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Article ; Online: The host targeting effect of chloroquine in malaria.

Coban, Cevayir

2020 Volume 66, Page(s) 98–107

Abstract: Due to the rapid onset and spread of the COVID-19 pandemic, the treatment of COVID-19 patients by hydroxychloroquine alone or in combination with other drugs has captured a great deal of attention and triggered considerable debate. Historically, the ... ...

Abstract	Due to the rapid onset and spread of the COVID-19 pandemic, the treatment of COVID-19 patients by hydroxychloroquine alone or in combination with other drugs has captured a great deal of attention and triggered considerable debate. Historically, the worldwide use of quinoline based-drugs has led to a spectacular reduction in death from malaria. Unfortunately, scientists have been forced to seek alternative drugs to treat malaria due to the emergence of chloroquine-resistant parasites in the 1960s. The repurposing of hydroxychloroquine against viral infections, various types of cancer and autoimmune diseases has been ongoing for more than 70 years, with no clear understanding of its mechanism of action (MOA). Here, we closely examine the MOA of this old but influential drug in and beyond malaria. Better insights into how chloroquine targets the host's cellular and immune responses may help to develop applications against to new pathogens and diseases, and perhaps even restore the clinical utility of chloroquine against malaria.
MeSH term(s)	Animals ; COVID-19/drug therapy ; Chloroquine/pharmacology ; Chloroquine/therapeutic use ; Humans ; Hydroxychloroquine/pharmacology ; Hydroxychloroquine/therapeutic use ; Malaria/drug therapy ; Pandemics/prevention & control ; SARS-CoV-2/drug effects
Chemical Substances	Hydroxychloroquine (4QWG6N8QKH) ; Chloroquine (886U3H6UFF)
Keywords	covid19
Language	English
Publishing date	2020-08-18
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1035767-1
ISSN	1879-0372 ; 0952-7915
ISSN (online)	1879-0372
ISSN	0952-7915
DOI	10.1016/j.coi.2020.07.005
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Article: The host targeting effect of chloroquine in malaria

Coban, Cevayir

Curr Opin Immunol

Abstract	Due to the rapid onset and spread of the COVID-19 pandemic, the treatment of COVID-19 patients by hydroxychloroquine alone or in combination with other drugs has captured a great deal of attention and triggered considerable debate. Historically, the worldwide use of quinoline based-drugs has led to a spectacular reduction in death from malaria. Unfortunately, scientists have been forced to seek alternative drugs to treat malaria due to the emergence of chloroquine-resistant parasites in the 1960s. The repurposing of hydroxychloroquine against viral infections, various types of cancer and autoimmune diseases has been ongoing for more than 70 years, with no clear understanding of its mechanism of action (MOA). Here, we closely examine the MOA of this old but influential drug in and beyond malaria. Better insights into how chloroquine targets the host's cellular and immune responses may help to develop applications against to new pathogens and diseases, and perhaps even restore the clinical utility of chloroquine against malaria.
Keywords	covid19
Publisher	WHO
Document type	Article
Note	WHO #Covidence: #718707
Database	COVID19

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Article: The Programmed Cell Death Ligand 1 and Lipocalin 2 Expressions in Primary Breast Cancer and Their Associations with Molecular Subtypes and Prognostic Factors.

Ekemen, Suheyla / Bilir, Ebru / Soultan, Hagar Elsayed Akram / Zafar, Sadia / Demir, Figen / Tabandeh, Babek / Toprak, Sadik / Yapicier, Ozlem / Coban, Cevayir

Breast cancer (Dove Medical Press)

2024 Volume 16, Page(s) 1–13

Abstract: Purpose: Breast cancers exhibit molecular heterogeneity, leading to diverse clinical outcomes and therapeutic responses. Immune checkpoint inhibitors targeting PD-L1 have shown promise in various malignancies, including breast cancer. Lipocalin 2 (LCN2) ...

