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Fulltext Viruses join the circular RNA world

Tan KE, Lim YY

FEBS J, 2021 08;288(15):4488-4502.
PMID: 33236482 DOI: 10.1111/febs.15639

Circular RNAs (circRNAs) are a recently discovered class of noncoding RNAs found in many species across the eukaryotic kingdom. These intriguing RNA species are formed through a unique mechanism that is known as back splicing in which the 5' and 3' termini are covalently joined. Recent research has revealed that viruses also encode a repertoire of circRNAs. Some of these viral circRNAs are abundantly expressed and are reported to play a role in disease pathogenesis. A growing number of studies also indicate that host circRNAs are involved in immune responses against virus infections with either an antiviral or proviral role. In this review, we briefly introduce circRNA, its biogenesis, and mechanism of action. We go on to summarize the latest research on the expression, regulation, and functions of viral and host-encoded circRNAs during the host-virus interaction, with the aim of highlighting the potential of viral and host circRNAs as a suitable target for diagnostic biomarker development and therapeutic treatment of viral-associated diseases. We conclude by discussing the current limitations in knowledge and significance of elucidating the roles of circRNAs in host-virus interactions, as well as future directions for this emerging field.
Fulltext Detection of Cytoplasmic and Nuclear Circular RNA via RT-qPCR

Tan KE, Ng WL, Ea CK, Lim YY

Bio Protoc, 2023 Sep 05;13(17):e4798.
PMID: 37849784 DOI: 10.21769/BioProtoc.4798

Circular RNA (circRNA) is an intriguing class of non-coding RNA that exists as a continuous closed loop. With the improvements in high throughput sequencing, biochemical analysis, and bioinformatic algorithms, studies on circRNA expression became abundant in recent years. However, functional studies of circRNA are still limited. Subcellular localization of circRNA may provide some clues in elucidating its biological functions by performing subcellular fractionation assay. Notably, circRNAs that are predominantly found in the cytoplasm are more likely to be involved in post-transcriptional gene regulation, e.g., acting as micoRNA sponge, whereas nuclear-retained circRNAs are predicted to play a role in transcriptional regulation. Subcellular fractionation could help researchers to narrow down and prioritize downstream experiments. The majority of the currently available protocols describe the steps for subcellular fractionation followed by western blot analysis for protein molecules. Here, we present a protocol for the subcellular fractionation of cells to detect circRNA via RT-qPCR with divergent primers. Moreover, detailed steps for the generation of specific circRNAs-enriched cDNA included in this protocol will enhance the amplification and detection of low-abundance circRNAs. This will be useful for researchers studying low-abundance circRNAs. Key features This protocol builds upon the method developed by Gagnon et al. (2014) and extends its application to circRNA study. Protocol for amplification of low levels of circRNA expression. Analysis takes into consideration the ratio of cytoplasmic RNA concentration to nuclear RNA concentration.
Fulltext Biogeography and evolution of Asian Gesneriaceae based on updated taxonomy

Tan K, Lu T, Ren MX

PhytoKeys, 2020;157:7-26.
PMID: 32934445 DOI: 10.3897/phytokeys.157.34032

Based on an updated taxonomy of Gesneriaceae, the biogeography and evolution of the Asian Gesneriaceae are outlined and discussed. Most of the Asian Gesneriaceae belongs to Didymocarpoideae, except Titanotrichum was recently moved into Gesnerioideae. Most basal taxa of the Asian Gesneriaceae are found in the Indian subcontinent and Indo-China Peninsula, suggesting Didymocarpoideae might originate in these regions. Four species diversification centers were recognized, i.e. Sino-Vietnam regions, Malay Peninsula, North Borneo and Northwest Yunnan (Hengduan Mountains). The first three regions are dominated by limestone landscapes, while the Northwest Yunnan is well-known for its numerous deep gorges and high mountains. The places with at least 25% species are neoendemics (newly evolved and narrowly endemic) which were determined as evolutionary hotspots, including Hengduan Mountains, boundary areas of Yunnan-Guizhou-Guangxi in Southwest China, North Borneo, Pahang and Terengganu in Malay Peninsula, and mountainous areas in North Thailand, North Sulawesi Island. Finally, the underlying mechanisms for biogeographical patterns and species diversification of the Asian Gesneriaceae are discussed.
Synthesis and x-ray single crystal study of 5-(4,4,5,5 – tetramethyl – 1,3,2 – dioxoborolane) – 10,20 – diphenylporphyrin

Nuur Haziqah Mohd Radzuan, Nawwar Hanun Abdul Malek, Nurul Izzaty Hassan, Muntaz Abu Bakar, Mohammad Fadzley Ngatiman, Tan Ke Xin, et al.

