Submit to IJMS Review for IJMS Propose a Special Issue

Journal Menu

Journal Browser

Drug, Herb, and Dietary Supplement Hepatotoxicity

Special Issue Editors
Special Issue Information
Keywords
Published Papers

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Toxicology".

Deadline for manuscript submissions: closed (29 February 2016) | Viewed by 164730

Share This Special Issue

Special Issue Editors

Prof. Dr. Rolf Teschke

E-Mail
Guest Editor

Department of Internal Medicine II, Division of Gastroenterology and Hepatology, Klinikum Hanau, Teaching Hospital of the Goethe University, 999035 Frankfurt, Germany
Interests: Heavy metals; Heavy metal uptake; Heavy metal disposition, Heavy metal homeostasis; Haber Weiss reaction; Fenton reaction; Benefits and risks for human health; Environmental pollution
Special Issues, Collections and Topics in MDPI journals

Dr. Raúl J. Andrade

E-Mail Website
Guest Editor

1. Liver Unit Gastroenterology Service, Institute for Biomedical Research of Malaga (IBIMA), Virgen de la Victoria University Hospital and School of Medicine, Malaga, Spain
2. “Centro de Investigación Biomédica en Red de Enfermedades Digestivas y Hepáticas” (CIBERehd), Spain
Interests: drug induced liver injury; pharmacogenomics; toxicogenomics; causality assessment; dietary supplements; regulatory issues

Special Issue Information

Dear Colleagues,

Drugs, herbs, and dietary supplements share the common feature of potential hepatotoxicity in a few susceptible individuals. Most of these hepatotoxic reactions are idiosyncratic and, hence, difficult to predict. Treatment commonly consists of the cessation of the incriminated product, but causality attribution may be cumbersome due to the current absence of valid diagnostic biomarkers. To aid diagnosis in hepatotoxicity cases, diagnostic tools are available, such as the CIOMS (Council for International Organization of Medical Sciences) scale, which is also called RUCAM (Rousell Uclaf Causality Assessing Method) and is based on specific diagnostic items with individual scoring, and the DILIN (Drug Induced Liver Injury Network) method, which is expert based. Whereas hepatotoxicity by synthetic drugs is fairly well recognized in clinical practice, hepatoxicity by herbs, herbal drugs, and dietary supplements are rarely suspected. The aim of this Special Issue is to provide a broad overview on these hepatotoxicity entities with their challenges and highlights. We therefore ask experts in the field to contribute their views on this emerging and fascinating topic. Since various topics are still controversial and disputed, we expect and appreciate lively discussions, in addition to well-settled issues, which are relevant to the clinical setting and require balanced statements.

Prof. Dr. Rolf Teschke
Prof. Dr. Raúl J. Andrade
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

Drug induced liver injury
Drug hepatotoxicity
Herb induced liver injury
Herbal hepatotoxicity
Liver injury by dietary supplements
Hepatotoxicity
Drugs
Herbs
Herbal traditional Chines medicine
Dietary supplements
Pharmacogenomics
Toxicogenomics
Prognosis
Chronicity

Published Papers (13 papers)

Download All Papers

Editorial

Jump to: Research, Review

183 KiB

Open AccessEditorial

Drug, Herb, and Dietary Supplement Hepatotoxicity

by Rolf Teschke and Raúl J. Andrade

Int. J. Mol. Sci. 2016, 17(9), 1488; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms17091488 - 06 Sep 2016

Cited by 22 | Viewed by 5105

Abstract

The past decade has witnessed drugs, herbs, and dietary supplements share the common feature of potential liver injury in a few susceptible individuals.[...] Full article

(This article belongs to the Special Issue Drug, Herb, and Dietary Supplement Hepatotoxicity)

Research

Jump to: Editorial, Review

464 KiB

Open AccessArticle

Herb-Induced Liver Injury in the Berlin Case-Control Surveillance Study

by Antonios Douros, Elisabeth Bronder, Frank Andersohn, Andreas Klimpel, Reinhold Kreutz, Edeltraut Garbe and Juliane Bolbrinker

