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Article ; Online: Modulation of IRAK enzymes as a therapeutic strategy against SARS-CoV-2 induced cytokine storm.

Mahmoud, Ismail Sami / Jarrar, Yazun Bashir / Febrimarsa

2023 Volume 23, Issue 6, Page(s) 2909–2923

Abstract: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of the current pandemic coronavirus disease 2019 (COVID-19). Dysregulated and excessive production of cytokines and chemokines, known as cytokine storm, is frequently seen in ... ...

Abstract	Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of the current pandemic coronavirus disease 2019 (COVID-19). Dysregulated and excessive production of cytokines and chemokines, known as cytokine storm, is frequently seen in patients with severe COVID-19 disease and it can provoke a severe systematic inflammation in the patients. The IL-1R/TLRs/IRAKs signaling network is a key pathway in immune cells that plays a central role in regulating innate immunity and inflammatory responses via stimulating the expression and production of various proinflammatory molecules including cytokines. Modulation of IRAKs activity has been proposed to be a promising strategy in the treatment of inflammatory disorders. In this review, we highlight the biochemical properties of IRAKs and their role in regulating inflammatory molecular signaling pathways and discuss the potential targeting of IRAKs to suppress the SARS-CoV-2-induced cytokine storm in COVID-19 patients.
MeSH term(s)	Humans ; COVID-19 ; Cytokine Release Syndrome/drug therapy ; Cytokines ; Immunity, Innate ; SARS-CoV-2
Chemical Substances	Cytokines
Language	English
Publishing date	2023-04-15
Publishing country	Italy
Document type	Journal Article ; Review
ZDB-ID	2053018-3
ISSN	1591-9528 ; 1591-8890
ISSN (online)	1591-9528
ISSN	1591-8890
DOI	10.1007/s10238-023-01064-7
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Article ; Online: Targeting the intestinal TMPRSS2 protease to prevent SARS-CoV-2 entry into enterocytes-prospects and challenges.

Mahmoud, Ismail Sami / Jarrar, Yazun Bashir

Molecular biology reports

2021 Volume 48, Issue 5, Page(s) 4667–4675

Abstract: The transmembrane protease serine 2 (TMPRSS2) is a membrane anchored protease that primarily expressed by epithelial cells of respiratory and gastrointestinal systems and has been linked to multiple pathological processes in humans including tumor growth, ...

Abstract	The transmembrane protease serine 2 (TMPRSS2) is a membrane anchored protease that primarily expressed by epithelial cells of respiratory and gastrointestinal systems and has been linked to multiple pathological processes in humans including tumor growth, metastasis and viral infections. Recent studies have shown that TMPRSS2 expressed on cell surface of host cells could play a crucial role in activation of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein which facilitates the rapid early entry of the virus into host cells. In addition, direct suppression of TMPRSS2 using small drug inhibitors has been demonstrated to be effective in decreasing SARS-CoV-2 infection in vitro, which presents TMPRSS2 protease as a potential therapeutic strategy for SARS-CoV-2 infection. Recently, SARS-CoV-2 has been shown to be capable of infecting gastrointestinal enterocytes and to provoke gastrointestinal disorders in patients with COVID-19 disease, which is considered as a new transmission route and target organ of SARS-CoV-2. In this review, we highlight the biochemical properties of TMPRSS2 protease and discuss the potential targeting of TMPRSS2 by inhibitors to prevent the SARS-CoV-2 spreading through gastro-intestinal tract system as well as the hurdles that need to be overcome.
MeSH term(s)	Antiviral Agents/pharmacology ; COVID-19/metabolism ; Drug Evaluation, Preclinical ; Enterocytes/drug effects ; Enterocytes/metabolism ; Enterocytes/virology ; Humans ; SARS-CoV-2/drug effects ; SARS-CoV-2/physiology ; Serine Endopeptidases/metabolism ; Serine Proteinase Inhibitors/pharmacology ; Small Molecule Libraries/pharmacology ; Spike Glycoprotein, Coronavirus/metabolism ; Virus Internalization/drug effects ; COVID-19 Drug Treatment
Chemical Substances	Antiviral Agents ; Serine Proteinase Inhibitors ; Small Molecule Libraries ; Spike Glycoprotein, Coronavirus ; spike protein, SARS-CoV-2 ; Serine Endopeptidases (EC 3.4.21.-) ; TMPRSS2 protein, human (EC 3.4.21.-)
Language	English
Publishing date	2021-05-22
Publishing country	Netherlands
Document type	Journal Article ; Review
ZDB-ID	186544-4
ISSN	1573-4978 ; 0301-4851
ISSN (online)	1573-4978
ISSN	0301-4851
DOI	10.1007/s11033-021-06390-1
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Article: Targeting the intestinal TMPRSS2 protease to prevent SARS-CoV-2 entry into enterocytes-prospects and challenges

