MicroRNAs in Bone Diseases: Progress and Prospects

With 19–25 nucleotides long, microRNAs (miRNAs) are small noncoding RNA molecules which play crucial roles in major cellular functions such as cell cycle control, apoptosis, metabolism, cell proliferation, and cell differentiation. Changes in the expression of miRNAs can cause significant effects to normal and aberrant cells. The dysregulation of miRNAs has been implicated in various human diseases such as brain tumor, osteoarthritis, schizophrenia, and breast cancer. Generally, miRNAs negatively regulate gene expression by binding to their specific mRNAs, thereby blocking their translation of the mRNAs. However, a few studies have reported that miRNAs could also upregulate the translation of certain proteins. This shows the important roles of miRNAs in various cell functions. This chapter will focus on the role of miRNAs in normal osteoblast and osteosarcoma cells. In addition, the great potential of miRNA as a new therapeutic approach to treat human bone diseases will also be discussed

Effect of food density on male appearance and ephippia production in a tropical cladoceran, Moina micrura Kurz, 1874

A study was conducted to investigate the effects of different food concentrations consisting of Nannochloropsis oculata (4 × 102, 4 × 104, 4 × 106 cells ml− 1 and control) on male and ephippia production in a tropical cladoceran, Moina micrura. The highest number of males (186.7 ± 13.4 males l− 1) was produced in cultures fed with 4 × 102 cells ml− 1 of N. oculata (FC 3) when the population density reached > 1600 individuals l− 1. Similarly, the highest total mean number of ephippia (160.0 ± 0.0 ephippia l− 1) was achieved in M. micrura culture supplied with 4 × 102 cells ml− 1 of N. oculata (FC 3). The second highest ephippia density was found in M. micrura cultures fed with 4 × 104 cells ml− 1 of N. oculata (FC 2) which produced a mean total of 93.3 ± 13.4 ephippia l− 1 in a population density of > 3000 individuals l− 1. However, with a population density of > 4000 individuals l− 1, but fed with the highest food concentration of 4 × 106 cells ml− 1 N. oculata (FC 1), no ephippia was produced although males were present in the culture. This study illustrates that ephippia were produced in high density cultures with the presence of males and insufficient food supply. Crowding could trigger the production of males, but was not an adequate stress factor for inducing the formation of ephippia. Similarly, food limitation alone did not induce the production of males and ephippia without crowding

The Regulatory Role of MicroRNAs in Breast Cancer

MicroRNAs (miRNAs) are small non-coding RNA molecules which function as critical post-transcriptional gene regulators of various biological functions. Generally, miRNAs negatively regulate gene expression by binding to their selective messenger RNAs (mRNAs), thereby leading to either mRNA degradation or translational repression, depending on the degree of complementarity with target mRNA sequences. Aberrant expression of these miRNAs has been linked etiologically with various human diseases including breast cancer. Different cellular pathways of breast cancer development such as cell proliferation, apoptotic response, metastasis, cancer recurrence and chemoresistance are regulated by either the oncogenic miRNA (oncomiR) or tumor suppressor miRNA (tsmiR). In this review, we highlight the current state of research into miRNA involved in breast cancer, with particular attention to articles published between the years 2000 to 2019, using detailed searches of the databases PubMed, Google Scholar, and Scopus. The post-transcriptional gene regulatory roles of various dysregulated miRNAs in breast cancer and their potential as therapeutic targets are also discussed

Functional and structural analysis of non-synonymous single nucleotide polymorphisms (nsSNPs) in the MYB oncoproteins associated with human cancer

MYB proteins are highly conserved DNA-binding domains (DBD) and mutations in MYB oncoproteins have been reported to cause aberrant and augmented cancer progression. Identification of MYB molecular biomarkers predictive of cancer progression can be used for improving cancer management. To address this, a biomarker discovery pipeline was employed in investigating deleterious non-synonymous single nucleotide polymorphisms (nsSNPs) in predicting damaging and potential alterations on the properties of proteins. The nsSNP of the MYB family; MYB, MYBL1, and MYBL2 was extracted from the NCBI database. Five in silico tools (PROVEAN, SIFT, PolyPhen-2, SNPs&GO and PhD-SNP) were utilized to investigate the outcomes of nsSNPs. A total of 45 nsSNPs were predicted as high-risk and damaging, and were subjected to PMut and I-Mutant 2.0 for protein stability analysis. This resulted in 32 nsSNPs with decreased stability with a DDG score lower than − 0.5, indicating damaging effect. G111S, N183S, G122S, and S178C located within the helix-turn-helix (HTH) domain were predicted to be conserved, further posttranslational modifications and 3-D protein analysis indicated these nsSNPs to shift DNA-binding specificity of the protein thus altering the protein function. Findings from this study would help in the field of pharmacogenomic and cancer therapy towards better intervention and management of cancer

