Showing papers by "Aamir Ahmad published in 2021"

Exosomal miR-2276-5p in Plasma Is a Potential Diagnostic and Prognostic Biomarker in Glioma

Abstract: Introduction Exosomal microRNAs (miRNAs) play an essential role in near and distant intercellular communication and are potential diagnostic and prognostic biomarkers for various cancers. This study focused on evaluation of exosomal miR-2276-5p in plasma as a diagnostic and prognostic biomarker for glioma. Methods Plasma exosomes from 124 patients with glioma and 36 non-tumor controls were collected and subjected to quantitative real-time polymerase chain reaction (qRT-PCR) analysis for the exosomal miR-2276-5p expression. Bioinformatic analyses were performed to identify a gene target, and CGGA and TCGA databases were checked for evaluation of prognostic relevance. Results The exosomal miR-2276-5p in glioma patients had a significantly decreased expression, compared with non-glioma patients (p < 0.01). Receiver operating characteristics (ROC) curve analyses were observed to regulate the diagnostic sensitivity and specificity of miR-2276-5p in glioma; the area under the curve (AUC) for miR-2276-5p was 0.8107. The lower expression of exosomal miR-2276-5p in patients with glioma correlated with poorer survival rates. RAB13 was identified as the target of miR-2276-5p which was high in glioma patients, especially those with higher tumor grades and correlated with poor survival. Conclusion The circulating exosomal miR-2276-5p is significantly reduced in the plasma of glioma patients, and thus, it could be a potential biomarker for patients with glioma for diagnostic and/or prognostic purposes.

The plasticity of pancreatic cancer stem cells: implications in therapeutic resistance.

Abstract: The ever-growing perception of cancer stem cells (CSCs) as a plastic state rather than a hardwired defined entity has evolved our understanding of the functional and biological plasticity of these elusive components in malignancies. Pancreatic cancer (PC), based on its biological features and clinical evolution, is a prototypical example of a CSC-driven disease. Since the discovery of pancreatic CSCs (PCSCs) in 2007, evidence has unraveled their control over many facets of the natural history of PC, including primary tumor growth, metastatic progression, disease recurrence, and acquired drug resistance. Consequently, the current near-ubiquitous treatment regimens for PC using aggressive cytotoxic agents, aimed at ‘‘tumor debulking’’ rather than eradication of CSCs, have proven ineffective in providing clinically convincing improvements in patients with this dreadful disease. Herein, we review the key hallmarks as well as the intrinsic and extrinsic resistance mechanisms of CSCs that mediate treatment failure in PC and enlist the potential CSC-targeting ‘natural agents’ that are gaining popularity in recent years. A better understanding of the molecular and functional landscape of PCSC-intrinsic evasion of chemotherapeutic drugs offers a facile opportunity for treating PC, an intractable cancer with a grim prognosis and in dire need of effective therapeutic advances.

The Role of MicroRNAs in Therapeutic Resistance of Malignant Primary Brain Tumors.

Abstract: Brain tumors in children and adults are challenging tumors to treat. Malignant primary brain tumors (MPBTs) such as glioblastoma have very poor outcomes, emphasizing the need to better understand their pathogenesis. Developing novel strategies to slow down or even stop the growth of brain tumors remains one of the major clinical challenges. Modern treatment strategies for MPBTs are based on open surgery, chemotherapy, and radiation therapy. However, none of these treatments, alone or in combination, are considered effective in controlling tumor progression. MicroRNAs (miRNAs) are 18-22 nucleotide long endogenous non-coding RNAs that regulate gene expression at the post-transcriptional level by interacting with 3'-untranslated regions (3'-UTR) of mRNA-targets. It has been proven that miRNAs play a significant role in various biological processes, including the cell cycle, apoptosis, proliferation, differentiation, etc. Over the last decade, there has been an emergence of a large number of studies devoted to the role of miRNAs in the oncogenesis of brain tumors and the development of resistance to radio- and chemotherapy. Wherein, among the variety of molecules secreted by tumor cells into the external environment, extracellular vesicles (EVs) (exosomes and microvesicles) play a special role. Various elements were found in the EVs, including miRNAs, which can be transported as part of these EVs both between neighboring cells and between remotely located cells of different tissues using biological fluids. Some of these miRNAs in EVs can contribute to the development of resistance to radio- and chemotherapy in MPBTs, including multidrug resistance (MDR). This comprehensive review examines the role of miRNAs in the resistance of MPBTs (e.g., high-grade meningiomas, medulloblastoma (MB), pituitary adenomas (PAs) with aggressive behavior, and glioblastoma) to chemoradiotherapy and pharmacological treatment. It is believed that miRNAs are future therapeutic targets in MPBTs and such the role of miRNAs needs to be critically evaluated to focus on solving the problems of resistance to therapy this kind of human tumors.

Anticancer Active Heterocyclic Chalcones: Recent Developments

Abstract: Background Chalcones are structurally simple compounds that are easily accessible by synthetic methods. Heterocyclic chalcones have gained the interest of scientists due to their diverse biological activities. The anti-tumor activities of heterocyclic chalcones are especially remarkable and the growing number of publications dealing with this topic warrants an up-to-date compilation. Methods Search for antitumor active heterocyclic chalcones was carried out using Pubmed and Scifinder as common web-based literature searching tools. Pertinent and current literature was covered from 2015/2016 to 2019. Chemical structures, biological activities and modes of action of anti-tumor active heterocyclic chalcones are summarized. Results Simply prepared chalcones have emerged over the last years with promising antitumor activities. Among them, there are a considerable number of tubulin polymerization inhibitors. But there are also new chalcones targeting special enzymes such as histone deacetylases or with DNA-binding properties. Conclusion This review provides a summary of recent heterocyclic chalcone derivatives with distinct antitumor activities.

