduced by aesculetin (≈52% reduction), in parallel with its increase in tissue inhibitor of metalloproteinases (TIMP) proteins (≈1.8-fold increase). In addition, aesculetin enhanced epithelial induction of tight junction proteins in mCM-/IL-8-exposed cells (≈2.3–2.5-fold induction). The inhalation of polyhexamethylene guanidine (PHMG) in mice accompanied neutrophil predominance in bronchoalveolar lavage fluid (BALF) and macrophage infiltration in alveoli, which was inhibited by orally administrating aesculetin to mice. Treating aesculetin to mice alleviated PHMG-induced IL-8-mediated subepithelial fibrosis and airway barrier disruption. Taken together, aesculetin may antagonize pulmonary fibrosis and alveolar epithelial barrier disruption stimulated by the infiltration of monocyte-derived macrophages, which is typical of PHMG toxicity, involving interaction of IL-8 and CXCR2. Aesculetin maybe a promising agent counteracting macrophage-mediated inflammation-associated pulmonary disorders. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Biomarkers in Drug-Induced Organ Injury)

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15 pages, 3433 KiB

Open AccessArticle

CYP3A5 Genotype as a Potential Pharmacodynamic Biomarker for Tacrolimus Therapy in Ulcerative Colitis in Japanese Patients

by Yuki Yamamoto, Hiroshi Nakase, Minoru Matsuura, Shihoko Maruyama and Satohiro Masuda

Int. J. Mol. Sci. 2020, 21(12), 4347; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21124347 - 18 Jun 2020

Cited by 4 | Viewed by 3263

Abstract

Tacrolimus has been used to induce remission in patients with steroid-refractory ulcerative colitis. It poses a problem of large individual differences in dosage necessary to attain target blood concentration and, often, this leads to drug inefficacy. We examined the difference in mRNA expression levels of ATP binding cassette transporter B1 (ABCB1) between inflamed and non-inflamed tissues, and the influence of CYP3A5 genotype on tacrolimus therapy. The mRNA expression of CYP3A4 in colonic mucosa and that of cytochrome p450 3A5 (CYP3A5) and ABCB1 in inflamed and non-inflamed areas were examined in 14 subjects. The mRNA expression levels of CYP3A5 were higher than that of CYP3A4. The mRNA expression of ABCB1 was lower in the inflamed than in the non-inflamed mucosa, despite that of CYP3A5 mRNA level being not significantly changed. Hence, the deterioration of the disease is related to the reduction of the barrier in the inflamed mucosa. The relationship between CYP3A5 genotype and blood concentration, dose, and concentration/dose (C/D) ratio of tacrolimus in 15 subjects was studied. The tacrolimus dose to maintain equivalent blood concentrations was lower in CYP3A5*3/*3 than in CYP3A5*1 carriers, and the C/D ratio was significantly higher in the latter. Thus, CYP3A5 polymorphism information played a role in determining the initial dose of tacrolimus. Furthermore, since the effect of tacrolimus appears earlier in CYP3A5*3/*3 than in CYP3A5*1/*1 and *1/*3, it seems necessary to change the evaluation time of therapeutic effect by CYP3A5 genotype. Additionally, the relationship between CYP3A5 genotype and C/D ratio of tacrolimus in colonic mucosa was investigated in 10 subjects. Tacrolimus concentration in the mucosa was two-fold higher in CYP3A5*3/*3 than in CYP3A5*1 carriers, although no significant difference in tacrolimus-blood levels was observed. Therefore, the local concentration of tacrolimus affected by CYP3A5 polymorphism might be related to its therapeutic effect. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Biomarkers in Drug-Induced Organ Injury)

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20 pages, 3116 KiB

Open AccessArticle

An Evaluation of the In Vitro Roles and Mechanisms of Silibinin in Reducing Pyrazinamide- and Isoniazid-Induced Hepatocellular Damage

by Zhang-He Goh, Jie Kai Tee and Han Kiat Ho

Int. J. Mol. Sci. 2020, 21(10), 3714; https://doi.org/10.3390/ijms21103714 - 25 May 2020