Ephippia production and genetic biodiversity in tropical cladoceran Moina micrura kurz

In Malaysia, the imported Artemia nauplii is a standard larval diet in aquaculture and hatchery production system due to its availability in dormant form. However, this imported live feed is expensive and they can only survive for few hours in freshwater. Therefore, an easily available inexpensive local live-feed alternative for this imported species is desirable. In this study, the effect of different food concentrations and feeding frequencies on the production of ephippia had been investigated. Different food concentrations consisting of Nannochloropsis oculata (4x106 cells/ml, 4x104 cells/ml, 4x102 cells/ml, no food supply as control) and different feeding frequencies (3 days,3 and 5 days, 5 days, 8 days, 8 and 3 days and daily) were used. The highest mean number of ephippia (7.33±1.53 ephippia) was produced when the cultures were fed every 3 and 5 days alternately. When the cultures were fed with 4x10⁶ cells/ml, no ephippia was produced due to the high amount of food available. In another set of experiment, parthenogenetic reproduction,appearance of males and production of ephippia in M. micrura were studied. Two hundreds female individuals aged less than 24 hours were used. The cultures were fed with N. oculata at different food concentrations (4x106 cells/ml, 4x104 cells/ml, 4x102 cells/ml, no food supply as control) for 12 days. The highest number of males (186.7±23.1 males/l) was produced in the cultures fed with 4x102 cells/ml of N. oculata when population density reached > 1600 individuals/l. Similarly, the highest total mean number of ephippia (160.0±0.0 ephippia/l) was achieved with M. micrura fed with 4x102 cells/ml of N. oculata when the population density reached > 2000 individuals/l. Combination of limited food supply and high population density were needed to trigger the ephippia production. The hatchability of the ephippia that were produced in the earlier experiments was studied. In this experiment, only the ephippia containing resting eggs were used. Under the optimum environmental parameters (temperature 25±2°C, pH 5-9,photoperiod ≥8 hours light per day) none of the ephippia containing resting eggs hatched. These “weak eggs” might be caused by the maternal factor where the production ephippia is not normally occurs. The mechanism for hatching process is not well developed yet in this clone of M. micrura. In the earlier experiments, M. micrura reproduced by both asexual and sexual reproduction. Hence, genetic variation within asexual and sexual generation of M. micrura was investigated. Gene sequences of 16S rRNA mtDNA and Cytochrome C Oxidase Subunit 1 were used. Both genes show 100% similarity of the nucleotide sequences between different generations of asexual M. micrura. However, comparison of the 16S rRNA mtDNA gene sequences between asexual and sexual generations shows that the level of similarity between the sequences was only 55.80 to 56.82%, whereas Cytochrome C Oxidase Subunit 1 gene sequences shows 49.50 to 58.86% of similarity. This study clearly illustrated that production of ephippia in tropical M. micrura requires combination of low food availability and crowding condition. The failure of the eggs to hatch could be due to low synchronization of male production and ephippia formation in tropical M.micrura. The study also showed that sexual reproduction produces a new generation of M. micrura with higher genetic variation

Antitumor and antioxidant effects of Clinacanthus nutans Lindau in 4T1 tumor-bearing mice

Background: Clinacanthus nutans Lindau (C. nutans) is a species of in Acanthaceae family and primarily used in South East Asian countries. C. nutans is well known as Sabah snake grass in Malaysia, and its leaves have diverse medicinal potential in conventional applications, including cancer treatments. On the basis of literature search, there is less conclusive evidence of the involvement of phytochemical constituents in breast cancer, in particular, animal tumor models. The current study aimed to determine the antitumor and antioxidant activities of C. nutans extract in 4 T1 tumor-bearing mice. Methods: C. nutans leaves were subjected to methanol extraction and divided into two different concentrations, 200 mg/kg (low-dose) and 1000 mg/kg (high-dose). The antitumor effects of C. nutans extracts were assessed using bone marrow smearing, clonogenic, and splenocyte immunotype analyses. In addition, hematoxylin and eosin, tumor weight and tumor volume profiles also used to indicate apoptosis appearance. Serum cytokine levels were examined using ELISA assay. In addition, nitric oxide assay reflecting antioxidant activity was performed. Results: From the results obtained, the methanol extract of C. nutans leaves at 200 mg/kg (P < 0.05) and 1000 mg/ kg (P < 0.05) showed a significant decrease in nitric oxide (NO) and malondialdehyde (MDA) levels in the blood. On the other hand, C. nutans extract (1000 mg/kg) also showed a significant decrease in the number of mitotic cells, tumor weight, and tumor volume. No inflammatory and adverse reactions related to splenocytes activities were found in all treated groups of mice. Despite its promising results, the concentration of both C. nutans extracts have also reduced the number of colonies formed in the liver and lungs. Conclusion: In conclusion, C. nutans extracts exert antitumor and antioxidant activities against 4 T1 mouse breast model with no adverse effect and inflammatory response at high dose of 1000 mg/kg, indicating an effective and complementary approach for cancer prevention and treatment

