Chemoresistance to the anticancer therapy is the main challenge for the recurrence of cancer and it is responsible for treatment failure and unfavorable clinical outcome. Understanding the mechanisms ...of chemoresistance in cancer would help to predict disease progression, develop new therapies and personalize systemic therapy. In the last few decades, cancer stem cells (CSC) have proven to play a key role in tumor initiation and may also act as a key factor for chemoresistance and recurrence of the disease following chemotherapy. Resistance to anticancer therapy in patients has been attributed towards a number of factors controlling the stemness character of the cancer stem cells which leads to therapeutic resistance.
Accumulating evidences show that the bone marrow (BM) niche is critical to the maintenance and retention of cancer stem cells. Undeniably, stromal cells within the BM niche provide a sanctuary where different signaling pathways and cell-cell interaction gives a protective nature to the diseased condition, and thereby evade chemotherapy-induced death.
In this review we have tried to highlight the factors which have important role in chemoresistance and are associated with bone marrow microenvironment. We have also discussed about the recent progresses regarding CSC-targeted therapies to throw light toward developing more effective therapeutic strategies to eradicate cancer in the patients concerned.
Pesticides aid in crop-protection against pests and increase yield. However, the xenobiotic stress exerted by pesticides leads to the deterioration of human and animal health. There is a lacuna in ...our knowledge about their impact on the ocular surface The present work sheds light on this gap by analysing the deterioration of visual acuity as a consequence of pesticide induced xenobiotic stress and Notch pathway dysregulation.
Alteration in the expression of vital components of the notch signalling was analyzed along the visual pathway with special focus on its two terminals-the cornea and the visual cortex, by mimicking the on-field scenario regarding chronic pesticide exposure in experimental murine model (Swiss albino mice; Mus musculus). Various aspects were taken into consideration through visual acuity tests, histological evaluations, culture analyses, wound healing assays, flowcytometric evaluation, fluorescence microscopic studies etc. Complete dysregulation of key players of the Notch signalling pathway was observed in both: cells of the ocular surface as well as those in the murine visual cortex post pesticide exposure, indicating activities relating to cell proliferation, differentiation and wound healing in the pesticide exposed samples. Ultra-microscopic analyses corroborated our findings by revealing the loss of fine neural processes in the visual cortex of the pesticide exposed murine samples, thereby hinting at delayed perception to visual stimuli. In vivo evaluations of the functional capacity of the neuroanatomical structures along the visual pathway also confirmed that pesticide exposure leads to severe damage along the various parts of the visual pathway, right from the ocular surface to the visual cortex.
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•Xenobiotic stress from pesticides deteriorates visual acuity.•In vivo evaluations of the functional visual-neuroanatomical capacity.•Major points along visual pathway analyzed-cornea, optic nerve and visual cortex.•Fine neural process loss observed on ultra-microscopic analyses.•Notch dysregulation along the visual pathway-cornea, optic nerve & visual cortex.
Pesticides are the commonest solution for controlling pests in developing nations, however the economic benefits from the increased crop-yield by pesticide usage come at the cost of health. This article analyses the deterioration of visual acuity incurred as a consequence of the xenobiotic stress exerted by pesticides and sheds light on the dysregulation of Notch signalling by evaluating its key molecules along the visual pathway with special focus on its two terminals-the cornea and the visual cortex.
Environmental exposure of N‐nitroso compounds (NOCs) from various sources like tobacco smoke, pesticides, smoked meat, and rubber manufacturing industries has been an alarming cause of ...carcinogenesis. Neonatal exposure to the carcinogenic N‐N′ethylnitrosourea (ENU), a NOC has been established to cause leukemogenesis. Our world is constantly battling against cancer with consistent investigations of new anti‐cancer therapeutics. Plant derived compounds have grasped worldwide attention of researchers for their promising anti‐cancer potentials. Eclipta prostrata is one such ayurvedic herb, renowned for its anti‐inflammatory properties. Currently, it has been explored in various cancer cell lines to establish its anti‐cancer effect, but rarely in in‐vivo cancer models. Wedelolactone (WDL), the major coumestan of E. prostrata is recognized as an inhibitor of IKK, a master regulator of the NF‐kB inflammatory pathway. As persistent inflammation and activated inflammasome contribute to leukemogenesis, we tried to observe anti‐leukemogenic efficacy of E. prostrata and its active compound WDL on the marrow cells of ENU induced experimental leukemic mice. Treatment groups were administered an oral gavage at a dose of 1200 mg/kg and 50 mg/kg b.w of crude extract and WDL respectively for 4 weeks. Various parameters like hemogram, survivability, cytological and histological investigations, migration assay, cell culture, flowcytometry and confocal microscopy were taken into consideration pre‐ and post‐treatment. Interestingly, the plant concoction portrayed maximum effects in comparison to WDL alone. The study suggests E. prostrata and WDL as vital complementary adjuncts for anti‐inflammasome mechanism in ENU‐induced leukemia.
