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Current Molecular Medicine - Online First
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Advances in Molecular Biology and Immunology of Spermatozoa and Fertilization in Domestic Animals: Implications for Infertility and Assisted Reproduction
Authors: Mounir Adnane, Moussa Ahmed and Aspinas ChapwanyaAvailable online: 21 November 2024More LessUnlocking the secrets of reproductive success in domestic animals requires a deep understanding of the molecular biology and immunology of spermatozoa, capacitation, fertilization, and conception. This review highlights the complex processes involved in spermatogenesis and sperm capacitation, including changes in membrane properties, signaling pathways, and the crucial acrosome reaction. The interaction with the zona pellucida in species-specific gamete recognition and binding is emphasized. The implications of fertilization defects for infertility and assisted reproduction are discussed, underscoring the challenges faced in breeding programs. The future directions for research in this field involve advancements in molecular techniques, understanding the immune regulation of spermatozoa, investigating environmental factors' impact, and integrating multi-omics approaches to enhance assisted reproduction techniques in domestic animals. This review contributes to our understanding of the intricate mechanisms underlying successful reproduction and provides insights into potential strategies for improving fertility outcomes in domestic animals.
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miR-144/451: A Regulatory Role in Inflammation
Authors: Jiahao Zhu, Yanhua Feng, Lingxiao Zhang, Xialing Pang, Sheng He and Lei FangAvailable online: 05 November 2024More LessBackgroundInflammation is the natural defense mechanism of the body in response to injury, infection, or other stimuli. Excessive or persistent inflammatory responses can lead to the development of inflammatory diseases. Therefore, elucidating the regulatory mechanisms of inflammatory cells is crucial for understanding the pathogenesis of such diseases and devising novel therapeutic approaches. Moreover, miR-144/451 plays an important role in erythroid maturity and tumour development. Herein, we have reviewed the regulatory role of miR-144/451 in inflammation.
MethodsPapers on miR-144, miR-451, and inflammation were retrieved from PubMed and Web of Science to be analysed and summarised.
ResultsmiR-144/451 plays a significant role in modulating inflammatory responses. Pro- and anti-inflammatory gene transcription is regulated by miR-144/451 binding to the 3′ untranslated regions. Studies have shown that miR-451 inhibits the activation of various inflammatory cells, including macrophages, neutrophils, and T lymphocytes, thereby reducing the release of inflammatory mediators. However, miR-144 expression varies in different inflammatory diseases. miR-144 expression is downregulated in macrophages after induction by lipopolysaccharide, cysteine, or Mycobacterium tuberculosis, which promotes the secretion of inflammatory mediators; nonetheless, miR-144-3p overexpression in macrophages can aggravate atherosclerosis. Meanwhile, miR-144 overexpression prevents disruption of the lung endothelial cell barrier, whereas it exacerbates endothelial cell injury in Crohn’s disease.
ConclusionmiR-144/451 may serve as a potential target for the treatment of inflammatory diseases.
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Cancer-associated Fibroblasts (CAFs) Regulate Lung Cancer Malignant Progression by Transferring SERPINE2 (PN1) via Exosomes
Authors: Yu Chen, Sihong Zhu, Ling Yang, YuFen Lu and Xiaoqun YeAvailable online: 25 October 2024More LessBackground and AimCancer-associated fibroblasts (CAFs), one of the most abundant stromal cell types in the tumor microenvironment (TME), are potential targets for cancer treatments such as lung cancer. However, the underlying mechanism by which CAFs promote lung cancer progression remains elusive.
MethodsWe obtained primary CAFs, normal fibroblasts (NFs), and their exosomes and constructed protease nexin-1 (PN1) stably silenced or over-expressed CAFs cells using lentivirus. Bioinformatics was used to obtain the expression of PN1 in lung cancer and normal tissues, the relationship with overall survival, and the enriched pathways. The MTT and Transwell assays were performed to detect the proliferation, migration, and invasion abilities of lung cancer cells after treatment. Western blotting, qRT-PCR, immunohistochemistry, and xenograft models were used to illustrate the role of CAFs in lung cancer progression via exosomes.
