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TEOA, a triterpenoid from Actinidia eriantha, induces autophagy in SW620 cells via endoplasmic reticulum stress and ROS-dependent mitophagy

Zhang D, Gao C, Li R, Zhang L, Tian J

Arch Pharm Res, 2017 May;40(5):579-591.
PMID: 28211011 DOI: 10.1007/s12272-017-0899-9

2α,3α,24-Thrihydroxyurs-12-en-28-oicacid (TEOA), a pentacyclic triterpenoid, isolated from the roots of Actinidia eriantha, exhibits significant cytotoxicity against SW620, BGC-823, HepG-2, A549 and PC-3 cancer cells. In this study, we investigated the underlying molecular mechanism of the anticancer activity of TEOA in SW620 cells. We demonstrated that TEOA induced apoptosis through cleavage of caspase-9 and PARP in SW620 cells. In addition, evidence of TEOA-mediated autophagy included the induction of autophagolysosomes and activation of autophagic markers LC-3B and p62. Further analysis illustrated that TEOA promoted the phosphorylation of PERK and elF2α, followed by up-regulation of the downstream protein CHOP, suggesting the involvement of PERK/eIF2α/CHOP pathway and ER stress in TEOA-induced autophagy in SW620 cells. Meanwhile, TEOA-mediated PINK1, Parkin, ubiquitin and p62 activation revealed that TEOA induced specific autophagy-mitophagy in SW620 cells. Additionally, an antioxidant NAC attenuated the TEOA-induced mitophagy, indicating that TEOA triggers mitophagy via a ROS-dependent pathway. Collectively, our findings revealed a novel cellular mechanism of TEOA in the colon cancer cell line SW620, thus providing a molecular basis for developing TEOA into an anti-tumor candidate.

Matched MeSH terms: Endoplasmic Reticulum Stress/drug effects*
Fulltext 3',4'-dihydroxyflavonol ameliorates endoplasmic reticulum stress-induced apoptosis and endothelial dysfunction in mice

Lau YS, Mustafa MR, Choy KW, Chan SMH, Potocnik S, Herbert TP, et al.

Sci Rep, 2018 01 29;8(1):1818.
PMID: 29379034 DOI: 10.1038/s41598-018-19584-8

Endoplasmic reticulum (ER) stress has been implicated in the development of hypertension 3 through the induction of endothelial impairment. As 3',4'-dihydroxyflavonol (DiOHF) 4 reduces vascular injury caused by ischaemia/reperfusion or diabetes, and flavonols have been demonstrated to attenuate ER stress, we investigated whether DiOHF can protect mice from ER stress-induced endothelial dysfunction. Male C57BLK/6 J mice were injected with tunicamycin to induce ER stress in the presence or absence of either DiOHF or tauroursodeoxycholic acid (TUDCA), an inhibitor of ER stress. Tunicamycin elevated blood pressure and impaired endothelium-dependent relaxation. Moreover, in aortae there was evidence of ER stress, oxidative stress and reduced NO production. This was coincident with increased NOX2 expression and reduced phosphorylation of endothelial nitric oxide synthase (eNOS) on Ser1176. Importantly, the effects of tunicamycin were significantly ameliorated by DiOHF or TUDCA. DiOHF also inhibited tunicamycin-induced ER stress and apoptosis in cultured human endothelial cells (HUVEC). These results provide evidence that ER stress is likely an important initiator of endothelial dysfunction through the induction of oxidative stress and a reduction in NO synthesis and that DiOHF directly protects against ER stress- induced injury. DiOHF may be useful to prevent ER and oxidative stress to preserve endothelial function, for example in hypertension.

Matched MeSH terms: Endoplasmic Reticulum Stress/drug effects*
Perilipin 5 Deletion Unmasks an Endoplasmic Reticulum Stress-Fibroblast Growth Factor 21 Axis in Skeletal Muscle

Montgomery MK, Mokhtar R, Bayliss J, Parkington HC, Suturin VM, Bruce CR, et al.