Int. J. Mol. Sci. 2016, 17(1), 114; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms17010114 - 15 Jan 2016

Cited by 30 | Viewed by 10416

Abstract

Herb-induced liver injury (HILI) has recently attracted attention due to increasing reports of hepatotoxicity associated with use of phytotherapeutics. Here, we present data on HILI from the Berlin Case-Control Surveillance Study. The study was initiated in 2000 to investigate the serious toxicity of drugs including herbal medicines. Potential cases of liver injury were ascertained in more than 180 Departments of all 51 Berlin hospitals from October 2002 to December 2011. Drug or herb intake was assessed through a standardized face-to-face interview. Drug or herbal aetiology was assessed based on the updated Council for International Organizations of Medical Sciences scale. In ten of all 198 cases of hepatotoxicity included in the study, herbal aetiology was assessed as probable (once ayurvedic herb) or possible (Valeriana five times, Mentha piperita once, Pelargonium sidoides once, Hypericum perforatum once, Eucalyptus globulus once). Mean age was 56.4 ± 9.7 years, and the predominant pattern of liver injury was hepatocellular. No cases of acute liver failure or death were observed. This case series corroborates known risks for ayurvedic herbs, supports the suspected association between Valeriana use and liver injury, and indicates a hepatotoxic potential for herbs such as Pelargonium sidoides, Hypericum perforatum or Mentha piperita that were rarely associated with liver injury before. However, given that possible causality does not prove clinical significance, further studies in this field are needed. Full article

(This article belongs to the Special Issue Drug, Herb, and Dietary Supplement Hepatotoxicity)

► Show Figures

Graphical abstract

Review

Jump to: Editorial, Research

528 KiB

Open AccessReview

Case Characterization, Clinical Features and Risk Factors in Drug-Induced Liver Injury

by Aida Ortega-Alonso, Camilla Stephens, M. Isabel Lucena and Raúl J. Andrade

Int. J. Mol. Sci. 2016, 17(5), 714; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms17050714 - 12 May 2016

Cited by 67 | Viewed by 8806

Abstract

Idiosyncratic drug-induced liver injury (DILI) caused by xenobiotics (drugs, herbals and dietary supplements) presents with a range of both phenotypes and severity, from acute hepatitis indistinguishable of viral hepatitis to autoimmune syndromes, steatosis or rare chronic vascular syndromes, and from asymptomatic liver test abnormalities to acute liver failure. DILI pathogenesis is complex, depending on the interaction of drug physicochemical properties and host factors. The awareness of risk factors for DILI is arising from the analysis of large databases of DILI cases included in Registries and Consortia networks around the world. These networks are also enabling in-depth phenotyping with the identification of predictors for severe outcome, including acute liver failure and mortality/liver transplantation. Genome wide association studies taking advantage of these large cohorts have identified several alleles from the major histocompatibility complex system indicating a fundamental role of the adaptive immune system in DILI pathogenesis. Correct case definition and characterization is crucial for appropriate phenotyping, which in turn will strengthen sample collection for genotypic and future biomarkers studies. Full article

(This article belongs to the Special Issue Drug, Herb, and Dietary Supplement Hepatotoxicity)

► Show Figures

Graphical abstract

1100 KiB

Open AccessReview

Herbal Hepatotoxicity: Clinical Characteristics and Listing Compilation

by Christian Frenzel and Rolf Teschke

Int. J. Mol. Sci. 2016, 17(5), 588; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms17050588 - 27 Apr 2016