Abstract	Purpose: Breast cancers exhibit molecular heterogeneity, leading to diverse clinical outcomes and therapeutic responses. Immune checkpoint inhibitors targeting PD-L1 have shown promise in various malignancies, including breast cancer. Lipocalin 2 (LCN2) has also been associated with tumor aggressiveness and prognostic potential in breast cancers. However, the expression of PD-L1 and LCN2 in breast cancer subtypes and their prognostic implications remains poorly investigated. Methods: A retrospective analysis of 89 primary breast cancer cases was conducted to assess PD-L1 and LCN2 expressions using immunohistochemistry. Cases were classified into four different molecular subtypes based on ER, PR, HER2, and Ki-67 status. Associations between PD-L1 and LCN2 expressions and various prognostic factors were examined. Results: Although low expression of LCN2 (Allred score of <3) was observed even in normal breast tissue, LCN2 expression with increasing Allred score (≥3) positively correlated with the histological grade, high Ki-67 proliferation index, and ER/PR negativity. Significant elevations of LCN2 and PD-L1 expressions were observed in triple-negative and HER2-positive breast cancers. Conclusion: The results of the study highlight the association of LCN2 with known prognostic factors and molecular subtypes. To identify potential immunotherapy recipients, it would be useful to evaluate LCN2 as well as PD-L1 immune targets in different subgroups of breast cancer patients. Further studies with larger patient numbers are warranted to validate these observations and establish standardized scoring criteria for LCN2 expression assessment.
Language	English
Publishing date	2024-01-03
Publishing country	New Zealand
Document type	Journal Article
ZDB-ID	2520722-2
ISSN	1179-1314
ISSN	1179-1314
DOI	10.2147/BCTT.S444077
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Article ; Online: 5,6-dimethylxanthenone-4-acetic acid (DMXAA), a partial STING agonist, competes for human STING activation.

Temizoz, Burcu / Shibahara, Takayuki / Hioki, Kou / Hayashi, Tomoya / Kobiyama, Kouji / Lee, Michelle Sue Jann / Surucu, Naz / Sag, Erdal / Kumanogoh, Atsushi / Yamamoto, Masahiro / Gursel, Mayda / Ozen, Seza / Kuroda, Etsushi / Coban, Cevayir / Ishii, Ken J

Frontiers in immunology

2024 Volume 15, Page(s) 1353336

Abstract: 5,6-dimethylxanthenone-4-acetic acid (DMXAA) is a mouse-selective stimulator of interferon gene (STING) agonist exerting STING-dependent anti-tumor activity. Although DMXAA cannot fully activate human STING, DMXAA reached phase III in lung cancer ... ...

Abstract	5,6-dimethylxanthenone-4-acetic acid (DMXAA) is a mouse-selective stimulator of interferon gene (STING) agonist exerting STING-dependent anti-tumor activity. Although DMXAA cannot fully activate human STING, DMXAA reached phase III in lung cancer clinical trials. How DMXAA is effective against human lung cancer is completely unknown. Here, we show that DMXAA is a partial STING agonist interfering with agonistic STING activation, which may explain its partial anti-tumor effect observed in humans, as STING was reported to be pro-tumorigenic for lung cancer cells with low antigenicity. Furthermore, we developed a DMXAA derivative-3-hydroxy-5-(4-hydroxybenzyl)-4-methyl-9
MeSH term(s)	Humans ; Mice ; Animals ; Membrane Proteins/metabolism ; Leukocytes, Mononuclear/metabolism ; Lung Neoplasms ; Lung/metabolism ; Xanthones
Chemical Substances	vadimezan (0829J8133H) ; Membrane Proteins ; Xanthones
Language	English
Publishing date	2024-03-12
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2024.1353336
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Article ; Online: Unforeseen pathologies caused by malaria.

Lee, Michelle Sue Jann / Coban, Cevayir

International immunology

2018 Volume 30, Issue 3, Page(s) 121–129

Abstract: Individuals from malaria-endemic regions often acquire partial immunity after multiple repeated infections throughout their lives. This partial immunity prevents them from developing severe complications and they often remain asymptomatic with a ... ...

