Displaying publications 1 - 20 of 74 in total

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  1. Exposure to polystyrene nanoplastics induces apoptosis, autophagy, histopathological damage, and intestinal microbiota dysbiosis of the Pacific whiteleg shrimp (Litopenaeus vannamei)
    Li Y, Ye Y, Yuan H, Rihan N, Han M, Liu X, et al.
    Sci Total Environ, 2024 Apr 01;919:170924.
    PMID: 38360329 DOI: 10.1016/j.scitotenv.2024.170924
    Nanoplastics (NPs) are widely distributed environmental pollutants that can disrupt intestinal immunity of crustaceans. In this study, the effects of NPs on gut immune enzyme activities, cell morphology, apoptosis, and microbiota diversity of Litopenaeus vannamei were investigated. L. vannamei was exposed to five concentrations of NPs (0, 0.1, 1, 5, and 10 mg/L) for 28 days. The results showed that higher concentrations of NPs damaged the intestinal villi, promoted formation of autophagosomes, increased intestinal non-specific immunoenzyme activities, and significantly increased apoptosis at 10 mg/L. In response to exposure to NPs, the expression levels of ATG3, ATG4, ATG12, Caspase-3, p53, and TNF initially increased and then decreased. In addition, the concentration of NPs was negatively correlated to the expression levels of the genes of interest and intestinal enzyme activities, suggesting that exposure to NPs inhibited apoptosis and immune function. The five dominant phyla of the gut microbiota (Proteobacteria, Firmicutes, Bacteroidetes, Acidobacteria, and Actinomycetes) were similar among groups exposed to different concentrations of NPs, but the abundances tended to differ. Notably, exposure to NPs increased the abundance of pathogenic bacteria. These results confirm that exposure to NPs negatively impacted intestinal immune function of L. vannamei. These findings provide useful references for efficient breeding of L. vannamei.
    Matched MeSH terms: Autophagy
  2. Autophagy inhibition suppresses Newcastle disease virus-induced cell death by inhibiting viral replication in human breast cancer cells
    Rozilah MI, Yusoff K, Chia SL, Ismail S
    Virology, 2024 Feb;590:109957.
    PMID: 38100982 DOI: 10.1016/j.virol.2023.109957
    Newcastle disease virus (NDV) is an oncolytic virus which selectively replicates in cancer cells without harming normal cells. Autophagy is a cellular mechanism that breaks down unused cytoplasmic constituents into nutrients. In previous studies, autophagy enhanced NDV-induced oncolysis in lung cancer and glioma cells. However, the effect of autophagy inhibition on NDV-induced oncolysis in breast cancer cells remains unknown. This study aimed to examine the effect of autophagy inhibition on NDV-induced oncolysis in human breast cancer cells, MCF7. To inhibit autophagy, we knocked down the expression of the autophagy protein beclin-1 (BECN1) by short interfering RNA (siRNA). The cells were infected with the recombinant NDV strain AF2240 expressing green fluorescent protein. We found that NDV induced autophagy and knockdown of BECN1 significantly reduced the NDV-induced autophagy in MCF7 cells. Importantly, BECN1 knockdown significantly suppressed cell death by inhibiting viral replication, as observed at 24 h post infection. Overall, our data suggest that autophagy inhibition may not be a suitable strategy to enhance NDV oncolytic efficacy against breast cancer.
    Matched MeSH terms: Autophagy
  3. Fulltext ATG16L1 rs2241880/T300A increases susceptibility to perianal Crohn's disease: An updated meta-analysis on inflammatory bowel disease risk and clinical outcomes
    Simovic I, Hilmi I, Ng RT, Chew KS, Wong SY, Lee WS, et al.
    United European Gastroenterol J, 2024 Feb;12(1):103-121.
    PMID: 37837511 DOI: 10.1002/ueg2.12477
    BACKGROUND: ATG16L1 plays a fundamental role in the degradative intracellular pathway known as autophagy, being a mediator of inflammation and microbial homeostasis. The variant rs2241880 can diminish these capabilities, potentially contributing to inflammatory bowel disease (IBD) pathogenesis.

