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Article: miRNA on the Battlefield of Cancer: Significance in Cancer Stem Cells, WNT Pathway, and Treatment.

Bhagtaney, Lekha / Dharmarajan, Arun / Warrier, Sudha

2024 Volume 16, Issue 5

Abstract: Carcinogenesis is a complex process characterized by intricate changes in organ histology, biochemistry, epigenetics, and genetics. Within this intricate landscape, cancer stem cells (CSCs) have emerged as distinct cell types possessing unique attributes ...

Abstract	Carcinogenesis is a complex process characterized by intricate changes in organ histology, biochemistry, epigenetics, and genetics. Within this intricate landscape, cancer stem cells (CSCs) have emerged as distinct cell types possessing unique attributes that significantly contribute to the pathogenesis of cancer. The WNT signaling pathway plays a critical role in maintaining somatic stem cell pluripotency. However, in cancer, overexpression of WNT mediators enhances the activity of β-catenin, resulting in phenomena such as recurrence and unfavorable survival outcomes. Notably, CSCs exhibit heightened WNT signaling compared to bulk cancer cells, providing intriguing insights into their functional characteristics. MicroRNAs (miRNAs), as post-transcriptional gene expression regulators, modulate various physiological processes in numerous diseases including cancer. Upregulation or downregulation of miRNAs can affect the production of pro-oncogenic or anti-oncogenic proteins, influencing cellular processes that maintain tissue homeostasis and promote either apoptosis or differentiation, even in cancer cells. In order to understand the dysregulation of miRNAs, it is essential to examine miRNA biogenesis and any possible alterations at each step. The potential of a miRNA as a biomarker in prognosis, diagnosis, and detection is being assessed using technologies such as next-generation sequencing. Extensive research has explored miRNA expression profiles in cancer, leading to their utilization as diagnostic tools and the development of personalized and targeted cancer therapies. This review delves into the role of miRNAs in carcinogenesis in relation to the WNT signaling pathway along with their potential as druggable compounds.
Language	English
Publishing date	2024-02-27
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers16050957
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Article ; Online: Unravelling the Road to Recovery: Mechanisms of Wnt Signalling in Spinal Cord Injury.

Ganesan, Suchita / Dharmarajan, Arun / Sudhir, G / Perumalsamy, Lakshmi R

Molecular neurobiology

2024

Abstract: Spinal cord injury (SCI) is a complex neurodegenerative pathology that consistently harbours a poor prognostic outcome. At present, there are few therapeutic strategies that can halt neuronal cell death and facilitate functional motor recovery. However, ... ...

Abstract	Spinal cord injury (SCI) is a complex neurodegenerative pathology that consistently harbours a poor prognostic outcome. At present, there are few therapeutic strategies that can halt neuronal cell death and facilitate functional motor recovery. However, recent studies have highlighted the Wnt pathway as a key promoter of axon regeneration following central nervous system (CNS) injuries. Emerging evidence also suggests that the temporal dysregulation of Wnt may drive cell death post-SCI. A major challenge in SCI treatment resides in developing therapeutics that can effectively target inflammation and facilitate glial scar repair. Before Wnt signalling is exploited for SCI therapy, further research is needed to clarify the implications of Wnt on neuroinflammation during chronic stages of injury. In this review, an attempt is made to dissect the impact of canonical and non-canonical Wnt pathways in relation to individual aspects of glial and fibrotic scar formation. Furthermore, it is also highlighted how modulating Wnt activity at chronic time points may aid in limiting lesion expansion and promoting axonal repair.
Language	English
Publishing date	2024-02-29
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	645020-9
ISSN	1559-1182 ; 0893-7648
ISSN (online)	1559-1182
ISSN	0893-7648
DOI	10.1007/s12035-024-04055-1
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Article: iPSC-Derived Glioblastoma Cells Have Enhanced Stemness Wnt/β-Catenin Activity Which Is Negatively Regulated by Wnt Antagonist sFRP4.

Yasmin, Ishmat Ara / Dharmarajan, Arun / Warrier, Sudha

Cancers

2023 Volume 15, Issue 14

Abstract: Growing evidence indicates that cancer stem cells (CSCs) endow the tumor with stem-like properties. Recently, induced pluripotent stem cells (iPSCs) have gained increased attention because of their easy derivation and availability and their potential to ... ...

