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Article ; Online: The stress-inducible ER chaperone GRP78/BiP is upregulated during SARS-CoV-2 infection and acts as a pro-viral protein.

Shin, Woo-Jin / Ha, Dat P / Machida, Keigo / Lee, Amy S

2022 Volume 13, Issue 1, Page(s) 6551

MeSH term(s)	Humans ; Endoplasmic Reticulum Chaperone BiP ; COVID-19 ; Viral Proteins ; SARS-CoV-2 ; Molecular Chaperones ; Endoplasmic Reticulum Stress
Chemical Substances	Endoplasmic Reticulum Chaperone BiP ; Viral Proteins ; Molecular Chaperones
Language	English
Publishing date	2022-11-14
Publishing country	England
Document type	Letter
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-022-34065-3
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Article ; Online: Insulin-like growth factor 1-receptor signaling stimulates GRP78 expression through the PI3K/AKT/mTOR/ATF4 axis.

Ha, Dat P / Lee, Amy S

Cellular signalling

2020 Volume 75, Page(s) 109736

Abstract: GRP78, a major molecular chaperone, is critical for the folding and maturation of membrane and secretory proteins and serves as the master regulator of the unfolded protein response. Thus, GRP78 is frequently upregulated in highly proliferative cells to ... ...

Abstract	GRP78, a major molecular chaperone, is critical for the folding and maturation of membrane and secretory proteins and serves as the master regulator of the unfolded protein response. Thus, GRP78 is frequently upregulated in highly proliferative cells to cope with elevated protein synthesis and metabolic stress. IGF-1 is a potent regulator of cell growth, metabolism and survival. Previously we discovered that GRP78 is a novel downstream target of IGF-1 signaling by utilizing mouse embryonic fibroblast model systems where the IGF-1 receptor (IGF-1R) was either overexpressed (R+) or knockout (R-). Here we investigated the mechanisms whereby GRP78 is upregulated in the R+ cells. Our studies revealed that suppression of PI3K/AKT/mTOR downstream of IGF-1R signaling resulted in concurrent decrease in GRP78 and the transcription factor ATF4. Through knock-down and overexpression studies, we established ATF4 as the essential downstream nodal of the PI3K/AKT/mTOR signaling pathway critical for GRP78 transcriptional upregulation mediated by IGF-1R.
MeSH term(s)	Animals ; Cell Line ; Fibroblasts/cytology ; Fibroblasts/metabolism ; Heat-Shock Proteins/metabolism ; Mice ; Phosphatidylinositol 3-Kinases/metabolism ; Receptor, IGF Type 1/metabolism ; TOR Serine-Threonine Kinases/metabolism
Chemical Substances	Heat-Shock Proteins ; Igf1r protein, mouse ; TOR Serine-Threonine Kinases (EC 2.7.1.1) ; mTOR protein, mouse (EC 2.7.1.1) ; Receptor, IGF Type 1 (EC 2.7.10.1) ; molecular chaperone GRP78 (YCYIS6GADR)
Language	English
Publishing date	2020-08-14
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	1002702-6
ISSN	1873-3913 ; 0898-6568
ISSN (online)	1873-3913
ISSN	0898-6568
DOI	10.1016/j.cellsig.2020.109736
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Zs.A 2579: Show issues

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Article ; Online: A prospective cohort study with serum anti-mullerian hormone levels change in patients undergoing uterine preservation after gestational trophoblastic neoplasia treatment with a methotrexate regimen.

Tuan Dat, D / Huyen Thuong, P T / Hong Hai, D / Khac Toan, N / Tai Duc, N / Duy Anh, N / Thi Thu Ha, N

La Clinica terapeutica

2024 Volume 175, Issue 2, Page(s) 128–134

Abstract: ... levels decline after 1st, 2nd, and 3rd chemotherapy cycles were 51.2%, 69.4%, and 84.6% (p<0.001 ...