    OBJECTIVES: To perform an updated meta-analysis on the association between ATG16L1 rs2241880 and IBD susceptibility by exploring the impact of age, ethnicity, and geography. Moreover, to investigate the association between rs2241880 and clinical features.

    METHODS: Literature searches up until September 2022 across 7 electronic public databases were performed for all case-control studies on ATG16L1 rs2241880 and IBD. Pooled odds ratios (ORP ) and 95% CI were calculated under the random effects model.

    RESULTS: Our analyses included a total of 30,606 IBD patients, comprising 21,270 Crohn's disease (CD) and 9336 ulcerative colitis (UC) patients, and 33,329 controls. ATG16L1 rs2241880 was significantly associated with CD susceptibility, where the A allele was protective (ORP : 0.74, 95% CI: 0.72-0.77, p-value: <0.001), while the G allele was a risk factor (ORP : 1.23, 95% CI: 1.09-1.39, p-value: 0.001), depending on the minor allele frequencies observed in this multi-ancestry study sample. rs2241880 was predominantly relevant in Caucasians from North America and Europe, and in Latin American populations. Importantly, CD patients harbouring the G allele were significantly more predisposed to perianal disease (ORP : 1.21, 95% CI: 1.07-1.38, p-value: 0.003).

    CONCLUSIONS: ATG16L1 rs2241880 (G allele) is a consistent risk factor for IBD in Caucasian cohorts and influences clinical outcomes. As its role in non-Caucasian populations remains ambiguous, further studies in under-reported populations are necessary.

    Matched MeSH terms: Autophagy-Related Proteins/genetics
  4. Fulltext Unveiling the dual role of autophagy in vascular remodelling and its related diseases
    Ren H, Dai R, Nik Nabil WN, Xi Z, Wang F, Xu H
    Biomed Pharmacother, 2023 Dec;168:115643.
    PMID: 37839111 DOI: 10.1016/j.biopha.2023.115643
    Vascular remodelling is an adaptive response to physiological and pathological stimuli that leads to structural and functional changes in the vascular intima, media, and adventitia. Pathological vascular remodelling is a hallmark feature of numerous vascular diseases, including atherosclerosis, hypertension, abdominal aortic aneurysm, pulmonary hypertension and preeclampsia. Autophagy is critical in maintaining cellular homeostasis, and its dysregulation has been implicated in the pathogenesis of various diseases, including vascular diseases. However, despite emerging evidence, the role of autophagy and its dual effects on vascular remodelling has garnered limited attention. Autophagy can exert protective and detrimental effects on the vascular intima, media and adventitia, thereby substantially influencing the course of vascular remodelling and its related vascular diseases. Currently, there has not been a review that thoroughly describes the regulation of autophagy in vascular remodelling and its impact on related diseases. Therefore, this review aimed to bridge this gap by focusing on the regulatory roles of autophagy in diseases related to vascular remodelling. This review also summarizes recent advancements in therapeutic agents targeting autophagy to regulate vascular remodelling. Additionally, this review offers an overview of recent breakthroughs in therapeutic agents targeting autophagy to regulate vascular remodelling. A deeper understanding of how autophagy orchestrates vascular remodelling can drive the development of targeted therapies for vascular diseases.
    Matched MeSH terms: Autophagy
  5. Estrogen receptor alpha mediates 17β-estradiol, up-regulates autophagy and alleviates hydrogen peroxide-induced vascular senescence
    Xiang X, Xie L, Lin J, Pare R, Huang G, Huang J, et al.
    Biogerontology, 2023 Oct;24(5):783-799.
