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Autophagy and autophagy enhancers

Autophagy and autophagy enhancers

These results also suggest the possibility that systemic enhancement of Autophagy and autophagy enhancers enhanfers may confer ahtophagy metabolic effects enhancrrs metabolic stress by enhancing cellular and Proper nutrition for injury prevention adaptive Autoophagy to the enhanncers. View enhancrrs Ulcer prevention guidelines. CAS PubMed PubMed Central Google Scholar. e WT and Tfeb knockout HeLa cells were treated with MSL, and cell extract was subjected to Western blot analysis using the indicated antibodies. Metab Brain Dis 33— Hill MP, Brotchie JM The adrenergic receptor agonist, clonidine, potentiates the anti-parkinsonian action of the selective κ-opioid receptor agonist, enadoline, in the monoamine-depleted rat. Massacesi C, di Tomaso E, Fretault N, Hirawat S Challenges in the clinical development of PI3K inhibitors. Autophagy and autophagy enhancers

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The chaperone activity and toxicity of ambroxol on Gaucher cells and normal mice. Brain Dev. Khanna R, Benjamin ER, Pellegrino L, Schilling A, Rigat BA, Soska R, et al. When we examined whether MSL-7 can induce autophagic activity in monkey islet cells using confocal microscopy upon transfection with mRFP-GFP-LC3 tandem construct, the numbers of both autophagosomes and autophagolysosomes were significantly increased after treatment with MSL-7 Fig.

When primary monkey islet cells were cultured in the presence of 3-MA, sIAPP oligomer stained with A11 antibody recognizing hIAPP oligomer 19 significantly accumulated which was not seen without 3-MA Fig. When monkey islet cells cultured in the presence of 3-MA were treated with MSL-7, accumulation of sIAPP oligomer was significantly reduced Fig.

Apoptosis of monkey islet cells incubated with 3-MA probably due to accumulation of endogenous sIAPP oligomer 3 was also significantly attenuated by MSL-7 Fig. While behavior of sIAPP oligomer would be similar to that of hIAPP oligomer, we further investigated effect of MSL-7 on hIAPP oligomer clearance employing human β-cells or β-cell lines.

We chose 1. MSL-7 treatment induced nuclear translocation of TFEB or TFE3, and enhanced formation of autophagosomes or autophagolysosomes in 1. MSL-7 reduced hIAPP oligomer accumulation and apoptosis in 1. MSL-7 induced expression of autophagy genes, lysosomal genes and TFEB or TFE3 in 1. Since behavior of 1.

hiPSCs were differentiated into β-cells using a kit STEMdiff TM Pancreatic Progenitor Kit, STEMCELL Technologies according to a modification of previously reported methods 23 , 24 , which was confirmed by immunofluorescence using anti-insulin antibody hiPSC-β-cells Fig.

When islet-like clusters differentiated from hiPSCs were incubated with 3-MA, hIAPP oligomer accumulation was clearly seen in insulin-producing cells as yellow puncta in double immunofluorescence using A11 and anti-insulin antibodies Fig.

Reduced hIAPP oligomer accumulation was accompanied by nuclear translocation of TFEB and TFE3 as identified by immunofluorescence using specific antibodies, which can be seen as reduced cytosolic yellow fluorescence due to colocalization of insulin with TFEB or TFE3 and increased cyan fluorescence due to colocalization of nuclear DAPI with TFEB or TFE3 after MSL-7 treatment Fig.

a Expression of insulin and nuclear translocation of TFEB left or TFE3 right in human β-cells differentiated from human induced pluripotent stem cells hiPSCs. Representative pictures are presented upper. Inset images were magnified to show cyan nuclei due to colocalization of TUNEL staining with nuclear DAPI.

Immunoblot analysis demonstrated the absence of TFEB or TFE3 expression in Tfeb- KO or Tfe3- KO cells, respectively Supplementary Fig.

Expression and nuclear translocation of TFE3 were not affected in Tfeb -KO cells, while those of TFEB were not affected in Tfe3 -KO cells Fig. When Tfeb -KO or Tfe3 -KO INS-1 cells were transfected with mRFP-GFP-LC3 plasmid and treated with MSL-7, the numbers of autophagosome and autophagolysosome were decreased in both Tfeb -KO and Tfe3 -KO cells compared to control cells Fig.