Abstract	Individuals from malaria-endemic regions often acquire partial immunity after multiple repeated infections throughout their lives. This partial immunity prevents them from developing severe complications and they often remain asymptomatic with a persistent, low parasite density in the blood, and therefore the necessity for treatment is neglected. These patients with chronic, asymptomatic malaria serve as a reservoir for Plasmodium parasite transmission, becoming a major obstacle for eradication efforts. The constant exposure to malaria infection may have benefits in the short term by conferring protection from acute, severe malaria; however, it may cause substantially more harm in the long term. Rather than the parasite burden itself, the complications induced by the dysregulated immune responses and the tissue damage done by the parasites and their products can cause chronic and irreversible suffering. Furthermore, the complete clearance of parasites in the body may not lead to complete recovery from the disease as complications can still persist. The fact that there are chronic pathologies caused by malaria that mostly remain obscure and have the potential to cause a serious burden has recently been gaining attention. Here, we present and discuss the evidence of unforeseen pathologies and the risks associated with malaria.
MeSH term(s)	Animals ; Humans ; Malaria/immunology ; Malaria/parasitology ; Malaria/pathology ; Plasmodium/immunology ; Plasmodium/pathogenicity
Language	English
Publishing date	2018-01-03
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1013745-2
ISSN	1460-2377 ; 0953-8178
ISSN (online)	1460-2377
ISSN	0953-8178
DOI	10.1093/intimm/dxx076
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Article ; Online: Acute malaria suppresses the B lymphocytic niche in the bone marrow through the alteration of CXCL12-abundant reticular cells.

Lee, Michelle Sue Jann / Matsuo Dapaah, Julia / Del Rosario Zorrilla, Camila / Omatsu, Yoshiki / Nagasawa, Takashi / Uemura, Shun / Iwama, Atsushi / Ishii, Ken J / Coban, Cevayir

International immunology

2024

Abstract: Bone marrow is a dynamic organ composed of stem cells that constantly receive signals from stromal cells and other hematopoietic cells in the niches of the bone marrow to maintain hematopoiesis and generate immune cells. Perturbation of the bone marrow ... ...

Abstract	Bone marrow is a dynamic organ composed of stem cells that constantly receive signals from stromal cells and other hematopoietic cells in the niches of the bone marrow to maintain hematopoiesis and generate immune cells. Perturbation of the bone marrow microenvironment by infection and inflammation affects hematopoiesis and may affect immune cell development. Little is known about the effect of malaria on the bone marrow stromal cells that govern the hematopoietic stem cell (HSC) niche. In this study, we demonstrate that the mesenchymal stromal CXCL12-abundant reticular (CAR) cell population is reduced during acute malaria infection. The reduction of CXCL12 and IL-7 signals in the bone marrow impairs the lymphopoietic niche, leading to the depletion of common lymphoid progenitors, B cell progenitors and mature B cells, including plasma cells in the bone marrow. We found that IFNγ is responsible for the upregulation of Sca1 on CAR cells, yet the decline in CAR cell and B cell populations in the bone marrow is IFNγ-independent. In contrast to the decline in B cell populations, HSCs and multipotent progenitors increased with expansion of myelopoiesis and erythropoiesis, indicating a bias in the differentiation of multipotent progenitors during malaria infection. These findings suggest that malaria may affect host immunity by modulating the bone marrow niche.
Language	English
Publishing date	2024-03-02
Publishing country	England
Document type	Journal Article
ZDB-ID	1013745-2
ISSN	1460-2377 ; 0953-8178
ISSN (online)	1460-2377
ISSN	0953-8178
DOI	10.1093/intimm/dxae012
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Article ; Online: MyD88 in osteoclast- and osteoblast-lineages differentially controls bone remodeling in homeostasis and malaria.

Alshaweesh, Jalal / Dash, Rashmi / Lee, Michelle S J / Kahyaoglu, Pinar / Erci, Ece / Xu, Mengling / Matsuo-Dapaah, Julia / Del Rosario Zorrilla, Camila / Aykac, Kubra / Ekemen, Suheyla / Kobiyama, Kouji / Ishii, Ken J / Coban, Cevayir

International immunology

2024

Abstract: Chronic bone loss is an under-recognized complication of malaria, the underlying mechanism of which remains incompletely understood. We have previously shown that persistent accumulation of Plasmodium products in the bone marrow leads to chronic ... ...

