Mesencephalic astrocyte-derived neurotrophic factor (MANF), a new player in endoplasmic reticulum diseases: structure, biology, and therapeutic roles

Kim, Yeawon; Park, Sun-Ji; Chen, Ying Maggie

doi:10.1016/j.trsl.2017.06.010

Cited by 36 publications

(26 citation statements)

References 64 publications

(111 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A large number of studies have suggested that MANF expression can be up-regulated to exert its neuroprotective effects in response to a variety of neurological insults. ER stress can also enhance the expression of MANF, which protects cells from the unfolded protein response (UPR) induced apoptosis [9,49]. In our study, a western blot analysis revealed that the level of MANF began to rise at 3 h and peaked at 24 h after t-SCI, Double immunofluorescence staining confirmed that the expression of MANF increased in neurons after t-SCI.…”

Section: The Neuroprotective Functions Of Manfsupporting

confidence: 59%

MANF attenuates neuronal apoptosis and promotes behavioral recovery via Akt/MDM‐2/p53 pathway after traumatic spinal cord injury in rats

Gao

Fan³

et al. 2018

BioFactors

View full text Add to dashboard Cite

The aim of this study was to investigate the potential effect and mechanism of action of MANF in attenuating neuronal apoptosis following t-SCI. A clip compressive model was used to induce a crush injury of the spinal cord in a total of 230 rats. The Basso, Beattie, and Bresnahan (BBB) score, spinal cord water content, and blood spinal cord barrier (BSCB) permeability were evaluated. The expression levels of MANF and its downstream proteins were examined by western blotting. Immunofluorescence staining of MANF, NeuN, GFAP, Iba-1, cleaved caspase-3, and TUNEL staining were also performed. Cells were counted in six randomly selected fields in the gray matter regions of the sections from two spinal cord sites (2 mm rostral and caudal to the epicenter of the injury) per sample. A cell-based mechanical injury model was also conducted using SH-SY5Y cells. Cell apoptosis and viability were assessed by flow cytometry, an MTT assay, and trypan blue staining. Subcellular structures were observed by transmission electron microscopy. MANF was mainly expressed in neurons. The expression levels of MANF, and its downstream target, p-Akt, were gradually increased and after t-SCI. Treatment with MANF increased Bcl-2 and decreased Bax and CC-3 levels; these effects were reversed on treatment with MK2206. The BBB score, spinal cord water content, and BSCB destruction were also ameliorated by MANF treatment. MANF decreases neuronal apoptosis and improves neurological function through Akt/MDM-2/p53 pathway after t-SCI. Therefore, MANF might be a potential treatment for patients with t-SCI.© 2018 BioFactors, 2018.

show abstract

Section: The Neuroprotective Functions Of Manfsupporting

confidence: 59%

MANF attenuates neuronal apoptosis and promotes behavioral recovery via Akt/MDM‐2/p53 pathway after traumatic spinal cord injury in rats

Gao

Fan³

et al. 2018

BioFactors

View full text Add to dashboard Cite

show abstract

“…Apostoloua et al (2) reported that ER stress can initiate UPR, which, in turn, activates adaptive and apoptotic pathways, and the 2 pathways have different roles in disease prognosis. MANF, as a UPR modulator, inhibits cell proliferation and ER-induced cell death (2,41). MANF is predominantly expressed in neurons and only slightly expressed in microglia and astrocytes (42)(43)(44).…”

Section: Discussionmentioning

confidence: 99%

Mesencephalic astrocyte‐derived neurotrophic factor affords neuroprotection to early brain injury induced by subarachnoid hemorrhage via activating Akt‐dependent prosurvival pathway and defending blood‐brain barrier integrity

Gao

et al. 2018

FASEB j.