Abstract	Objectives: To monitor changes in serum anti-Mullerian hormone (AMH) levels of the patients with gestational trophoblastic neoplasia (GTN) who have undergone uterine preservation during treatment with a Methotrexate (MTX) regimen and associations with AMH variations. Methods: This observational prospective cohort study included 35 patients with low-risk GTN with uterine preservation during single-agent MTX chemotherapy at Hanoi Obstetrics and Gynecology Hospital from August 2021 to August 2022. Serum AMH levels were measured before initiation of chemotherapy and after the 1st, 2nd, and 3rd chemotherapy cycles. AMH evolution and its associations with some factors were analyzed. Results: The median basal AMH level before chemotherapy was 2.87 ng/mL (0.96 - 7.9 ng/mL) and negatively correlated with age. The serum AMH levels decreased significantly after each chemotherapy cycle (2.87 vs. 1.16, 0.91, 0.41 ng/mL). The median magnitude of the AMH levels decline after 1st, 2nd, and 3rd chemotherapy cycles were 51.2%, 69.4%, and 84.6% (p<0.001), respectively. AMH variation was associated with the basal AMH level, but not with age, βhCG at diagnosis and menstrual status. Conclusion: Our study has shown that the serum AMH levels declined rapidly and steadily in all patients during chemotherapy for GTN. Although AMH cannot be used to monitor fertility potential lonely, these new studies improve our knowledge of ovarian toxicity and ovarian reserve during chemotherapy and strongly support the use of fertility preservation strategies.
MeSH term(s)	Pregnancy ; Female ; Humans ; Methotrexate/therapeutic use ; Anti-Mullerian Hormone/therapeutic use ; Prospective Studies ; Gestational Trophoblastic Disease/drug therapy ; Ovary
Chemical Substances	Methotrexate (YL5FZ2Y5U1) ; Anti-Mullerian Hormone (80497-65-0)
Language	English
Publishing date	2024-04-01
Publishing country	Italy
Document type	Observational Study
ZDB-ID	123320-8
ISSN	1972-6007 ; 0009-9074
ISSN (online)	1972-6007
ISSN	0009-9074
DOI	10.7417/CT.2024.5045
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Article ; Online: ER chaperone GRP78/BiP translocates to the nucleus under stress and acts as a transcriptional regulator.

Liu, Ze / Liu, Guanlin / Ha, Dat P / Wang, Justin / Xiong, Min / Lee, Amy S

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

2023 Volume 120, Issue 31, Page(s) e2303448120

Abstract: Cancer cells are commonly subjected to endoplasmic reticulum (ER) stress. To gain survival advantage, cancer cells exploit the adaptive aspects of the unfolded protein response such as upregulation of the ER luminal chaperone GRP78. The finding that when ...

Abstract	Cancer cells are commonly subjected to endoplasmic reticulum (ER) stress. To gain survival advantage, cancer cells exploit the adaptive aspects of the unfolded protein response such as upregulation of the ER luminal chaperone GRP78. The finding that when overexpressed, GRP78 can escape to other cellular compartments to gain new functions regulating homeostasis and tumorigenesis represents a paradigm shift. Here, toward deciphering the mechanisms whereby GRP78 knockdown suppresses
MeSH term(s)	Humans ; Endoplasmic Reticulum Chaperone BiP ; Cell Nucleus ; Carcinogenesis ; Cell Movement ; Cell Transformation, Neoplastic
Chemical Substances	Endoplasmic Reticulum Chaperone BiP
Language	English
Publishing date	2023-07-24
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.2303448120
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Zs.A 1148: Show issues

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Article ; Online: Suppression of ER-stress induction of GRP78 as an anti-neoplastic mechanism of the cardiac glycoside Lanatoside C in pancreatic cancer: Lanatoside C suppresses GRP78 stress induction.

Ha, Dat P / Tsai, Yuan-Li / Lee, Amy S

Neoplasia (New York, N.Y.)

2021 Volume 23, Issue 12, Page(s) 1213–1226

Abstract: The 78 kilodalton glucose-regulated protein (GRP78) is a major endoplasmic reticulum (ER) molecular chaperone with antiapoptotic properties and a key regulator of the unfolded protein response (UPR). ER-stress induction of GRP78 in cancer cells ... ...

Abstract	The 78 kilodalton glucose-regulated protein (GRP78) is a major endoplasmic reticulum (ER) molecular chaperone with antiapoptotic properties and a key regulator of the unfolded protein response (UPR). ER-stress induction of GRP78 in cancer cells represents a major pro-survival branch of the UPR. Pancreatic ductal adenocarcinoma (PDAC) remains a highly lethal disease and high level of GRP78 is associated with aggressive disease and poor survival. Recently, we reported that PDAC exhibited high level of ER stress and that GRP78 haploinsufficiency is sufficient to suppress pancreatic tumorigenesis in mice, suggesting the utility of inhibitors of GRP78 expression in combating pancreatic cancer. Screening of clinically relevant compound libraries revealed that cardiac glycosides (CGs) can inhibit ER-stress induction of GRP78 in pancreatic and other types of human cancers. Using the FDA-approved CG compound Lanatoside C (LanC) and human pancreatic cancer cell lines as model systems, we discovered that LanC preferably suppressed ER stress induction of GRP78 and to a lesser extent GRP94. The suppression is at the post-transcriptional level and dependent on the Na
MeSH term(s)	Carcinoma, Pancreatic Ductal/metabolism ; Cardiac Glycosides/pharmacology ; Cell Line, Tumor ; Endoplasmic Reticulum Chaperone BiP/drug effects ; Endoplasmic Reticulum Chaperone BiP/metabolism ; Endoplasmic Reticulum Stress/drug effects ; Humans ; Lanatosides/pharmacology ; Pancreatic Neoplasms/metabolism ; Unfolded Protein Response/drug effects ; Pancreatic Neoplasms
Chemical Substances	Cardiac Glycosides ; Endoplasmic Reticulum Chaperone BiP ; HSPA5 protein, human ; Lanatosides ; lanatoside C (5RR3JFZ771)
Language	English
Publishing date	2021-11-09
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	1483840-0
ISSN	1476-5586 ; 1522-8002
ISSN (online)	1476-5586
ISSN	1522-8002
DOI	10.1016/j.neo.2021.10.004
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Zs.A 5203: Show issues

