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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 -
British Journal of Haematology Sep 2007Over time, Waldenström macroglobulinaemia (WM) has evolved conceptually from a clinical syndrome to a distinct clinicopathological entity. Progress is being made in... (Review)
Review
Over time, Waldenström macroglobulinaemia (WM) has evolved conceptually from a clinical syndrome to a distinct clinicopathological entity. Progress is being made in standardization of the disease definition and treatment response criteria, although nosologic controversies persist. According to the Second International Workshop on WM, the disease is defined as a B-cell neoplasm characterized by a lymphoplasmacytic infiltrate in the bone marrow, with an associated immunoglobulin (Ig) M paraprotein. Disease symptoms are often divided into those related to tumour infiltration and those related to the rheological effects of the monoclonal IgM. As with other low-grade lymphomas, asymptomatic patients are observed only, with treatment reserved for symptomatic patients. There is no standard treatment for WM and choices include rituximab, alkylating agents, purine nucleoside analogues, alone or in combination, as well as autologous peripheral blood stem cell transplant in eligible patients. Novel treatments, such as bortezomib, oblimersen sodium, perifosine and others are being evaluated.
Topics: Antineoplastic Combined Chemotherapy Protocols; Diagnosis, Differential; Humans; Plasmapheresis; Splenectomy; Waldenstrom Macroglobulinemia
PubMed: 17672883
DOI: 10.1111/j.1365-2141.2007.06724.x -
EXCLI Journal 2020Endometrial cancer is the most common cancer of the female reproductive system. Combination treatment with specific agents has been widely used as a targeted therapy for...
Endometrial cancer is the most common cancer of the female reproductive system. Combination treatment with specific agents has been widely used as a targeted therapy for cancer. In this study, we aimed to investigate the anti-proliferative and apoptotic effects of varying concentrations of perifosine and vitamin D on the human endometrial cancer cell line (HEC-1A). HEC-1A cells were exposed to perifosine (10 μM, 30 μM), vitamin D (50 nM, 200 nM) and combinations of both for 48 h and 72 h. Monitoring of cell proliferation in a time-dependent manner was performed with the xCELLigence RTCA DP system. The levels of BCL2, BAX and P53 mRNA expression were examined using RT-qPCR. Apoptosis was determined using Annexin V, which were followed by flow cytometry analysis. Ultra-structural morphology of cells was analyzed by transmission electron microscopy (TEM) for 72 h. The anti-proliferative and apoptotic effects of the perifosine+vitamin D combination (30 μM + 200 nM at 48 h and 10 μM + 200 nM at 72 h) on HEC-1A cells were higher than in perifosine and vitamin D alone. It was observed that perifosine has increased the expression of BAX mRNA in HEC-1A cells in a dose-dependent manner. While perifosine+vitamin D combinations increased P53 mRNA expression in HEC-1A cells we did not find any significant change in BCL2, BAX mRNA expression levels. In TEM examinations of HEC-1A cells, perifosine appeared to lead autophagic cell death, whereas vitamin D caused paraptosis-like cell death and combination of perifosine+vitamin D caused apoptotic and non-apoptotic (paraptotic, autophagic and necrotic) cell death. Therefore, it is considered that the combination of both drugs in the treatment of endometrial cancer might be an alternative and effective treatment option through activating the apoptotic and non-apoptotic cell death mechanisms in cancer cells.
PubMed: 32483402
DOI: 10.17179/excli2019-1834 -
Cancer Letters Oct 2008In the past years, new developments have occurred both in the understanding of the biology of Waldenstrom Macroglobulinemia (WM) and in therapeutic options for WM. WM is...
In the past years, new developments have occurred both in the understanding of the biology of Waldenstrom Macroglobulinemia (WM) and in therapeutic options for WM. WM is a B-cell disorder characterized primarily by bone marrow infiltration with lymphoplasmacytic cells, along with demonstration of an IgM monoclonal gammopathy. Despite advances in therapy, WM remains incurable, with 5-6 years median overall survival of patients in symptomatic WM. Therapy is postponed for asymptomatic patients, and progressive anemia is the most common indication for initiation of treatment. The main therapeutic options include alkylating agents, nucleoside analogues, and rituximab. Studies involving combination chemotherapy are ongoing, and preliminary results are encouraging. No specific agent or regimen has been shown to be superior to another for treatment of WM. As such, novel therapeutic agents are needed for the treatment of WM. In ongoing efforts, we and others have sought to exploit advances made in the understanding of the biology of WM so as to better target therapeutics for this malignancy. These efforts have led to the development of several novel agents including the proteasome inhibitor bortezomib, and several Akt/mTor inhibitors, perifosine and Rad001, and immunomodulatory agents such as thalidomide and lenalidomide. Studies with monoclonal antibodies are ongoing and promising including the use of alemtuzumab, SGN-70, and the APRIL/BLYS blocking protein TACI-Ig atacicept. Other agents currently being tested in clinical trials include the PKC inhibitor enzastaurin, the natural product resveratrol, as well as the statin simvastatin. This report provides an update of the current preclinical studies and clinical efforts for the development of novel agents in the treatment of WM.
Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Combined Chemotherapy Protocols; Diagnosis, Differential; Humans; Lenalidomide; Prognosis; Proteasome Inhibitors; Rituximab; Signal Transduction; Thalidomide; Waldenstrom Macroglobulinemia
PubMed: 18555588
DOI: 10.1016/j.canlet.2008.04.040 -
Journal of Cellular and Molecular... Jan 2023An acidic environment and hypoxia within the tumour are hallmarks of cancer that contribute to cell resistance to therapy. Deregulation of the PI3K/Akt pathway is common...
An acidic environment and hypoxia within the tumour are hallmarks of cancer that contribute to cell resistance to therapy. Deregulation of the PI3K/Akt pathway is common in colon cancer. Numerous Akt-targeted therapies are being developed, the activity of Akt-inhibitors is, however, strongly pH-dependent. Combination therapy thus represents an opportunity to increase their efficacy. In this study, the cytotoxicity of the Akt inhibitor perifosine and the Bcl-2/Bcl-xL inhibitor ABT-737 was tested in colon cancer HT-29 and HCT-116 cells cultured in monolayer or in the form of spheroids. The efficacy of single drugs and their combination was analysed in different tumour-specific environments including acidosis and hypoxia using a series of viability assays. Changes in protein content and distribution were determined by immunoblotting and a "peeling analysis" of immunohistochemical signals. While the cytotoxicity of single agents was influenced by the tumour-specific microenvironment, perifosine and ABT-737 in combination synergistically induced apoptosis in cells cultured in both 2D and 3D independently on pH and oxygen level. Thus, the combined therapy of perifosine and ABT-737 could be considered as a potential treatment strategy for colon cancer.
Topics: Humans; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Colonic Neoplasms; Drug Synergism; Phosphatidylinositol 3-Kinases; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Tumor Microenvironment; Phosphorylcholine
PubMed: 36523175
DOI: 10.1111/jcmm.17636 -
Blood Jun 2007In the past 36 months, new developments have occurred both in the understanding of the biology of Waldenström macroglobulinemia (WM) and in therapeutic options for WM.... (Review)
Review
In the past 36 months, new developments have occurred both in the understanding of the biology of Waldenström macroglobulinemia (WM) and in therapeutic options for WM. Here, we review the classification, clinical features, and diagnostic criteria of the disease. WM is a B-cell neoplasm characterized by lymphoplasmacytic infiltration of the bone marrow and a monoclonal immunoglobulin M (IgM) protein. The symptoms of WM are attributable to the extent of tumor infiltration and to elevated IgM levels. The most common symptom is fatigue attributable to anemia. The prognostic factors predictive of survival include the patient's age, beta(2)-microglobulin level, monoclonal protein level, hemoglobin concentration, and platelet count. Therapy is postponed for asymptomatic patients, and progressive anemia is the most common indication for initiation of treatment. The main therapeutic options include alkylating agents, nucleoside analogues, and rituximab. Studies involving combination chemotherapy are ongoing, and preliminary results are encouraging. No specific agent or regimen has been shown to be superior to another for treatment of WM. Novel agents such as bortezomib, perifosine, atacicept, oblimersen sodium, and tositumomab show promise as rational targeted therapy for WM.
Topics: Antineoplastic Agents; Cytogenetic Analysis; Diagnosis, Differential; Humans; Immunoglobulin M; Immunophenotyping; Neoplasm Invasiveness; Waldenstrom Macroglobulinemia
PubMed: 17303694
DOI: 10.1182/blood-2006-11-055012 -
Scientific Reports Feb 2017Perifosine, an Akt inhibitor, has been shown to be effective in controlling neuroblastoma tumor growth. However, studies indicate that in addition to the ability to...
