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Human Reproduction Update Feb 2022Autophagy is an intracellular catabolic process of degrading and recycling proteins and organelles to modulate various physiological and pathological events, including... (Review)
Review
BACKGROUND
Autophagy is an intracellular catabolic process of degrading and recycling proteins and organelles to modulate various physiological and pathological events, including cell differentiation and development. Emerging data indicate that autophagy is closely associated with male reproduction, especially the biosynthetic and catabolic processes of sperm. Throughout the fate of sperm, a series of highly specialized cellular events occur, involving pre-testicular, testicular and post-testicular events. Nonetheless, the most fundamental question of whether autophagy plays a protective or harmful role in male reproduction, especially in sperm, remains unclear.
OBJECTIVE AND RATIONALE
We summarize the functional roles of autophagy in the pre-testicular (hypothalamic-pituitary-testis (HPG) axis), testicular (spermatocytogenesis, spermatidogenesis, spermiogenesis, spermiation) and post-testicular (sperm maturation and fertilization) processes according to the timeline of sperm fate. Additionally, critical mechanisms of the action and clinical impacts of autophagy on sperm are identified, laying the foundation for the treatment of male infertility.
SEARCH METHODS
In this narrative review, the PubMed database was used to search peer-reviewed publications for summarizing the functional roles of autophagy in the fate of sperm using the following terms: 'autophagy', 'sperm', 'hypothalamic-pituitary-testis axis', 'spermatogenesis', 'spermatocytogenesis', 'spermatidogenesis', 'spermiogenesis', 'spermiation', 'sperm maturation', 'fertilization', 'capacitation' and 'acrosome' in combination with autophagy-related proteins. We also performed a bibliographic search for the clinical impact of the autophagy process using the keywords of autophagy inhibitors such as 'bafilomycin A1', 'chloroquine', 'hydroxychloroquine', '3-Methyl Adenine (3-MA)', 'lucanthone', 'wortmannin' and autophagy activators such as 'rapamycin', 'perifosine', 'metformin' in combination with 'disease', 'treatment', 'therapy', 'male infertility' and equivalent terms. In addition, reference lists of primary and review articles were reviewed for additional relevant publications. All relevant publications until August 2021 were critically evaluated and discussed on the basis of relevance, quality and timelines.
OUTCOMES
(i) In pre-testicular processes, autophagy-related genes are involved in the regulation of the HPG axis; and (ii) in testicular processes, mTORC1, the main gate to autophagy, is crucial for spermatogonia stem cell (SCCs) proliferation, differentiation, meiotic progression, inactivation of sex chromosomes and spermiogenesis. During spermatidogenesis, autophagy maintains haploid round spermatid chromatoid body homeostasis for differentiation. During spermiogenesis, autophagy participates in acrosome biogenesis, flagella assembly, head shaping and the removal of cytoplasm from elongating spermatid. After spermatogenesis, through PDLIM1, autophagy orchestrates apical ectoplasmic specialization and basal ectoplasmic specialization to handle cytoskeleton assembly, governing spermatid movement and release during spermiation. In post-testicular processes, there is no direct evidence that autophagy participates in the process of capacitation. However, autophagy modulates the acrosome reaction, paternal mitochondria elimination and clearance of membranous organelles during fertilization.
WIDER IMPLICATIONS
Deciphering the roles of autophagy in the entire fate of sperm will provide valuable insights into therapies for diseases, especially male infertility.
Topics: Autophagy; Humans; Infertility, Male; Male; Spermatids; Spermatogenesis; Spermatozoa
PubMed: 34967891
DOI: 10.1093/humupd/dmab043 -
Frontiers in Immunology 2022The severe coronavirus disease 2019 (COVID-19) is an infectious disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which has resulted in...