ResultsCAFs-derived exosomes, in which PN1 was more highly expressed than that in NFs-derived ones, effectively promoted the proliferation, migration, and invasion potentials of lung cancer cells A549 and H1975. Meanwhile, the PN1 expression was higher in lung cancer tissues than that in normal tissues and was negatively associated with the overall survival rate of lung cancer patients. More importantly, over-expressing or silencing of PN1 in A549 and H1975 cells promoted or inhibited cell proliferation, migration, and invasion, correspondingly. Furthermore, treated with PN1 overexpressing CAFs-derived exosomes, the lung cancer cells proliferation, migration, and invasion varied positively and were accompanied by activation of Toll-like and NF-κB signaling pathways. However, this phenomenon can be reversed by AN-3485, an antagonist of the Toll-like pathway. Finally, overexpression of PN1 leads to accelerated tumor growth by increasing the expression of the proliferation biomarker Ki67 and activation of the NF-κB signaling pathway in vivo.
ConclusionCAFs promoted lung cancer progression by transferring PN1 and activating the Toll-like/NF-κB signaling pathway via exosomes.
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wM2-like Macrophages-derived CCL17 Promotes Esophageal Squamous Cell Carcinoma Metastasis and Stemness via Activating CCR4-mediated ERK/PD-L1 Pathway
Authors: Chun Jin, Liangliang Lu, Jian Gao and Ling ChenAvailable online: 25 October 2024More LessBackground and objectiveHigh morbidity, high mortality and poor prognosis of esophageal squamous cell carcinoma (ESCC) highlights the urgent need for novel therapeutic strategies against ESCC. The current study addresses the precise role of M2-like macrophages-derived CCL17 in ESCC progression and to thoroughly elucidate the intrinsic molecular mechanisms.
MethodsIn this work, for functional experiments, Eca109 cells cultivated in M2-CM were treated with anti-IgG (50 µg/ml) or anti-CCL17 (50 µg/ml) to expound the tumor-promoting effects of M2-like macrophage-derived CCL17 in ESCC. Moreover, for rescue experiments, Eca109 cells were treated with CCL17 (50 ng/ml) and/or CCR4 antagonist AZD2098 (20 µM) to probe whether CCL17 could influence the malignant behaviors including migration, invasion and stemness of ESCC cells via activating CCR4/ERK/PD-L1 pathway.
ResultsMarkedly enhanced CCL17 secretion was observed in M2-like macrophages. CCL17 bound to CCR4 to activate ERK/PD-L1 signaling. M2-like macrophages-derived CCL17 facilitated ESCC cell migration and invasion and enhanced stemness characteristics of ESCC cells, which were partially reserved by AZD2098 treatment. The tumor-promoting effects of M2-like macrophages-derived CCL17 on ECSS was depended on the activation of CCR4/ERK/PD-L1 pathway.
ConclusionTo conclude, M2-like macrophages-derived CCL17 could facilitate ESCC cell migration and invasion and enhance stemness characteristics of ESCC cells via activating CCR4/ERK/PD-L1 signaling.
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CircRNA in Digestive Diseases: Recent Advances in Fundamental Mechanism and Clinical Potential
Authors: Yuanye Ji, Shun Zhang, Ting Cai, Liyun Fu, Qinzhi Deng and Peng ZhuAvailable online: 17 October 2024More LessCircular RNAs (circRNAs), a class of non-coding RNAs characterized by their closed-loop structure, are widely present in the body and exhibit greater stability compared to conventional linear RNAs. With the development of molecular biology, circRNAs are gradually considered as a prognostic indicator and therapeutic target for various diseases. Research on the mechanism of circRNA in various diseases has become an important direction. In addition, digestive diseases are becoming more common as people's eating habits change, and the incidence and mortality of severe digestive system tumors are increasing year by year. The study of circRNA in digestive diseases provides us with a new way to improve the diagnosis and treatment of digestive diseases. This article provides a comprehensive review of the research literature on circRNAs in digestive system diseases over the past five years (2019-2023) and covers aspects such as circRNA functions and underlying mechanisms. CircRNA has been implicated in a variety of digestive diseases. In these diseases, circRNA primarily acts as a microRNA (miRNA) sponge, interacting with miRNA to regulate the expression levels of genes associated with signaling pathways, and there is abundant research on the effects of circRNAs on drug resistance, cell proliferation, invasion, apoptosis, and poor prognosis. This article aima to discuss the current status of research on circular RNA and its key areas in digestive system diseases. The review aims to provide valuable insights for further research on the role of circular RNA in digestive system diseases and a reference for subsequent research.