Cited by 10 | Viewed by 3844

Abstract

Tuberculosis remains a significant infectious lung disease that affects millions of patients worldwide. Despite numerous existing drug regimens for tuberculosis, drug-induced liver injury is a major challenge that limits the effectiveness of these therapeutics. Two drugs that form the backbone of the commonly administered quadruple antitubercular regimen, that is, pyrazinamide (PZA) and isoniazid (INH), are associated with such hepatotoxicity. Yet, we lack safe and effective alternatives to the antitubercular regimen. Consequently, current research largely focuses on exploiting the hepatoprotective effect of nutraceutical compounds as complementary therapy. Silibinin, a herbal product widely believed to protect against various liver diseases, potentially provides a useful solution given its hepatoprotective mechanisms. In our study, we identified silibinin’s role in mitigating PZA- and INH-induced hepatotoxicity and elucidated a deeper mechanistic understanding of silibinin’s hepatoprotective ability. Silibinin preserved the viability of human foetal hepatocyte line LO2 when co-administered with 80 mM INH and decreased apoptosis induced by a combination of 40 mM INH and 10 mM PZA by reducing oxidative damage to mitochondria, proteins, and lipids. Taken together, this proof-of-concept forms the rational basis for the further investigation of silibinin’s hepatoprotective effect in subsequent preclinical studies and clinical trials. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Biomarkers in Drug-Induced Organ Injury)

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11 pages, 1601 KiB

Open AccessArticle

Donor CYP3A5 Gene Polymorphism Alone Cannot Predict Tacrolimus Intrarenal Concentration in Renal Transplant Recipients

by Mengyu Zhang, Soichiro Tajima, Tomohiro Shigematsu, Rao Fu, Hiroshi Noguchi, Keizo Kaku, Akihiro Tsuchimoto, Yasuhiro Okabe, Nobuaki Egashira and Satohiro Masuda

Int. J. Mol. Sci. 2020, 21(8), 2976; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21082976 - 23 Apr 2020

Cited by 6 | Viewed by 2856

Abstract

CYP3A5 gene polymorphism in recipients plays an important role in tacrolimus blood pharmacokinetics after renal transplantation. Even though CYP3A5 protein is expressed in renal tubular cells, little is known about the influence on the tacrolimus intrarenal exposure and hence graft outcome. The aim of our study was to investigate how the tacrolimus intrarenal concentration (C_tissue) could be predicted based on donor CYP3A5 gene polymorphism in renal transplant recipients. A total of 52 Japanese renal transplant patients receiving tacrolimus were enrolled in this study. Seventy-four renal biopsy specimens were obtained at 3 months and 1 year after transplantation to determine the donor CYP3A5 polymorphism and measure the C_tissue by liquid chromatography-tandem mass spectrometry (LC-MS-MS). The tacrolimus C_tissue ranged from 52 to 399 pg/mg tissue (n = 74) and was weak but significantly correlated with tacrolimus trough concentration (C₀) at 3 months after transplantation (Spearman, r = 0.3560, p = 0.0096). No significant relationship was observed between the donor CYP3A5 gene polymorphism and C_tissue or C_tissue/C₀. These data showed that the tacrolimus systemic level has an impact on tacrolimus renal accumulation after renal transplantation. However, donor CYP3A5 gene polymorphism alone cannot be used to predict tacrolimus intrarenal exposure_. This study may be valuable for exploring tacrolimus renal metabolism and toxicology mechanism in renal transplant recipients. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Biomarkers in Drug-Induced Organ Injury)

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17 pages, 4287 KiB

Open AccessArticle

Influence of POR*28 Polymorphisms on CYP3A5*3-Associated Variations in Tacrolimus Blood Levels at an Early Stage after Liver Transplantation

by Takahiro Nakamura, Mio Fukuda, Ryosuke Matsukane, Kimitaka Suetsugu, Noboru Harada, Tomoharu Yoshizumi, Nobuaki Egashira, Masaki Mori and Satohiro Masuda

Int. J. Mol. Sci. 2020, 21(7), 2287; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21072287 - 26 Mar 2020