Abstract	Chronic bone loss is an under-recognized complication of malaria, the underlying mechanism of which remains incompletely understood. We have previously shown that persistent accumulation of Plasmodium products in the bone marrow leads to chronic inflammation in osteoblast (OB) and osteoclast (OC) precursors causing bone loss through MyD88, an adaptor molecule for diverse inflammatory signals. However, the specific contribution of MyD88 signaling in OB or OC precursors in malaria-induced bone loss remains elusive. To assess the direct cell-intrinsic role of MyD88 signaling in adult bone metabolism under physiological and infection conditions, we used the Lox-Cre system to specifically deplete MyD88 in the OB or OC lineages. Mice lacking MyD88 primarily in the maturing OBs showed a comparable decrease in trabecular bone density by microcomputed tomography (µCT) to that of controls after PyNL infection. In contrast, mice lacking MyD88 in OC precursors showed significantly less trabecular bone loss than controls, suggesting that malaria-mediated inflammatory mediators are primarily controlled by MyD88 in the OC lineage. Surprisingly, however, depletion of MyD88 in OB, but not in OC precursors, resulted in reduced bone mass with decreased bone formation rates in the trabecular areas of femurs under physiological conditions. Notably, IGF-1, a key molecule for OB differentiation, was significantly lower locally and systemically when MyD88 was depleted in OBs. Thus, our data demonstrate an indispensable intrinsic role for MyD88 signaling in OB differentiation and bone formation, while MyD88 signaling in OC lineages plays a partial role in controlling malaria-induced inflammatory mediators and following bone pathology. These findings may lead to the identification of novel targets for specific intervention of bone pathologies, particularly in malaria-endemic regions.
Language	English
Publishing date	2024-04-20
Publishing country	England
Document type	Journal Article
ZDB-ID	1013745-2
ISSN	1460-2377 ; 0953-8178
ISSN (online)	1460-2377
ISSN	0953-8178
DOI	10.1093/intimm/dxae023
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Article ; Online: Histone H3.3 variant plays a critical role on zygote-to-oocyst development in malaria parasites.

Tateishi, Yuki S / Araki, Tamasa / Kawai, Satoru / Koide, Shuhei / Umeki, Yuko / Imai, Takashi / Saito-Nakano, Yumiko / Kikuchi, Masaki / Iwama, Atsushi / Hisaeda, Hajime / Coban, Cevayir / Annoura, Takeshi

Parasitology international

2024 Volume 100, Page(s) 102856

Abstract: The Plasmodium life cycle involves differentiation into multiple morphologically distinct forms, a process regulated by developmental stage-specific gene expression. Histone proteins are involved in epigenetic regulation in eukaryotes, and the histone ... ...

Abstract	The Plasmodium life cycle involves differentiation into multiple morphologically distinct forms, a process regulated by developmental stage-specific gene expression. Histone proteins are involved in epigenetic regulation in eukaryotes, and the histone variant H3.3 plays a key role in the regulation of gene expression and maintenance of genomic integrity during embryonic development in mice. However, the function of H3.3 through multiple developmental stages in Plasmodium remains unknown. To examine the function of H3.3, h3.3-deficient mutants (Δh3.3) were generated in P. berghei. The deletion of h3.3 was not lethal in blood stage parasites, although it had a minor effect of the growth rate in blood stage; however, the in vitro ookinete conversion rate was significantly reduced, and the production of the degenerated form was increased. Regarding the mosquito stage development of Δh3.3, oocysts number was significantly reduced, and no sporozoite production was observed. The h3.3 gene complemented mutant have normal development in mosquito stage producing mature oocysts and salivary glands contained sporozoites, and interestingly, the majority of H3.3 protein was detected in female gametocytes. However, Δh3.3 male and female gametocyte production levels were comparable to the wild-type levels. Transcriptome analysis of Δh3.3 male and female gametocytes revealed the upregulation of several male-specific genes in female gametocytes, suggesting that H3.3 functions as a transcription repressor of male-specific genes to maintain sexual identity in female gametocytes. This study provides new insights into the molecular biology of histone variants H3.3 which plays a critical role on zygote-to-oocyst development in primitive unicellular eukaryotes.
MeSH term(s)	Male ; Female ; Animals ; Mice ; Oocysts ; Histones/genetics ; Parasites ; Zygote/metabolism ; Epigenesis, Genetic ; Sporozoites/physiology ; Plasmodium ; Malaria/parasitology ; Plasmodium berghei/physiology ; Protozoan Proteins/genetics ; Protozoan Proteins/metabolism ; Rodent Diseases
Chemical Substances	Histones ; Protozoan Proteins
Language	English
Publishing date	2024-01-09
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	1363151-2
ISSN	1873-0329 ; 1383-5769
ISSN (online)	1873-0329
ISSN	1383-5769
DOI	10.1016/j.parint.2024.102856
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Article ; Online: IFN-γ protects hepatocytes against Plasmodium vivax infection via LAP-like degradation of sporozoites.