Diabetes, 2018 04;67(4):594-606.
PMID: 29378767 DOI: 10.2337/db17-0923

Lipid droplets (LDs) are critical for the regulation of lipid metabolism, and dysregulated lipid metabolism contributes to the pathogenesis of several diseases, including type 2 diabetes. We generated mice with muscle-specific deletion of the LD-associated protein perilipin 5 (PLIN5, Plin5MKO ) and investigated PLIN5's role in regulating skeletal muscle lipid metabolism, intracellular signaling, and whole-body metabolic homeostasis. High-fat feeding induced changes in muscle lipid metabolism of Plin5MKO mice, which included increased fatty acid oxidation and oxidative stress but, surprisingly, a reduction in inflammation and endoplasmic reticulum (ER) stress. These muscle-specific effects were accompanied by whole-body glucose intolerance, adipose tissue insulin resistance, and reduced circulating insulin and C-peptide levels in Plin5MKO mice. This coincided with reduced secretion of fibroblast growth factor 21 (FGF21) from skeletal muscle and liver, resulting in reduced circulating FGF21. Intriguingly, muscle-secreted factors from Plin5MKO , but not wild-type mice, reduced hepatocyte FGF21 secretion. Exogenous correction of FGF21 levels restored glycemic control and insulin secretion in Plin5MKO mice. These results show that changes in lipid metabolism resulting from PLIN5 deletion reduce ER stress in muscle, decrease FGF21 production by muscle and liver, and impair glycemic control. Further, these studies highlight the importance for muscle-liver cross talk in metabolic regulation.

Matched MeSH terms: Endoplasmic Reticulum Stress/genetics*
Fulltext Current Status of Endoplasmic Reticulum Stress in Type II Diabetes

Mustapha S, Mohammed M, Azemi AK, Jatau AI, Shehu A, Mustapha L, et al.

Molecules, 2021 Jul 19;26(14).
PMID: 34299638 DOI: 10.3390/molecules26144362

The endoplasmic reticulum (ER) plays a multifunctional role in lipid biosynthesis, calcium storage, protein folding, and processing. Thus, maintaining ER homeostasis is essential for cellular functions. Several pathophysiological conditions and pharmacological agents are known to disrupt ER homeostasis, thereby, causing ER stress. The cells react to ER stress by initiating an adaptive signaling process called the unfolded protein response (UPR). However, the ER initiates death signaling pathways when ER stress persists. ER stress is linked to several diseases, such as cancer, obesity, and diabetes. Thus, its regulation can provide possible therapeutic targets for these. Current evidence suggests that chronic hyperglycemia and hyperlipidemia linked to type II diabetes disrupt ER homeostasis, thereby, resulting in irreversible UPR activation and cell death. Despite progress in understanding the pathophysiology of the UPR and ER stress, to date, the mechanisms of ER stress in relation to type II diabetes remain unclear. This review provides up-to-date information regarding the UPR, ER stress mechanisms, insulin dysfunction, oxidative stress, and the therapeutic potential of targeting specific ER stress pathways.

Matched MeSH terms: Endoplasmic Reticulum Stress*
Fulltext Tocotrienols and oxidative stress in ocytes and developing embryos

Yuhaniza Shafinie Kamsani, Mohd Hamim Rajikin

Journal of Clinical and Health Sciences, 2017;2:8-18.

This review summarizes the impact of tocotrienols (TCTs) as antioxidants in minimizing
oxidative stress (OS), particularly in embryos exposed to OS causing agents. OS level is
increased, for example, by nicotine, a major alkaloid content in cigarette, which is also a source
of exogenous reactive oxygen species (ROS). Increased nicotine-induced OS increases cell
stress response, which is a common trigger leading to embryonic cell death. Having more
profound anti-oxidative stress effects than its counterpart tocopherol, TCTs improve blastocyst
implantation, foetal growth, pregnancy outcome and survival of the neonates affected by
nicotine. In reversing cell developmental arrest caused by nicotine-induced OS, TCTs enhances
PDK-1 expression in the P13K/Akt pathway and permit embryonic development beyond the 4-
cell stage with the production of more morulae. At the cytoskeletal level, TCTs increase the
number of nicotine-induced apoptotic cells, through caspase 8 activation in the mitochondria.
TCTs facilitate rough endoplasmic reticulum (rER) stress-mediated apoptosis and autophagy,
resulting from nicotine-induced OS. Reduced vesicular population in TCT supplemented
oocytes on the other hand may suggest reduced secretion of apoptotic cell bodies thus probably
minimizing vesicular apoptosis during oocyte maturation. Further extensive research is
required to develop TCTs as a tool in specific therapeutic approaches to overcome the
detrimental effects of OS.

Matched MeSH terms: Endoplasmic Reticulum, Rough
Thioredoxin-albumin fusion protein prevents copper enhanced zinc-induced neurotoxicity via its antioxidative activity

Tanaka KI, Shimoda M, Chuang VTG, Nishida K, Kawahara M, Ishida T, et al.