Furthermore, induction of autophagy genes and lysosomal genes by MSL-7 treatment was reduced in Tfeb -KO or Tfe3 -KO INS-1 cells compared to control Cas9-treated cells, accounting for the decrease of MSLinduced autophagy in these cells Supplementary Fig.

After DAPI staining, cells were subjected to confocal microscopy. Inset images were magnified to show red autophagolysosomes , green, and yellow autophagosomes puncta. not significant Source data are provided as a Source Data file.

We also studied whether Tfeb or Tfe3 KO affects hIAPP oligomer clearance by MSL When cells were transfected with prepro-hIAPP-HA , intensity of hIAPP dimer bands before MSL-7 treatment was notably higher in both Tfeb -KO and Tfe3 -KO INS-1 cells compared to control cells compare 3rd with 7th or 11th lane from the left of Fig.

When Tfeb -KO or Tfe3 -KO INS-1 cells transfected with prepro-hIAPP-HA were treated with MSL-7, decreases of hIAPP dimer band intensity relative to vehicle Veh -treated Tfeb -KO or Tfe3 -KO cells were small and statistically insignificant in both KO cells compare 7th with 8th lane or 11th with 12th lane from the left of Fig.

Thus, when normalized to the vehicle-treated respective KO cells, intensity of hIAPP dimer band after treatment of Tfeb -KO or Tfe3 -KO INS-1 cells with MSL-7 was significantly higher than that after treatment of wild-type control cells with MSL-7 compare 2nd with 4th or 6th bar from the left of Fig.

Likely due to reduced constitutive clearance of hIAPP dimer, a small but significant apoptosis was observed after transfection of Tfeb -KO or Tfe3 -KO INS-1 cells with prepro-hIAPP in the absence of 3-MA compare 9th and 11th bars from the left of Fig.

Apoptosis of Tfeb -KO or Tfe3 -KO INS-1 cells after prepro-hIAPP transfection in the absence of 3-MA was not significantly reduced by MSL-7 compare 11th and 12th bars from the left of Fig. Apoptosis of Tfeb -KO or Tfe3 -KO INS-1 cells after prepro-hIAPP transfection in the presence of 3-MA was also not significantly reduced by MSL-7 compare 7th and 8th or 11th and 12th bars from the left of Fig.

Residual effect of MSL-7 in Tfeb- KO or Tfe3 -KO INS-1 cells such as induction of low-level autophagy Fig. Furthermore, TFE3 expression is intact in Tfeb -KO cells and TFEB expression is intact in Tfe3 -KO cells Supplementary Fig. However, autophagy induction in these cells was significantly reduced compared to wild-type cells, showing a significant role of Tfeb or Tfe3 in autophagy induction by MSL We also studied possible effect of MSL-7 on mitochondrial dysfunction caused by hIAPP oligomer 26 , 27 which can affect glucose-induced insulin release a Scheme of MSL-7 treatment.

b MSL-7 was administered intraperitoneally i. To investigate whether improved glucose profile and β-cell function in vivo by MSL-7 administration were due to the increased clearance of toxic hIAPP oligomer, we conducted immunofluorescence of pancreatic islets using A11 antibody.

Representative TUNEL staining is shown left. Representative insulin immunochemistry is shown left. In these mice, we studied whether in vivo effects of MSL-7 is affected by Tfeb of β-cells.

Representative pictures were presented left. not significant. We here have demonstrated that the autophagy enhancer small molecule, MSL-7 that could improve metabolic profile of obese mice by activating TFEB and enhancing lysosomal biogenesis or autophagy gene expression, can also improve glucose profile and pancreatic β-cell function of transgenic mice expressing amyloidogenic hIAPP fed HFD.

Improvement of pancreatic β-cell function in vivo can be explained by expedited clearance of hIAPP oligomer and amelioration of pancreatic β-cell death caused by hIAPP oligomer accumulation.

MSLinduced reduction of amyloidogenic IAPP oligomer accumulation and resultant cell death in the presence of 3-MA was observed not only when hIAPP was overexpressed by genetic methods but also when primary monkey islet cells expressing endogenous amyloidogenic sIAPP or hiPSC-derived β-cells expressing hIAPP were employed, suggesting physiological relevance of MSL-7 effect improving pancreatic β-cell viability.