BACKGROUND
The severe coronavirus disease 2019 (COVID-19) is an infectious disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which has resulted in the most devastating pandemic in modern history. Human immunodeficiency virus (HIV) destroys immune system cells and weakens the body's ability to resist daily infections and diseases. Furthermore, HIV-infected individuals had double COVID-19 mortality risk and experienced worse COVID-related outcomes. However, the existing research still lacks the understanding of the molecular mechanism underlying crosstalk between COVID-19 and HIV. The aim of our work was to illustrate blood transcriptome crosstalk between COVID-19 and HIV and to provide potential drugs that might be useful for the treatment of HIV-infected COVID-19 patients.
METHODS
COVID-19 datasets (GSE171110 and GSE152418) were downloaded from Gene Expression Omnibus (GEO) database, including 54 whole-blood samples and 33 peripheral blood mononuclear cells samples, respectively. HIV dataset (GSE37250) was also obtained from GEO database, containing 537 whole-blood samples. Next, the "Deseq2" package was used to identify differentially expressed genes (DEGs) between COVID-19 datasets (GSE171110 and GSE152418) and the "limma" package was utilized to identify DEGs between HIV dataset (GSE37250). By intersecting these two DEG sets, we generated common DEGs for further analysis, containing Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and Gene Ontology (GO) functional enrichment analysis, protein-protein interaction (PPI) analysis, transcription factor (TF) candidate identification, microRNAs (miRNAs) candidate identification and drug candidate identification.
RESULTS
In this study, a total of 3213 DEGs were identified from the merged COVID-19 dataset (GSE171110 and GSE152418), and 1718 DEGs were obtained from GSE37250 dataset. Then, we identified 394 common DEGs from the intersection of the DEGs in COVID-19 and HIV datasets. GO and KEGG enrichment analysis indicated that common DEGs were mainly gathered in chromosome-related and cell cycle-related signal pathways. Top ten hub genes (CCNA2, CCNB1, CDC20, TOP2A, AURKB, PLK1, BUB1B, KIF11, DLGAP5, RRM2) were ranked according to their scores, which were screened out using degree algorithm on the basis of common DEGs. Moreover, top ten drug candidates (LUCANTHONE, Dasatinib, etoposide, Enterolactone, troglitazone, testosterone, estradiol, calcitriol, resveratrol, tetradioxin) ranked by their P values were screened out, which maybe be beneficial for the treatment of HIV-infected COVID-19 patients.
CONCLUSION
In this study, we provide potential molecular targets, signaling pathways, small molecular compounds, and promising biomarkers that contribute to worse COVID-19 prognosis in patients with HIV, which might contribute to precise diagnosis and treatment for HIV-infected COVID-19 patients.
Topics: Humans; Transcriptome; COVID-19; Leukocytes, Mononuclear; Computational Biology; SARS-CoV-2; Gene Expression Profiling; HIV Infections
PubMed: 36389792
DOI: 10.3389/fimmu.2022.1008653 -
Frontiers in Oncology 2022Glioblastoma is the most common and aggressive primary brain tumor in adults. Median survival time remains at 16-20 months despite multimodal treatment with surgical...
Glioblastoma is the most common and aggressive primary brain tumor in adults. Median survival time remains at 16-20 months despite multimodal treatment with surgical resection, radiation, temozolomide and tumor-treating fields therapy. After genotoxic stress glioma cells initiate cytoprotective autophagy, which contributes to treatment resistance, limiting the efficacy of these therapies and providing an avenue for glioma recurrence. Antagonism of autophagy steps has recently gained attention as it may enhance the efficacy of classical chemotherapies and newer immune-stimulating therapies. The modulation of autophagy in the clinic is limited by the low potency of common autophagy inhibitors and the inability of newer ones to cross the blood-brain barrier. Herein, we leverage lucanthone, an anti-schistosomal agent which crosses the blood-brain barrier and was recently reported to act as an autophagy inhibitor in breast cancer cells. Our studies show that lucanthone was toxic to glioma cells by inhibiting autophagy. It enhanced anti-glioma temozolomide (TMZ) efficacy at sub-cytotoxic concentrations, and suppressed the growth of stem-like glioma cells and temozolomide-resistant glioma stem cells. lucanthone slowed tumor growth: reduced numbers of Olig2 glioma cells, normalized tumor vasculature, and reduced tumor hypoxia. We propose that lucanthone may serve to perturb a mechanism of temozolomide resistance and allow for successful treatment of TMZ-resistant glioblastoma.