Mahmoud, Ismail Sami / Jarrar, Yazun Bashir

Molecular biology reports. 2021 May, v. 48, no. 5

2021

Abstract	The transmembrane protease serine 2 (TMPRSS2) is a membrane anchored protease that primarily expressed by epithelial cells of respiratory and gastrointestinal systems and has been linked to multiple pathological processes in humans including tumor growth, metastasis and viral infections. Recent studies have shown that TMPRSS2 expressed on cell surface of host cells could play a crucial role in activation of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein which facilitates the rapid early entry of the virus into host cells. In addition, direct suppression of TMPRSS2 using small drug inhibitors has been demonstrated to be effective in decreasing SARS-CoV-2 infection in vitro, which presents TMPRSS2 protease as a potential therapeutic strategy for SARS-CoV-2 infection. Recently, SARS-CoV-2 has been shown to be capable of infecting gastrointestinal enterocytes and to provoke gastrointestinal disorders in patients with COVID-19 disease, which is considered as a new transmission route and target organ of SARS-CoV-2. In this review, we highlight the biochemical properties of TMPRSS2 protease and discuss the potential targeting of TMPRSS2 by inhibitors to prevent the SARS-CoV-2 spreading through gastro-intestinal tract system as well as the hurdles that need to be overcome.
Keywords	COVID-19 infection ; Severe acute respiratory syndrome coronavirus 2 ; digestive tract ; drugs ; enterocytes ; metastasis ; molecular biology ; neoplasms ; proteinases ; serine ; therapeutics ; viruses
Language	English
Dates of publication	2021-05
Size	p. 4667-4675.
Publishing place	Springer Netherlands
Document type	Article
Note	Review
ZDB-ID	186544-4
ISSN	1573-4978 ; 0301-4851
ISSN (online)	1573-4978
ISSN	0301-4851
DOI	10.1007/s11033-021-06390-1
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Article ; Online: 1,4-Naphthoquinone Induces FcRn Protein Expression and Albumin Recycling in Human THP-1 Cells.

Esawi, Ezaldeen Ismael / Mahmoud, Ismail Sami / Abdullah, Mohammad Salah / Abuarqoub, Duaa Azmi / Ahram, Mamoun Ahmad / Alshaer, Walhan Mohammad

ACS omega

2023 Volume 8, Issue 18, Page(s) 16491–16499

Abstract: The neonatal Fc receptor (FcRn) has been established as a major factor in regulating the metabolism of albumin and IgG in humans by protecting them from intracellular degradation after they are endocytosed into cells. We assume that increasing the levels ...

Abstract	The neonatal Fc receptor (FcRn) has been established as a major factor in regulating the metabolism of albumin and IgG in humans by protecting them from intracellular degradation after they are endocytosed into cells. We assume that increasing the levels of endogenous FcRn proteins in cells would be beneficial to enhance the recycling of these molecules. In this study, we identify the compound 1,4-naphthoquinone as an efficient stimulator of FcRn protein expression in human THP-1 monocytic cells with potency at the submicromolar range. Also, the compound increased the subcellular localization of FcRn to the endocytic recycling compartment and enhanced human serum albumin recycling in the PMA-induced THP-1 cells. These results suggest that 1,4-naphthoquinone stimulates FcRn expression and activity in human monocytic cells
Language	English
Publishing date	2023-04-25
Publishing country	United States
Document type	Journal Article
ISSN	2470-1343
ISSN (online)	2470-1343
DOI	10.1021/acsomega.3c01678
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Article ; Online: Doxorubicin conjugates: a practical approach for its cardiotoxicity alleviation.