    PMID: 36683095 DOI: 10.1007/s10522-023-10015-4
    Atherosclerosis threatens human health by developing cardiovascular diseases, the deadliest disease world widely. The major mechanism contributing to the formation of atherosclerosis is mainly due to vascular endothelial cell (VECs) senescence. We have shown that 17β-estradiol (17β-E2) may protect VECs from senescence by upregulating autophagy. However, little is known about how 17β-E2 activates the autophagy pathway to alleviate cellular senescence. Therefore, the aim of this study is to determine the role of estrogen receptor (ER) α and β in the effects of 17β-E2 on vascular autophagy and aging through in vitro and in vivo models. Hydrogen peroxide (H2O2) was used to establish Human Umbilical Vein Endothelial Cells (HUVECs) senescence. Autophagy activity was measured through immunofluorescence and immunohistochemistry staining of light chain 3 (LC3) expression. Inhibition of ER activity was established using shRNA gene silencing and ER antagonist. Compared with ER-β knockdown, we found that knockdown of ER-α resulted in a significant increase in the extent of HUVEC senescence and senescence-associated secretory phenotype (SASP) secretion. ER-α-specific shRNA was found to reduce 17β-E2-induced autophagy, promote HUVEC senescence, disrupt the morphology of HUVECs, and increase the expression of Rb dephosphorylation and SASP. These in vitro findings were found consistent with the in vivo results. In conclusion, our data suggest that 17β-E2 activates the activity of ER-α and then increases the formation of autophagosomes (LC3 high expression) and decreases the fusion of lysosomes with autophagic vesicles (P62 low expression), which in turn serves to decrease the secretion of SASP caused by H2O2 and consequently inhibit H2O2-induced senescence in HUVEC cells.
    Matched MeSH terms: Autophagy
  6. Autophagy, a critical element in the aging male reproductive disorders and prostate cancer: a therapeutic point of view
    Raee P, Tan SC, Najafi S, Zandsalimi F, Low TY, Aghamiri S, et al.
    Reprod Biol Endocrinol, 2023 Sep 26;21(1):88.
    PMID: 37749573 DOI: 10.1186/s12958-023-01134-1
    Autophagy is a highly conserved, lysosome-dependent biological mechanism involved in the degradation and recycling of cellular components. There is growing evidence that autophagy is related to male reproductive biology, particularly spermatogenic and endocrinologic processes closely associated with male sexual and reproductive health. In recent decades, problems such as decreasing sperm count, erectile dysfunction, and infertility have worsened. In addition, reproductive health is closely related to overall health and comorbidity in aging men. In this review, we will outline the role of autophagy as a new player in aging male reproductive dysfunction and prostate cancer. We first provide an overview of the mechanisms of autophagy and its role in regulating male reproductive cells. We then focus on the link between autophagy and aging-related diseases. This is followed by a discussion of therapeutic strategies targeting autophagy before we end with limitations of current studies and suggestions for future developments in the field.
    Matched MeSH terms: Autophagy
  7. MYTHO is a novel regulator of skeletal muscle autophagy and integrity
    Leduc-Gaudet JP, Franco-Romero A, Cefis M, Moamer A, Broering FE, Milan G, et al.
    Nat Commun, 2023 Mar 02;14(1):1199.
    PMID: 36864049 DOI: 10.1038/s41467-023-36817-1
    Autophagy is a critical process in the regulation of muscle mass, function and integrity. The molecular mechanisms regulating autophagy are complex and still partly understood. Here, we identify and characterize a novel FoxO-dependent gene, d230025d16rik which we named Mytho (Macroautophagy and YouTH Optimizer), as a regulator of autophagy and skeletal muscle integrity in vivo. Mytho is significantly up-regulated in various mouse models of skeletal muscle atrophy. Short term depletion of MYTHO in mice attenuates muscle atrophy caused by fasting, denervation, cancer cachexia and sepsis. While MYTHO overexpression is sufficient to trigger muscle atrophy, MYTHO knockdown results in a progressive increase in muscle mass associated with a sustained activation of the mTORC1 signaling pathway. Prolonged MYTHO knockdown is associated with severe myopathic features, including impaired autophagy, muscle weakness, myofiber degeneration, and extensive ultrastructural defects, such as accumulation of autophagic vacuoles and tubular aggregates. Inhibition of the mTORC1 signaling pathway in mice using rapamycin treatment attenuates the myopathic phenotype triggered by MYTHO knockdown. Skeletal muscles from human patients diagnosed with myotonic dystrophy type 1 (DM1) display reduced Mytho expression, activation of the mTORC1 signaling pathway and impaired autophagy, raising the possibility that low Mytho expression might contribute to the progression of the disease. We conclude that MYTHO is a key regulator of muscle autophagy and integrity.