PubMed: 35494072
DOI: 10.3389/fonc.2022.852940 -
PloS One 2011Lucanthone and hycanthone are thioxanthenone DNA intercalators used in the 1980s as antitumor agents. Lucanthone is in Phase I clinical trial, whereas hycanthone was...
Lucanthone and hycanthone are thioxanthenone DNA intercalators used in the 1980s as antitumor agents. Lucanthone is in Phase I clinical trial, whereas hycanthone was pulled out of Phase II trials. Their potential mechanism of action includes DNA intercalation, inhibition of nucleic acid biosyntheses, and inhibition of enzymes like topoisomerases and the dual function base excision repair enzyme apurinic endonuclease 1 (APE1). Lucanthone inhibits the endonuclease activity of APE1, without affecting its redox activity. Our goal was to decipher the precise mechanism of APE1 inhibition as a prerequisite towards development of improved therapeutics that can counteract higher APE1 activity often seen in tumors. The IC(50) values for inhibition of APE1 incision of depurinated plasmid DNA by lucanthone and hycanthone were 5 µM and 80 nM, respectively. The K(D) values (affinity constants) for APE1, as determined by BIACORE binding studies, were 89 nM for lucanthone/10 nM for hycanthone. APE1 structures reveal a hydrophobic pocket where hydrophobic small molecules like thioxanthenones can bind, and our modeling studies confirmed such docking. Circular dichroism spectra uncovered change in the helical structure of APE1 in the presence of lucanthone/hycanthone, and notably, this effect was decreased (Phe266Ala or Phe266Cys or Trp280Leu) or abolished (Phe266Ala/Trp280Ala) when hydrophobic site mutants were employed. Reduced inhibition by lucanthone of the diminished endonuclease activity of hydrophobic mutant proteins (as compared to wild type APE1) supports that binding of lucanthone to the hydrophobic pocket dictates APE1 inhibition. The DNA binding capacity of APE1 was marginally inhibited by lucanthone, and not at all by hycanthone, supporting our hypothesis that thioxanthenones inhibit APE1, predominantly, by direct interaction. Finally, lucanthone-induced degradation was drastically reduced in the presence of short and long lived free radical scavengers, e.g., TRIS and DMSO, suggesting that the mechanism of APE1 breakdown may involve free radical-induced peptide bond cleavage.
Topics: Cell Line, Tumor; Circular Dichroism; DNA; DNA-(Apurinic or Apyrimidinic Site) Lyase; Glioblastoma; Humans; Hycanthone; Hydrogen Bonding; Indoles; Inhibitory Concentration 50; Lucanthone; Mutation; Oxidation-Reduction; Plasmids; Protein Binding; Recombinant Proteins; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
PubMed: 21935361
DOI: 10.1371/journal.pone.0023679 -
International Journal of Molecular... Dec 2021A lucanthone, one of the family of thioxanthenones, has been reported for its inhibitory effects of apurinic endonuclease-1 and autophagy. In this study, we investigated...
