117 research outputs found
Stress response to genotoxic agents and to infection
Insects have evolved various physiological responses to cope with stressors such as
pathogens, toxins and environmental factors. It is known that the responses resulting
from infection or DNA damage share some of the same pathways. Exposure of
Drosophila melanogaster and the dung beetle Euoniticellus intermedius to stress led
to changes in the expression of proteins involved in metabolism, development, protein
degradation, mRNA processing and stress responses. Stress responses in D.
melanogaster are well characterised. However, the role played by Drosophila p53
(Dmp53) and a member of the retinoblastoma binding protein 6 (RBBP6) family,
Snama, are unknown. Snama has been proposed to play a role in Dmp53 regulation.
Following DNA damage we investigated the role of Dmp53 and Snama. Flies
recovering from camptothecin treatment display a glycolytic flux, involving a
metabolic shift, different to that observed in cancer cells. Camptothecin treatment
leads to an increase in the mortality of both sexes. Furthermore, females show a
specific decrease in fecundity which is due to an increase in Dmp53 dependent
apoptosis in the ovaries and is accompanied by a depletion of Snama and an increase
in Dmp53 transcripts. Expression data indicated that Dmp53 activity may be largely
regulated at the protein level. Bypassing glycolysis through methyl pyruvate
supplementation led to differential expression of Dmp53 and Snama and improved
reproduction and embryonic development. These results highlight differences
between the metabolic strategies used by cancerous and non-cancerous cells which
may be exploited in future chemotherapies. While immune responses amongst insect
orders are evolutionarily conserved, many remain uncharacterised. To investigate the
immune system of an organism that lives in a microbe rich environment, E.
intermedius was infected with the fungal pathogen Beauveria bassiana. This resulted
in decreased lifespan and fecundity. Homologs of proteins involved in the immune
response of insects were identified in E. intermedius, including a member of the Toll
family of proteins, an insect defensin (present in the hemolymph) as well as a homolog of the serine protease Persephone. These results show that immune
signalling pathways are conserved in this dung beetle
Current Immunotherapeutic Treatments in Colon Cancer
The immune system is able to act against cancer cells and consequently these cells have developed a range of responses to evade or suppress the immune systems anticancer responses. The concept of cancer immunotherapy is based on techniques developed to restore or boost the ability of the immune system to recognize and target tumor cells. It is known that colon cancer does initiate an immune response and that this type of cancer initiates pathways and responses to evade or suppress the immune system. This chapter will discuss some of the dominant therapies being developed to treat colon cancer based on the concept of cancer immunotherapy. Cancer vaccines are based on the concept of providing the immune system with antigen targets derived from tumor-specific molecules, while monoclonal antibodies involve the development of antibodies specifically targeting proteins expressed on the surface of tumor cells. Antibody-based immunotherapy has further applications in the use of bispecific antibodies (BsAb), which are synthetic antibodies designed to be able to recognize two different antigens or epitopes and in this way can increase the immunoresponse and limit immune evasion observed in mono-targeted therapy. Immune checkpoint inhibitors target proteins that are responsible for keeping immune responses in check. Tumor cells overexpress these proteins in order to evade the immune response. Blocking these proteins will lead to an increased immune response against these cells. Cytokine-based immunotherapies involve the use of the immune systems’ own molecular messengers that are responsible for a robust immune response, to boost the antitumor response of the immune system. Oncolytic viral therapy is based on the use of viruses that selectively infect and replicate in cancer and associated endothelial cells and subsequently kills these cells. Adoptive immunotherapy involves the use of immune cells from the patient to be cultured and altered in the laboratory and then reintroduced to boost the immune response. This is normally performed with T cells. Immunotherapy may be the next logical step in the development of an effective therapy for colon cancer and other cancers. The combination of these therapies with traditional chemotherapy or radiotherapy has shown promise in cancer treatment
Splicing machinery genomics events in acute myeloid leukaemia (AML) : in search for therapeutic targets, diagnostic and prognostic biomarkers
Acute myeloid leukemia (AML) is the most common form of acute leukaemia and has the highest mortality rate. Screening for mutations in patients with AML has shown that in many cases genes carrying mutations are involved in the alternate splicing of mRNA. These include members of the Serine Arginine (SR) family of splicing factors, as well as components of the spliceosome. Mutations in associated genes also affect the function of members of the heterogeneous nuclear ribonucleoproteins (hnRNPs). These mutations in splicing factors can lead to changes in the expression of different isoforms whose splicing is controlled by these splicing factors. These different isoforms may have completely different functions, for example, members of the BCl-2 family are alternately spliced to give rise to pro and anti-apoptotic members. Mutations in the splicing factors that control the splicing of these mRNAs can lead to changes in the expression level of these isoforms. In this review we will examine the mechanics of the regulation of the various splice isoforms and how this drives the development of tumors. This information is pertinent for drug discovery, and the splicing factors with the most promise for pharmacological control will be discussed.http://www.ajcr.ushj2021Medical Oncolog
Exploiting the molecular basis of oesophageal cancer for targeted therapies and biomarkers for drug response : guiding clinical decision-making
Worldwide, oesophageal cancer is the sixth leading cause of deaths related to cancer and
represents a major health concern. Sub-Saharan Africa is one of the regions of the world with the
highest incidence and mortality rates for oesophageal cancer and most of the cases of oesophageal
cancer in this region are oesophageal squamous cell carcinoma (OSCC). The development and
progression of OSCC is characterized by genomic changes which can be utilized as diagnostic or
prognostic markers. These include changes in the expression of various genes involved in signaling
pathways that regulate pathways that regulate processes that are related to the hallmarks of cancer,
changes in the tumor mutational burden, changes in alternate splicing and changes in the expression
of non-coding RNAs such as miRNA. These genomic changes give rise to characteristic profiles of
altered proteins, transcriptomes, spliceosomes and genomes which can be used in clinical applications
to monitor specific disease related parameters. Some of these profiles are characteristic of more
aggressive forms of cancer or are indicative of treatment resistance or tumors that will be difficult
to treat or require more specialized specific treatments. In Sub-Saharan region of Africa there is
a high incidence of viral infections such as HPV and HIV, which are both risk factors for OSCC.