Int J Pharm, 2018 Jan 15;535(1-2):140-147.
PMID: 29122608 DOI: 10.1016/j.ijpharm.2017.11.012

Zinc (Zn) is a co-factor for a vast number of enzymes, and functions as a regulator for immune mechanism and protein synthesis. However, excessive Zn release induced in pathological situations such as stroke or transient global ischemia is toxic. Previously, we demonstrated that the interaction of Zn and copper (Cu) is involved in the pathogenesis of Alzheimer's disease and vascular dementia. Furthermore, oxidative stress has been shown to play a significant role in the pathogenesis of various metal ions induced neuronal death. Thioredoxin-Albumin fusion (HSA-Trx) is a derivative of thioredoxin (Trx), an antioxidative protein, with improved plasma retention and stability of Trx. In this study, we examined the effect of HSA-Trx on Cu2+/Zn2+-induced neurotoxicity. Firstly, HSA-Trx was found to clearly suppress Cu2+/Zn2+-induced neuronal cell death in mouse hypothalamic neuronal cells (GT1-7 cells). Moreover, HSA-Trx markedly suppressed Cu2+/Zn2+-induced ROS production and the expression of oxidative stress related genes, such as heme oxygenase-1. In contrast, HSA-Trx did not affect the intracellular levels of both Cu2+ and Zn2+ after Cu2+/Zn2+ treatment. Finally, HSA-Trx was found to significantly suppress endoplasmic reticulum (ER) stress response induced by Cu2+/Zn2+ treatment in a dose dependent manner. These results suggest that HSA-Trx counteracted Cu2+/Zn2+-induced neurotoxicity by suppressing the production of ROS via interfering the related gene expressions, in addition to the highly possible radical scavenging activity of the fusion protein. Based on these findings, HSA-Trx has great potential as a promising therapeutic agent for the treatment of refractory neurological diseases.

Matched MeSH terms: Endoplasmic Reticulum
Fulltext Tocotrienols and oxidative stress in ocytes and developing embryos

Yuhaniza Shafinie Kamsani, Mohd Hamim Rajikin

Journal of Clinical and Health Sciences, 2017;2(2):8-18.
MyJurnal

This review summarizes the impact of tocotrienols (TCTs) as antioxidants in minimizing oxidative stress (OS), particularly in embryos exposed to OS causing agents. OS level is increased, for example, by nicotine, a major alkaloid content in cigarette, which is also a source of exogenous reactive oxygen species (ROS). Increased nicotine-induced OS increases cell stress response, which is a common trigger leading to embryonic cell death. Having more profound anti-oxidative stress effects than its counterpart tocopherol, TCTs improve blastocyst implantation, foetal growth, pregnancy outcome and survival of the neonates affected by nicotine. In reversing cell developmental arrest caused by nicotine-induced OS, TCTs enhances PDK-1 expression in the P13K/Akt pathway and permit embryonic development beyond the 4-cell stage with the production of more morulae. At the cytoskeletal level, TCTs increase the number of nicotine-induced apoptotic cells, through caspase 8 activation in the mitochondria. TCTs facilitate rough endoplasmic reticulum (rER) stress-mediated apoptosis and autophagy, resulting from nicotine-induced OS. Reduced vesicular population in TCT supplemented oocytes on the other hand may suggest reduced secretion of apoptotic cell bodies thus probably minimizing vesicular apoptosis during oocyte maturation. Further extensive research is required to develop TCTs as a tool in specific therapeutic approaches to overcome the detrimental effects of OS.

Matched MeSH terms: Endoplasmic Reticulum, Rough
Effect of Gibberellin and Heat Shock on the Lipid Composition of Endoplasmic Reticulum in Barley Aleurone Layers

Grindstaff KK, Fielding LA, Brodl MR

Plant Physiol, 1996 Feb;110(2):571-581.
PMID: 12226205

The heat-shock responses of barley (Hordeum vulgare L. cv Hi- malaya) aleurone layers incubated with or without gibberellic acid (GA3) were compared. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis revealed that heat shock blocked the synthesis and secretion of secretory proteins from GA3-treated layers but not untreated layers. This suppression of secretory protein synthesis has been correlated with changes in endoplasmic reticulum (ER) membranes (F.C. Belanger, M. R. Brodl, T.-h.D. Ho [1986] Proc Natl Acad Sci USA 83: 1354-1358; L. Sticher, A.K. Biswas, D.S. Bush, R.L. Jones [1990] Plant Physiol 92: 506-513). Our secretion data suggested that the ER membranes of aleurone layers incubated without GA3 may be more heat shock tolerant. To investigate this, the lipid profiles of membrane extracts in aleurone layers labeled with [14C]glycerol were examined. Heat shock markedly increased [14C]glycerol incorporation into phosphatidylcholine (PC), and gas chromatography revealed an increase in the amount of saturated fatty acids associated with thin layer chromatography-purified PC in GA3-treated layers. In contrast, aleurone layers incubated without GA3 at normal temperature contained PC-associated fatty acids with a greater degree of saturation than GA3-treated layers. Heat shock modestly increased the degree of fatty acid saturation in untreated aleurone layers. This same trend was noted in fatty acids isolated from ER membranes purified by continuous sucrose density centrifugation. We propose that increased fatty acid saturation may help sustain ER membrane function in heat-shocked aleurone layers incubated in the absence of GA3.