Cited by 96 | Viewed by 16338

Abstract

Herb induced liver injury (HILI) and drug induced liver injury (DILI) share the common characteristic of chemical compounds as their causative agents, which were either produced by the plant or synthetic processes. Both, natural and synthetic chemicals are foreign products to the body and need metabolic degradation to be eliminated. During this process, hepatotoxic metabolites may be generated causing liver injury in susceptible patients. There is uncertainty, whether risk factors such as high lipophilicity or high daily and cumulative doses play a pathogenetic role for HILI, as these are under discussion for DILI. It is also often unclear, whether a HILI case has an idiosyncratic or an intrinsic background. Treatment with herbs of Western medicine or traditional Chinese medicine (TCM) rarely causes elevated liver tests (LT). However, HILI can develop to acute liver failure requiring liver transplantation in single cases. HILI is a diagnosis of exclusion, because clinical features of HILI are not specific as they are also found in many other liver diseases unrelated to herbal use. In strikingly increased liver tests signifying severe liver injury, herbal use has to be stopped. To establish HILI as the cause of liver damage, RUCAM (Roussel Uclaf Causality Assessment Method) is a useful tool. Diagnostic problems may emerge when alternative causes were not carefully excluded and the correct therapy is withheld. Future strategies should focus on RUCAM based causality assessment in suspected HILI cases and more regulatory efforts to provide all herbal medicines and herbal dietary supplements used as medicine with strict regulatory surveillance, considering them as herbal drugs and ascertaining an appropriate risk benefit balance. Full article

(This article belongs to the Special Issue Drug, Herb, and Dietary Supplement Hepatotoxicity)

► Show Figures

Figure 1

1941 KiB

Open AccessReview

Hepatotoxicity Induced by “the 3Ks”: Kava, Kratom and Khat

by Flaminia Pantano, Roberta Tittarelli, Giulio Mannocchi, Simona Zaami, Serafino Ricci, Raffaele Giorgetti, Daniela Terranova, Francesco P. Busardò and Enrico Marinelli

Int. J. Mol. Sci. 2016, 17(4), 580; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms17040580 - 16 Apr 2016

Cited by 69 | Viewed by 20450

Abstract

The 3Ks (kava, kratom and khat) are herbals that can potentially induce liver injuries. On the one hand, growing controversial data have been reported about the hepatotoxicity of kratom, while, on the other hand, even though kava and khat hepatotoxicity has been investigated, the hepatotoxic effects are still not clear. Chronic recreational use of kratom has been associated with rare instances of acute liver injury. Several studies and case reports have suggested that khat is hepatotoxic, leading to deranged liver enzymes and also histopathological evidence of acute hepatocellular degeneration. Numerous reports of severe hepatotoxicity potentially induced by kava have also been highlighted, both in the USA and Europe. The aim of this review is to focus on the different patterns and the mechanisms of hepatotoxicity induced by “the 3Ks”, while trying to clarify the numerous aspects that still need to be addressed. Full article

(This article belongs to the Special Issue Drug, Herb, and Dietary Supplement Hepatotoxicity)

► Show Figures

Figure 1

287 KiB

Open AccessReview

Hepatotoxicity by Dietary Supplements: A Tabular Listing and Clinical Characteristics

by Miren García-Cortés, Mercedes Robles-Díaz, Aida Ortega-Alonso, Inmaculada Medina-Caliz and Raul J. Andrade

Int. J. Mol. Sci. 2016, 17(4), 537; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms17040537 - 09 Apr 2016

Cited by 99 | Viewed by 19558

Abstract

Dietary supplements (DS) are extensively consumed worldwide despite unproven efficacy. The true incidence of DS-induced liver injury (DSILI) is unknown but is probably under-diagnosed due to the general belief of safety of these products. Reported cases of herbals and DS-induced liver injury are increasing worldwide. The aim of this manuscript is to report a tabular listing with a description of DS associated with hepatotoxicity as well as review the phenotype and severity of DSILI. Natural remedies related to hepatotoxicity can be divided into herbal product-induced liver injury and DS-induced liver injury. In this article, we describe different DS associated with liver injury, some of them manufactured DS containing several ingredients (Herbalife™ products, Hydroxycut™, LipoKinetix™, UCP-1 and OxyELITE™) while others have a single ingredient (green tea extract, linoleic acid, usnic acid, 1,3-Dimethylamylamine, vitamin A, Garcinia cambogia and ma huang). Additional DS containing some of the aforementioned ingredients implicated in liver injury are also covered. We have also included illicit androgenic anabolic steroids for bodybuilding in this work, as they are frequently sold under the denomination of DS despite being conventional drugs. Full article