A lucanthone, one of the family of thioxanthenones, has been reported for its inhibitory effects of apurinic endonuclease-1 and autophagy. In this study, we investigated whether lucanthone could enhance tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in various cancer cells. Combined treatment with lucanthone and TRAIL significantly induced apoptosis in human renal carcinoma (Caki and ACHN), prostate carcinoma (PC3), and lung carcinoma (A549) cells. However, combined treatment did not induce apoptosis in normal mouse kidney cells (TCMK-1) and normal human skin fibroblast (HSF). Lucanthone downregulated protein expression of deubiquitinase DUB3, and a decreased expression level of markedly led to enhance TRAIL-induced apoptosis. Ectopic expression of DUB3 inhibited combined treatment with lucanthone and TRAIL-induced apoptosis. Moreover, lucanthone increased expression level of mRNA via downregulation of . Transfection of mimics suppressed the lucanthone-induced DR5 upregulation. Taken together, these results provide the first evidence that lucanthone enhances TRAIL-induced apoptosis through DR5 upregulation by downregulation of and DUB3-dependent Mcl-1 downregulation in human renal carcinoma cells.
Topics: A549 Cells; Animals; Autophagy; Cell Line, Tumor; Cell Proliferation; Cell Survival; Down-Regulation; Drug Synergism; Endopeptidases; Gene Expression Regulation, Neoplastic; Humans; Lucanthone; Mice; MicroRNAs; Myeloid Cell Leukemia Sequence 1 Protein; Neoplasms; PC-3 Cells; Receptors, TNF-Related Apoptosis-Inducing Ligand; TNF-Related Apoptosis-Inducing Ligand; Up-Regulation
PubMed: 35008442
DOI: 10.3390/ijms23010017 -
Pharmaceuticals (Basel, Switzerland) Oct 2020Leishmaniases are neglected diseases that are endemic in many tropical and sub-tropical Countries. Therapy is based on different classes of drugs which are burdened by...
Leishmaniases are neglected diseases that are endemic in many tropical and sub-tropical Countries. Therapy is based on different classes of drugs which are burdened by severe side effects, occurrence of resistance and high costs, thereby creating the need for more efficacious, safer and inexpensive drugs. Herein, sixteen 9-thioxanthenone derivatives (lucanthone analogues) and four compounds embodying the diarylethene substructure of amitriptyline (amitriptyline analogues) were tested in vitro for activity against and promastigotes. All compounds were characterized by the presence of a bulky quinolizidinylalkyl moiety. All compounds displayed activity against both species of with IC values in the low micromolar range, resulting in several fold more potency than miltefosine, comparable to that of lucanthone, and endowed with substantially lower cytotoxicity to Vero-76 cells, for the best of them. Thus, 4-amino-1-(quinolizidinylethyl)aminothioxanthen-9-one () and 9-(quinolizidinylmethylidene)fluorene (), with selectivity index (SI) in the range 16-24, represent promising leads for the development of improved antileishmanial agents. These two compounds also exhibited comparable activity against intramacrophagic amastigotes of . Docking studies have suggested that the inhibition of trypanothione reductase (TryR) may be at the basis (eventually besides other mechanisms) of the observed antileishmanial activity. Therefore, these investigated derivatives may deserve further structural improvements and more in-depth biological studies of their mechanisms of action in order to develop more efficient antiparasitic agents.
PubMed: 33113777
DOI: 10.3390/ph13110339 -
The Journal of Biological Chemistry Feb 2011Cellular stress induced by nutrient deprivation, hypoxia, and exposure to many chemotherapeutic agents activates an evolutionarily conserved cell survival pathway termed...