Lelliott, Patrick M / Coban, Cevayir

Proceedings of the National Academy of Sciences of the United States of America

2016 Volume 113, Issue 25, Page(s) 6813–6815

MeSH term(s)	Animals ; Hepatocytes ; Humans ; Malaria ; Malaria, Vivax ; Plasmodium vivax ; Sporozoites
Language	English
Publishing date	2016--21
Publishing country	United States
Document type	Editorial ; Research Support, Non-U.S. Gov't ; Comment
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.1607007113
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Article ; Online: Using a new three-dimensional CUBIC tissue-clearing method to examine the brain during experimental cerebral malaria.

Matsuo-Dapaah, Julia / Lee, Michelle Sue Jann / Ishii, Ken J / Tainaka, Kazuki / Coban, Cevayir

International immunology

2021 Volume 33, Issue 11, Page(s) 587–594

Abstract: Cerebral malaria (CM) is a life-threatening complication of the malaria disease caused by Plasmodium falciparum infection and is responsible for the death of half a million people annually. The molecular pathogenesis underlying CM in humans is not ... ...

Abstract	Cerebral malaria (CM) is a life-threatening complication of the malaria disease caused by Plasmodium falciparum infection and is responsible for the death of half a million people annually. The molecular pathogenesis underlying CM in humans is not completely understood, although sequestration of infected erythrocytes in cerebral microvessels is thought to play a major role. In contrast, experimental cerebral malaria (ECM) models in mice have been thought to be distinct from human CM, and are mainly caused by inflammatory mediators. Here, to understand the spatial distribution and the potential sequestration of parasites in the whole-brain microvessels during a mouse model of ECM, we utilized the new tissue-clearing method CUBIC (Clear, Unobstructed, Brain/Body Imaging Cocktails and Computational analysis) with light-sheet fluorescent microscopy (LSFM), and reconstructed images in three dimensions (3D). We demonstrated significantly greater accumulation of Plasmodium berghei ANKA (PbANKA) parasites in the olfactory bulb (OB) of mice, compared with the other parts of the brain, including the cerebral cortex, cerebellum and brainstem. Furthermore, we show that PbANKA parasites preferentially accumulate in the brainstem when the OB is surgically removed. This study therefore not only highlights a successful application of CUBIC tissue-clearing technology to visualize the whole brain and its microvessels during ECM, but it also shows CUBIC's future potential for visualizing pathological events in the whole ECM brain at the cellular level, an achievement that would greatly advance our understanding of human cerebral malaria.
MeSH term(s)	Animals ; Brain/immunology ; Brain/parasitology ; Brain/pathology ; Disease Models, Animal ; Malaria, Cerebral/immunology ; Malaria, Cerebral/parasitology ; Malaria, Cerebral/pathology ; Mice ; Mice, Inbred C57BL ; Plasmodium berghei/immunology
Language	English
Publishing date	2021-08-18
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1013745-2
ISSN	1460-2377 ; 0953-8178
ISSN (online)	1460-2377
ISSN	0953-8178
DOI	10.1093/intimm/dxab060
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