Abstract	Growing evidence indicates that cancer stem cells (CSCs) endow the tumor with stem-like properties. Recently, induced pluripotent stem cells (iPSCs) have gained increased attention because of their easy derivation and availability and their potential to differentiate into any cell type. A CSC model derived from iPSCs of human origin would help understand the driving force of tumor initiation and early progression. We report the efficient generation of feeder-free SSEA4, TRA-1-60 and TRA-1-81 positive iPSCs from amniotic membrane-derived mesenchymal stem cells (AMMSCs), which successfully differentiated into three germ layers. We then developed human iPSC-derived glioblastoma multiforme (GBM) model using conditioned media (CM) from U87MG cell line and CSCs derived from U87MG, which confer iPSCs with GBM and GSC-like phenotypes within five days. Both cell types overexpress MGMT and GLI2, but only GSCs overexpress CD133, CD44, ABCG2 and ABCC2. We also observed overexpression of LEF1 and β-catenin in both cell types. Down-regulation of Wnt antagonist secreted frizzled-related protein 4 (sFRP4) in GBM and GSCs, indicating activation of the Wnt/β-catenin pathway, which could be involved in the conversion of iPSCs to CSCs. From future perspectives, our study will help in the creation of a rapid cell-based platform for understanding the complexity of GBM.
Language	English
Publishing date	2023-07-14
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers15143622
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Article ; Online: Want of Wnt in Parkinson's disease: Could sFRP disrupt interplay between Nurr1 and Wnt signaling?

Gamit, Naisarg / Dharmarajan, Arun / Sethi, Gautam / Warrier, Sudha

Biochemical pharmacology

2023 Volume 212, Page(s) 115566

Abstract: Nuclear receptor related 1 (Nurr1) is a transcription factor known to regulate the development and maintenance of midbrain dopaminergic (mDA) neurons. Reports have confirmed that defect or obliteration of Nurr1 results in neurodegeneration and motor ... ...

Abstract	Nuclear receptor related 1 (Nurr1) is a transcription factor known to regulate the development and maintenance of midbrain dopaminergic (mDA) neurons. Reports have confirmed that defect or obliteration of Nurr1 results in neurodegeneration and motor function impairment leading to Parkinson's disease (PD). Studies have also indicated that Nurr1 regulates the expression of alpha-synuclein (α-SYN) and mutations in Nurr1 cause α-SYN overexpression, thereby increasing the risk of PD. Nurr1 is modulated via various pathways including Wnt signaling pathway which is known to play an important role in neurogenesis, and deregulation of it contributes to PD pathogenesis. Both Wnt/β-catenin dependent and independent pathways are implicated in the activation of Nurr1 and subsequent downregulation of α-SYN. This review highlights the interaction between Nurr1 and Wnt signaling pathways in mDA neuronal development. We further hypothesize how modulation of Wnt signaling pathway by its antagonist, secreted frizzled related proteins (sFRPs) could be a potential route to treat PD.
MeSH term(s)	Humans ; Parkinson Disease/genetics ; Parkinson Disease/metabolism ; Wnt Signaling Pathway/physiology ; Dopaminergic Neurons/metabolism ; Transcription Factors/metabolism ; Receptors, Cytoplasmic and Nuclear/metabolism
Chemical Substances	Transcription Factors ; Receptors, Cytoplasmic and Nuclear
Language	English
Publishing date	2023-04-22
Publishing country	England
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	208787-x
ISSN	1873-2968 ; 0006-2952
ISSN (online)	1873-2968
ISSN	0006-2952
DOI	10.1016/j.bcp.2023.115566
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Zs.A 19: Show issues

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Article ; Online: Predominant factors influencing reactive oxygen species in cancer stem cells.

Soundararajan, Loshini / Warrier, Sudha / Dharmarajan, Arun / Bhaskaran, Natarajan

Journal of cellular biochemistry

2023 Volume 125, Issue 1, Page(s) 3–21

Abstract: Reactive oxygen species (ROS) and its related signaling pathways and regulating molecules play a major role in the growth and development of cancer stem cells. The concept of ROS and cancer stem cells (CSCs) has been gaining much attention since the past ...