Myelodysplastic syndrome (MDS) is regarded as a spectrum of bone marrow failure disorders that share hemato‐pathological state of cellular dysplasia and cytopenia. The modern treatment of cancers ...like chemotherapy and radiation therapy sometimes severely pounce on the basic hematopoietic stem/progenitor cellular (HSPC) compartment which gradually disclose the clinical symptoms of MDS. The present study involves flowcytometric protein expression analysis of insulin growth factor receptor (IGFR), PI3K‐Akt‐mTOR pathway, the autophagy related proteins (ATG's), the status of antioxidative molecules SOD2 and SDF1 and apoptosis profiling in ethyl‐nitroso‐urea induced myelodysplasia. The redox status that is, reactive oxygen species was estimated with dihydroetidium and the status of mitochondria and lysosomes were checked by Janus green B and neutral red staining respectively, pre and post quercetin treatment in MDS bone marrow. The results revealed the activated IGFR/PI3K/Akt axis in MDS bone marrow but unconventionally both p‐mTOR and autophagy (p‐ATG1, p‐AT6, ATG7, ATG12) was downregulated. Interestingly, post quercetin treatment an upregulation of basal autophagocytosis, reversal of oxidative damage and proper functionality of mitochondria and lysosome was recorded. Taken together, the study hinted that the PI3K‐Akt‐mTOR pathway does not rule over the process of autophagocytosis in HSPC's of MDS bone marrow and the isoflavanoid quercetin remarkably restored autophagocytosis and hematopoietic oxidative status toward normalcy during the progression of myelodysplasia.
The consequences of chronic pesticide exposure on the ocular surface are not yet fully known and lacunae exist regarding the repercussions of this xenobiotic insult on cellular turnover. The present ...work aims to establish the mechanistic relationship between ocular morbidity and chronic pesticide exposure by analyzing the impact on key regulators responsible for cell cycle and death.
Vital components of cell cycle and death were primarily explored in this study by mimicking the on-field scenario regarding chronic pesticide exposure in a murine model. Various cellular aspects were taken into consideration through culture analyses, flowcytometric evaluation, fluorescence microscopic studies etc. We observed downregulation of key players of the cell-cycle at different stages (viz. Cyclin-D1, CDK4, pRb, PCNA, PP1, PP2A, p-cdc 25c and Aurora kinase A) with a corresponding increase in the expression of cell-cycle inhibitors like p18 and p21, which lead to hypoproliferation of corneal epithelial cells post pesticide exposure. The expression of GSK 3β, a master-molecule involved in both cell cycle and apoptotic pathways corresponded well with the scientific theme and indicated towards cellular hypoproliferation and increase of apoptosis. Key players of both the intrinsic (viz. Bax/Bcl2, JNK) and extrinsic (viz. CD 95) apoptotic pathways were found to be activated leading to enhanced cleaved Caspase 3 expression and corresponding cell death.
We tried to highlight the mechanistic correlation between the alterations in cellular turnover as the reason behind the heightened ocular morbidity due to ‘chronic pesticide exposure’- the xenobiotic stress exerted by these ‘farmers’ friends'.
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•Altered corneal cellular turnover causes ocular morbidity post pesticide exposure.•Key cell-cycle regulators (viz. Cyclin-D1, CDK4, PCNA, PP1, PP2A & AuroraKinaseA) downregulated.•Increase in expression of cell-cycle inhibitors (viz. p18 and p21) & apoptosis inducer (ASK-1).•Over-expression of apoptotic pathway regulators (viz. Bax/Bcl2, JNK, CD 95 & Caspase 3).•Consequential hypoproliferation & heightened apoptosis of corneal epithelial cells.