Cited by 9 | Viewed by 2929

Abstract

It is well known that the CYP3A5*3 polymorphism is an important marker that correlates with the tacrolimus dose requirement after organ transplantation. Recently, it has been revealed that the POR*28 polymorphism affects the pharmacokinetics of tacrolimus in renal transplant patients. In this study, we examined whether POR*28 as well as CYP3A5*3 polymorphism in Japanese recipients and donors would be another biomarker for the variation of tacrolimus blood levels in the recipients during the first month after living-donor liver transplantation. We enrolled 65 patients treated with tacrolimus, who underwent liver transplantation between July 2016 and January 2019. Genomic DNA was extracted from whole-blood samples, and genotyping was performed to examine the presence of CYP3A5*3 and POR*28 polymorphisms in the recipients and donors. The CYP3A5*3/*3 genotype (defective CYP3A5) of the recipient (standard partial regression coefficient [median C/D ratio of CYP3A5 expressor vs. CYP3A5 non-expressor, p value]: Pod 1–7, β= −0.389 [1.76 vs. 2.73, p < 0.001]; Pod 8–14, β = −0.345 [2.03 vs. 2.83, p < 0.001]; Pod 15–21, β= −0.417 [1.75 vs. 2.94, p < 0.001]; Pod 22–28, β = −0.627 [1.55 vs. 2.90, p < 0.001]) rather than donor (Pod 1–7, β = n/a [1.88 vs. 2.76]; Pod 8–14, β = n/a [1.99 vs. 2.93]; Pod 15–21, β = −0.175 [1.91 vs. 2.94, p = 0.004]; Pod 22–28, β = n/a [1.61 vs. 2.67]) significantly contributed to the increase in the concentration/dose (C/D) ratio of tacrolimus for at least one month after surgery. We found that the tacrolimus C/D ratio significantly decreased from the third week after transplantation when the recipient carried both CYP3A5*1 (functional CYP3A5) and POR*28 (n = 19 [29.2%], median C/D ratio [inter quartile range] = 1.58 [1.39–2.17]), compared with that in the recipients carrying CYP3A5*1 and POR*1/*1 (n = 8 [12.3%], median C/D ratio [inter quartile range] = 2.23 [2.05–3.06]) (p < 0.001). In conclusion, to our knowledge, this is the first report suggesting that the POR*28 polymorphism is another biomarker for the tacrolimus oral dosage after liver transplantation in patients carrying CYP3A5*1 rather than CYP3A5*3/*3. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Biomarkers in Drug-Induced Organ Injury)

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12 pages, 1507 KiB

Open AccessArticle

Loss of Tumor Suppressor CYLD Expression Triggers Cisplatin Resistance in Oral Squamous Cell Carcinoma

by Naoki Suenaga, Mimi Kuramitsu, Kanae Komure, Ayumi Kanemaru, Kanako Takano, Kazuya Ozeki, Yuka Nishimura, Ryoji Yoshida, Hideki Nakayama, Satoru Shinriki, Hideyuki Saito and Hirofumi Jono

Int. J. Mol. Sci. 2019, 20(20), 5194; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20205194 - 20 Oct 2019

Cited by 28 | Viewed by 2999

Abstract

Cisplatin is one of the most effective chemotherapeutic agents commonly used for several malignancies including oral squamous cell carcinoma (OSCC). Although cisplatin resistance is a major obstacle to effective treatment and is associated with poor prognosis of OSCC patients, the molecular mechanisms by which it develops are largely unknown. Cylindromatosis (CYLD), a deubiquitinating enzyme, acts as a tumor suppressor in several malignancies. Our previous studies have shown that loss of CYLD expression in OSCC tissues is significantly associated with poor prognosis of OSCC patients. Here, we focused on CYLD expression in OSCC cells and determined whether loss of CYLD expression is involved in cisplatin resistance in OSCC and elucidated its molecular mechanism. In this study, to assess the effect of CYLD down-regulation on cisplatin resistance in human OSCC cell lines (SAS), we knocked-down the CYLD expression by using CYLD-specific siRNA. In cisplatin treatment, cell survival rates in CYLD knockdown SAS cells were significantly increased, indicating that CYLD down-regulation caused cisplatin resistance to SAS cells. Our results suggested that cisplatin resistance caused by CYLD down-regulation was associated with the mechanism through which both the reduction of intracellular cisplatin accumulation and the suppression of cisplatin-induced apoptosis via the NF-κB hyperactivation. Moreover, the combination of cisplatin and bortezomib treatment exhibited significant anti-tumor effects on cisplatin resistance caused by CYLD down-regulation in SAS cells. These findings suggest the possibility that loss of CYLD expression may cause cisplatin resistance in OSCC patients through NF-κB hyperactivation and may be associated with poor prognosis in OSCC patients. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Biomarkers in Drug-Induced Organ Injury)