    Matched MeSH terms: Autophagy/genetics
  8. 17β-estradiol suppresses H2O2-induced senescence in human umbilical vein endothelial cells by inducing autophagy through the PVT1/miR-31/SIRT3 axis
    Xiang X, Wang Y, Huang G, Huang J, Gao M, Sun M, et al.
    J Steroid Biochem Mol Biol, 2023 Mar;227:106244.
    PMID: 36584773 DOI: 10.1016/j.jsbmb.2022.106244
    OBJECTIVE: 17β-estradiol (17β-E2) has been implicated in activating autophagy by upregulating SIRT3 (Sirtuin 3) expression, thereby inhibiting the senescence of vascular endothelial cells. Herein, we further examined the molecular mechanisms that regulate SIRT3 expression in 17β-E2-induced autophagy.

    METHODS: Reverse-transcription-polymerase chain reaction was employed to measure the expression of plasmacytoma variant translocation 1 (PVT1), microRNAs (miRNAs), and SIRT3, and the dual-luciferase assay was used to determine their interaction. Electron microscopy observes autophagosomes, green fluorescent protein-microtubule-associated protein 1 light chain 3 (GFP-LC3) staining, and immunoblot analysis with antibodies against LC3，beclin-1, and P62 were conducted to measure autophagy. Cellular senescence was determined using immunoblot analysis with anti-phosphorylated retinoblastoma and senescence-associated β-galactosidase staining.

    RESULTS: Women with higher estrogen levels (during the 10-13th day of the menstrual cycle or premenopausal) exhibit markedly higher serum levels of PVT1 than women with lower estrogen levels (during the menstrual period or postmenopausal). The dual-luciferase assay showed that PVT1 acts as a sponge for miR-31, and miR-31 binds to its target gene, SIRT3. The 17β-E2 treatment increased the expression of PVT1 and SIRT3 and downregulated miR-31 expression in human umbilical vein endothelial cells (HUVECs). Consistently, PVT1 overexpression suppresses miR-31 expression, promotes 17β-E2-induced autophagy, and inhibits H2O2-induced senescence. miR-31 inhibitor increases SIRT3 expression and leads to activation of 17β-E2-induced autophagy and suppression of H2O2-induced senescence.

    CONCLUSION: Our findings demonstrated that 17β-E2 upregulates PVT1 gene expression and PVT1 functions as a sponge to inhibit miR-31, resulting in the upregulation of SIRT3 expression and activation of autophagy and subsequent inhibition of H2O2-induced senescence in HUVECs.

    Matched MeSH terms: Autophagy
  9. Targeting and regulation of autophagy in hepatocellular carcinoma: revisiting the molecular interactions and mechanisms for new therapy approaches
    Hashemi M, Nadafzadeh N, Imani MH, Rajabi R, Ziaolhagh S, Bayanzadeh SD, et al.
    Cell Commun Signal, 2023 Feb 09;21(1):32.