Cellular stress induced by nutrient deprivation, hypoxia, and exposure to many chemotherapeutic agents activates an evolutionarily conserved cell survival pathway termed autophagy. This pathway enables cancer cells to undergo self-digestion to generate ATP and other essential biosynthetic molecules to temporarily avoid cell death. Therefore, disruption of autophagy may sensitize cancer cells to cell death and augment chemotherapy-induced apoptosis. Chloroquine and its analog hydroxychloroquine are the only clinically relevant autophagy inhibitors. Because both of these agents induce ocular toxicity, novel inhibitors of autophagy with a better therapeutic index are needed. Here we demonstrate that the small molecule lucanthone inhibits autophagy, induces lysosomal membrane permeabilization, and possesses significantly more potent activity in breast cancer models compared with chloroquine. Exposure to lucanthone resulted in processing and recruitment of microtubule-associated protein 1 light chain 3 (LC3) to autophagosomes, but impaired autophagic degradation as revealed by transmission electron microscopy and the accumulation of p62/SQSTM1. Microarray analysis, qRT-PCR, and immunoblotting determined that lucanthone stimulated a large induction in cathepsin D, which correlated with cell death. Accordingly, knockdown of cathepsin D reduced lucanthone-mediated apoptosis. Subsequent studies using p53(+/+) and p53(-/-) HCT116 cells established that lucanthone induced cathepsin D expression and reduced cancer cell viability independently of p53 status. In addition, lucanthone enhanced the anticancer activity of the histone deacetylase inhibitor vorinostat. Collectively, our results demonstrate that lucanthone is a novel autophagic inhibitor that induces apoptosis via cathepsin D accumulation and enhances vorinostat-mediated cell death in breast cancer models.
Topics: Adaptor Proteins, Signal Transducing; Antineoplastic Agents; Apoptosis; Autophagy; Breast Neoplasms; Cathepsin D; Cell Line, Tumor; Drug Synergism; Gene Expression Profiling; Humans; Hydroxamic Acids; Intracellular Membranes; Lucanthone; Lysosomes; Microtubule-Associated Proteins; Oligonucleotide Array Sequence Analysis; Permeability; Phagosomes; Reverse Transcriptase Polymerase Chain Reaction; Schistosomicides; Sequestosome-1 Protein; Tumor Suppressor Protein p53; Vorinostat
PubMed: 21148553
DOI: 10.1074/jbc.M110.151324 -
Frontiers in Immunology 2023COVID-19, a serious respiratory disease that has the potential to affect numerous organs, is a serious threat to the health of people around the world. The objective of...
BACKGROUND
COVID-19, a serious respiratory disease that has the potential to affect numerous organs, is a serious threat to the health of people around the world. The objective of this article is to investigate the potential biological targets and mechanisms by which SARS-CoV-2 affects benign prostatic hyperplasia (BPH) and related symptoms.
METHODS
We downloaded the COVID-19 datasets (GSE157103 and GSE166253) and the BPH datasets (GSE7307 and GSE132714) from the Gene Expression Omnibus (GEO) database. In GSE157103 and GSE7307, differentially expressed genes (DEGs) were found using the "Limma" package, and the intersection was utilized to obtain common DEGs. Further analyses followed, including those using Protein-Protein Interaction (PPI), Gene Ontology (GO) function enrichment analysis, and the Kyoto Encyclopedia of Genes and Genomes (KEGG). Potential hub genes were screened using three machine learning methods, and they were later verified using GSE132714 and GSE166253. The CIBERSORT analysis and the identification of transcription factors, miRNAs, and drugs as candidates were among the subsequent analyses.
RESULTS
We identified 97 common DEGs from GSE157103 and GSE7307. According to the GO and KEGG analyses, the primary gene enrichment pathways were immune-related pathways. Machine learning methods were used to identify five hub genes (BIRC5, DNAJC4, DTL, LILRB2, and NDC80). They had good diagnostic properties in the training sets and were validated in the validation sets. According to CIBERSORT analysis, hub genes were closely related to CD4 memory activated of T cells, T cells regulatory and NK cells activated. The top 10 drug candidates (lucanthone, phytoestrogens, etoposide, dasatinib, piroxicam, pyrvinium, rapamycin, niclosamide, genistein, and testosterone) will also be evaluated by the value, which is expected to be helpful for the treatment of COVID-19-infected patients with BPH.
CONCLUSION
Our findings reveal common signaling pathways, possible biological targets, and promising small molecule drugs for BPH and COVID-19. This is crucial to understand the potential common pathogenic and susceptibility pathways between them.