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10 pages, 1084 KiB

Open AccessArticle

Urinary Human Epididymis Secretory Protein 4 as a Useful Biomarker for Subclinical Acute Rejection Three Months after Kidney Transplantation

by Soichiro Tajima, Rao Fu, Tomohiro Shigematsu, Hiroshi Noguchi, Keizo Kaku, Akihiro Tsuchimoto, Yasuhiro Okabe and Satohiro Masuda

Int. J. Mol. Sci. 2019, 20(19), 4699; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20194699 - 22 Sep 2019

Cited by 9 | Viewed by 2968

Abstract

Kidney transplantation is the treatment of choice for patients with advanced chronic kidney disease (CKD) and end stage renal disease (ESRD). However, acute rejection (AR) is a common complication in kidney transplantation and is associated with reduced graft survival. Current diagnosis of AR relies mainly on clinical monitoring including serum creatinine, proteinuria, and confirmation by histopathologic assessment in the biopsy specimen of graft kidney. Although an early protocol biopsy is indispensable for depicting the severity of pathologic lesions in subclinical acute rejection (subAR), it is not acceptable in some cases and cannot be performed because of its invasive nature. Therefore, we examined the detection of noninvasive biomarkers that are closely related to the pathology of subAR in protocol biopsies three months after kidney transplantation. In this study, the urinary level of microtubule-associated protein 1 light chain 3 (LC3), monocyte chemotactic protein-1 (MCP-1), liver-type fatty acid-binding protein (L-FABP), neutrophil gelatinase-associated lipocalin (NGAL), and human epididymis secretory protein 4 (HE4) were measured three months after kidney transplantation. Urine samples of 80 patients undergoing kidney transplantation between August 2014 to September 2016, were prospectively collected after three months. SubAR was observed in 11 patients (13.8%) in protocol biopsy. The urinary levels of LC3, MCP-1, NGAL, and HE4 were significantly higher in patients with subAR than in those without, while those of L-FABP did not differ between the two groups. Multivariate regression models, receiver-operating characteristics (ROC), and areas under ROC curves (AUC) were used to identify predicted values of subAR. Urinary HE4 levels were able to better identify subAR (AUC = 0.808) than the other four urinary biomarkers. In conclusion, urinary HE4 is increased in kidney transplant recipients of subAR three months after kidney transplantation, suggesting that HE4 has the potential to be used as a novel clinical biomarker for predicting subAR. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Biomarkers in Drug-Induced Organ Injury)

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11 pages, 1790 KiB

Open AccessArticle

Edoxaban Exerts Antioxidant Effects Through FXa Inhibition and Direct Radical-Scavenging Activity

by Yuki Narita, Kana Hamamura, Mami Kashiyama, Sara Utsumi, Yutaka Kakizoe, Yuki Kondo, Yoichi Ishitsuka, Hirofumi Jono, Tetsumi Irie, Masashi Mukoyama, Hideyuki Saito, Daisuke Kadowaki, Sumio Hirata and Kenichiro Kitamura

Int. J. Mol. Sci. 2019, 20(17), 4140; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20174140 - 24 Aug 2019

Cited by 8 | Viewed by 2938

Abstract

The interplay between oxidative stress, inflammation, and tissue fibrosis leads to the progression of chronic kidney disease (CKD). Edoxaban, an activated blood coagulation factor Xa (FXa) inhibitor, ameliorates kidney disease by suppressing inflammation and tissue fibrosis in animal models. Interestingly, rivaroxaban, another FXa inhibitor, suppresses oxidative stress induced by FXa. Thus, FXa inhibitors could be multitargeted drugs for the three aforementioned risk factors for the progression of CKD. However, the exact mechanism responsible for eliciting the antioxidant effect of FXa inhibitors remains unclear. In this study, the antioxidant effect of edoxaban was evaluated. First, the intracellular antioxidant properties of edoxaban were evaluated using human proximal tubular cells (HK-2 cells). Next, direct radical scavenging activity was measured using the electron spin resonance and fluorescence analysis methods. Results show that edoxaban exhibited antioxidant effects on oxidative stress induced by FXa, indoxyl sulfate, and angiotensin II in HK-2 cells, as well as the FXa inhibitory activity, was involved in part of the antioxidant mechanism. Moreover, edoxaban exerted its antioxidative effect through its structure-specific direct radical scavenging activity. Edoxaban exerts antioxidant effects by inhibiting FXa and through direct radical-scavenging activity, and thus, may serve as multitargeted drugs for the three primary risk factors associated with progression of CKD. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Biomarkers in Drug-Induced Organ Injury)