    PMID: 36759819 DOI: 10.1186/s12964-023-01053-z
    Autophagy is an evolutionarily conserved process that plays a role in regulating homeostasis under physiological conditions. However, dysregulation of autophagy is observed in the development of human diseases, especially cancer. Autophagy has reciprocal functions in cancer and may be responsible for either survival or death. Hepatocellular carcinoma (HCC) is one of the most lethal and common malignancies of the liver, and smoking, infection, and alcohol consumption can lead to its development. Genetic mutations and alterations in molecular processes can exacerbate the progression of HCC. The function of autophagy in HCC is controversial and may be both tumor suppressive and tumor promoting. Activation of autophagy may affect apoptosis in HCC and is a regulator of proliferation and glucose metabolism. Induction of autophagy may promote tumor metastasis via induction of EMT. In addition, autophagy is a regulator of stem cell formation in HCC, and pro-survival autophagy leads to cancer cell resistance to chemotherapy and radiotherapy. Targeting autophagy impairs growth and metastasis in HCC and improves tumor cell response to therapy. Of note, a large number of signaling pathways such as STAT3, Wnt, miRNAs, lncRNAs, and circRNAs regulate autophagy in HCC. Moreover, regulation of autophagy (induction or inhibition) by antitumor agents could be suggested for effective treatment of HCC. In this paper, we comprehensively review the role and mechanisms of autophagy in HCC and discuss the potential benefit of targeting this process in the treatment of the cancer. Video Abstract.
    Matched MeSH terms: Autophagy
  10. Fulltext Saikosaponin A enhances Docetaxel efficacy by selectively inducing death of dormant prostate cancer cells through excessive autophagy
    Feng J, Xi Z, Jiang X, Li Y, Nik Nabil WN, Liu M, et al.
    Cancer Lett, 2023 Feb 01;554:216011.
    PMID: 36442771 DOI: 10.1016/j.canlet.2022.216011
    Quiescent cancer cells (QCCs), also known as dormant cancer cells, resist and survive chemo- and radiotherapy, resulting in treatment failure and later cancer recurrence when QCCs resume cell cycle progression. However, drugs selectively targeting QCCs are lacking. Saikosaponin A (SSA) derived from Bupleurum DC., is highly potent in eradicating multidrug-resistant prostate QCCs compared with proliferative prostate cancer cells. By further exacerbating the already increased autophagy through inactivation of Akt-mTOR signaling, SSA triggered cell death in QCCs. Contrarily, inhibition of autophagy or activation of Akt signaling pathway prevented SSA-induced cell death. The multicycle of Docetaxel treatments increased the proportion of QCCs, whereas administering SSA at intervals of Docetaxel treatments aggravated cell death in vitro and led to tumor growth arrest and cell death in vivo. In conclusion, SSA is posed as a novel QCCs-eradicating agent by aggravating autophagy in QCCs. In combination with the current therapy, SSA has potential to improve treatment effectiveness and to prevent cancer recurrence.
    Matched MeSH terms: Autophagy
  11. Fulltext The role of autophagy-related proteins in the pathogenesis of neuromyelitis optica spectrum disorders
    Guo HL, Shen XR, Liang XT, Li LZ
    Bioengineered, 2022 Jun;13(6):14329-14338.
    PMID: 36694421 DOI: 10.1080/21655979.2022.2084273
    This study aimed to investigate the expression of autophagy-related proteins in a mouse model of neuromyelitis optica (NMO). Mice were assigned to one of four groups: an animal experimental model group (NMO-EAE group, given with exogenous IL-17A), Interleukin-17 monoclonal antibody intervention group (NMO-EAE_0IL17inb), No exogenous interleukin-17 enhanced immune intervention group (NMO-EAE_0IL17), and a control group. Behavioral scores were assessed in each group, and the protein expressions of sequestosome 1 (P62), Beclin-1, the mammalian target of rapamycin (mTOR), phosphoinositide 3-kinase (PI3K-I), and LC3II/LC3I were detected using Western blotting. In the NMO-EAE_0IL17 group, the expression of Beclin-1 decreased, the LC3II/LC3I ratio was lower, and the expressions of P62, mTOR, and PI3K-I increased; after administration of IL-17A inhibitor into the brain tissue, however, the expression of Beclin-1 increased significantly, along with the LC3II/LC3I ratio, while the expressions of P62, mTOR and PI3K-I protein decreased significantly. In terms of behavioral scores, the scores of optic neuritis and myelitis were more serious, onset occurred earlier and the progress was faster, after the administration of IL-17A. In the mechanism of NMO animal model, IL-17A may regulate autophagy and affect the disease process through the activation of the PI3K-mTOR signaling pathway.