While we observed similar cell death following inhibition of autophagy in both genetic overexpression of hIAPP and endogenous amyloidogenic hIAPP models, accumulated hIAPP species were different between them because pro-hIAPP dimer or trimer was observed in INS-1 cells transfected with prepro-hIAPP-HA , while hIAPP oligomer stained with A11 antibody was observed in hiPSC-derived β-cells expressing endogenous amyloidogenic hIAPP.

We have no direct biochemical evidence showing the progression from pro-hIAPP dimer to high- n hIAPP oligomer or amyloid. However, we have observed the proportional relationship between pro-hIAPP dimer and hIAPP oligomer in the same cells — monkey islet cells transfected with prepro-hIAPP-HA 3 , and it is likely that pro- hIAPP dimer or trimer acts as a seed for high- n hIAPP oligomer Our study also suggests the possibility that while pro-hIAPP dimer may exist in unstressed β-cells and is not cytotoxic, further progression into high- n oligomer occurs in the presence of autophagy impairment or metabolic stress 3.

It should also be noted that A11 antibody that was raised against human Aβ oligomer and has been used to detect hIAPP oligomer, can recognize other proteins such as heat-shock proteins Consistently, dephosphorylation and nuclear translocation by MSL-7 occurred in both TFEB and TFE3 proteins, which could be dependent on calcineurin 9.

We have previously reported that autophagy enhancers such as MSL-7 could be a therapeutic agent against diabetes or metabolic syndrome associated with obesity based on our data using mouse models.

However, human diabetes is different from murine diabetes in that islet amyloid is found in most patients with type 2 diabetes due to the amyloidogenic propensity of hIAPP 2 , Since the aggregate-prone or amyloid proteins are cleared preferentially by autophagy rather than by the proteasomal degradation pathway 6 , the role of autophagy or the effect of autophagy modulators may be more important in human type 2 diabetes than in murine type 2 diabetes, which was strengthened by our observation that MSL-7 can expedite clearance of hIAPP oligomer accumulation in hiPSC-β-cells and protect those cells from hIAPP oligomer-induced cell death.

MSL-7 or other autophagy enhancers could be therapeutic agents against human diabetes associated with islet amyloid accumulation. Cynomolgus monkeys purchased from Guangxi Grandforest Scientific Primate Company Ltd. were maintained in the Orientbio Animal Facility 3. All animals were maintained in a specific pathogen free SPF facility accredited by the Association for the Assessment and Accreditation of Laboratory Animal Care International AAALAC.

All animal experiments were approved by the Institutional Animal Care and Use Committee of Yonsei University Health System IACUC of YUHS and were conducted in accordance with the Public Health Service Policy on Humane Care and Use of Laboratory Animals. Monkey experiments were approved by the IACUC of Orientbio, another AAALAC-accredited unit.

To study MSL-7 effect on STZ-induced hIAPP oligomer accumulation, STZ Sigma dissolved in 0. Twenty-four h later, MSL-7 administration was started and continued every other day for a total of 3 times.

The isolation chamber was gently shaken during digestion, and serial samples were examined under a light microscope after dithizone Sigma Aldrich staining. Islets were then isolated by continuous density gradient centrifugation using a COBE Cell Processor Terumo BCT Inc.

Primary murine islets were isolated from fasted mice using the collagenase digestion technique as previously described In brief, after injection of 2.

Islets were collected from the interface using micropipettes. INS-1 cells kindly provided by Dr. All cells were free of mycoplasma contamination. All in vitro experiments were repeated at least three times to confirm reproducibility.

hiPSCs were derived by umbilical cord blood mononuclear cells, and reprogramming was conducted using CytoTune-iPS Sendai Reprogramming Kit Life Technologies. Healthy human cord blood had been obtained from newborn after obtaining informed parental consent at Catholic Hematopoietic Stem Cell Bank of Korea.

hiPSCs were adapted to feeder-free conditions on vitronectin VTN-N Gibco -coated plates in TeSR TM -E8 TM medium STEMCELL Technologies. To initiate differentiation, confluent hiPSCs were dissociated into single cell suspension using TrypLE and seeded at 1.