Perifosine, an Akt inhibitor, has been shown to be effective in controlling neuroblastoma tumor growth. However, studies indicate that in addition to the ability to inhibit Akt, other mechanisms contribute to perifosine's anti-tumor activity. To gain insight into perifosine anti-tumor activity in neuroblastoma we have studied changes in the proteome and acetylome after perifosine treatment in SK-N-AS neuroblastoma cells using SILAC labeling, affinity enrichment, high-resolution and LC-MS/MS analysis. Bioinformatic analysis indicates that, a total of 5,880 proteins and 3,415 lysine acetylation sites were quantified in SK-N-AS cells and 216 differentially expressed proteins and 115 differentially expressed lysine acetylation sites were obtained. These differentially expressed proteins and lysine acetylated proteins were involved in a number of different biological functions, metabolic pathways and pathophysiological processes. This study details the impact of perifosine on proteome and lysine acetylome in SK-N-AS cells and expands our understanding of the mechanisms of perifosine action in neuroblastoma.
Topics: Acetylation; Amino Acids; Antineoplastic Agents; Cell Line, Tumor; Chromatography, Liquid; Humans; Lysine; Metabolic Networks and Pathways; Neuroblastoma; Phosphorylcholine; Proteome; Tandem Mass Spectrometry
PubMed: 28165023
DOI: 10.1038/srep42062 -
European Journal of Haematology Jan 2009Waldenström macroglobulinemia (WM) is a B-cell disorder characterized primarily by bone marrow infiltration with lymphoplasmacytic cells (LPCs), along with... (Review)
Review
Waldenström macroglobulinemia (WM) is a B-cell disorder characterized primarily by bone marrow infiltration with lymphoplasmacytic cells (LPCs), along with demonstration of an IgM monoclonal gammopathy in the blood. WM remains incurable, with 5-6 yr median overall survival for patients with symptomatic WM. The main therapeutic options include alkylating agents, nucleoside analogues, and rituximab, either in monotherapy or in combination. Studies involving combination chemotherapy are ongoing, and preliminary results are encouraging. However, there are several limitations to these approaches. The complete response rate is low and the treatment free survival are short in many patients, no specific agent or regimen has been shown to be superior to another, and no treatment has been specifically approved for WM. As such, novel therapeutic agents are needed for the treatment of WM. In ongoing efforts, we and others have sought to exploit advances made in the understanding of the biology of WM so as to develop new targeted therapeutics for this malignancy. These efforts have led to the development of proteasome inhibitors, of them bortezomib, several Akt/mTor inhibitors, such as perifosine and Rad001, and immunomodulatory agents such as thalidomide and lenalidomide. Many agents and monoclonal antibodies are currently being tested in clinical trials and seem promising. This report provides an update of the current preclinical studies and clinical efforts for the development of novel agents in the treatment of WM.
Topics: Antineoplastic Agents; Combined Modality Therapy; Diagnosis, Differential; Humans; Immunotherapy; Signal Transduction; Waldenstrom Macroglobulinemia
PubMed: 19087134
DOI: 10.1111/j.1600-0609.2008.01171.x -
ACS Omega Aug 2023Non-small cell lung carcinoma (NSCLC) is the most common cancer globally. Phytochemicals and small molecule inhibitors significantly prevent varying types of cancers,... (Review)
Review
Non-small cell lung carcinoma (NSCLC) is the most common cancer globally. Phytochemicals and small molecule inhibitors significantly prevent varying types of cancers, including NSCLC. These therapeutic molecules serve as important sources for new drugs that interfere with cellular proliferation, apoptosis, metastasis, and angiogenesis by regulating signaling pathways. These molecules affect several cellular signaling cascades, including p53, NF-κB, STAT3, RAS, MAPK/ERK, Wnt, and AKT/PI3K, and are thus implicated in the therapeutic management of cancers. This review aims to describe the bioactive compounds and small-molecule inhibitors, their anticancer action, and targeting cellular signaling cascades in NSCLC. We highlighted the therapeutic potential of Epigallocatechin gallate (EGCG), Perifosine, ABT-737, Thymoquinine, Quercetin, Venetoclax, Gefitinib, and Genistein. These compounds are implicated in the therapeutic management of NSCLC. This review further offers deeper mechanistic insights into different signaling pathways that could be targeted for NSCLC therapy by phytochemicals and small-molecule inhibitors.
PubMed: 37546685
DOI: 10.1021/acsomega.3c02424