    Matched MeSH terms: Autophagy-Related Proteins
  12. Fulltext Pharmacological Effects of Grifolin: Focusing on Anticancer Mechanisms
    Bouyahya A, El Allam A, Zeouk I, Taha D, Zengin G, Goh BH, et al.
    Molecules, 2022 Jan 03;27(1).
    PMID: 35011516 DOI: 10.3390/molecules27010284
    Grifolin is a volatile compound contained in essential oils of several medicinal plants. Several studies show that this substance has been the subject of numerous pharmacological investigations, which have yielded interesting results. Grifolin demonstrated beneficial effects for health via its multiple pharmacological activities. It has anti-microbial properties against bacteria, fungi, and parasites. In addition, grifolin exhibited remarkable anti-cancer effects on different human cancer cells. The anticancer action of this molecule is related to its ability to act at cellular and molecular levels on different checkpoints controlling the signaling pathways of human cancer cell lines. Grifolin can induce apoptosis, cell cycle arrest, autophagy, and senescence in these cells. Despite its major pharmacological properties, grifolin has only been investigated in vitro and in vivo. Therefore, further investigations concerning pharmacodynamic and pharmacokinetic tests are required for any possible pharmaceutical application of this substance. Moreover, toxicological tests and other investigations involving humans as a study model are required to validate the safety and clinical applications of grifolin.
    Matched MeSH terms: Autophagy/drug effects*
  13. Fulltext MicroRNAs Regulate Cell Cycle and Cell Death Pathways in Glioblastoma
    Sati ISEE, Parhar I
    Int J Mol Sci, 2021 Dec 17;22(24).
    PMID: 34948346 DOI: 10.3390/ijms222413550
    Glioblastoma (GBM), a grade IV brain tumor, is known for its heterogenicity and its resistance to the current treatment regimen. Over the last few decades, a significant amount of new molecular and genetic findings has been reported regarding factors contributing to GBM's development into a lethal phenotype and its overall poor prognosis. MicroRNA (miRNAs) are small non-coding sequences of RNA that regulate and influence the expression of multiple genes. Many research findings have highlighted the importance of miRNAs in facilitating and controlling normal biological functions, including cell differentiation, proliferation, and apoptosis. Furthermore, miRNAs' ability to initiate and promote cancer development, directly or indirectly, has been shown in many types of cancer. There is a clear association between alteration in miRNAs expression in GBM's ability to escape apoptosis, proliferation, and resistance to treatment. Further, miRNAs regulate the already altered pathways in GBM, including P53, RB, and PI3K-AKT pathways. Furthermore, miRNAs also contribute to autophagy at multiple stages. In this review, we summarize the functions of miRNAs in GBM pathways linked to dysregulation of cell cycle control, apoptosis and resistance to treatment, and the possible use of miRNAs in clinical settings as treatment and prediction biomarkers.
    Matched MeSH terms: Autophagy
  14. Fulltext Role of neurotoxicants in the pathogenesis of Alzheimer's disease: a mechanistic insight
    Nisa FY, Rahman MA, Hossen MA, Khan MF, Khan MAN, Majid M, et al.
    Ann Med, 2021 Dec;53(1):1476-1501.