Matched MeSH terms: Endoplasmic Reticulum
Fulltext Kainic Acid-Induced Excitotoxicity Experimental Model: Protective Merits of Natural Products and Plant Extracts

Mohd Sairazi NS, Sirajudeen KN, Asari MA, Muzaimi M, Mummedy S, Sulaiman SA

Evid Based Complement Alternat Med, 2015;2015:972623.
PMID: 26793262 DOI: 10.1155/2015/972623

Excitotoxicity is well recognized as a major pathological process of neuronal death in neurodegenerative diseases involving the central nervous system (CNS). In the animal models of neurodegeneration, excitotoxicity is commonly induced experimentally by chemical convulsants, particularly kainic acid (KA). KA-induced excitotoxicity in rodent models has been shown to result in seizures, behavioral changes, oxidative stress, glial activation, inflammatory mediator production, endoplasmic reticulum stress, mitochondrial dysfunction, and selective neurodegeneration in the brain upon KA administration. Recently, there is an emerging trend to search for natural sources to combat against excitotoxicity-associated neurodegenerative diseases. Natural products and plant extracts had attracted a considerable amount of attention because of their reported beneficial effects on the CNS, particularly their neuroprotective effect against excitotoxicity. They provide significant reduction and/or protection against the development and progression of acute and chronic neurodegeneration. This indicates that natural products and plants extracts may be useful in protecting against excitotoxicity-associated neurodegeneration. Thus, targeting of multiple pathways simultaneously may be the strategy to maximize the neuroprotection effect. This review summarizes the mechanisms involved in KA-induced excitotoxicity and attempts to collate the various researches related to the protective effect of natural products and plant extracts in the KA model of neurodegeneration.

Matched MeSH terms: Endoplasmic Reticulum Stress
Fulltext The Effect of Amygdalin on Endoplasmic Reticulum (ER) Stress Induced Hepatic Steatosis in Mice

Moslehi A, Farahabadi M, Chavoshzadeh SA, Barati A, Ababzadeh S, Mohammadbeigi A

Malays J Med Sci, 2018 Feb;25(1):16-23.
PMID: 29599631 DOI: 10.21315/mjms2018.25.1.3

Background: Endoplasmic reticulum (ER) stress creates abnormalities in the insulin action, inflammatory responses, lipoprotein B100 degradation, and hepatic lipogenesis. Hepatic steatosis leads to a broad spectrum of hepatic disorders such as nonalcoholic fatty liver disease (NAFLD) and NASH. Amygdalin has beneficial effects on asthma, bronchitis, diabetes, and atherosclerosis. We designed this study to evaluate the effect of amygdalin on the ER stress induced hepatic steatosis.
Methods: Inbred mice received saline, DMSO and amygdalin, as control groups. ER stress was induced by tunicamycin (TM) injection. Amygdalin was administered 1 h before the TM challenge (Amy + TM group). Mice body and liver weights were measured. Hematoxylin and eosin (H&E) and oil red O staining from liver tissue, were performed. Alanin aminotransferase (ALT), aspartate aminotransferase (AST), triglyceride and cholesterol levels were measured.
Results: Histological evaluation revealed that amygdalin was unable to decrease the TM induced liver steatosis; however, ALT and AST levels decreased [ALT: 35.33(2.15) U/L versus 92.33(6.66) U/L; (57.000, (50.63, 63.36),P< 0.001) and AST: 93(5.09) U/L versus 345(97.3) U/L, (252, (163.37, 340.62),P< 0.001)]. Amygdalin also decreased triglyceride and cholesterol plasma levels in the Amy + TM group [TG: 42.66(2.15) versus 53.33(7.24) mg/dL; (10.67, (3.80, 17.54),P= 0.006) and TC: 9.33(3.55) versus 112.66(4.31) mg/dL, (103.33, (98.25, 108.40)P< 0.001)].
Conclusion: Amygdalin improved the ALT, AST, and lipid serum levels after the TM challenge; however, it could not attenuate hepatic steatosis.

Matched MeSH terms: Endoplasmic Reticulum
Fulltext Angiotensin 1-7 Protects against Angiotensin II-Induced Endoplasmic Reticulum Stress and Endothelial Dysfunction via Mas Receptor