Sains Malaysiana, 2018;47:2083-2090.

Borylated porphyrin is one of building blocks in coupling reactions to obtain the multiporphyrin containing two,
three or more subunits of porphyrins. In this study, one of borylated porphyrin derivatives, 5-(4,4,5,5 – tetramethyl
– 1,3,2 – dioxoborolane) -10,20 – diphenylporphyrin (B-DPP) was synthesized through four steps of reactions. The
building block of porphyrin, dipyrromethane was synthesized through a condensation reaction in the presence of
trifluoroacetic acid as catalyst. Subsequently, A2
B2 type of porphyrin was obtained by Lindsey condensation reaction
followed by bromination reaction to produce porphyrin halide. Suzuki cross coupling reaction between porphyrin
halide and pinacolborane with Pd (II) catalyst afforded 40% of borylayed porphyrin. The product was successfully
characterized by using nuclear magnetic resonance spectroscopy (NMR) and UV-Visible spectroscopy (UV-Vis). This
compound crystallized from a mixture of dichloromethane/methanol to give violet needle-like crystal. Crystallographic
studies showed this compound crystallized in monoclinic system with space group of P21
/c.
CircRNA-miRNA interactions in atherogenesis

Tong KL, Tan KE, Lim YY, Tien XY, Wong PF

Mol Cell Biochem, 2022 Dec;477(12):2703-2733.
PMID: 35604519 DOI: 10.1007/s11010-022-04455-8

Atherosclerosis is the major cause of coronary artery disease (CAD) which includes unstable angina, myocardial infarction, and heart failure. The onset of atherogenesis, a process of atherosclerotic lesion formation in the intima of arteries, is driven by lipid accumulation, a vicious cycle of reactive oxygen species (ROS)-induced oxidative stress and inflammatory reactions leading to endothelial cell (EC) dysfunction, vascular smooth muscle cell (VSMC) activation, and foam cell formation which further fuel plaque formation and destabilization. In recent years, there is a surge in the number of publications reporting the involvement of circular RNAs (circRNAs) in the pathogenesis of cardiovascular diseases, cancers, and metabolic syndromes. These studies have advanced our understanding on the biological functions of circRNAs. One of the most common mechanism of action of circRNAs reported is the sponging of microRNAs (miRNAs) by binding to the miRNAs response element (MRE), thereby indirectly increases the transcription of their target messenger RNAs (mRNAs). Individual networks of circRNA-miRNA-mRNA associated with atherogenesis have been extensively reported, however, there is a need to connect these findings for a complete overview. This review aims to provide an update on atherogenesis-related circRNAs and analyze the circRNA-miRNA-mRNA interactions in atherogenesis. The atherogenic mechanisms and clinical relevance of each atherogenesis-related circRNA were systematically discussed for better understanding of the knowledge gap in this area.
Fulltext Quantifying full-length circular RNAs in cancer

Yu KH, Shi CH, Wang B, Chow SH, Chung GT, Lung RW, et al.