(This article belongs to the Special Issue Drug, Herb, and Dietary Supplement Hepatotoxicity)

► Show Figures

Graphical abstract

379 KiB

Open AccessReview

The Honolulu Liver Disease Cluster at the Medical Center: Its Mysteries and Challenges

by Rolf Teschke and Axel Eickhoff

Int. J. Mol. Sci. 2016, 17(4), 476; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms17040476 - 31 Mar 2016

Cited by 26 | Viewed by 6412

Abstract

In 2013, physicians at the Honolulu Queen’s Medical Center (QMC) noticed that seven liver disease patients reported the use of OxyELITE Pro (OEP), a widely consumed dietary supplement (DS). Assuming a temporal association between OEP use and disease, they argued that OEP was the cause of this mysterious cluster. Subsequent reexamination, however, has revealed that this QMC cohort is heterogeneous and not a cluster with a single agent causing a single disease. It is heterogeneous because patients used multiple DS’s and drugs and because patients appeared to have suffered from multiple liver diseases: liver cirrhosis, liver failure by acetaminophen, hepatotoxicity by non-steroidal antiinflammatory drugs (NSAIDs), resolving acute viral hepatitis by hepatitis B virus (HBV), herpes simplex virus (HSV), and varicella zoster virus (VZV), and suspected hepatitis E virus (HEV). Failing to exclude these confounders and to consider more viable diagnoses, the QMC physicians may have missed specific treatment options in some of their patients. The QMC physicians unjustifiably upgraded their Roussel Uclaf Causality Assessment Method (RUCAM) causality scores so that all patients would appear to be “probable” for OEP. However, subsequent RUCAM reassessments by our group demonstrated a lack of causality for OEP in the evaluated QMC cases. The QMC’s questionable approaches explain the extraordinary accumulation of suspected OEP cases at the QMC in Hawaii as single place, whereas similar cohorts were not published by any larger US liver center, substantiating that the problem is with the QMC. In this review article, we present and discuss new case data and critically evaluate upcoming developments of problematic regulatory assessments by the US Centers for Disease Control and Prevention (CDC), the Hawaii Department of Health (HDOH), and the Food and Drug Administration (FDA), as based on invalid QMC conclusions, clarifying now also basic facts and facilitating constructive discussions. Full article

(This article belongs to the Special Issue Drug, Herb, and Dietary Supplement Hepatotoxicity)

► Show Figures

Graphical abstract

317 KiB

Open AccessReview

Scientific and Regulatory Perspectives in Herbal and Dietary Supplement Associated Hepatotoxicity in the United States

by Mark I. Avigan, Robert P. Mozersky and Leonard B. Seeff

Int. J. Mol. Sci. 2016, 17(3), 331; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms17030331 - 03 Mar 2016

Cited by 84 | Viewed by 13463

Abstract

In the United States (US), the risk of hepatotoxicity linked to the widespread use of certain herbal products has gained increased attention among regulatory scientists. Based on current US law, all dietary supplements sold domestically, including botanical supplements, are regulated by the Food and Drug Administration (FDA) as a special category of foods. Under this designation, regulatory scientists do not routinely evaluate the efficacy of these products prior to their marketing, despite the content variability and phytochemical complexity that often characterizes them. Nonetheless, there has been notable progress in the development of advanced scientific methods to qualitatively and quantitatively measure ingredients and screen for contaminants and adulterants in botanical products when hepatotoxicity is recognized. Full article

(This article belongs to the Special Issue Drug, Herb, and Dietary Supplement Hepatotoxicity)