The genomic changes that occur due to these infections can serve as diagnostic markers for OSCC
related to viral infection. Clinically this is an important distinction as it influences treatment as well
as disease progression and treatment monitoring practices. This underlines the importance of the
characterization of the molecular landscape of OSCC in order to provide the best treatment, care,
diagnosis and screening options for the management of OSCC.The South African Medical Research Council (SAMRC), The National Research Foundation (NRF) and Discovery Health.https://www.mdpi.com/journal/biomedicinesam2023Medical OncologySurger
Reports of plant-derived nanoparticles for prostate cancer therapy
Plants have demonstrated potential in providing various types of phytomedicines with
chemopreventive properties that can combat prostate cancer. However, despite their promising
in vitro activity, the incorporation of these phytochemicals into the market as anticancer agents
has been hindered by their poor bioavailability, mainly due to their inadequate aqueous solubility,
chemical instability, and unsatisfactory circulation time. To overcome these drawbacks, it has been
suggested that the incorporation of phytochemicals as nanoparticles can offer a solution. The use
of plant-based chemicals can also improve the biocompatibility of the formulated nanoparticles
by avoiding the use of certain hazardous chemicals in the synthesis, leading to decreased toxicity
in vivo. Moreover, in some cases, phytochemicals can act as targeting agents to tumour sites. This
review will focus on and summarize the following points: the different types of nanoparticles that
contain individual phytochemicals or plant extracts in their design with the aim of improving the
bioavailability of the phytochemicals; the therapeutic evaluation of these nanoparticles against
prostate cancer both in vitro and in vivo and the reported mode of action and the different types of
anticancer experiments used; how the phytochemicals can also improve the targeting effects of these
nanoparticles in some instances; and the potential toxicity of these nanoparticles
The profiling, identification, quantification and analysis of differentially expressed genes (DEGs) in response to drug treatment in lung cancer
The profiling and identification of genes that are differentially expressed is frequently used to underpin the underlying molecular mechanisms of biological conditions and provides a molecular foothold on biological questions of interest. However, this can be a daunting task since there is a cross talk and overlap of some of the components of the signalling pathways. The deregulation of the cell cycle signalling pathway is a hallmark of cancer, including lung cancer. Proper regulation of the cell cycle results in cellular homeostasis between cell proliferation and cell death. The comprehension of the cell cycle regulation in drug metabolism studies is of significance. This study aimed at elucidating the regulation of cell cycle genes’ in response to LPV/r in lung cells. Thus, this study describes methodology for revealing molecular mechanisms employed by LPV/r to induce stress on genomic DNA. This approach is based on the interrogation of a panel of 84 genes related to the cell cycle pathway, and how the differentially expressed genes’ expression pattern corroborates loss in nuclear integrity (phenotypic observation). MAD2L2, AURKB and CASP3 gene expressions were further confirmed by RT- qPCR. Furthermore, the use of in-silico bioinformatics tools integrates the molecular profiles and phenotypic changes. This approach revealed the activation of the DNA damage response (DDR) pathway in response to LPV/r treatment. The proposed methodology will aid in the comprehension of drug metabolism at genotypic and phenotypic levels. •Gene profiling often reveals the underlying molecular mechanisms. •RT 2 PCR gene arrays have integrated patented quality controls and allow reliable gene expression analysis. •In-silico bioinformatics analysis help reveal pathways affected, that often correspond to phenotypic changes/features.The South African Medical Research Council (SAMRC)http://www.elsevier.com/locate/mexam2022Internal Medicin
Mitotic syndicates Aurora Kinase B (AURKB) and mitotic arrest deficient 2 like 2 (MAD2L2) in cohorts of DNA damage response (DDR) and tumorigenesis
Aurora Kinase B (AURKB) and Mitotic Arrest Deficient 2 Like 2 (MAD2L2) are emerging anticancer
therapeutic targets. AURKB and MAD2L2 are the least well studied members of their protein families,
compared to AURKA and MAD2L1. Both AURKB and MAD2L2 play a critical role in mitosis, cell cycle
checkpoint, DNA damage response (DDR) and normal physiological processes. However, the oncogenic
roles of AURKB and MAD2L2 in tumorigenesis and genomic instability have also been reported. DDR acts
as an arbitrator for cell fate by either repairing the damage or directing the cell to self-destruction. While