Genome Res, 2021 Dec;31(12):2340-2353.
PMID: 34663689 DOI: 10.1101/gr.275348.121

Circular RNAs (circRNAs) are abundantly expressed in cancer. Their resistance to exonucleases enables them to have potentially stable interactions with different types of biomolecules. Alternative splicing can create different circRNA isoforms that have different sequences and unequal interaction potentials. The study of circRNA function thus requires knowledge of complete circRNA sequences. Here we describe psirc, a method that can identify full-length circRNA isoforms and quantify their expression levels from RNA sequencing data. We confirm the effectiveness and computational efficiency of psirc using both simulated and actual experimental data. Applying psirc on transcriptome profiles from nasopharyngeal carcinoma and normal nasopharynx samples, we discover and validate circRNA isoforms differentially expressed between the two groups. Compared with the assumed circular isoforms derived from linear transcript annotations, some of the alternatively spliced circular isoforms have 100 times higher expression and contain substantially fewer microRNA response elements, showing the importance of quantifying full-length circRNA isoforms.
Fulltext Parents are poor at labelling wheeze in children: a cross-sectional study

Shanmugam S, Nathan AM, Zaki R, Tan KE, Eg KP, Thavagnanam S, et al.

BMC Pediatr, 2016 06 23;16:80.
PMID: 27339265 DOI: 10.1186/s12887-016-0616-8

BACKGROUND: Noisy breathing is a common presenting symptom in children. The purpose of this study is to (a) assess parental ability to label wheeze, (b) compare the ability of parents of children with and without asthma to label wheeze and (c) determine factors affecting parental ability to label wheeze correctly.
METHODS: This cross-sectional study in a tertiary hospital in Kuala Lumpur, Malaysia involved parents of children with asthma. Parents of children without asthma were the control group. Eleven validated video clips showing wheeze, stridor, transmitted noises, snoring or normal breathing were shown to the parents. Parents were asked, in English or Malay, "What do you call the sound this child is making?" and "Where do you think the sound is coming from?"
RESULTS: Two hundred parents participated in this study: 100 had children with asthma while 100 did not. Most (71.5 %) answered in Malay. Only 38.5 % of parents correctly labelled wheeze. Parents were significantly better at locating than labelling wheeze (OR 2.4, 95 % CI 1.64-3.73). Parents with asthmatic children were not better at labelling wheeze than those without asthma (OR1.04, 95 % CI 0.59-1.84). Answering in English (OR 3.4, 95 % CI 1.69-7.14) and having older children with asthma (OR 9.09, 95 % CI 3.13-26.32) were associated with correct labelling of wheeze. Other sounds were mislabelled as wheeze by 16.5 % of respondents.
CONCLUSION: Parental labelling of wheeze was inaccurate especially in the Malay language. Parents were better at identifying the origin of wheeze rather than labelling it. Physicians should be wary about parental reporting of wheeze as it may be inaccurate.
Fulltext Identification and characterization of a novel Epstein-Barr Virus-encoded circular RNA from LMP-2 Gene

Tan KE, Ng WL, Marinov GK, Yu KH, Tan LP, Liau ES, et al.

Sci Rep, 2021 Jul 13;11(1):14392.
PMID: 34257379 DOI: 10.1038/s41598-021-93781-w

Epstein-Barr virus (EBV) has been recently found to generate novel circular RNAs (circRNAs) through backsplicing. However, comprehensive catalogs of EBV circRNAs in other cell lines and their functional characterization are still lacking. In this study, we have identified a list of putative EBV circRNAs in GM12878, an EBV-transformed lymphoblastoid cell line, with a significant majority encoded from the EBV latent genes. A novel EBV circRNA derived from the exon 5 of LMP-2 gene which exhibited highest prevalence, was further validated using RNase R assay and Sanger sequencing. This circRNA, which we term circLMP-2_e5, can be universally detected in a panel of EBV-positive cell lines modelling different latency programs. It ranges from lower expression in nasopharyngeal carcinoma (NPC) cells to higher expression in B cells, and is localized to both the cytoplasm and the nucleus. We provide evidence that circLMP-2_e5 is expressed concomitantly with its cognate linear LMP-2 RNA upon EBV lytic reactivation, and may be produced as a result of exon skipping, with its circularization possibly occurring without the involvement of cis elements in the short flanking introns. Furthermore, we show that circLMP-2_e5 is not involved in regulating cell proliferation, host innate immune response, its linear parental transcripts, or EBV lytic reactivation. Taken together, our study expands the current repertoire of putative EBV circRNAs, broadens our understanding of the biology of EBV circRNAs, and lays the foundation for further investigation of their function in the EBV life cycle and disease development.
Fulltext Co-inhibition of BCL-XL and MCL-1 with selective BCL-2 family inhibitors enhances cytotoxicity of cervical cancer cell lines

Abdul Rahman SF, Muniandy K, Soo YK, Tiew EYH, Tan KX, Bates TE, et al.