    PMID: 34433343 DOI: 10.1080/07853890.2021.1966088
    Alzheimer's disease (AD) is the most conspicuous chronic neurodegenerative syndrome, which has become a significant challenge for the global healthcare system. Multiple studies have corroborated a clear association of neurotoxicants with AD pathogenicity, such as Amyloid beta (Aβ) proteins and neurofibrillary tangles (NFTs), signalling pathway modifications, cellular stress, cognitive dysfunctions, neuronal apoptosis, neuroinflammation, epigenetic modification, and so on. This review, therefore, aimed to address several essential mechanisms and signalling cascades, including Wnt (wingless and int.) signalling pathway, autophagy, mammalian target of rapamycin (mTOR), protein kinase C (PKC) signalling cascades, cellular redox status, energy metabolism, glutamatergic neurotransmissions, immune cell stimulations (e.g. microglia, astrocytes) as well as an amyloid precursor protein (APP), presenilin-1 (PSEN1), presenilin-2 (PSEN2) and other AD-related gene expressions that have been pretentious and modulated by the various neurotoxicants. This review concluded that neurotoxicants play a momentous role in developing AD through modulating various signalling cascades. Nevertheless, comprehension of this risk agent-induced neurotoxicity is far too little. More in-depth epidemiological and systematic investigations are needed to understand the potential mechanisms better to address these neurotoxicants and improve approaches to their risk exposure that aid in AD pathogenesis.Key messagesInevitable cascade mechanisms of how Alzheimer's Disease-related (AD-related) gene expressions are modulated by neurotoxicants have been discussed.Involvement of the neurotoxicants-induced pathways caused an extended risk of AD is explicited.Integration of cell culture, animals and population-based analysis on the clinical severity of AD is addressed.
    Matched MeSH terms: Autophagy
  15. Fulltext Small Molecules Targeting Programmed Cell Death in Breast Cancer Cells
    Maniam S, Maniam S
    Int J Mol Sci, 2021 Sep 08;22(18).
    PMID: 34575883 DOI: 10.3390/ijms22189722
    Targeted chemotherapy has become the forefront for cancer treatment in recent years. The selective and specific features allow more effective treatment with reduced side effects. Most targeted therapies, which include small molecules, act on specific molecular targets that are altered in tumour cells, mainly in cancers such as breast, lung, colorectal, lymphoma and leukaemia. With the recent exponential progress in drug development, programmed cell death, which includes apoptosis and autophagy, has become a promising therapeutic target. The research in identifying effective small molecules that target compensatory mechanisms in tumour cells alleviates the emergence of drug resistance. Due to the heterogenous nature of breast cancer, various attempts were made to overcome chemoresistance. Amongst breast cancers, triple negative breast cancer (TNBC) is of particular interest due to its heterogeneous nature in response to chemotherapy. TNBC represents approximately 15% of all breast tumours, however, and still has a poor prognosis. Unlike other breast tumours, signature targets lack for TNBCs, causing high morbidity and mortality. This review highlights several small molecules with promising preclinical data that target autophagy and apoptosis to induce cell death in TNBC cells.
    Matched MeSH terms: Autophagy/drug effects; Autophagy/genetics
  16. Impact of the apelin/APJ axis in the pathogenesis of Parkinson's disease with therapeutic potential
    Angelopoulou E, Paudel YN, Bougea A, Piperi C
    J Neurosci Res, 2021 Sep;99(9):2117-2133.
    PMID: 34115895 DOI: 10.1002/jnr.24895
    The pathogenesis of Parkinson's disease (PD) remains elusive. There is still no available disease-modifying strategy against PD, whose management is mainly symptomatic. A growing amount of preclinical evidence shows that a complex interplay between autophagy dysregulation, mitochondrial impairment, endoplasmic reticulum stress, oxidative stress, and excessive neuroinflammation underlies PD pathogenesis. Identifying key molecules linking these pathological cellular processes may substantially aid in our deeper understanding of PD pathophysiology and the development of novel effective therapeutic approaches. Emerging preclinical evidence indicates that apelin, an endogenous neuropeptide acting as a ligand of the orphan G protein-coupled receptor APJ, may play a key neuroprotective role in PD pathogenesis, via inhibition of apoptosis and dopaminergic neuronal loss, autophagy enhancement, antioxidant effects, endoplasmic reticulum stress suppression, as well as prevention of synaptic dysregulation in the striatum, excessive neuroinflammation, and glutamate-induced excitotoxicity. Underlying signaling pathways involve phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin, extracellular signal-regulated kinase 1/2, and inositol requiring kinase 1α/XBP1/C/EBP homologous protein. Herein, we discuss the role of apelin/APJ axis and associated molecular mechanisms on the pathogenesis of PD in vitro and in vivo and provide evidence for its challenging therapeutic potential.