there is strong evidence of interphase DDR, evidence of mitotic DDR is just emerging and remains largely
unelucidated. To date, inhibitors of the DDR components show effective anti-cancer roles. Contrarily,
long-term resistance towards drugs that target only one DDR target is becoming a challenge. Targeting
interactions between protein-protein or protein-DNA holds prominent therapeutic potential. Both
AURKB and MAD2L2 play critical roles in the success of mitosis and their emerging roles in mitotic DDR
cannot be ignored. Small molecule inhibitors for AURKB are in clinical trials. A few lead compounds
towards MAD2L2 inhibition have been discovered. Targeting mitotic DDR components and their
interaction is emerging as a potent next generation anti-cancer therapeutic target. This can be done by
developing small molecule inhibitors for AURKB and MAD2L2, thereby targeting DDR components as
anti-cancer therapeutic targets and/or targeting mitotic DDR. This review focuses on AURKB and MAD2L2
prospective synergy to deregulate the p53 DDR pathway and promote favourable conditions for
uncontrolled cell proliferation.http://www.elsevier.com/locate/reviewsmrhttp://www.elsevier.com/locate/mutrespm2022Internal Medicin
Efavirenz induces DNA damage response pathway in lung cancer
The cell-cycle related genes are potential gene targets in understanding the
effects of efavirenz (EFV) in lung cancer. The present study aimed at investigating
the expression changes of cell-cycle related genes in response to EFV drug treatment
in human non-small cell lung carcinoma (A549) and normal lung fibroblast (MRC-5)
cells. The loss in nuclear integrity in response to EFV was detected by 4′, 6-diamidino2-phenylindole (DAPI) staining. Gene expression profiling was performed using
human cell cycle PathwayFinder RT2 Profiler™ PCR Array. The expression changes
of 84 genes key to the cell cycle pathway in humans following EFV treatment was
examined. The R2 PCR Array analysis revealed a change in expression of selected
gene targets (including MAD2L2, CASP3, AURKB). This change in gene expression was
at least a two-fold between test (EFV treated) and the control. RT-qPCR confirmed
the PCR array data. In addition to this, the ATM signaling pathway was shown to be
upregulated following EFV treatment in MRC-5 cells. In particular, ATM’s upstream
activation resulted in p53 upregulation in normal lung fibroblasts. Interestingly, the
p53 signaling pathway was activated irrespective of the repressed ATM pathway in
A549 cells as revealed by the Ingenuity Pathway Analysis (IPA). These EFV effects
are similar to those of ionizing radiation and this suggests that EFV has anti-tumour
properties.South African Medical Research Council (SAMRC)http://www.impactjournals.com/oncotargethj2021Internal Medicin
The dual protease inhibitor lopinavir/ritonavir (LPV/r) exerts genotoxic stress on lung cells
The Sub-Saharan countries, particularly South Africa has the largest number of people living with HIV,
accompanied by the largest antiretroviral treatment (ART) programme in the world. The Highly Active Antiretroviral Treatment (HAART) is the most effective regimen against HIV/AIDS and has improved the lifespan and
quality of life of HIV positive patients. HAART has also led to a decrease in the incidence of AIDS defining cancers
(ADCs) while there is an increased incidence of the non-AIDS Defining Cancers (NADCs), such as lung cancer in
the HAART era. The association between lung tumourigenesis and the use of HAART components such as the
dual protease inhibitor (PI) lopinavir/ritonavir (LPV/r) is poorly understood. Using cell and molecular biological
approaches, this study aimed at elucidating the effects of LPV/r on the regulation of the cell cycle related genes in
normal (MRC-5) and adenocarcinoma (A549) lung cells. Initially, the nuclear integrity of these cells in response
to LPV/r was determined using DAPI staining. The effect of LPV/r on cell cycle genes was evaluated through the
use of a RT2 PCR gene array of 84 genes related to the cell cycle signaling pathway. The PCR array data was
validated by Real-Time Quantification PCR (RT-qPCR). Ingenuity Pathway Analysis (IPA) bio-informatics tool
was employed to disclose the molecular mechanism/s observed at cellular and gene expression levels. Loss of
nuclear integrity and the upregulation of the p53 DNA damage response (DDR) pathway was revealed by DAPI
staining, differential gene expression and IPA core analysis. Furthermore, MAD2L2 and AURKB which also play a
role in the DDR pathway were shown to be differentially expressed. The activation of the CASP3 gene in response
to LPV/r in A549 cells was also observed. The findings of this study suggest genotoxic properties of LPV/r in
healthy normal lung fibroblasts cells and anti-tumour properties in the A549 cells.The South African Medical Research Council (SAMRC)http://www.elsevier.com/locate/biophapm2020Internal Medicin
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