Murugan D, Lau YS, Lau CW, Lau WC, Mustafa MR, Huang Y

PLoS One, 2015;10(12):e0145413.
PMID: 26709511 DOI: 10.1371/journal.pone.0145413

Angiotensin 1-7 (Ang 1-7) counter-regulates the cardiovascular actions of angiotensin II (Ang II). The present study investigated the protective effect of Ang 1-7 against Ang II-induced endoplasmic reticulum (ER) stress and endothelial dysfunction. Ex vivo treatment with Ang II (0.5 μM, 24 hours) impaired endothelium-dependent relaxation in mouse aortas; this harmful effect of Ang II was reversed by co-treatment with ER stress inhibitors, l4-phenylbutyric acid (PBA) and tauroursodeoxycholic acid (TUDCA) as well as Ang 1-7. The Mas receptor antagonist, A779, antagonized the effect of Ang 1-7. The elevated mRNA expression of CHOP, Grp78 and ATF4 or protein expression of p-eIF2α and ATF6 (ER stress markers) in Ang II-treated human umbilical vein endothelial cells (HUVECs) and mouse aortas were blunted by co-treatment with Ang 1-7 and the latter effect was reversed by A779. Furthermore, Ang II-induced reduction in both eNOS phosphorylation and NO production was inhibited by Ang 1-7. In addition, Ang 1-7 decreased the levels of ER stress markers and augmented NO production in HUVECs treated with ER stress inducer, tunicamycin. The present study provides new evidence for functional antagonism between the two arms of the renin-angiotensin system in endothelial cells by demonstrating that Ang 1-7 ameliorates Ang II-stimulated ER stress to raise NO bioavailability, and subsequently preserves endothelial function.

Matched MeSH terms: Endoplasmic Reticulum Stress/drug effects*
Fulltext Flavokawain C Inhibits Cell Cycle and Promotes Apoptosis, Associated with Endoplasmic Reticulum Stress and Regulation of MAPKs and Akt Signaling Pathways in HCT 116 Human Colon Carcinoma Cells

Phang CW, Karsani SA, Sethi G, Abd Malek SN

PLoS One, 2016;11(2):e0148775.
PMID: 26859847 DOI: 10.1371/journal.pone.0148775

Flavokawain C (FKC) is a naturally occurring chalcone which can be found in Kava (Piper methysticum Forst) root. The present study evaluated the effect of FKC on the growth of various human cancer cell lines and the underlying associated mechanisms. FKC showed higher cytotoxic activity against HCT 116 cells in a time- and dose-dependent manner in comparison to other cell lines (MCF-7, HT-29, A549 and CaSki), with minimal toxicity on normal human colon cells. The apoptosis-inducing capability of FKC on HCT 116 cells was evidenced by cell shrinkage, chromatin condensation, DNA fragmentation and increased phosphatidylserine externalization. FKC was found to disrupt mitochondrial membrane potential, resulting in the release of Smac/DIABLO, AIF and cytochrome c into the cytoplasm. Our results also revealed that FKC induced intrinsic and extrinsic apoptosis via upregulation of the levels of pro-apoptotic proteins (Bak) and death receptors (DR5), while downregulation of the levels of anti-apoptotic proteins (XIAP, cIAP-1, c-FlipL, Bcl-xL and survivin), resulting in the activation of caspase-3, -8 and -9 and cleavage of poly(ADP-ribose) polymerase (PARP). FKC was also found to cause endoplasmic reticulum (ER) stress, as suggested by the elevation of GADD153 protein after FKC treatment. After the cells were exposed to FKC (60μM) over 18hrs, there was a substantial increase in the phosphorylation of ERK 1/2. The expression of phosphorylated Akt was also reduced. FKC also caused cell cycle arrest in the S phase in HCT 116 cells in a time- and dose-dependent manner and with accumulation of cells in the sub-G1 phase. This was accompanied by the downregulation of cyclin-dependent kinases (CDK2 and CDK4), consistent with the upregulation of CDK inhibitors (p21Cip1 and p27Kip1), and hypophosphorylation of Rb.

Matched MeSH terms: Endoplasmic Reticulum Stress/drug effects
Fulltext Transcription Factor CREB3L1 Regulates Endoplasmic Reticulum Stress Response Genes in the Osmotically Challenged Rat Hypothalamus