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Article ; Online: An efficient and green synthesis of 2-phenylquinazolin-4(3H)-ones via t-BuONa-mediated oxidative condensation of 2-aminobenzamides and benzyl alcohols under solvent- and transition metal-free conditions

Nguyen Vy T. B. / Tran Dat P. / Nguyen Tung T. / Nguyen Khoa D. / Le Ha V.

Green Processing and Synthesis, Vol 12, Iss 1, Pp 3475-

2023 Volume 6

Abstract: Quinazolinone synthesis usually requires employing sensitive substrates, hazardous solvents, large excess oxidants, and expensive catalysts. In this study, an efficient and environmentally benign pathway was developed to synthesize 2-phenylquinazolin-4( ... ...

Abstract	Quinazolinone synthesis usually requires employing sensitive substrates, hazardous solvents, large excess oxidants, and expensive catalysts. In this study, an efficient and environmentally benign pathway was developed to synthesize 2-phenylquinazolin-4(3H)-one via oxidative coupling between commercially available and stable chemicals, including 2-aminobenzamide and benzyl alcohol without toxic oxidizing agents and transition-metal catalysts. A high yield of the desired product (up to 84%) was obtained at 120°C for 24 h in the presence of oxygen as a green oxidant and t-BuONa as a base. Importantly, the study scope was expanded toward successfully producing various 2-phenylquinazolin-4(3H)-one derivatives in moderate-to-good yields. Furthermore, control experiments proposed that the conversion involved the initial partial oxidation of benzyl alcohol to the benzaldehyde intermediate under basic conditions, followed by the condensation, intramolecular nucleophilic addition, and oxidative dehydrogenation to 2-phenylquinazolin-4(3H)-one.
Keywords	2-phenylquinazolin-4(3h)-one ; benzyl alcohol ; green conditions ; oxidative coupling ; Chemistry ; QD1-999
Subject code	540
Language	English
Publishing date	2023-05-01T00:00:00Z
Publisher	De Gruyter
Document type	Article ; Online
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Article ; Online: GRP78 Inhibitor YUM70 Suppresses SARS-CoV-2 Viral Entry, Spike Protein Production and Ameliorates Lung Damage.

Ha, Dat P / Shin, Woo-Jin / Hernandez, Juan Carlos / Neamati, Nouri / Dubeau, Louis / Machida, Keigo / Lee, Amy S

Viruses

2023 Volume 15, Issue 5

Abstract: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of the COVID-19 pandemic, has given rise to many new variants with increased transmissibility and the ability to evade vaccine protection. The 78-kDa glucose-regulated ... ...

