Discovery of Aromatic Carbamates that Confer Neuroprotective Activity by Enhancing Autophagy and Inducing the Anti-Apoptotic Protein B-Cell Lymphoma 2 (Bcl-2)

Kinarivala, Nihar; Boustany, Rose‐Mary; Al‐Ahmad, Abraham; Trippier, Paul C.

doi:10.1021/acs.jmedchem.7b01199

Cited by 37 publications

(42 citation statements)

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“…It is generally believed that cell death may involve necrosis, apoptosis and autophagy, and the balance between apoptosis and autophagy plays an important role in cell survival. 44,45 Besides ROS-induced cell necrosis, apoptosis and autophagy are also important in cell death in IR. Apoptosis is related to the severity of ischemia and the time of reperfusion.…”

Section: Discussionmentioning

confidence: 99%

Bergenin Exerts Hepatoprotective Effects by Inhibiting the Release of Inflammatory Factors, Apoptosis and Autophagy via the PPAR-γ Pathway

Xiang

Chen

et al. 2020

DDDT

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These authors contributed equally to this workObjective: Hepatic ischemia reperfusion (IR) limits the development of liver transplantation technology. The aim of this study was to explore the protective effects of Bergenin on hepatic IR, particularly the elimination of reactive oxygen species (ROS) and activation of the peroxisome proliferators activated receptor γ (PPAR-γ) pathway. Methods: Initial experiments were performed to confirm the non-toxicity of Bergenin. Mice were randomly divided into sham, IR, and IR + Bergenin (10, 20 and 40 mg/kg) groups, and serum and tissue samples were obtained at 2, 8 and 24 h for detection of liver enzymes (ALT and AST), inflammatory factors (TNF-α, IL-6 and IL-1β), ROS, cell death markers (Bcl-2, Bax, Beclin-1 and LC3) and related important pathways (PPAR-γ, P38 MAPK, NF-κB p65 and JAK2/STAT1). Results: Bergenin reduced the release of ROS, down-regulated inflammatory factors, and inhibited apoptosis and autophagy. Additionally, expression of PPAR-γ-related genes was increased and phosphorylation of P38 MAPK, NF-κB p65 and JAK2/STAT1-related proteins was decreased in Bergenin pre-treatment groups in a dose-dependent manner. Conclusion: Bergenin exerts hepatic protection by eliminating ROS, affecting the release of inflammatory factors, and influencing apoptosis-and autophagy-related genes via the PPAR-γ pathway in this model of hepatic IR injury.

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Section: Discussionmentioning

confidence: 99%

Bergenin Exerts Hepatoprotective Effects by Inhibiting the Release of Inflammatory Factors, Apoptosis and Autophagy via the PPAR-γ Pathway

Xiang

Chen

et al. 2020

DDDT

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“…31 Moreover, autophagy showed an increase in the expression of autophagy-related proteins such as LC3-II, Beclin-1, and ATG5, with a decrease in the expression of p62. 32 Kinarivala et al 33 reported that the activated Beclin-1 could induce autophagy. In this study, we investigated the effect of Genipin on autophagy in OSCC for the first time.…”

Section: Discussionmentioning

confidence: 99%

Genipin Induces Autophagy and Suppresses Cell Growth of Oral Squamous Cell Carcinoma via PI3K/AKT/MTOR Pathway

Wei

Liu

et al. 2020

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Background: Oral squamous cell carcinoma (OSCC) is a common malignant tumor of the head and neck, and it accounts for more than 90% of oral cancer. Due to high mortality, limitations of traditional treatment and many complications, new treatment methods are urgently needed. This study aimed to look into the effect of new potential anti-tumor drug, genipin, on OSCC treatment. Methods: In vitro, CCK-8, colony formation, and flow cytometry were used to detect the effect of genipin on SCC-9 and SCC-15 cell lines. Immunofluorescence, real-time PCR, and Western blotting were used to investigate its mechanism. Xenograft tumor model was used to explore the role of genipin in vivo. Results: We found that genipin suppressed cell growth and induced apoptosis in vitro. In addition, the expression of p62 was down-regulated while Beclin1 and LC3II were up-regulated in SCC-25 and SCC-9 cells. 3-methyladenine (3-MA) significantly decreased LC3 (LC3II) + puncta, but genipin rescuect 3d this reduction. Furthermore, genipin also reduced the expression of p-PI3K, p-AKT, and p-mTOR. In vivo experiment showed that genipin significantly curbed the tumor size and weight. The positive expression of Ki67 protein and number of apoptotic cells were increased. Conclusion: Conclusively, this study implicated that genipin suppresses cell proliferation and stimulated apoptosis, and is the first exploration showing that genipin induces OSCC cell autophagy via PI3K/AKT/mTOR pathway inhibition.