Greenwood M, Greenwood MP, Paton JF, Murphy D

PLoS One, 2015;10(4):e0124956.
PMID: 25915053 DOI: 10.1371/journal.pone.0124956

Arginine vasopressin (AVP) is synthesised in magnocellular neurons (MCNs) of supraoptic nucleus (SON) and paraventricular nucleus (PVN) of the hypothalamus. In response to the hyperosmotic stressors of dehydration (complete fluid deprivation, DH) or salt loading (drinking 2% salt solution, SL), AVP synthesis increases in MCNs, which over-burdens the protein folding machinery in the endoplasmic reticulum (ER). ER stress and the unfolded protein response (UPR) are signaling pathways that improve ER function in response to the accumulation of misfold/unfold protein. We asked whether an ER stress response was activated in the SON and PVN of DH and SL rats. We observed increased mRNA expression for the immunoglobulin heavy chain binding protein (BiP), activating transcription factor 4 (Atf4), C/EBP-homologous protein (Chop), and cAMP responsive element binding protein 3 like 1 (Creb3l1) in both SON and PVN of DH and SL rats. Although we found no changes in the splicing pattern of X box-binding protein 1 (Xbp1), an increase in the level of the unspliced form of Xbp1 (Xbp1U) was observed in DH and SL rats. CREB3L1, a novel ER stress inducer, has been shown to be activated by ER stress to regulate the expression of target genes. We have previously shown that CREB3L1 is a transcriptional regulator of the AVP gene; however, a role for CREB3L1 in the response to ER stress has yet to be investigated in MCNs. Here, we used lentiviral vectors to introduce a dominant negative form of CREB3L1 (CREB3L1DN) in the rat SON. Expression of CREB3L1DN in the SON decreased Chop and Xbp1U mRNA levels, but not BiP and Atf4 transcript expression. CREB3L1 is thus implicated as a transcriptional mediator of the ER stress response in the osmotically stimulated SON.

Matched MeSH terms: Endoplasmic Reticulum Stress*
Fulltext Melatonin Induces Autophagy via Reactive Oxygen Species-Mediated Endoplasmic Reticulum Stress Pathway in Colorectal Cancer Cells

Chok KC, Koh RY, Ng MG, Ng PY, Chye SM

Molecules, 2021 Aug 20;26(16).
PMID: 34443626 DOI: 10.3390/molecules26165038

Even though an increasing number of anticancer treatments have been discovered, the mortality rates of colorectal cancer (CRC) have still been high in the past few years. It has been discovered that melatonin has pro-apoptotic properties and counteracts inflammation, proliferation, angiogenesis, cell invasion, and cell migration. In previous studies, melatonin has been shown to have an anticancer effect in multiple tumors, including CRC, but the underlying mechanisms of melatonin action on CRC have not been fully explored. Thus, in this study, we investigated the role of autophagy pathways in CRC cells treated with melatonin. In vitro CRC cell models, HT-29, SW48, and Caco-2, were treated with melatonin. CRC cell death, oxidative stress, and autophagic vacuoles formation were induced by melatonin in a dose-dependent manner. Several autophagy pathways were examined, including the endoplasmic reticulum (ER) stress, 5'-adenosine monophosphate-activated protein kinase (AMPK), phosphoinositide 3-kinase (PI3K), serine/threonine-specific protein kinase (Akt), and mammalian target of rapamycin (mTOR) signaling pathways. Our results showed that melatonin significantly induced autophagy via the ER stress pathway in CRC cells. In conclusion, melatonin demonstrated a potential as an anticancer drug for CRC.

Matched MeSH terms: Endoplasmic Reticulum Stress/drug effects*
The superoxide dismutase mimetic tempol blunts diabetes-induced upregulation of NADPH oxidase and endoplasmic reticulum stress in a rat model of diabetic nephropathy

De Blasio MJ, Ramalingam A, Cao AH, Prakoso D, Ye JM, Pickering R, et al.

Eur J Pharmacol, 2017 Jul 15;807:12-20.
PMID: 28438648 DOI: 10.1016/j.ejphar.2017.04.026

Endoplasmic reticulum (ER) stress contributes to progression of diabetic nephropathy, which promotes end-stage renal failure in diabetic patients. This study was undertaken to investigate the actions of tempol and ramipril, pharmacological agents that target the consequences of NADPH oxidase, on diabetic nephropathy in a rat model of type 1 diabetes, with an emphasis on markers of ER stress. Male Sprague-Dawley rats were injected intravenously with a single bolus of streptozotocin (55mg/kg) to induce type 1 diabetes. An additional age-matched group of rats was administered with citrate vehicle as controls. After 4 weeks of untreated diabetes, rats received tempol (1.5mM/kg/day subcutaneously, n=8), ramipril (1mg/kg/day in drinking water, n=8) or remained untreated for an additional 4 weeks (n=7). After 8 weeks of diabetes in total, kidneys were collected for histological analysis, gene expression and protein abundance. Tempol and ramipril blunted diabetes-induced upregulation of NADPH oxidase isoforms (Nox4, Nox2, p47phox), accompanied by an amelioration of diabetes-induced glomerular injury (podocin, nephrin, Kim-1), tubulo-interstitial fibrosis (TGFβ1, TGFβ-R2, pSMAD3, α-SMA) and pro-inflammatory cytokines (TNFα, MCP-1, ANX-A1, FPR2) expression. In addition, the diabetes-induced renal ER stress, evidenced by increased expression of GRP-78 chaperone and stress-associated markers ATF4, TRB3, as well as XBP1s, phospho-p38 mitogen-activated protein kinase (MAPK) and 3-nitrotyrosination, were all attenuated by tempol and ramipril. These observations suggest that antioxidant approaches that blunt NADPH upregulation may attenuate diabetic nephropathy, at least in part by negatively regulating ER stress and inflammation, and hence ameliorating kidney damage.