Topics: Humans; Male; Prostatic Hyperplasia; COVID-19; SARS-CoV-2; Genes, cdc; Algorithms
PubMed: 37426635
DOI: 10.3389/fimmu.2023.1172724 -
ACS Omega Dec 2022Cancer and COVID-19 have killed millions of people worldwide. COVID-19 is even more dangerous to people with comorbidities such as cancer. Thus, it is imperative to...
Cancer and COVID-19 have killed millions of people worldwide. COVID-19 is even more dangerous to people with comorbidities such as cancer. Thus, it is imperative to identify the key human genes or biomarkers that can be targeted to develop novel prognosis and therapeutic strategies. The transcriptomic data provided by the next-generation sequencing technique makes this identification very convenient. Hence, mRNA (messenger ribonucleic acid) expression data of 2265 cancer and 282 normal patients were considered, while for COVID-19 assessment, 784 and 425 COVID-19 and normal patients were taken, respectively. Initially, volcano plots were used to identify the up- and down-regulated genes for both cancer and COVID-19. Thereafter, protein-protein interaction (PPI) networks were prepared by combining all the up- and down-regulated genes for each of cancer and COVID-19. Subsequently, such networks were analyzed to identify the top 10 genes with the highest degree of connection to provide the biomarkers. Interestingly, these genes were all up-regulated for cancer, while they were down-regulated for COVID-19. This study had also identified common genes between cancer and COVID-19, all of which were up-regulated in both the diseases. This analysis revealed that 1 was highly up-regulated in different organs for cancer, while was dysregulated in most organs affected by COVID-19. Then, functional enrichment analysis was performed to identify significant biological processes. Finally, the drugs for cancer and COVID-19 biomarkers and the common genes between them were identified using the Enrichr online web tool. These drugs include lucanthone, etoposide, and methotrexate, targeting the biomarkers for cancer, while paclitaxel is an important drug for COVID-19.
PubMed: 36506181
DOI: 10.1021/acsomega.2c04389 -
Neurosurgery Jan 2021Chordomas are aggressive bone tumors that often recur despite maximal resection and adjuvant radiation. To date there are no Food and Drug Administration (FDA)-approved...
BACKGROUND
Chordomas are aggressive bone tumors that often recur despite maximal resection and adjuvant radiation. To date there are no Food and Drug Administration (FDA)-approved chemotherapies. Computational drug repositioning is an expanding approach to identify pharmacotherapies for clinical trials.
OBJECTIVE
To identify FDA-approved compounds for repurposing in chordoma.
METHODS
Previously identified highly differentially expressed genes from chordoma tissue samples at our institution were compared with pharmacogenomic interactions in the Comparative Toxicogenomics Database (CTD) using ksRepo, a drug-repositioning platform. Compounds selected by ksRepo were then validated in CH22 and UM-Chor1 human chordoma cells in Vitro.
RESULTS
A total of 13 chemical compounds were identified in silico from the CTD, and 6 were selected for preclinical validation in human chordoma cell lines based on their clinical relevance. Of these, 3 identified drugs are FDA-approved chemotherapies for other malignancies (cisplatin, cytarabine, and lucanthone). Cytarabine, a deoxyribonucleic acid polymerase inhibitor approved for the treatment of various leukemias, exhibited a significant concentration-dependent effect against CH22 and UM-Chor1 cells when compared to positive (THZ1) and negative (venetoclax) controls. Tretinoin exhibited a significant concentration-dependent cytotoxic effect in CH22, sacral chordoma-derived cell lines but to a much lesser extent in UM-Chor1, a cell line derived from skull base chordoma.
CONCLUSION
Cytarabine administration reduces the viability of human chordoma cells. The equally effective reduction in viability seen with tretinoin seems to be cell line dependent. Based on our findings, we recommend the evaluation of cytarabine and tretinoin in an expanded set of human chordoma cell lines and animal models.
Topics: Animals; Antineoplastic Agents; Bone Neoplasms; Chordoma; Computer Simulation; Drug Repositioning; Humans
PubMed: 33017025
DOI: 10.1093/neuros/nyaa398