View full text Add to dashboard Cite

This study aimed to explore the neuroprotective effect of mesencephalic astrocyte-derived neurotrophic factor (MANF) protein on early brain injury caused by subarachnoid hemorrhage (SAH) and the relevant mechanisms in experimental rats, expecting to understand whether MANF was a potential therapeutic target for SAH treatment. A perforation model of SAH was introduced into the study. Recombinant human MANF (rh-MANF) and protein kinase B (Akt) inhibitor (MK2206) were used to explore the effect and the mechanisms. Multiple approaches for systemic assessment were employed in the research, including the Garcia test, the SAH grade, Evans blue (EB) dye leakage, brain-water content (BWC), the rotarod test, and the Morris water-navigation task, as were biotechniques, such as immunohistochemistry, Western blot, transmission electron microscopy, and flow cytometry. MANF was mainly expressed in rat neurons, and its expression increased significantly at 3 h after SAH induction and peaked at 24 h. Stereotactic injection of rh-MANF into the cerebroventricle significantly increased the level of MANF, p-Akt, p-mouse double minute 2 homolog (p-MDM2), and B-cell lymphoma 2 (Bcl-2) in brain tissue, whereas it down-regulated the expression of P53, Bcl-2-associated X protein (Bax), and cleaved caspase-3, which indicated that neuronal apoptosis was remarkably suppressed. Expression of matrix metallopeptidase 9 (MMP-9) was also suppressed by the rh-MANF injection. Furthermore, neurologic deficits, EB dye leakage, and BWC were reduced, and long-lasting neuroprotection was noted with rh-MANF administration. The antiapoptotic and blood-brain barrier (BBB) protective effect could be offset by administering MK2206. MANF could alleviate neuronal apoptosis by activating Akt-dependent prosurvival pathway and abate BBB damage via MMP-9 suppression. MANF showed not only transient but also long-lasting neuroprotective properties. The rh-MANF as a potential drug for treating SAH might be of clinical use.-Li, T., Xu, W., Gao, L., Guan, G., Zhang, Z., He, P., Xu, H., Fan, L., Yan, F., Chen, G. Mesencephalic astrocyte-derived neurotrophic factor affords neuroprotection to early brain injury induced by subarachnoid hemorrhage via activating Akt-dependent prosurvival pathway and defending blood-brain barrier integrity.

show abstract

“…However, humans excrete approximately 25% of the total absorbed TCC in urine. Furthermore, in renal tubular cells, ER dysfunction induces tubular injury and apoptosis and plays a pathogenic role in the onset and progression of renal tubulo‐interstitial disease, which ultimately advances to end‐stage renal disease . According to WISH, hspa5 and hsp90b1 were both enhanced in intrinsically expressing sites, head, pharyngeal region, pectoral fin bud, and intestinal tract after exposure to 10 μg/L TCC for 16 hours.…”

Section: Discussionmentioning

confidence: 99%

Triclocarban at environmentally relevant concentrations induces the endoplasmic reticulum stress in zebrafish

Zhou

Wei

et al. 2018

Environmental Toxicology

View full text Add to dashboard Cite

Triclocarban (TCC) is an antibacterial agent commonly found in environmental, wildlife, and human samples. However, with in-depth study of TCC, its negative effects are increasingly presented.Toxicological studies of TCC at environmentally relevant concentrations have been conducted in zebrafish embryos and indicated that TCC leads to deformity of development causes developmental deformities. However, the molecular mechanisms underlying the toxicity of TCC in zebrafish embryos have not been entirely elucidated. We investigated whether exposure to TCC at environmentally relevant concentrations induces endoplasmic reticulum (ER) stress and unfolded protein response (UPR) in zebrafish. Zebrafish embryos were grown to 32 hours post fertilization and exposed to 2.5, 5, and 10 μg/L TCC and used in whole-mount in situ hybridization to visualize the expression of ER chaperone hspa5 and ER stress-related apoptosis factor chop. Zebrafish livers were exposed to different concentrations of TCC to elaborate the relationships between fatty degeneration and ER stress. Then, a human hepatic cell line (HL-7702) was used to test whether TCC induced ER stress in human livers similar to those of zebrafish. In zebrafish embryos, TCC induced high hspa5 expression, which could defend against external stimulations. Furthermore, hapa5, hsp90b1, and chop exhibited ectopic expressions in the neuromast, intestinal tract, and tail tip of zebrafish embryos. On the one hand, significant differences were observed in the mRNA and protein expressions of the ER stress molecular chaperone pPERK-pEIF2a-ATF4 and ATF6 pathways in HL-7702 cells exposed to TCC. On the other hand, lipid droplet accumulation slightly increased in zebrafish livers exposed to 10 μg/L TCC in vitro. These results demonstrate that TCC not only damages the development of zebrafish embryos and structure of zebrafish liver but also influences human hepatic cells by activating ER stress and the UPR signaling pathway. K E Y W O R D S endoplasmic reticulum stress, HL-7702, triclocarban, unfolded protein response, zebrafish embryos

show abstract

Mesencephalic astrocyte-derived neurotrophic factor (MANF), a new player in endoplasmic reticulum diseases: structure, biology, and therapeutic roles

Cited by 36 publications

References 64 publications

MANF attenuates neuronal apoptosis and promotes behavioral recovery via Akt/MDM‐2/p53 pathway after traumatic spinal cord injury in rats

MANF attenuates neuronal apoptosis and promotes behavioral recovery via Akt/MDM‐2/p53 pathway after traumatic spinal cord injury in rats

Mesencephalic astrocyte‐derived neurotrophic factor affords neuroprotection to early brain injury induced by subarachnoid hemorrhage via activating Akt‐dependent prosurvival pathway and defending blood‐brain barrier integrity

Triclocarban at environmentally relevant concentrations induces the endoplasmic reticulum stress in zebrafish

Contact Info

Product

Resources

About