Matched MeSH terms: Endoplasmic Reticulum Stress/drug effects*
Fulltext Hyperhomocysteinemia causes ER stress and impaired autophagy that is reversed by Vitamin B supplementation

Tripathi M, Zhang CW, Singh BK, Sinha RA, Moe KT, DeSilva DA, et al.

Cell Death Dis, 2016 12 08;7(12):e2513.
PMID: 27929536 DOI: 10.1038/cddis.2016.374

Hyperhomocysteinemia (HHcy) is a well-known risk factor for stroke; however, its underlying molecular mechanism remains unclear. Using both mouse and cell culture models, we have provided evidence that impairment of autophagy has a central role in HHcy-induced cellular injury in the mouse brain. We observed accumulation of LC3B-II and p62 that was associated with increased MTOR signaling in human and mouse primary astrocyte cell cultures as well as a diet-induced mouse model of HHcy, HHcy decreased lysosomal membrane protein LAMP2, vacuolar ATPase (ATP6V0A2), and protease cathepsin D, suggesting that lysosomal dysfunction also contributed to the autophagic defect. Moreover, HHcy increased unfolded protein response. Interestingly, Vitamin B supplementation restored autophagic flux, alleviated ER stress, and reversed lysosomal dysfunction due to HHCy. Furthermore, the autophagy inducer, rapamycin was able to relieve ER stress and reverse lysosomal dysfunction caused by HHcy in vitro. Inhibition of autophagy by HHcy exacerbated cellular injury during oxygen and glucose deprivation and reperfusion (OGD/R), and oxidative stress. These effects were prevented by Vitamin B co-treatment, suggesting that it may be helpful in relieving detrimental effects of HHcy in ischemia/reperfusion or oxidative stress. Collectively, these findings show that Vitamin B therapy can reverse defects in cellular autophagy and ER stress due to HHcy; and thus may be a potential treatment to reduce ischemic damage caused by stroke in patients with HHcy.

Matched MeSH terms: Endoplasmic Reticulum Stress/drug effects*
Fulltext Chalcomoracin is a potent anticancer agent acting through triggering Oxidative stress via a mitophagy- and paraptosis-dependent mechanism

Han H, Chou CC, Li R, Liu J, Zhang L, Zhu W, et al.

Sci Rep, 2018 06 22;8(1):9566.
PMID: 29934599 DOI: 10.1038/s41598-018-27724-3

Chalocomoracin (CMR), one of the major secondary metabolites found in fungus-infected mulberry leaves, is a potent anticancer agent. However, its anticancer mechanism remains elusive. Here, we demonstrated the potent anti-tumor activity and molecular mechanism of CMR both in vitro and in vivo. We showed for the first time that CMR treatment markedly promoted paraptosis along with extensive cytoplasmic vacuolation derived from the endoplasmic reticulum, rather than apoptosis, in PC-3 and MDA-MB-231cell lines. Additional studies revealed that ectopic expression of Myc-PINK1 (PTEN-induced kinase 1), a key regulator of mitophagy, rendered LNCap cells susceptible to CMR-induced paraptosis, suggesting that the mitophagy-dependent pathway plays a crucial role in inducing paraptosis by activating PINK1. CMR treatment directly upregulated PINK1 and downregulated Alix genes in MDA-MB-231 and PC-3 cell lines. Furthermore, mitophagy signaling and paraptosis with cytoplasmic vacuolation could be blocked by antioxidant N-acetylcysteine (NAC), indicating the novel pathway was triggered by reactive oxygen species (ROS) production. An in vivo MDA-MB-231 xenograft tumor model revealed that CMR suppressed tumor growth by inducing vacuolation production through the same signal changes as those observed in vitro. These data suggest that CMR is a potential therapeutic entity for cancer treatment through a non-apoptotic pathway.

Matched MeSH terms: Endoplasmic Reticulum Stress/drug effects
Fulltext A novel Diels-Alder adduct of mulberry leaves exerts anticancer effect through autophagy-mediated cell death

Shu YH, Yuan HH, Xu MT, Hong YT, Gao CC, Wu ZP, et al.