Abstract	The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of the COVID-19 pandemic, has given rise to many new variants with increased transmissibility and the ability to evade vaccine protection. The 78-kDa glucose-regulated protein (GRP78) is a major endoplasmic reticulum (ER) chaperone that has been recently implicated as an essential host factor for SARS-CoV-2 entry and infection. In this study, we investigated the efficacy of YUM70, a small molecule inhibitor of GRP78, to block SARS-CoV-2 viral entry and infection in vitro and in vivo. Using human lung epithelial cells and pseudoviral particles carrying spike proteins from different SARS-CoV-2 variants, we found that YUM70 was equally effective at blocking viral entry mediated by original and variant spike proteins. Furthermore, YUM70 reduced SARS-CoV-2 infection without impacting cell viability in vitro and suppressed viral protein production following SARS-CoV-2 infection. Additionally, YUM70 rescued the cell viability of multi-cellular human lung and liver 3D organoids transfected with a SARS-CoV-2 replicon. Importantly, YUM70 treatment ameliorated lung damage in transgenic mice infected with SARS-CoV-2, which correlated with reduced weight loss and longer survival. Thus, GRP78 inhibition may be a promising approach to augment existing therapies to block SARS-CoV-2, its variants, and other viruses that utilize GRP78 for entry and infection.
MeSH term(s)	Animals ; Mice ; Humans ; SARS-CoV-2/physiology ; COVID-19 ; Endoplasmic Reticulum Chaperone BiP ; Virus Internalization ; Spike Glycoprotein, Coronavirus ; Pandemics ; Lung
Chemical Substances	Endoplasmic Reticulum Chaperone BiP ; spike protein, SARS-CoV-2 ; Spike Glycoprotein, Coronavirus
Language	English
Publishing date	2023-05-06
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2516098-9
ISSN	1999-4915 ; 1999-4915
ISSN (online)	1999-4915
ISSN	1999-4915
DOI	10.3390/v15051118
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Article ; Online: Spatial Analysis of Drug-Susceptible and Multidrug-Resistant Cases of Tuberculosis, Ho Chi Minh City, Vietnam, 2020-2023.

Spies, Ruan / Hong, Hanh N / Trieu, Phu P / Lan, Luong K / Lan, Kim / Hue, N N / Huong, Nguyen T L / Thao, Tran T L N / Quang, Nguyen L / Anh, Thu D D / Vinh, Truong V / Ha, Dang T M / Dat, Phan T / Hai, Nguyen P / Van, Le H / Thwaites, Guy E / Thuong, Nguyen T T / Watson, James A / Walker, Timothy M

Emerging infectious diseases

2024 Volume 30, Issue 3, Page(s) 499–509

Abstract: We characterized the spatial distribution of drug-susceptible (DS) and multidrug-resistant (MDR) tuberculosis (TB) cases in Ho Chi Minh City, Vietnam, a major metropolis in southeastern Asia, and explored demographic and socioeconomic factors associated ... ...

Abstract	We characterized the spatial distribution of drug-susceptible (DS) and multidrug-resistant (MDR) tuberculosis (TB) cases in Ho Chi Minh City, Vietnam, a major metropolis in southeastern Asia, and explored demographic and socioeconomic factors associated with local TB burden. Hot spots of DS and MDR TB incidence were observed in the central parts of Ho Chi Minh City, and substantial heterogeneity was observed across wards. Positive spatial autocorrelation was observed for both DS TB and MDR TB. Ward-level TB incidence was associated with HIV prevalence and the male proportion of the population. No ward-level demographic and socioeconomic indicators were associated with MDR TB case count relative to total TB case count. Our findings might inform spatially targeted TB control strategies and provide insights for generating hypotheses about the nature of the relationship between DS and MDR TB in Ho Chi Minh City and the wider southeastern region of Asia.
MeSH term(s)	Male ; Humans ; Vietnam/epidemiology ; Tuberculosis ; Tuberculosis, Multidrug-Resistant/epidemiology ; Asia ; Spatial Analysis
Language	English
Publishing date	2024-02-15
Publishing country	United States
Document type	Journal Article
ZDB-ID	1380686-5
ISSN	1080-6059 ; 1080-6040
ISSN (online)	1080-6059
ISSN	1080-6040
DOI	10.3201/eid3003.231309
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Zs.A 4778: Show issues

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Article ; Online: Obstetric and Perinatal Outcomes of Dichorionic-Diamniotic Twin Pregnancies Conceived by IVF/ICSI Compared with Those Conceived Spontaneously.

Duy Anh, N / Thu Ha, N T / Khac Toan, N / Tuan Dat, D / Huyen Thuong, P T / Tra Giang, D T / Anh Duc, T / Xuan Anh, B / Manh Ha, N / Minh Duc, N

La Clinica terapeutica

2022 Volume 173, Issue 2, Page(s) 155–163

Abstract: ... delivered at an earlier gestational age (36.2 vs. 36.7 weeks, p < 0.001), had slightly lower mean birth ... weights (2298 vs. 2367 g, p = 0.005), and required more respiratory support (aOR: 0.69; 95% Cl: 0.48-0.98 ...