► Show Figures

Graphical abstract

554 KiB

Open AccessReview

The Latin American DILI Registry Experience: A Successful Ongoing Collaborative Strategic Initiative

by Fernando Bessone, Nelia Hernandez, M. Isabel Lucena, Raúl J. Andrade and On behalf of the Latin DILI Network (LATINDILIN) and Spanish DILI Registry

Int. J. Mol. Sci. 2016, 17(3), 313; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms17030313 - 29 Feb 2016

Cited by 48 | Viewed by 5980

Abstract

Drug induced liver injury (DILI) is a rare but well recognized serious adverse reaction. Pre-marketing studies may not detect liver injury, and DILI becomes very often apparent after the drug is launched to the market. Specific biomarkers for DILI prediction or diagnosis are not available. Toxic liver reactions present with a wide spectrum of phenotypes and severity, and our knowledge on the mechanisms underlying idiosyncratic reactions and individual susceptibility is still limited. To overcome these limitations, country-based registries and multicenter research networks have been created in Europe and North America. Reliable epidemiological data on DILI in Latin America (LA), a region with a large variety of ethnic groups, were however lacking. Fortunately, a LA network of DILI was set up in 2011, with the support of the Spanish DILI Registry from the University of Malaga. The primary aim of the Latin DILI Network (LATINDILIN) Registry was to prospectively identify bona fide DILI cases and to collect biological samples to study genetic biomarkers. Physicians involved in the project must complete a structured report form describing the DILI case presentation and follow-up which is submitted to a Coordinator Center in each country, where it is further assessed for completeness. During the last four years, several LA countries (Argentina, Uruguay, Chile, Mexico, Paraguay, Brazil, Ecuador, Peru, Venezuela and Colombia) have joined the network and committed with this project. At that point, to identify both our strengths and weaknesses was a very important issue. In this review, we will describe how the LATINDILI Registry was created. The aims and methods to achieve these objectives will be discussed in depth. Additionally, both the difficulties we have faced and the strategies to solve them will be also pinpointed. Finally, we will report on our preliminary results, and discuss ideas to expand and to keep running this network. Full article

(This article belongs to the Special Issue Drug, Herb, and Dietary Supplement Hepatotoxicity)

► Show Figures

Graphical abstract

698 KiB

Open AccessReview

Herbal Medicine in Mexico: A Cause of Hepatotoxicity. A Critical Review

by Bárbara Valdivia-Correa, Cristina Gómez-Gutiérrez, Misael Uribe and Nahum Méndez-Sánchez

Int. J. Mol. Sci. 2016, 17(2), 235; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms17020235 - 15 Feb 2016

Cited by 39 | Viewed by 10597

Abstract

In Mexico, herbal products are commonly used as therapeutic tools. The analysis of several publications reveals that there are dozens of different herbs and herbal products used for different reasons, some of which have been implicated in causing toxic liver disease. However, methodological aspects limit the attribution of causality, and the precise incidence and clinical manifestations of herb-induced liver injury have not been well characterized. This review outlines the history of traditional herbal medicine in Mexico, critically summarizes the mechanisms and adverse effects of commonly used herbal plants, and examines the regulatory issues regarding the legal use of these products. Full article

(This article belongs to the Special Issue Drug, Herb, and Dietary Supplement Hepatotoxicity)

► Show Figures

Figure 1

175 KiB

Open AccessReview

Hepatotoxicity by Drugs: The Most Common Implicated Agents

by Einar S. Björnsson

Int. J. Mol. Sci. 2016, 17(2), 224; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms17020224 - 06 Feb 2016

Cited by 176 | Viewed by 14254

Abstract

Idiosyncratic drug-induced liver injury (DILI) is an underreported and underestimated adverse drug reaction. Information on the documented hepatotoxicity of drugs has recently been made available by a website that can be accessed in the public domain: LiverTox (http://livertox.nlm.nih.gov). According to critical analysis of the hepatotoxicity of drugs in LiverTox, 53% of drugs had at least one case report of convincing reports of liver injury. Only 48 drugs had more than 50 case reports of DILI. Amoxicillin-clavulanate is the most commonly implicated agent leading to DILI in the prospective series. In a recent prospective study, liver injury due to amoxicillin-clavulanate was found to occur in approximately one out of 2300 users. Drugs with the highest risk of DILI in this study were azathioprine and infliximab. Full article