Acta Pharmacol Sin, 2021 May;42(5):780-790.
PMID: 32814819 DOI: 10.1038/s41401-020-0492-5

Guangsangon E (GSE) is a novel Diels-Alder adduct isolated from leaves of Morus alba L, a traditional Chinese medicine widely applied in respiratory diseases. It is reported that GSE has cytotoxic effect on cancer cells. In our research, we investigated its anticancer effect on respiratory cancer and revealed that GSE induces autophagy and apoptosis in lung and nasopharyngeal cancer cells. We first observed that GSE inhibits cell proliferation and induces apoptosis in A549 and CNE1 cells. Meanwhile, the upregulation of autophagosome marker LC3 and increased formation of GFP-LC3 puncta demonstrates the induction of autophagy in GSE-treated cells. Moreover, GSE increases the autophagy flux by enhancing lysosomal activity and the fusion of autophagosomes and lysosomes. Next, we investigated that endoplasmic reticulum (ER) stress is involved in autophagy induction by GSE. GSE activates the ER stress through reactive oxygen species (ROS) accumulation, which can be blocked by ROS scavenger NAC. Finally, inhibition of autophagy attenuates GSE-caused cell death, termed as "autophagy-mediated cell death." Taken together, we revealed the molecular mechanism of GSE against respiratory cancer, which demonstrates great potential of GSE in the treatment of representative cancer.

Matched MeSH terms: Endoplasmic Reticulum Stress/drug effects
Paeonol protects against endoplasmic reticulum stress-induced endothelial dysfunction via AMPK/PPARδ signaling pathway

Choy KW, Mustafa MR, Lau YS, Liu J, Murugan D, Lau CW, et al.

Biochem Pharmacol, 2016 09 15;116:51-62.
PMID: 27449753 DOI: 10.1016/j.bcp.2016.07.013

Endoplasmic reticulum (ER) stress in endothelial cells often leads to endothelial dysfunction which underlies the pathogenesis of cardiovascular diseases. Paeonol, a major phenolic component extracted from Moutan Cortex, possesses various medicinal benefits which have been used extensively in traditional Chinese medicine. The present study investigated the protective mechanism of paeonol against tunicamycin-induced ER stress in isolated mouse aortas and human umbilical vein endothelial cells (HUVECs). Vascular reactivity in aorta was measured using a wire myograph. The effects of paeonol on protein expression of ER stress markers, reactive oxygen species (ROS) production, nitric oxide (NO) bioavailability and peroxisome proliferator-activated receptor δ (PPARδ) activity in the vascular wall were assessed by Western blot, dihydroethidium fluorescence (DHE) or lucigenin enhanced-chemiluminescence, 4-amino-5-methylamino-2',7'-difluorofluorescein (DAF-FM DA) and dual luciferase reporter assay, respectively. Ex vivo treatment with paeonol (0.1μM) for 16h reversed the impaired endothelium-dependent relaxations in C57BJ/6J and PPARδ wild type (WT) mouse aortas following incubation with tunicamycin (0.5μg/mL). Elevated ER stress markers, oxidative stress and reduction of NO bioavailability induced by tunicamycin in HUVECs, C57BJ/6J and PPARδ WT mouse aortas were reversed by paeonol treatment. These beneficial effects of paeonol were diminished in PPARδ knockout (KO) mouse aortas. Paeonol increased the expression of 5' adenosine monophosphate-activated protein kinase (AMPK) and PPARδ expression and activity while restoring the decreased phosphorylation of eNOS. The present study delineates that paeonol protects against tunicamycin-induced vascular endothelial dysfunction by inhibition of ER stress and oxidative stress, thus elevating NO bioavailability via the AMPK/PPARδ signaling pathway.

Matched MeSH terms: Endoplasmic Reticulum Stress/drug effects*
Fulltext Mutations in KEOPS-complex genes cause nephrotic syndrome with primary microcephaly

Braun DA, Rao J, Mollet G, Schapiro D, Daugeron MC, Tan W, et al.

Nat Genet, 2017 Oct;49(10):1529-1538.
PMID: 28805828 DOI: 10.1038/ng.3933

Galloway-Mowat syndrome (GAMOS) is an autosomal-recessive disease characterized by the combination of early-onset nephrotic syndrome (SRNS) and microcephaly with brain anomalies. Here we identified recessive mutations in OSGEP, TP53RK, TPRKB, and LAGE3, genes encoding the four subunits of the KEOPS complex, in 37 individuals from 32 families with GAMOS. CRISPR-Cas9 knockout in zebrafish and mice recapitulated the human phenotype of primary microcephaly and resulted in early lethality. Knockdown of OSGEP, TP53RK, or TPRKB inhibited cell proliferation, which human mutations did not rescue. Furthermore, knockdown of these genes impaired protein translation, caused endoplasmic reticulum stress, activated DNA-damage-response signaling, and ultimately induced apoptosis. Knockdown of OSGEP or TP53RK induced defects in the actin cytoskeleton and decreased the migration rate of human podocytes, an established intermediate phenotype of SRNS. We thus identified four new monogenic causes of GAMOS, describe a link between KEOPS function and human disease, and delineate potential pathogenic mechanisms.

Matched MeSH terms: Endoplasmic Reticulum Stress/genetics

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