Ibrahim, Abed Alqader / Nsairat, Hamdi / Al-Sulaibi, Mazen / El-Tanani, Mohamed / Jaber, Areej M / Lafi, Zainab / Barakat, Rahmeh / Abuarqoub, Duaa Azmi / Mahmoud, Ismail Sami / Obare, Sherine O / Aljabali, Alaa A A / Alkilany, Alaaldin M / Alshaer, Walhan

Expert opinion on drug delivery

2024 , Page(s) 1–24

Abstract: Introduction: Doxorubicin (DOX) emerges as a cornerstone in the arsenal of potent chemotherapeutic agents. Yet, the clinical deployment of DOX is tarnished by its proclivity to induce severe cardiotoxic effects, culminating in heart failure and other ... ...

Abstract	Introduction: Doxorubicin (DOX) emerges as a cornerstone in the arsenal of potent chemotherapeutic agents. Yet, the clinical deployment of DOX is tarnished by its proclivity to induce severe cardiotoxic effects, culminating in heart failure and other consequential morbidities. In response, a panoply of strategies has undergone rigorous exploration over recent decades, all aimed at attenuating DOX's cardiotoxic impact. The advent of encapsulating DOX within lipidic or polymeric nanocarriers has yielded a dual triumph, augmenting DOX's therapeutic efficacy while mitigating its deleterious side effects. Areas covered: Recent strides have spotlighted the emergence of DOX conjugates as particularly auspicious avenues for ameliorating DOX-induced cardiotoxicity. These conjugates entail the fusion of DOX through physical or chemical bonds with diminutive natural or synthetic moieties, polymers, biomolecules, and nanoparticles. This spectrum encompasses interventions that impinge upon DOX's cardiotoxic mechanism, modulate cellular uptake and localization, confer antioxidative properties, or refine cellular targeting. Expert opinion: The endorsement of DOX conjugates as a compelling stratagem to mitigate DOX-induced cardiotoxicity resounds from this exegesis, amplifying safety margins and the therapeutic profile of this venerated chemotherapeutic agent. Within this ambit, DOX conjugates stand as a beacon of promise in the perpetual pursuit of refining chemotherapy-induced cardiac compromise.
Language	English
Publishing date	2024-04-21
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	2167286-6
ISSN	1744-7593 ; 1742-5247
ISSN (online)	1744-7593
ISSN	1742-5247
DOI	10.1080/17425247.2024.2343882
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Article ; Online: SARS-CoV-2 entry in host cells-multiple targets for treatment and prevention.

Mahmoud, Ismail Sami / Jarrar, Yazun Bashir / Alshaer, Walhan / Ismail, Said

Biochimie

2020 Volume 175, Page(s) 93–98

Abstract: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a new viral disease that has gained global attention owing to its ability to provoke community and health-care-associated outbreaks of severe infections in human populations. The virus poses ...

Abstract	Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a new viral disease that has gained global attention owing to its ability to provoke community and health-care-associated outbreaks of severe infections in human populations. The virus poses serious challenges to clinical management because there are still no approved anti- SARS-CoV-2 drugs available. In this mini-review, we summarize the much updated published reports that demonstrate the mechanism of SARS-CoV-2 entry into host cells, and discuss the availability and development of attractive host-based therapeutic options for SARS-CoV-2 infections.
MeSH term(s)	Betacoronavirus/metabolism ; Betacoronavirus/pathogenicity ; COVID-19 ; Coronavirus Infections/metabolism ; Coronavirus Infections/therapy ; Host-Pathogen Interactions/physiology ; Humans ; Pandemics ; Pneumonia, Viral/metabolism ; Pneumonia, Viral/therapy ; SARS-CoV-2 ; Virus Internalization
Keywords	covid19
Language	English
Publishing date	2020-05-29
Publishing country	France
Document type	Journal Article ; Review
ZDB-ID	120345-9
ISSN	1638-6183 ; 0300-9084
ISSN (online)	1638-6183
ISSN	0300-9084
DOI	10.1016/j.biochi.2020.05.012
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Article ; Online: Aptamer-Aptamer Chimera for Targeted Delivery and ATP-Responsive Release of Doxorubicin into Cancer Cells.