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10 pages, 2268 KiB

Open AccessArticle

Neutrophil Gelatinase-Associated Lipocalin Is Not Associated with Tacrolimus-Induced Acute Kidney Injury in Liver Transplant Patients Who Received Mycophenolate Mofetil with Delayed Introduction of Tacrolimus

by Mio Fukuda, Kimitaka Suetsugu, Soichiro Tajima, Yurie Katsube, Hiroyuki Watanabe, Noboru Harada, Tomoharu Yoshizumi, Nobuaki Egashira, Masaki Mori and Satohiro Masuda

Int. J. Mol. Sci. 2019, 20(12), 3103; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20123103 - 25 Jun 2019

Cited by 3 | Viewed by 4934

Abstract

Tacrolimus is widely used as an immunosuppressant in liver transplantation, and tacrolimus-induced acute kidney injury (AKI) is a serious complication. The urinary neutrophil gelatinase-associated lipocalin (NGAL) level has been linked to tacrolimus-induced AKI in patients starting tacrolimus treatment the morning after liver transplantation. Here we tested this association using a different immunosuppression protocol: Mycophenolate mofetil administration beginning on Postoperative Day 1 and tacrolimus administration beginning on Postoperative Day 2 or 3. Urine samples were collected from 26 living donor liver transplant recipients before (Postoperative Day 1) and after (Postoperative Day 7 or 14) tacrolimus administration. NGAL levels were measured via enzyme-linked immunosorbent assays, as were those of three additional urinary biomarkers for kidney diseases: Monocyte chemotactic protein-1 (MCP-1), liver-type fatty acid-binding protein (L-FABP), and human epididymis secretory protein 4 (HE4). HE4 levels after tacrolimus administration were significantly higher in patients who developed AKI (n = 6) than in those who did not (n = 20), whereas NGAL, MCP-1, and L-FABP levels did not differ significantly before or after tacrolimus administration. These findings indicate that NGAL may not be a universal biomarker of AKI in tacrolimus-treated liver transplant recipients. To reduce the likelihood of tacrolimus-induced AKI, our immunosuppression protocol is recommended. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Biomarkers in Drug-Induced Organ Injury)

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16 pages, 957 KiB

Open AccessArticle

Impact of CYP3A5, POR, and CYP2C19 Polymorphisms on Trough Concentration to Dose Ratio of Tacrolimus in Allogeneic Hematopoietic Stem Cell Transplantation

by Kimitaka Suetsugu, Yasuo Mori, Nanae Yamamoto, Tomohiro Shigematsu, Toshihiro Miyamoto, Nobuaki Egashira, Koichi Akashi and Satohiro Masuda

Int. J. Mol. Sci. 2019, 20(10), 2413; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20102413 - 15 May 2019

Cited by 24 | Viewed by 3937

Abstract

Single nucleotide polymorphisms in drug-metabolizing genes may affect tacrolimus pharmacokinetics. Here, we investigated the influence of genotypes of CYP3A5, CYP2C19, and POR on the concentration/dose (C/D) ratio of tacrolimus and episodes of acute graft-versus-host disease (GVHD) in Japanese recipients of allogeneic hematopoietic stem cell transplantation (HSCT). Thirty-six patients receiving the first HSCT using tacrolimus-based GVHD prophylaxis were enrolled with written informed consent. During continuous intravenous infusion, HSCT recipients carrying the CYP3A5*1 allele, particularly those with at least one POR*28 allele, had a significantly lower tacrolimus C/D ratio throughout all three post-HSCT weeks compared to that in recipients with POR*1/*1 (p < 0.05). The CYP3A5*3/*3 genotype and the concomitant use of voriconazole were independent predictors of an increased tacrolimus C/D ratio during the switch from continuous intravenous infusion to oral administration (p < 0.05). In recipients receiving concomitant administration of voriconazole, our results suggest an impact of not only CYP3A5 and CYP2C19 genotypes, but also plasma voriconazole concentration. Although switching from intravenous to oral administration at a ratio of 1:5 was seemingly appropriate in recipients with CYP3A5*1, a lower conversion ratio (1:2–3) was appropriate in recipients with CYP3A5*3/*3. Our results suggest that CYP3A5, POR, and CYP2C19 polymorphisms are useful biomarkers for individualized dosage adjustment of tacrolimus in HSCT recipients. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Biomarkers in Drug-Induced Organ Injury)