Crosstalk between fatty acid metabolism and tumour-associated macrophages in cancer progression

Over the last few decades, cancer has been regarded as an independent and selfsustaining progression. The earliest hallmarks of cancer comprise of sustaining proliferative signalling, avoiding growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, and activating invasion and metastasis. Nonetheless, two emerging hallmarks are being described: aberrant metabolic pathways and evasion of immune destruction. Changes in tumour cell metabolism are not restricted to tumour cells alone; the products of the altered metabolism have a direct impact on the activity of immune cells inside the tumour microenvironment, particularly tumour-associated macrophages (TAMs). The complicated process of cancer growth is orchestrated by metabolic changes dictating the tight mutual connection between these cells. Here, we discuss approaches to exploit the interaction of cancer cells' abnormal metabolic activity and TAMs. We also describe ways to exploit it by reprogramming fatty acid metabolism via TAM

Post-Transcriptional Regulatory Crosstalk between MicroRNAs and Canonical TGF-β/BMP Signalling Cascades on Osteoblast Lineage: A Comprehensive Review

MicroRNAs (miRNAs) are a family of small, single-stranded, and non-protein coding RNAs about 19 to 22 nucleotides in length, that have been reported to have important roles in the control of bone development. MiRNAs have a strong influence on osteoblast differentiation through stages of lineage commitment and maturation, as well as via controlling the activities of osteogenic signal transduction pathways. Generally, miRNAs may modulate cell stemness, proliferation, differentiation, and apoptosis by binding the 3′-untranslated regions (3′-UTRs) of the target genes, which then can subsequently undergo messenger RNA (mRNA) degradation or protein translational repression. MiRNAs manage the gene expression in osteogenic differentiation by regulating multiple signalling cascades and essential transcription factors, including the transforming growth factor-beta (TGF-β)/bone morphogenic protein (BMP), Wingless/Int-1(Wnt)/β-catenin, Notch, and Hedgehog signalling pathways; the Runt-related transcription factor 2 (RUNX2); and osterix (Osx). This shows that miRNAs are essential in regulating diverse osteoblast cell functions. TGF-βs and BMPs transduce signals and exert diverse functions in osteoblastogenesis, skeletal development and bone formation, bone homeostasis, and diseases. Herein, we highlighted the current state of in vitro and in vivo research describing miRNA regulation on the canonical TGF-β/BMP signalling, their effects on osteoblast linage, and understand their mechanism of action for the development of possible therapeutics. In this review, particular attention and comprehensive database searches are focused on related works published between the years 2000 to 2022, using the resources from PubMed, Google Scholar, Scopus, and Web of Science

CD36-Fatty Acid-Mediated Metastasis via the Bidirectional Interactions of Cancer Cells and Macrophages

Tumour heterogeneity refers to the complexity of cell subpopulations coexisting within the tumour microenvironment (TME), such as proliferating tumour cells, tumour stromal cells and infiltrating immune cells. The bidirectional interactions between cancer and the surrounding microenvironment mark the tumour survival and promotion functions, which allow the cancer cells to become invasive and initiate the metastatic cascade. Importantly, these interactions have been closely associated with metabolic reprogramming, which can modulate the differentiation and functions of immune cells and thus initiate the antitumour response. The purpose of this report is to review the CD36 receptor, a prominent cell receptor in metabolic activity specifically in fatty acid (FA) uptake, for the metabolic symbiosis of cancer&ndash;macrophage. In this review, we provide an update on metabolic communication between tumour cells and macrophages, as well as how the immunometabolism indirectly orchestrates the tumour metastasis