Esawi, Ezaldeen / Alshaer, Walhan / Mahmoud, Ismail Sami / Alqudah, Dana A / Azab, Bilal / Awidi, Abdalla

International journal of molecular sciences

2021 Volume 22, Issue 23

Abstract: Aptamers offer a great opportunity to develop innovative drug delivery systems that can deliver cargos specifically into targeted cells. In this study, a chimera consisting of two aptamers was developed to deliver doxorubicin into cancer cells and ... ...

Abstract	Aptamers offer a great opportunity to develop innovative drug delivery systems that can deliver cargos specifically into targeted cells. In this study, a chimera consisting of two aptamers was developed to deliver doxorubicin into cancer cells and release the drug in cytoplasm in response to adenosine-5'-triphosphate (ATP) binding. The chimera was composed of the AS1411 anti-nucleolin aptamer for cancer cell targeting and the ATP aptamer for loading and triggering the release of doxorubicin in cells. The chimera was first produced by hybridizing the ATP aptamer with its complementary DNA sequence, which is linked with the AS1411 aptamer via a poly-thymine linker. Doxorubicin was then loaded inside the hybridized DNA region of the chimera. Our results show that the AS1411-ATP aptamer chimera was able to release loaded doxorubicin in cells in response to ATP. In addition, selective uptake of the chimera into cancer cells was demonstrated using flow cytometry. Furthermore, confocal laser scanning microscopy showed the successful delivery of the doxorubicin loaded in chimeras to the nuclei of targeted cells. Moreover, the doxorubicin-loaded chimeras effectively inhibited the growth of cancer cell lines and reduced the cytotoxic effect on the normal cells. Overall, the results of this study show that the AS1411-ATP aptamer chimera could be used as an innovative approach for the selective delivery of doxorubicin to cancer cells, which may improve the therapeutic potency and decrease the off-target cytotoxicity of doxorubicin.
MeSH term(s)	Humans ; Adenosine Triphosphate/metabolism ; Aptamers, Nucleotide/administration & dosage ; Aptamers, Nucleotide/blood ; Aptamers, Nucleotide/genetics ; Cell Line, Tumor ; Doxorubicin/administration & dosage ; Drug Delivery Systems/methods ; Drug Design ; Drug Stability ; In Vitro Techniques ; MCF-7 Cells ; Molecular Targeted Therapy ; Neoplasms/drug therapy ; Oligodeoxyribonucleotides/administration & dosage ; Oligodeoxyribonucleotides/blood ; Oligodeoxyribonucleotides/genetics ; Phosphoproteins/antagonists & inhibitors ; RNA-Binding Proteins/antagonists & inhibitors ; Nucleolin
Chemical Substances	Adenosine Triphosphate (8L70Q75FXE) ; AGRO 100 ; Aptamers, Nucleotide ; Doxorubicin (80168379AG) ; Oligodeoxyribonucleotides ; Phosphoproteins ; RNA-Binding Proteins
Language	English
Publishing date	2021-11-30
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms222312940
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Article: SARS-CoV-2 entry in host cells-multiple targets for treatment and prevention

Mahmoud, Ismail Sami / Jarrar, Yazun Bashir / Alshaer, Walhan / Ismail, Said

Biochimie. 2020 Aug., v. 175

2020

Abstract	Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a new viral disease that has gained global attention owing to its ability to provoke community and health-care-associated outbreaks of severe infections in human populations. The virus poses serious challenges to clinical management because there are still no approved anti- SARS-CoV-2 drugs available. In this mini-review, we summarize the much updated published reports that demonstrate the mechanism of SARS-CoV-2 entry into host cells, and discuss the availability and development of attractive host-based therapeutic options for SARS-CoV-2 infections.
Keywords	Severe acute respiratory syndrome coronavirus 2 ; humans ; therapeutics ; viruses
Language	English
Dates of publication	2020-08
Size	p. 93-98.
Publishing place	Elsevier B.V.
Document type	Article
Note	NAL-AP-2-clean
ZDB-ID	120345-9
ISSN	0300-9084
ISSN	0300-9084
DOI	10.1016/j.biochi.2020.05.012
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Article ; Online: 1,4-Naphthoquinone Is a Potent Inhibitor of IRAK1 Kinases and the Production of Inflammatory Cytokines in THP-1 Differentiated Macrophages.