Abstract	Reactive oxygen species (ROS) and its related signaling pathways and regulating molecules play a major role in the growth and development of cancer stem cells. The concept of ROS and cancer stem cells (CSCs) has been gaining much attention since the past decade and the evidence show that these CSCs possess robust self-renewal and tumorigenic potential and are resistant to conventional chemo- and radiotherapy and believed to be responsible for tumor progression, metastasis, and recurrence. It seems reasonable to say that cancer can be cured only if the CSCs are eradicated. ROS are Janus-faced molecules that can regulate cellular physiology as well as induce cytotoxicity, depending on the magnitude, duration, and site of generation. Unlike normal cancer cells, CSCs expel ROS efficiently by upregulating ROS scavengers. This unique redox regulation in CSCs protects them from ROS-mediated cell death and nullifies the effect of radiation, leading to chemoresistance and radioresistance. However, how these CSCs control ROS production by scavenging free radicals and how they maintain low levels of ROS is a challenging to understand and these attributes make CSCs as prime therapeutic targets. Here, we summarize the mechanisms of redox regulation in CSCs, with a focus on therapy resistance, its various pathways and microRNAs regulation, and the potential therapeutic implications of manipulating the ROS levels to eradicate CSCs. A better understanding of these molecules, their interactions in the CSCs may help us to adopt proper control and treatment measures.
MeSH term(s)	Humans ; Reactive Oxygen Species/metabolism ; Neoplasms/metabolism ; MicroRNAs/metabolism ; Oxidation-Reduction ; Neoplastic Stem Cells/metabolism
Chemical Substances	Reactive Oxygen Species ; MicroRNAs
Language	English
Publishing date	2023-11-24
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	392402-6
ISSN	1097-4644 ; 0730-2312
ISSN (online)	1097-4644
ISSN	0730-2312
DOI	10.1002/jcb.30506
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Zs.A 1114: Show issues

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Article: Identification of a Novel Wnt Antagonist Based Therapeutic and Diagnostic Target for Alzheimer's Disease Using a Stem Cell-Derived Model.

Patil, Manasi / Gamit, Naisarg / Dharmarajan, Arun / Sethi, Gautam / Warrier, Sudha

Bioengineering (Basel, Switzerland)

2023 Volume 10, Issue 2

Abstract: Currently, all the existing treatments for Alzheimer's disease (AD) fail to stall progression due to longer duration of time between onset of the symptoms and diagnosis of the disease, raising the necessity of effective diagnostics and novel treatment. ... ...

Abstract	Currently, all the existing treatments for Alzheimer's disease (AD) fail to stall progression due to longer duration of time between onset of the symptoms and diagnosis of the disease, raising the necessity of effective diagnostics and novel treatment. Specific molecular regulation of the onset and progression of disease is not yet elucidated. This warranted investigation of the role of Wnt signaling regulators which are thought to be involved in neurogenesis. The AD model was established using amyloid beta (Aβ) in human mesenchymal stem cells derived from amniotic membranes which were differentiated into neuronal cell types. In vivo studies were carried out with Aβ or a Wnt antagonist, AD201, belonging to the sFRP family. We further created an AD201-knockdown in vitro model to determine the role of Wnt antagonism. BACE1 upregulation, ChAT and α7nAChR downregulation with synapse and functionality loss with increases in ROS confirmed the neurodegeneration. Reduced β-catenin and increased AD201 expression indicated Wnt/canonical pathway inhibition. Similar results were exhibited in the in vivo study along with AD-associated behavioural and molecular changes. AD201-knockdown rescued neurons from Aβ-induced toxicity. We demonstrated for the first time a role of AD201 in Alzheimer's disease manifestation, which indicates a promising disease target and biomarker.
Language	English
Publishing date	2023-02-02
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2746191-9
ISSN	2306-5354
ISSN	2306-5354
DOI	10.3390/bioengineering10020192
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Article ; Online: Potential therapeutic role for pigment epithelium-derived factor in post-menopausal breast cancer bone metastasis.

Brook, Naomi / Dharmarajan, Arun / Chan, Arlene / Dass, Crispin R

The Journal of pharmacy and pharmacology

2023 Volume 75, Issue 7, Page(s) 873–885

Abstract: Objectives: This review discusses key oestrogens associated with the circulating pre- and post-menopausal milieu and how they may impact intratumoral oestrogen levels and breast cancer (BC) metastasis. It also identifies critical steps in BC metastasis ... ...