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“…Intrathecal injection of TPP1 slows down CLN2 disease in mice and humans. Flupirtine and aromatic carbamate derivatives antiapoptotic properties provide the basis for use as potential therapies in NCL disease.…”

Section: Introductionmentioning

confidence: 99%

Flupirtine derivatives as potential treatment for the neuronal ceroid lipofuscinoses

Makoukji

Saadeh

Mansour

et al. 2018

Ann Clin Transl Neurol

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ObjectiveNeuronal Ceroid Lipofuscinoses (NCL) are fatal inherited neurodegenerative diseases with established neuronal cell death and increased ceramide levels in brain, hence, a need for disease‐modifying drug candidates, with potential to enhance growth, reduce apoptosis and lower ceramide in neuronal precursor PC12 cells and human NCL cell lines using enhanced flupirtine aromatic carbamate derivatives in vitro.MethodsAromatic carbamate derivatives were tested by establishing growth curves under pro‐apoptotic conditions and activity evaluated by trypan blue and JC‐1 staining, as well as a drop in pro‐apoptotic ceramide in neuronal precursor PC12 cells following siRNA knockdown of the CLN3 gene, and CLN1‐/CLN2‐/CLN3‐/CLN6‐/CLN8 patient‐derived lymphoblasts. Ceramide levels were determined in CLN1‐/CLN2‐/CLN3‐/CLN6‐/CLN8 patient‐derived lymphoblasts before and after treatment. Expression of BCL‐2, ceramide synthesis enzymes (CERS2/CERS6/SMPD1/DEGS2) and Caspases 3/8/9 levels were compared in treated versus untreated CLN3‐deficient PC12 cells by qRT‐PCR.ResultsRetigabine, the benzyl‐derivatized carbamate and an allyl carbamate derivative were neuroprotective in CLN3‐defective PC12 cells and rescued CLN1‐/CLN2‐/CLN3‐/CLN6‐/CLN8 patient‐derived lymphoblasts from diminished growth and accelerated apoptosis. All drugs decreased ceramide in CLN1‐/CLN2‐/CLN3‐/CLN6‐/CLN8 patient‐derived lymphoblasts. Increased BCL‐2 and decreased ceramide synthesis enzyme expression were established in CLN3‐derived PC12 cells treated with the benzyl and allyl carbamate derivatives. They down‐regulated Caspase 3/Caspase 8 expression. Caspase 9 expression was reduced by the benzyl‐derivatized carbamate.InterpretationThese findings establish that compounds analogous to flupirtine demonstrate anti‐apoptotic activity with potential for treatment of NCL disease and use of ceramide as a marker for these diseases.

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Discovery of Aromatic Carbamates that Confer Neuroprotective Activity by Enhancing Autophagy and Inducing the Anti-Apoptotic Protein B-Cell Lymphoma 2 (Bcl-2)

Cited by 37 publications

References 50 publications

<p>Bergenin Exerts Hepatoprotective Effects by Inhibiting the Release of Inflammatory Factors, Apoptosis and Autophagy via the PPAR-γ Pathway</p>

<p>Bergenin Exerts Hepatoprotective Effects by Inhibiting the Release of Inflammatory Factors, Apoptosis and Autophagy via the PPAR-γ Pathway</p>

<p>Genipin Induces Autophagy and Suppresses Cell Growth of Oral Squamous Cell Carcinoma via PI3K/AKT/MTOR Pathway</p>

Flupirtine derivatives as potential treatment for the neuronal ceroid lipofuscinoses

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