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Exploring the Dual Role of MALAT1 in Thyroid Tumorigenesis: Oncogenic or Tumor Suppressor?
Available online: 17 October 2024More LessThyroid cancer is the most prevalent form of endocrine cancer. Therefore, the administration of new therapeutic agents for thyroid cancer patients is necessary. One of the recent successes in thyroid cancer research is the identification of the role of signaling pathways in the pathogenesis of the disease. Emerging evidence reveals that long non-coding RNAs (lncRNAs) can serve as novel therapeutic approaches for the diagnosis and treatment of thyroid cancer. The lncRNA metastasis-associated lung adenocarcinoma transcript-1 (MALAT1) plays key roles in gene expression, RNA processing, and epigenetic regulation. It is believed that MALAT1 can regulate several cancer-related processes, including tumour cell growth, proliferation, and metastasis. MALAT1 is involved in the pathogenesis of thzroid cancers by targeting multiple downstream targets and miRNA/mRNA axes. Here, we summarize the emerging roles of MALAT1 in this cancer.
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The Apoptotic, Cytotoxic, and Anti-migration Effects of Sodium Deoxycholate in a Breast Cancer Cell Line and its Modulation on PON1 as a Predictive Risk Marker
Authors: Yasin Tülüce, Huda Alhammud, Ahmet Yasin Keleş and Sedat KöstekciAvailable online: 14 October 2024More LessIntroductionBreast cancer is the most prevalent cancer among women and is usually treated with antineoplastic drugs. The present study examines the influence of sodium deoxycholate on the molecular pathways underlying apoptosis, cytotoxicity, and the modulation of PON1 in the MCF-7 breast cancer cell line. Various doses were administered to test the hypothesis that it could potentially affect cancer cells.
MethodThe study examined the cytotoxic effect of sodium deoxycholate on MCF-7 cells and human mammary epithelial cells (CRL-4010) using the MTT method to detect its anticancer properties. Subsequently, the efficacy of the active dose on DNA fragmentation and apoptosis was examined using the apoptotic DNA ladder and Western blot methods. Additionally, oxidative stress index and cell migration tests were conducted. Notably, sodium deoxycholate did not cause DNA damage despite demonstrating cytotoxic effects on cells.
ResultsThe study found that sodium deoxycholate increased the levels of several pro-apoptotic proteins, leading to apoptosis. Moreover, it markedly diminishes the activity of paraoxonase and arylesterase of PON1, which are predictive risk markers for cancer. Furthermore, it was found to delay cell migration in a time-dependent manner.
ConclusionThese findings suggest that sodium deoxycholate exhibits an antimetastatic effect in breast cancer cells, could be a valuable subject for further cancer research.