Abstract	Introduction: This study aimed to investigate differences in mater-nal and perinatal outcomes between dichorionic-diamniotic (DCDA) twin pregnancies between those conceived spontaneously and those conceived through in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI). Methods: This study was a single-center, retrospective cohort study. All women with DCDA twin pregnancies were considered for inclusion. Monochorionic twins and higher-order multiple pre-gnancies were excluded. All data related to maternal and perinatal outcomes were extracted from the hospital database and compared between spontaneously conceived DCDA twin pregnancies and those conceived by IVF/ICSI. Multivariable logistic regression was used to adjust for confounders to determine factors associated with maternal and perinatal outcomes. Results: Of 739 identified DCDA twin pregnancies, 483 (65.4%) were conceived through IVF/ICSI treatment (IVF/ICSI group), and 256 (34.6%) were spontaneously conceived (SC group). Women in the IVF/ICSI group were older and had fewer previous live births than women in the SC group. The women in the IVF/ICSI group had significantly higher risks of preeclampsia (adjusted odds ratio [aOR]: 2.50; 95% confidence interval [CI]: 1.12-5.55), cesarean delivery (aOR: 2.0; 95% CI: 1.27-3.17), an postpartum hemorrhage following cesarean section (aOR: 3.15; 95% CI: 1.53-6.45). The DCDA twins in the IVF/ICSI group were delivered at an earlier gestational age (36.2 vs. 36.7 weeks, p < 0.001), had slightly lower mean birth weights (2298 vs. 2367 g, p = 0.005), and required more respiratory support (aOR: 0.69; 95% Cl: 0.48-0.98) than those in the SC group. Conclusions: Our study demonstrated that women with DCDA twin pregnancies conceived through IVF/ICSI experienced more complications than those with SC DCDA twin pregnancies. Newborns in the IVF/ICSI group had a slightly lower mean birth weight and required respiratory support more frequently, but no other significant differences in perinatal outcomes or perinatal mortality were observed between the two groups.
MeSH term(s)	Cesarean Section ; Female ; Fertilization in Vitro ; Humans ; Infant, Newborn ; Pregnancy ; Pregnancy Outcome/epidemiology ; Pregnancy, Twin ; Retrospective Studies ; Sperm Injections, Intracytoplasmic
Language	English
Publishing date	2022-04-01
Publishing country	Italy
Document type	Journal Article
ZDB-ID	123320-8
ISSN	1972-6007 ; 0009-9074
ISSN (online)	1972-6007
ISSN	0009-9074
DOI	10.7417/CT.2022.2410
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Article ; Online: ER residential chaperone GRP78 unconventionally relocalizes to the cell surface via endosomal transport.

Van Krieken, Richard / Tsai, Yuan-Li / Carlos, Anthony J / Ha, Dat P / Lee, Amy S

Cellular and molecular life sciences : CMLS

2021 Volume 78, Issue 12, Page(s) 5179–5195

Abstract: Despite new advances on the functions of ER chaperones at the cell surface, the translocation mechanisms whereby these chaperones can escape from the ER to the cell surface are just emerging. Previously we reported that in many cancer types, upon ER ... ...

Abstract	Despite new advances on the functions of ER chaperones at the cell surface, the translocation mechanisms whereby these chaperones can escape from the ER to the cell surface are just emerging. Previously we reported that in many cancer types, upon ER stress, IRE1α binds to and triggers SRC activation resulting in KDEL receptor dispersion from the Golgi and suppression of retrograde transport. In this study, using a combination of molecular, biochemical, and imaging approaches, we discovered that in colon and lung cancer, upon ER stress, ER chaperones, such as GRP78 bypass the Golgi and unconventionally traffic to the cell surface via endosomal transport mediated by Rab GTPases (Rab4, 11 and 15). Such unconventional transport is driven by membrane fusion between ER-derived vesicles and endosomes requiring the v-SNARE BET1 and t-SNARE Syntaxin 13. Furthermore, GRP78 loading into ER-derived vesicles requires the co-chaperone DNAJC3 that is regulated by ER-stress induced PERK-AKT-mTOR signaling.
MeSH term(s)	Cell Membrane/metabolism ; Colonic Neoplasms/genetics ; Colonic Neoplasms/metabolism ; Colonic Neoplasms/pathology ; Endoplasmic Reticulum/metabolism ; Golgi Apparatus/metabolism ; Heat-Shock Proteins/genetics ; Heat-Shock Proteins/metabolism ; Humans ; Lung Neoplasms/genetics ; Lung Neoplasms/metabolism ; Lung Neoplasms/pathology ; Mutagenesis, Site-Directed ; Mutation ; Protein Transport ; Signal Transduction ; Tumor Cells, Cultured
Chemical Substances	Heat-Shock Proteins ; molecular chaperone GRP78 (YCYIS6GADR)
Language	English
Publishing date	2021-05-11
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	1358415-7
ISSN	1420-9071 ; 1420-682X
ISSN (online)	1420-9071
ISSN	1420-682X
DOI	10.1007/s00018-021-03849-z
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