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•Hematopoietic catastrophe during marrow aplasia associated with ROS generation.•Increased ROS and disruption of hematopoietic niche under aplastic stress.•Decline of stromal ...components and deregulation of Notch-1/ Jagged-1 signaling axis in aplastic marrow.•Altered DNA methylation and H-3 phosphorylation status associated with redox imbalance in aplastic marrow.
Aplastic anemia or bone marrow failure often develops as an effect of chemotherapeutic drug application for the treatment of various pathophysiological conditions including cancer. The long-term bone marrow injury affects the basic hematopoietic population including hematopoietic stem/progenitor cells (HSPCs). The present study aimed in unearthing the underlying mechanisms of chemotherapeutics mediated bone marrow aplasia with special focus on altered redox status and associated effects on hematopoietic microenvironment and epigenetic status of hematopoietic cells. The study involves the development of busulfan and cyclophosphamide mediated mouse model for aplastic anemia, characterization of the disease with blood and marrow analysis, cytochemical examinations of bone marrow, flowcytometric analysis of hematopoietic population and microenvironmental components, determination of ROS generation, apoptosis profiling, expressional studies of Notch-1 signaling cascade molecules, investigation of epigenetic modifications including global CpG methylation of DNA, phosphorylation of histone-3 with their effects on bone marrow kinetics and expressional analysis of the anti-oxidative molecules viz; SOD-2 and Sdf-1. Severe hematopoietic catastrophic condition was observed during aplastic anemia which involved peripheral blood pancytopenia, marrow hypocellularity and decreased hematopoietic stem/progenitor population. Generation of ROS was found to play a central role in the cellular devastation in aplastic marrow which on one hand can be correlated with the destruction of hematopoiesis supportive niche components and alteration of vital Notch-1 signaling and on other hand was found to be associated with the epigenetic chromatin modifications viz; global DNA CpG hypo-methylation, histone-3 phosphorylation promoting cellular apoptosis. Decline of anti-oxidant components viz; Sdf-1 and SOD-2 hinted towards the irreversible nature of the oxidative damage during marrow aplasia. Collectively, the findings hinted towards the mechanistic correlation among ROS generation, microenvironmental impairment and epigenetic alterations that led to hematopoietic catastrophe under aplastic stress. The findings may potentiate successful therapeutic strategy development for the dreadful condition concerned.
Exposure to N-nitroso compounds (NOCs) in our environment via pesticides, tobacco, and smoked meat can be potentially carcinogenic. The induction of N-N' ethylnitrosourea (ENU), a genotoxic NOC, ...leads to leukemogenesis. The study aimed to explore the ameliorating effect of the Ayurvedic herb Eclipta alba on the bone marrow cells of ENU-induced leukemic mice. Eclipta alba is investigated for its anti-cancer effect on various cell lines, but never on haematological malignant models. Theefficacy of the extract was explored on leukemia by changes in body weight, survivability, peripheral blood hemogram, bone marrow cytological, histological, and cell culture studies pre-and post-treatment. The treated group revealed significant immunomodulation of the expressional profile of NF-kB family and IL-1β in marrow cells, by flow-cytometry, and immunofluorescence study. Through our experimental endeavour we depicted the cellular mechanism, signaling modality and tried to establish the anti-cancer potency of Eclipta alba on ENU-induced leukemia.
The etiologic link between pesticide toxicity and aplastic anemia in agricultural and agro‐industrial setting has been frequently reported in epidemiological studies conducted worldwide. Chronic ...pesticide toxicity causes long‐term bone marrow injury and perturbs the normal hematopoietic physiology, including survival of hematopoietic progenitor cells and bone marrow's blood cell forming ability. The purpose of this study is to understand the mechanism of pesticide toxicity‐mediated bone marrow aplasia by studying Wnt/β‐catenin signaling pathway and microenvironmental stromal components. An agricultural pesticide formulation comprising of cypermethrin, chlorpyriphos, and hexaconazole was used to induce bone marrow aplasia in inbred Swiss albino mice. Marrow failure followed by the onset of aplastic condition was confirmed by pancytopenic peripheral blood and hypocellular bone marrow filled with adipocytes. Significant downregulation of canonical Wnt/β‐catenin signaling was identified by expression analysis of Wnt3a, β‐catenin, and telomerase reverse transcriptase in the aplastic bone marrow hematopoietic stem/progenitor compartment. Along with signaling deregulation, disruption in both the osteoblastic and vascular stromal components was observed in the pesticide‐exposed bone marrow microenvironment when compared to control. In this study, we tried to establish the correlation among disease pathophysiology, signaling deregulation in the hematopoietic cells, and bone marrow microenvironmental alteration during environmental exposure‐mediated aplastic hematopoietic catastrophe, which may shed light on the unexplored mechanistic perspective of this fatal blood disease.