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Potentiation of Tumor Hallmarks by the Loss of GULO, a Vitamin C Biosynthesis Gene in Humans
Available online: 14 October 2024More LessVitamin C plays a significant role in various physiological functions. Humans depend on external sources of vitamin C due to the loss of the L-gulono-γ-lactone oxidase (GULO) gene that contributes to the synthesis of vitamin C. During the evolutionary loss of the GULO gene, physical, chemical, and biological factors were different from the present environmental settings. Besides the evolutionary genetic loss of the GULO gene, there is a gap in the insightful discussion on the potential implications of the non-functional GULO gene towards the predisposition of humans to cancer that faces hostile and carcinogenic environments. Various methods by which vitamin C modulates cellular processes related to cancer, including DNA repair, epigenetic changes, and redox balance, are discussed. Furthermore, we present experimental and clinical evidence indicating that vitamin C deficiency promotes tumor growth, metastasis, and therapy resistance, emphasizing its potential as a cancer phenotypic modulator. Therapeutic implications of restoring vitamin C levels in cancer treatment range from improving the efficacy of conventional medicines to exploiting metabolic vulnerabilities in tumors. The relevance of assessing vitamin C status in cancer patients and the basis for additional research into vitamin C supplementation as an adjuvant therapy is emphasized. This paper presents a comprehensive overview of the implications associated with the functional deficiency of the GULO gene in human subjects exhibiting diverse tumor hallmarks, encompassing ECM remodeling, hypoxia, epigenetic reprogramming, oxidative stress, and drug responsiveness.
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Contribution of the Activated mTOR-STAT3 Pathway to the Pathogenesis of Focal Cortical Dysplasia Type IIIa in Pediatric Patients through Astrocyte Proliferation Mediation
Authors: Jiangya Wang, Jiang Wu, Yang Li, Yuanyuan Lv, Xinying Zhang and Lin KangAvailable online: 04 October 2024More LessObjectiveThe aim of this study was to detect the association between the mTOR-STAT3 pathway and focal cortical dysplasia type IIIa (FCD IIIa) in children.
MethodsA retrospective review was conducted based on 26 pediatric patients diagnosed with FCD IIIa who underwent surgical intervention. These patients were selected from a cohort of 157 individuals presenting with temporal lobe epilepsy. For comparative analysis, a control group consisting of 5 children who underwent intracranial decompression was established. Immunohistochemistry, immunofluorescence, and western blot techniques were used to assess the expression levels of mTOR, P-mTOR, P-70s6k, STAT3, P-STAT3, and GFAP in brain tissue specimens obtained from the two groups.
ResultsThe mTOR-STAT3 pathway exhibited activation in the FCD IIIa group (all P < 0.01). Additionally, immunofluorescence analysis revealed that cells positive for P-STAT3 were identified as astrocytes. Moreover, within the FCD IIIa group, there was a marked elevation in the expression of the mTOR-STAT3 pathway in the hippocampus compared to the brain cortex tissue.
ConclusionThe mTOR-STAT3 pathway was demonstrated to be substantially associated with FCD IIIa in pediatric patients. The activation of the mTOR-STAT3 signaling pathway may contribute to the pathogenesis of FCD IIIa in pediatric patients by modulating the proliferation of astrocytes.
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The AMPK/cAMP Metabolic Signaling Axis as a Possible Therapeutic Target for Diabetes
Available online: 09 September 2024More LessDiabetes is a complex disease, despite the availability of numerous treatments, its progression and complications can only be mitigated and managed to a certain extent. After the onset, diabetes cannot be reversed. Its global expansion makes it challenging for governments to control the considerable costs of treating people with diabetes. Many studies have been carried out by widely recognized pharmaceutical companies that are considering the development of new drugs for diabetic treatments. Diets, sedentary habits, and lifestyles that are currently prevalent have an enormous influence on the global spread of diabetes. The tools available to clinicians for therapy do not solve the problem. It is known that a patient, when diagnosed, would already have had diabetes for more than three years. Studies on diabetes signaling consider the effects of hyperglycemia but also highlight the roles of insulin receptor activation and resistance.
Understanding the intricate signaling network and its interactions with hyperglycemia-induced pathways is crucial. In this context, the cyclic AMP/AMPK axis emerges as a promising therapeutic target for diabetes. However, there is a noticeable lack of literature exploring the metabolic network induced by hyperglycemia and its interconnected pathways. Therefore, investigating the cyclic cAMP/AMPK axis could provide valuable insights, given its complex connections with various metabolic pathways. This mini-review aims to delve into the metabolic signaling of the AMPK/cAMP axis in the context of diabetes, highlighting its metabolic interactions and potential implications.
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