Abstract	Objectives: This review discusses key oestrogens associated with the circulating pre- and post-menopausal milieu and how they may impact intratumoral oestrogen levels and breast cancer (BC) metastasis. It also identifies critical steps in BC metastasis to bone from the viewpoint of pigment epithelium-derived factor (PEDF) function, and discusses the role of several associated pro-metastatic biomarkers in BC bone metastasis. Key findings: PEDF is regulated by oestrogen in a number of oestrogen-sensitive tissues. Changes in circulating oestrogen levels associated with menopause may enhance the growth of BC bone metastases, leading to the establishment of a pre-metastatic niche. The establishment of such a pre-metastatic niche is driven by several key mediators, with pro-osteoclastic and pro-metastatic function which are upregulated by BC cells. These mediators appear to be regulated by oestrogen, as well as differentially affected by menopausal status. PEDF interacts with several pro-metastatic, pro-osteoclastic biomarkers, including C-X-C motif chemokine receptor 4 (CXCR4) and nuclear factor kappa B (NFκB) in BC bone metastasis. Conclusion: Mediators such as CXCR4 and MT1-MMP underpin the ability of PEDF to function as an antimetastatic in other cancers such as osteosarcoma, highlighting the possibility that this serpin could be used as a therapeutic against BC metastasis in future.
MeSH term(s)	Female ; Humans ; Breast Neoplasms/drug therapy ; Breast Neoplasms/pathology ; Serpins ; Postmenopause ; Estrogens ; Eye Proteins ; Bone Neoplasms/drug therapy ; Bone Neoplasms/pathology ; Biomarkers ; Neoplasm Metastasis
Chemical Substances	pigment epithelium-derived factor ; Serpins ; Estrogens ; Eye Proteins ; Biomarkers
Language	English
Publishing date	2023-04-28
Publishing country	England
Document type	Review ; Journal Article
ZDB-ID	3107-0
ISSN	2042-7158 ; 0022-3573 ; 0373-1022
ISSN (online)	2042-7158
ISSN	0022-3573 ; 0373-1022
DOI	10.1093/jpp/rgad039
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Article ; Online: Short peptide domains of the Wnt inhibitor sFRP4 target ovarian cancer stem cells by neutralizing the Wnt β-catenin pathway, disrupting the interaction between β-catenin and CD24 and suppressing autophagy

Sundaram, S. Mohana / Varier, Lavanya / Fathima, Khan Zahara / Dharmarajan, Arun / Warrier, Sudha

Life Sciences. 2023 Mar., v. 316 p.121384-

2023

Abstract: One of the hallmarks of cancer stem cells (CSC) is hyperactive Wnt β-catenin signaling due to the decreased presence of Wnt antagonists such as secreted frizzled related protein 4 (SFRP4). Cysteine-rich domain (CRD) and netrin-like domain (NLD) are the ... ...

Abstract	One of the hallmarks of cancer stem cells (CSC) is hyperactive Wnt β-catenin signaling due to the decreased presence of Wnt antagonists such as secreted frizzled related protein 4 (SFRP4). Cysteine-rich domain (CRD) and netrin-like domain (NLD) are the two functional domains of SFRP4 having anti-tumor properties. In this study, we have explored the effectiveness of short micropeptides SC-301 (from CRD) and SC-401 (from NLD) on CSC properties, EMT, apoptosis and autophagy in ovarian CSCs enriched from PA-1 and SKOV-3 cell lines. Gene expression analysis, Western blot and immunocytochemistry were performed on ovarian CSCs to evaluate the inhibitory potential of micropeptides to various CSC associated oncogenic properties. Co-immunoprecipitation was performed to detect the binding of CD24 to β-catenin protein complex. CYTO-ID Autophagy Detection Kit 2.0 was used to monitor autophagic flux in peptide treated CSCs. It is clearly seen that the micropeptides derived from both the domains inhibit Wnt pathway, initiate apoptosis, inhibit migration and chemosensitize CSCs. Specifically, CD24, a defining marker of ovarian CSC was suppressed by peptide treatment. Notably, interaction between CD24 and β-catenin was disrupted upon peptide treatment. SFRP4 peptide treatment also suppressed the autophagic process which is crucial for CSC survival. The study demonstrated that although both peptides have inhibitory effects, SC-401 was emphatically more effective in targeting CSC properties and down regulating the Wnt β-catenin machinery.
Keywords	Western blotting ; apoptosis ; autophagy ; gene expression ; immunocytochemistry ; ovarian neoplasms ; peptides ; precipitin tests ; CD24 ; EMT ; Ovarian cancer stem cells ; SFRP4 ; Wnt antagonist
Language	English
Dates of publication	2023-03
Publishing place	Elsevier Inc.
Document type	Article ; Online
ZDB-ID	3378-9
ISSN	1879-0631 ; 0024-3205
ISSN (online)	1879-0631
ISSN	0024-3205
DOI	10.1016/j.lfs.2023.121384
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Microvascular cells: A special focus on heterogeneity of pericytes in diabetes associated complications.