At the stage for pancreatic progenitor generation, 0. For immunofluorescence or TUNEL staining of iPSC-β-cells, islet-like clusters were pre-embedded in agar before paraffin embedding. All experiments using hiPSC were conducted in accordance with the protocol approved by the IRB of the Catholic University of Korea.

Deparaffinized pancreatic sections were incubated with TUNEL reagent Roche Applied Science and DAB Life Technologies as the color substrate. Insulin immunochemistry was then conducted by serial incubation with anti-insulin antibody Cell Signaling Technology, , biotinylated anti-rabbit antibody Vector Laboratories, , streptavidin-alkaline phosphatase, and then with Vector® Blue alkaline phosphatase substrate 3 Vector Laboratories.

Relative β-cell mass was determined by analyzing more than 30 islets per mouse more than islets per group. After insulin immunohistochemistry using anti-insulin antibody and DAB, point counting morphometry was conducted as previously described 3.

The transient transfection of prepro-hIAPP-HA and prepro-mIAPP - HA 3 was conducted using jetPEI® DNA transfection reagent Polyplus Transfection 3. Cells with mismatched mutations were isolated by the low-density seeding method.

Gene KO was confirmed by nucleotide sequencing using an automatic DNA analyzer Bioneer. For TFEB immunostaining of INS-1, 1. For TFE3 immunostaining, cells with bright nuclear TFE3 without cytosolic TFE3 were considered to be activated because faint nuclear TFE3 was observed in untreated cells, while bright nuclear TFE3 staining without cytosolic TFE3 staining was observed in most cells after MSL-7 treatment.

hIAPP oligomer in frozen tissue sections or in cells cultured in a Lab-Tak® II Chamber Slide Thermo Fisher Scientific was identified by immunostaining using A11 antibody Merck Millipore, and Alexa anti-rabbit IgG Life Technologies, To investigate colocalization of A11 puncta with autophagosome, immunostaining using A11 antibody was followed by immunostaining using anti-LC3 antibody MBL, and then with Alexa anti-mouse IgG Life Technologies, Confocal microscopy was conducted using LSM microscope, and the number of yellow puncta autophagosome colocalized with A11 was counted manually in more than 20 cells.

FSB staining for tissue amyloid was conducted using a modification of previously reported methods 36 , Mean pixel intensity per islet area was determined in more than 25 islets per mouse more than islets per group using ImageJ software NIH.

Cells were transiently transfected with plasmids such as Tfeb-GFP or Tfe3-GFP using jetPEI® DNA transfection reagent. Nuclear translocation of Tfeb-GFP or Tfe3-GFP was determined after treatment of transfected INS-1, 1.

To examine autophagosomes and autophagolysosomes, tandem mRFP - GFP - LC3 was transfected using lipofectamine Life Technologies. GFP or RFP puncta were defined as non-nuclear punctate structures with discrete fluorescent signal on a dark background which was clearly visible with fluorescent confocal microscopy.

The numbers of yellow puncta autophagosomes and red puncta autophagolysosomes in more than 20 cells were counted manually. Protein concentration was determined using the Bradford method. Antibodies against the following proteins were used: SQSTM1 Progen Biotechnik, , LC3 Novus Biologicals, , TFEB Bethyl Laboratories, , TFE3 Sigma Aldrich, , phospho-STFEB Merk Millipore, , phospho- Ser binding motif Cell Signaling Technology, , protein Cell Signaling Technology, , β-actin ACTB Santa Cruz Biotechnology, , HA Cell Signaling Technology, or Lamin A Santa Cruz Biotechnology, Densitometry of the protein bands was performed using ImageJ.

Immunoblotting was conducted using primary antibody anti-phospho- Ser binding motif antibody or anti-pan antibody from Cell Signaling Technology , horseradish peroxidase HRP -conjugated anti-rabbit IgG Cell Signaling Technology , and then, an ECL kit for detection of chemiluminescence.

Both nuclear and cytoplasmic fractions were resuspended in a sample buffer Life Technologies for immunoblot analysis. Real-time RT-PCR was performed using AccuPower® GreenStar TM qPCR master mix Bioneer in a QuantStudio3 Real-Time PCR System Applied Biosystems.