Aplastic anemia is the bone marrow failure condition characterized by the development of hypocellularity in both marrow and peripheral blood compartments. Anti-tumor chemotherapeutic agents often ...exert secondary effect on hematopoietic system leading to aplastic anemia by marrow failure. The precise mechanisms behind the marrow ablative effects of the drugs remain yet to be established. The present study holds a mechanistic approach to unveil the mystery. Aplastic anemia was generated in mice with the administration of busulfan and cyclophosphamide followed by the characterization of the disease with peripheral blood hemogram, histopathological and cytochemical examinations of bone marrow. To gain deep knowledge about the molecular mechanisms of the hematopoietic disruption, cytotoxicity assay, DNA damage measurement, apoptosis study, replicative senescence analysis, redox balance study, mitochondrial membrane potential change assessment, flowcytometric expressional analysis of p21, p53, ATM, Chk-2, Necdin, Gfi-1, c-myc, KU-80 and Sod-2 were done with marrow hematopoietic stem/ progenitor cells (HSPCs). Severe blood pancytopenia and marrow hypocellularity was found in aplastic mice. Proliferative hindrance and apoptosis of marrow cells were identified as the cause behind the hematopoietic catastrophe. The genotoxic effects of the drugs triggered chromatin damage and induced replicative senescence in aplastic HSPCs by upregulating p21 in a p53 independent manner. Moreover, accumulation of genomic insults also caused apoptotic elimination of marrow cells due to disruption of mitochondrial membrane potential by generating redox imbalance. The study established the underlying mechanisms behind hematopoietic disruption during drug induced marrow aplasia. Outcome of the study may be helpful in successful designing of therapeutic strategies for the disease concerned.
The ocular surface is subject to a range of potentially hazardous environmental factors and substances, owing to its anatomical location, sensitivity, and physiological makeup. Xenobiotic stress ...exerted by chronic pesticide exposure on the cornea is primarily responsible for ocular irritation, excessive tear production (hyper-lacrimation), corneal abrasions and decreased visual acuity. Traditional medicine hails the humble onion (Allium cepa) for its multi-faceted properties including but not limited to anti-microbial, antioxidant, anti-inflammatory and wound healing. However, there is a lacuna regarding its impact on the ocular surface.
Thereby, the current study investigated whether topical application of crude extract of Allium cepa aided in mitigating pesticide-induced damage to the ocular surface. The deleterious effects of pesticide exposure and their mitigation through the topical application of herbal extract of Allium cepa were analysed initially through in vitro evaluation on cell lines and then on the ocular surface via various in-vivo and ex-vivo techniques. Pathophysiological alterations to the ocular surface that impacted vision were explored through detailed neurophysiological screening with special emphasis on visual acuity wherein it was observed that the murine group treated with topical application of Allium cepa extract had comparable visual capacity to the non-pesticide exposed group. Additionally, SOD2 was utilized as an oxidative stress marker along with the expression of cellular apoptotic markers such as Bcl-xL to analyse the impact of pesticide exposure and subsequent herbal intervention on oxidative stress-induced corneal damage. The impact on the corneal epithelial progenitor cell population (ABCG2 and TERT positive cells) was also flowcytometrically analysed. Therefore, from our observations, it can be postulated that the topical application of Allium cepa extract might serve as an effective strategy to alleviate pesticide exposure related ocular damage.
•Chronic exposure to pesticide reduces visual acuity.•Allium cepa extract application mitigates pesticide induced ocular damage.•Key molecules like SOD2, Bcl-xL and TERT are down-regulated post pesticide exposure.•Corneal progenitor cell population (ABCG2+) is negatively impacted by pesticide exposure.•Improved visual acuity is observed post treatment with Allium cepa extract.