Rajendran, Sharmila / Seetharaman, Shanmuganathan / Dharmarajan, Arun / Kuppan, Kaviarasan

The international journal of biochemistry & cell biology

2021 Volume 134, Page(s) 105971

Abstract: Pericytes (PC) are microvascular mural cells that make specific cell-to-cell contacts with the endothelial cells (EC). These cells are obligatory constituents of the microvessels including the retinal vasculature and they serve as regulators of vascular ... ...

Abstract	Pericytes (PC) are microvascular mural cells that make specific cell-to-cell contacts with the endothelial cells (EC). These cells are obligatory constituents of the microvessels including the retinal vasculature and they serve as regulators of vascular development, stabilization, maturation and remodeling. During early stages of diabetic retinopathy (DR), apoptotic loss of PC surrounding the retinal vasculature occurs. This may lead to reduced vessel stability, the onset of EC apoptosis, and subsequent retinal ischemia leading to angiogenesis and eventually, severe vision loss due to late proliferative diabetic retinopathy (PDR). Similarly, diabetic nephropathy (DN) is a chronic kidney disease due to hyperglycemia that particularly affects renal PC. Chronic high blood glucose level causes migration of peritubular PC away from the capillary into the interstitial space, which destabilizes the micro vessels, resulting in microvascular rarefaction. In both diabetes associated complications, the identification of specific biomarkers is necessary to stabilize the PC at an early stage. This review largely covers the importance of PC towards the pathogenesis of diabetes associated complications, and their heterogeneity in healthy and angiogenic vasculature.
MeSH term(s)	Animals ; Apoptosis/physiology ; Diabetes Mellitus/physiopathology ; Diabetic Nephropathies/epidemiology ; Diabetic Nephropathies/metabolism ; Diabetic Nephropathies/pathology ; Diabetic Retinopathy/epidemiology ; Diabetic Retinopathy/metabolism ; Diabetic Retinopathy/pathology ; Endothelial Cells/metabolism ; Endothelial Cells/pathology ; Humans ; Microvessels/metabolism ; Microvessels/pathology ; Neovascularization, Pathologic/pathology ; Pericytes/metabolism ; Pericytes/pathology
Language	English
Publishing date	2021-03-26
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1228429-4
ISSN	1878-5875 ; 1357-2725
ISSN (online)	1878-5875
ISSN	1357-2725
DOI	10.1016/j.biocel.2021.105971
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Zs.A 431: Show issues

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Article ; Online: Unwinding the role of Wnt signaling cascade and molecular triggers of motor neuron degeneration in amyotrophic lateral sclerosis (ALS).

Soumya, B S / Shreenidhi, V P / Agarwal, Apoorvaa / Gandhirajan, Rajesh Kumar / Dharmarajan, Arun / Warrier, Sudha

Cellular signalling

2023 Volume 110, Page(s) 110807

Abstract: Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative condition, triggered by various factors causing the degeneration of upper and lower motor neurons, resulting in progressive muscle wasting, paralysis, and death. Multiple in vivo and ... ...

Abstract	Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative condition, triggered by various factors causing the degeneration of upper and lower motor neurons, resulting in progressive muscle wasting, paralysis, and death. Multiple in vivo and in vitro models have been established to unravel the molecular events leading to the deterioration of motor neurons in ALS. The canonical and non-canonical Wnt signaling pathway has been implicated to play a crucial role in the progression of neurodegenerative disorders. This review discusses the role of Wnt signaling in the reported causes of ALS such as oxidative stress, mitochondrial dysfunction, autophagy, and apoptosis. Mutations in ALS-associated genes such as SOD1, C9orf72, TDP43, FUS, and OPTN cause an imbalance in neuronal integrity and homeostasis leading to motor neuron demise. Wnt signaling is also observed to play a crucial role in the muscle sparing of oculomotor neurons. The non-canonical Wnt/Ca
MeSH term(s)	Humans ; Animals ; Amyotrophic Lateral Sclerosis/metabolism ; Wnt Signaling Pathway ; Motor Neurons/metabolism ; Oxidative Stress ; Nerve Degeneration/metabolism ; Nerve Degeneration/pathology ; Disease Models, Animal
Language	English
Publishing date	2023-07-16
Publishing country	England
Document type	Review ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1002702-6
ISSN	1873-3913 ; 0898-6568
ISSN (online)	1873-3913
ISSN	0898-6568
DOI	10.1016/j.cellsig.2023.110807
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