Mahmoud, Ismail Sami / Hatmal, Ma'mon M / Abuarqoub, Duaa / Esawi, Ezaldeen / Zalloum, Hiba / Wehaibi, Suha / Nsairat, Hamdi / Alshaer, Walhan

ACS omega

2021 Volume 6, Issue 39, Page(s) 25299–25310

Abstract: Quinones are a class of cyclic organic compounds that are widely distributed in nature and have been shown to exhibit anti-inflammatory, antioxidant, and anticancerous activities. However, the molecular mechanisms/signaling by which these molecules exert ...

Abstract	Quinones are a class of cyclic organic compounds that are widely distributed in nature and have been shown to exhibit anti-inflammatory, antioxidant, and anticancerous activities. However, the molecular mechanisms/signaling by which these molecules exert their effect are still not fully understood. In this study, a group of quinone-derived compounds were examined for their potential inhibitory effect against human IRAK1 and IRAK4 kinases
Language	English
Publishing date	2021-09-17
Publishing country	United States
Document type	Journal Article
ISSN	2470-1343
ISSN (online)	2470-1343
DOI	10.1021/acsomega.1c03081
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Article ; Online: No impact of soluble epoxide hydrolase rs4149243, rs2234914 and rs751142 genetic variants on the development of type II diabetes and its hypertensive complication among Jordanian patients.

Khamees, Maysoon / Jarrar, Yazun / Al-Qirim, Tariq / Mahmoud, Ismail Sami / Hatmal, Ma'mon M / Alshaer, Walhan / Lee, Su-Jun

International journal of clinical practice

2021 Volume 75, Issue 5, Page(s) e14036

Abstract: Background: Human soluble epoxide hydrolase plays a major role in cardiovascular homoeostasis. Genetic variants in the EPHX2 gene among different ethnic groups are associated with cardiovascular complications, such as hypertension. However, no reports ... ...

Abstract	Background: Human soluble epoxide hydrolase plays a major role in cardiovascular homoeostasis. Genetic variants in the EPHX2 gene among different ethnic groups are associated with cardiovascular complications, such as hypertension. However, no reports regarding the association of EPHX2 genotype with hypertension among type II diabetic (T2D) patients of Middle Eastern Jordanian origin exist. Objective: The current study aimed to elucidate the association of the EPHX2 allele, genotype and haplotype with T2D, hypertension and parameters of lipid profile parameters among Jordanian T2D patients. Methods: Ninety-three genomic DNA samples of non-diabetic controls and 97 samples from T2D patients were genotyped for EPHX2 rs4149243, rs2234914 and rs751142 genetic variants. The DNA samples were amplified using polymerase chain reaction (PCR) and then sequenced using Applied Biosystems Model (ABI3730x1). The functionality of intronic EPHX2 variants was predicted using the in silico Berkely Drosophila Genome Project software. Results: We found no significant (P >.05) association between the EPHX2 rs4149243, rs2234914 and rs751142 allele, genotype and haplotype and the incidence of T2D and hypertension. Additionally, no association (P >.05) between these EPHX2 genetic variants with the baseline total cholesterol, low- and high-density lipoproteins and triglycerides among both non-diabetic and diabetic volunteers was found. However, we found an inter-ethnic variation (χ Conclusions: It can be concluded from this study that EPHX2 rs4149243, rs2234914 and rs751142 genetic variants do not play a role in the development of T2D and hypertension among Jordanian T2D patients. Further genetic studies with larger sample sizes are needed to find out the association of other functional EPHX2 variants with cardiovascular diseases among T2D patients in Jordan.
MeSH term(s)	Diabetes Mellitus, Type 2/genetics ; Epoxide Hydrolases/genetics ; Genetic Predisposition to Disease ; Genotype ; Haplotypes ; Humans ; Jordan ; Polymorphism, Single Nucleotide/genetics
Chemical Substances	Epoxide Hydrolases (EC 3.3.2.-)
Language	English
Publishing date	2021-02-06
Publishing country	India
Document type	Journal Article
ZDB-ID	1386246-7
ISSN	1742-1241 ; 1368-5031
ISSN (online)	1742-1241
ISSN	1368-5031
DOI	10.1111/ijcp.14036
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