Thiostrepton inhibits growth and induces apoptosis by targeting FoxM1/SKP2/MTH1 axis in B-precursor acute lymphoblastic leukemia cells.

Abstract: Forkhead box M1 (FoxM1) is a transcription factor that plays an important role in the etiology of many cancers, however, its role has not been elucidated in B-precursor acute lymphoblastic leukemia (B-pre-ALL). In the current study, we showed that the downregulation of FoxM1 by its inhibitor thiostrepton inhibited cell viability and induced caspase-dependent apoptosis in a panel of B-pre-ALL cell lines. Thiostrepton led downregulation of FoxM1 accompanied by decreased expression of Aurora kinase A, B, matrix metalloproteinases, and oncogene SKP2 as well as MTH1. Downregulation of the FoxM1/SKP2/MTH1 axis led to increase in the Bax/Bcl2 ratio and suppression of antiapoptotic proteins. Thiostrepton-mediated apoptosis was prevented by N-acetyl cysteine, a scavenger of reactive oxygen species. Co-treatment of B-pre-ALL with subtoxic doses of thiostrepton and bortezomib potentiated the proapoptotic action. Altogether, our results suggest that targeting FoxM1expression could be an attractive strategy for the treatment of B-pre-ALL.

Transcriptional control of the oxidative stress response and implications of using plant derived molecules for therapeutic interventions in cancer.

Abstract: Oxidative stress response is critical for the malignant cells. It plays dual role by helping cancer cells survive and proliferate but also causing apoptosis and apoptosis like cell death. The oxidative stress response is characterized by a tight regulation of gene expression by a series of transcription factors (OSRts; oxidative stress response transcription factors). In this communication, we review the role of OSRts, notably NRF2 and p53 as well as other transcription factors, that modulate the response. We discuss how the oxidative stress response is hierarchal and controls 'live or die' signals. This is followed by a discussion on how plant derived molecules, including polyphenols, which are described both as prooxidants and antioxidants within the cancer cells, have been reported to affect the activities of OSRts. Deriving an example from preliminary data from our group, we discuss how plant derived molecules might modulate the oxidative stress response by causing structural perturbations in the proteinacious transcription factors, notably Nrf2 and p53. We look at this information in the light of understanding how plant derived molecules maybe used as lead compounds to develop modulators of the oxidative stress response.

Sex differences in cardiopulmonary effects of acute bromine exposure.

Abstract: Accidental occupational bromine (Br>2>) exposures are common, leading to significant morbidity and mortality; however, the specific effects of Br>2> inhalation in female victims are unclear. Our studies demonstrated that acute high-concentration Br>2> inhalation is fatal, and cardiac injury and dysfunction play an important role in Br>2> toxicity in males. In this study, we exposed female Sprague Dawley rats, age-matched to those males from previously studied, to 600 ppm Br>2> for 45 min and assessed their survival, cardiopulmonary injury and cardiac function after exposure. Br>2> exposure caused serious mortality in female rats (59%) 48 h after exposure. Rats had severe clinical distress, reduced heart rates and oxygen saturation after Br>2> inhalation as was previously reported with male animals. There was significant lung injury and edema when measured 24 h after exposure. Cardiac injury biomarkers were also significantly elevated 24 h after Br>2> inhalation. Echocardiography and hemodynamic studies were also performed and revealed that the mean arterial pressure was not significantly elevated in females. Other functional cardiac parameters were also altered. Aside from the lack of elevation of blood pressure, all other changes observed in female animals were also present in male animals as reported in our previous study. These studies are important to understand the toxicity mechanisms to generate therapies and better-equip first responders to deal with these specific scenarios after bromine spill disasters.>.

Plant-derived small molecule inhibitors as modulators of EMT pathway in cancer chemoprevention

Abstract: Recent global data have reported a disturbing trend with an estimated rise in cancer burden to 18.1 million incidences and 9.6 million cancer-related deaths in 2018 worldwide. It is increasingly becoming evident that the global battle against cancer cannot be sustained with treatment alone, and thus strategies concurrently engaging both effective interventional and preventive measures are required in the premises of chemoprevention. Small molecule inhibitors are low molecular weight organic molecules that have the ability to enter the cell and influence or otherwise interfere in the biological processes within. Studies both in vitro and in vivo have shown that such molecules derived from plants are effective in impeding cancer growth, migration, and metastasis. These molecules are often abundantly present in fruits, vegetables, and cereals, which are a regular part of the human diet. As reported in the literature, they influence multiple cellular targets that are fundamentally involved in cell division, differentiation, and death. It has been realized that cell differentiation pathways are key components in cancer cell metastasis and grants the process certain aggressive features that are required to evade inherent defenses and acquire resistance. In this chapter, we provide a brief overview of epithelial–mesenchymal transition (EMT) as a core element of metastatic potential in cancer and provide evidence for plant-derived small molecules as natural modulators of EMT.