    Matched MeSH terms: Autophagy/drug effects; Autophagy/physiology
  17. 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: Autophagy/drug effects*
  18. Anticancer activities of dietary benzyl isothiocyanate: A comprehensive review
    Dinh TN, Parat MO, Ong YS, Khaw KY
    Pharmacol Res, 2021 07;169:105666.
    PMID: 33989764 DOI: 10.1016/j.phrs.2021.105666
    Benzyl isothiocyanate (BITC) is one of the common isothiocyanates found in cruciferous vegetables such as broccoli, cabbage or watercress. Preclinical studies report of its effectiveness in the prevention and treatment against several cancers. This review aims to report and discuss findings on anticancer activities of BITC and its modes of action against 14 types of cancer. A literature search was conducted using the keywords "BITC" and "anticancer" from PubMed, Google Scholar and CINAHL Plus to obtain relevant research articles. This review highlights the anticancer efficacy of BITC through modulation of various signaling pathways involved in apoptosis, cell proliferation, cell cycle arrest, metastasis, angiogenesis, autophagy and the effects of BITC in combination with other drugs. With the available pharmacology evidence, we conclude that further studies are needed to validate its effectiveness in humans for further development and translation into prophylaxis or therapy by promoting optimal therapeutic effects and minimizing toxicity in cancer treatment.
    Matched MeSH terms: Autophagy/drug effects
  19. 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: Autophagy/drug effects*
  20. Fulltext Meta-Analysis of Quantitative Traits Loci (QTL) Identified in Drought Response in Rice (Oryza sativa L.)
    Selamat N, Nadarajah KK
    Plants (Basel), 2021 Apr 07;10(4).
    PMID: 33917162 DOI: 10.3390/plants10040716
    Rice is an important grain that is the staple food for most of the world's population. Drought is one of the major stresses that negatively affects rice yield. The nature of drought tolerance in rice is complex as it is determined by various components and has low heritability. Therefore, to ensure success in breeding programs for drought tolerant rice, QTLs (quantitative trait loci) of interest must be stable in a variety of plant genotypes and environments. This study identified stable QTLs in rice chromosomes in a variety of backgrounds and environments and conducted a meta-QTL analysis of stable QTLs that have been reported by previous research for use in breeding programs. A total of 653 QTLs for drought tolerance in rice from 27 genetic maps were recorded for analysis. The QTLs recorded were related to 13 traits in rice that respond to drought. Through the use of BioMercartor V4.2, a consensus map containing QTLs and molecular markers were generated using 27 genetic maps that were extracted from the previous 20 studies and meta-QTL analysis was conducted on the consensus map. A total of 70 MQTLs were identified and a total of 453 QTLs were mapped into the meta-QTL areas. Five meta-QTLs from chromosome 1 (MQTL 1.5 and MQTL 1.6), chromosome 2 (MQTL2.1 and MQTL 2.2) and chromosome 3 (MQTL 3.1) were selected for functional annotation as these regions have high number of QTLs and include many traits in rice that respond to drought. A number of genes in MQTL1.5 (268 genes), MQTL1.6 (640 genes), MQTL 2.1 (319 genes), MQTL 2.2 (19 genes) and MQTL 3.1 (787 genes) were annotated through Blast2GO. Few major proteins that respond to drought stress were identified in the meta-QTL areas which are Abscisic Acid-Insensitive Protein 5 (ABI5), the G-box binding factor 4 (GBF4), protein kinase PINOID (PID), histidine kinase 2 (AHK2), protein related to autophagy 18A (ATG18A), mitochondrial transcription termination factor (MTERF), aquaporin PIP 1-2, protein detoxification 48 (DTX48) and inositol-tetrakisphosphate 1-kinase 2 (ITPK2). These proteins are regulatory proteins involved in the regulation of signal transduction and gene expression that respond to drought stress. The meta-QTLs derived from this study and the genes that have been identified can be used effectively in molecular breeding and in genetic engineering for drought resistance/tolerance in rice.
    Matched MeSH terms: Autophagy
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