Biochem Biophys Rep, 2020 Jul;22:100756.
PMID: 32346617 DOI: 10.1016/j.bbrep.2020.100756

Development of resistance to chemo- and radiotherapy in patients suffering from advanced cervical cancer narrows the therapeutic window for conventional therapies. Previously we reported that a combination of the selective BCL-2 family inhibitors ABT-263 and A-1210477 decreased cell proliferation in C33A, SiHa and CaSki human cervical cancer cell lines. As ABT-263 binds to both BCL-2 and BCL-XL with high affinity, it was unclear whether the synergism of the drug combination was driven either by singly inhibiting BCL-2 or BCL-XL, or inhibition of both. In this present study, we used the BCL-2 selective inhibitor ABT-199 and the BCL-XL selective inhibitor A1331852 to resolve the individual antitumor activities of ABT-263 into BCL-2 and BCL-XL dependent mechanisms. A-1210477 was substituted for the orally bioavailable S63845. Four cervical cancer cell lines were treated with the selective BCL-2 family inhibitors ABT-199, A1331852 and S63845 alone and in combination using 2-dimensional (2D) and 3-dimensional (3D) cell culture models. The SiHa, C33A and CaSki cell lines were resistant to single agent treatment of all three drugs, suggesting that none of the BCL-2 family of proteins mediate survival of the cells in isolation. HeLa cells were resistant to single agent treatment of ABT-199 and A1331852 but were sensitive to S63845 indicating that they depend on MCL-1 for survival. Co-inhibition of BCL-2 and MCL-1 with ABT-199 and S63845, inhibited cell proliferation of all cancer cell lines, except SiHa. However, the effect of the combination was not as pronounced as combination of A1331852 and S63845. Co-inhibition of BCL-XL and MCL-1 with A1331852 and S63845 significantly inhibited cell proliferation of all four cell lines. Similar data were obtained with 3-dimensional spheroid cell culture models generated from two cervical cancer cell lines in vitro. Treatment with a combination of A1331852 and S63845 resulted in inhibition of growth and invasion of the 3D spheroids. Collectively, our data demonstrate that the combination of MCL-1-selective inhibitors with either selective inhibitors of either BCL-XL or BCL-2 may be potentially useful as treatment strategies for the management of cervical cancer.
FDA-approved CAR T-cell Therapy: A Decade of Progress and Challenges

Ong MZ, Kimberly SA, Lee WH, Ling M, Lee M, Tan KW, et al.

Curr Pharm Biotechnol, 2024;25(11):1377-1393.
PMID: 39034731 DOI: 10.2174/0113892010257212231001082741

CAR T-cell therapy is a promising approach for cancer treatment, utilizing a patient's own T-cells (autologous cell) or T-cells from a healthy donor (allogeneic cell) to target and destroy cancer cells. Over the last decade, significant advancements have been made in this field, including the development of novel CAR constructs, improved understanding of biology and mechanisms of action, and expanded clinical applications for treating a wider range of cancers. In this review, we provide an overview of the steps involved in the production of CAR T-cells and their mechanism of action. We also introduce different CAR T-cell therapies available, including their implementation, dosage, administration, treatment cost, efficacy, and resistance. Common side effects of CAR T-cell therapy are also discussed. The CAR T-cell products highlighted in this review are FDA-approved products, which include Kymriah® (tisagenlecleucel), Tecartus® (brexucabtagene autoleucel), Abecma® (Idecabtagene vicleucel), Breyanzi® (lisocabtagene maraleucel), and Yescarta® (axicabtagene ciloleucel). In conclusion, CAR T-cell therapy has made tremendous progress over the past decade and has the potential to revolutionize cancer treatment. This review paper provides insights into the progress, challenges, and future directions of CAR T-cell therapy, offering valuable information for researchers, clinicians, and patients.

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