All expression values were normalized to Rpl32 mRNA level. The sequences of primers used for real-time RT-PCR are listed in the Supplementary Tables 1 and 2. Primary monkey islets or 1.

Apoptosis of wild-type INS-1 cells, Tfeb -KO or Tfe3 -KO INS-1 cells after transfection of prepro-IAPP-HA was determined using the same method of oligonucleosome detection.

Pancreatic insulin was extracted and insulin content was measured by ELISA according to the protocol recommended by the manufacturer, and normalized to the total pancreas Islet seeding was done by inserting pipette tip directly over the central depressed chamber into the wells of the spheroid microplate.

Mitochondrial respiration was measured using the Seahorse extracellular flux analyzer equipped with a spheroid microplate-compatible thermal tray. O 2 consumption was analyzed using a software Wave TM , Agilent Technologies. Further information on research design is available in the Nature Research Reporting Summary linked to this article.

The data generated or analyzed during this study are available from the corresponding author on reasonable request. Source data are provided with this paper. Dolenšek, J. Structural similarities and differences between the human and the mouse pancreas.

Islets 7 , e Article Google Scholar. Westermark, P. Islet amyloid polypeptide, islet amyloid, and diabetes mellitus. Article CAS Google Scholar. Kim, J. et al. Amyloidogenic peptide oligomer accumulation in autophagy-deficient b-cells leads to diabetes.

Rivera, J. Autophagy defends pancreatic b-cells from human islet amyloid polypeptide-induced toxicity. Shigihara, N. Human IAPP-induced pancreatic beta-cell toxicity and its regulation by autophagy. Rubinsztein, D. The roles of intracellular protein-degradation pathways in neurodegeneration.

Nature , — Article ADS CAS Google Scholar. Sarkar, S. Henry, K. Paumier, L. Li, K. Mou, J. Dunlop, Z. Berger, W. doi: Li, S. Nadanaciva, Z. Berger, K. Paumier, W. Shen, J. Schwartz, K. Dunlop, W. Human A53T α-synuclein causes reversible deficits in mitochondrial function and dynamics in primary mouse cortical neurons.

PLoS One Dec 31;8 12 :e eCollection PLoS One. Submitted manuscript: Berger Z. submitted PLosOne. Diverse effects of aggregate-prone proteins and potential autophagy enhancers on autophagy flux in primary neurons. Drug Discovery Efforts in Autophagy - Therapeutic Targets for Alzheimer's and Parkinson's Diseases.

New York Academy of Sciences, oral presentation, New York, USA. Berger Z. Assessing autophagy flux in primary neurons and other cell based assays — evaluation of putative autophagy enhancers.

Gordon Research Conference, Ventura, CA. Shen W.

Thank you for visiting Enhancres. You are enahncers a Autopahgy version with Aytophagy support for CSS. To Autophagy and autophagy enhancers the best experience, Nootropic for Depression recommend you use a more up to date browser or turn off compatibility mode in Internet Explorer. In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript. Autophagy is a critical regulator of cellular homeostasis, dysregulation of which is associated with diverse diseases. Molecular Cancer volume 19Article enhancerw 12 Cite this article. Metrics Ulcer prevention guidelines. Autophagy, as a type II enhqncers Ulcer prevention guidelines death, Fast-acting pre-workout crucial roles Aufophagy autophagy-related ATG proteins in cancer. Autophagy plays a Antivenom dosage guidelines tumor-suppressive or tumor-promoting role in different contexts and stages of cancer development. In the early tumorigenesis, autophagy, as a survival pathway and quality-control mechanism, prevents tumor initiation and suppresses cancer progression. Once the tumors progress to late stage and are established and subjected to the environmental stresses, autophagy, as a dynamic degradation and recycling system, contributes to the survival and growth of the established tumors and promotes aggressiveness of the cancers by facilitating metastasis.

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1 thoughts on “Autophagy and autophagy enhancers

  1. Es ist schade, dass ich mich jetzt nicht aussprechen kann - ist erzwungen, wegzugehen. Aber ich werde befreit werden - unbedingt werde ich schreiben dass ich denke.

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