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Review

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19 pages, 1992 KiB

Open AccessReview

Protocols for Enzymatic Fluorometric Assays to Quantify Phospholipid Classes

by Shin-ya Morita, Tokuji Tsuji and Tomohiro Terada

Int. J. Mol. Sci. 2020, 21(3), 1032; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21031032 - 04 Feb 2020

Cited by 14 | Viewed by 5125

Abstract

Phospholipids, consisting of a hydrophilic head group and two hydrophobic acyl chains, are essential for the structures of cell membranes, plasma lipoproteins, biliary mixed micelles, pulmonary surfactants, and extracellular vesicles. Beyond their structural roles, phospholipids have important roles in numerous biological processes. Thus, abnormalities in the metabolism and transport of phospholipids are involved in many diseases, including dyslipidemia, atherosclerosis, cholestasis, drug-induced liver injury, neurological diseases, autoimmune diseases, respiratory diseases, myopathies, and cancers. To further clarify the physiological, pathological, and molecular mechanisms and to identify disease biomarkers, we have recently developed enzymatic fluorometric assays for quantifying all major phospholipid classes, phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidic acid, phosphatidylinositol, phosphatidylglycerol + cardiolipin, and sphingomyelin. These assays are specific, sensitive, simple, and high-throughput, and will be applicable to cells, intracellular organelles, tissues, fluids, lipoproteins, and extracellular vesicles. In this review, we present the detailed protocols for the enzymatic fluorometric measurements of phospholipid classes in cultured cells. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Biomarkers in Drug-Induced Organ Injury)

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Diagnostic Biomarkers in Liver Injury by Drugs, Herbs, and Alcohol: Tricky Dilemma after EMA Correctly and Officially Retracted Letter of Support

by Rolf Teschke, Axel Eickhoff, Amy C. Brown, Manuela G. Neuman and Johannes Schulze

Int. J. Mol. Sci. 2020, 21(1), 212; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21010212 - 27 Dec 2019

Cited by 24 | Viewed by 3713

Abstract

Liver injuries caused by the use of exogenous compounds such as drugs, herbs, and alcohol are commonly well diagnosed using laboratory tests, toxin analyses, or eventually reactive intermediates generated during metabolic degradation of the respective chemical in the liver and subject to covalent binding by target proteins. Conditions are somewhat different for idiosyncratic drug induced liver injury (DILI), for which metabolic intermediates as diagnostic aids are rarely available. Although the diagnosis of idiosyncratic DILI can well be established using the validated, liver specific, structured, and quantitative RUCAM (Roussel Uclaf Causality Assessment Method), there is an ongoing search for new diagnostic biomarkers that could assist in and also confirm RUCAM-based DILI diagnoses. With respect to idiosyncratic DILI and following previous regulatory letters of recommendations, selected biomarkers reached the clinical focus, including microRNA-122, microRNA-192, cytokeratin analogues, glutamate dehydrogenase, total HMGB-1 (High Mobility Group Box), and hyperacetylated HMGB-1 proteins. However, the new parameters total HMGB-1, and even more so the acetylated HMGB-1, came under critical scientific fire after misconduct at one of the collaborating partner centers, leading the EMA to recommend no longer the exploratory hyperacetylated HMGB1 isoform biomarkers in clinical studies. The overall promising nature of the recommended biomarkers was considered by EMA as highly dependent on the outstanding results of the now incriminated biomarker hyperacetylated HMGB-1. The EMA therefore correctly decided to officially retract its Letter of Support affecting all biomarkers listed above. New biomarkers are now under heavy scrutiny that will require re-evaluations prior to newly adapted recommendations. With Integrin beta 3 (ITGB3), however, a new diagnostic biomarker may emerge, possibly being drug specific but tested in only 16 patients; due to substantial remaining uncertainties, final recommendations would be premature. In conclusion, most of the currently recommended new biomarkers have lost regulatory support due to scientific misconduct, requiring now innovative approaches and re-evaluation before they can be assimilated into clinical practice. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Biomarkers in Drug-Induced Organ Injury)

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