(This article belongs to the Special Issue Drug, Herb, and Dietary Supplement Hepatotoxicity)

721 KiB

Open AccessReview

Drug-Induced Liver Injury Network Causality Assessment: Criteria and Experience in the United States

by Paul H. Hayashi

Int. J. Mol. Sci. 2016, 17(2), 201; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms17020201 - 04 Feb 2016

Cited by 53 | Viewed by 6132

Abstract

Hepatotoxicity due to drugs, herbal or dietary supplements remains largely a clinical diagnosis based on meticulous history taking and exclusion of other causes of liver injury. In 2004, the U.S. Drug-Induced Liver Injury Network (DILIN) was created under the auspices of the U.S. National Institute of Diabetes and Digestive and Kidney Diseases with the aims of establishing a large registry of cases for clinical, epidemiological and mechanistic study. From inception, the DILIN has used an expert opinion process that incorporates consensus amongst three different DILIN hepatologists assigned to each case. It is the most well-established, well-described and vigorous expert opinion process for DILI to date, and yet it is an imperfect standard. This review will discuss the DILIN expert opinion process, its strengths and weaknesses, psychometric performance and future. Full article

(This article belongs to the Special Issue Drug, Herb, and Dietary Supplement Hepatotoxicity)

► Show Figures

Figure 1

629 KiB

Open AccessReview

RUCAM in Drug and Herb Induced Liver Injury: The Update

by Gaby Danan and Rolf Teschke

Int. J. Mol. Sci. 2016, 17(1), 14; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms17010014 - 24 Dec 2015

Cited by 460 | Viewed by 25875

Abstract

RUCAM (Roussel Uclaf Causality Assessment Method) or its previous synonym CIOMS (Council for International Organizations of Medical Sciences) is a well established tool in common use to quantitatively assess causality in cases of suspected drug induced liver injury (DILI) and herb induced liver injury (HILI). Historical background and the original work confirm the use of RUCAM as single term for future cases, dismissing now the term CIOMS for reasons of simplicity and clarity. RUCAM represents a structured, standardized, validated, and hepatotoxicity specific diagnostic approach that attributes scores to individual key items, providing final quantitative gradings of causality for each suspect drug/herb in a case report. Experts from Europe and the United States had previously established in consensus meetings the first criteria of RUCAM to meet the requirements of clinicians and practitioners in care for their patients with suspected DILI and HILI. RUCAM was completed by additional criteria and validated, assisting to establish the timely diagnosis with a high degree of certainty. In many countries and for more than two decades, physicians, regulatory agencies, case report authors, and pharmaceutical companies successfully applied RUCAM for suspected DILI and HILI. Their practical experience, emerging new data on DILI and HILI characteristics, and few ambiguous questions in domains such alcohol use and exclusions of non-drug causes led to the present update of RUCAM. The aim was to reduce interobserver and intraobserver variability, to provide accurately defined, objective core elements, and to simplify the handling of the items. We now present the update of the well accepted original RUCAM scale and recommend its use for clinical, regulatory, publication, and expert purposes to validly establish causality in cases of suspected DILI and HILI, facilitating a straightforward application and an internationally harmonized approach of causality assessment as a common basic tool. Full article

(This article belongs to the Special Issue Drug, Herb, and Dietary Supplement Hepatotoxicity)

► Show Figures

Figure 1

Journal Menu

Journal Browser

Drug, Herb, and Dietary Supplement Hepatotoxicity

Share This Special Issue

Special Issue Editors

Special Issue Information

Keywords

Published Papers (13 papers)

Editorial

Research

Review

Further Information

Guidelines

MDPI Initiatives

Follow MDPI