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Fulltext Therapeutic potential of coumarins as antiviral agents

Hassan MZ, Osman H, Ali MA, Ahsan MJ

Eur J Med Chem, 2016 Nov 10;123:236-255.
PMID: 27484512 DOI: 10.1016/j.ejmech.2016.07.056

Coumarins have received a considerable attention in the last three decades as a lead structures for the discovery of orally bioavailable non-peptidic antiviral agents. A lot of structurally diverse coumarins analogues were found to display remarkable array of affinity with the different molecular targets for antiviral agents and slight modifications around the central motif result in pronounced changes in its antiviral spectrum. This manuscript thoroughly reviews the design, discovery and structure-activity relationship studies of the coumarin analogues as antiviral agents focusing mainly on lead optimization and its development into clinical candidates.

Matched MeSH terms: Molecular Targeted Therapy
Fulltext Therapeutic radionuclides in nuclear medicine: current and future prospects

Yeong CH, Cheng MH, Ng KH

J Zhejiang Univ Sci B, 2014 Oct;15(10):845-63.
PMID: 25294374 DOI: 10.1631/jzus.B1400131

The potential use of radionuclides in therapy has been recognized for many decades. A number of radionuclides, such as iodine-131 ((131)I), phosphorous-32 ((32)P), strontium-90 ((90)Sr), and yttrium-90 ((90)Y), have been used successfully for the treatment of many benign and malignant disorders. Recently, the rapid growth of this branch of nuclear medicine has been stimulated by the introduction of a number of new radionuclides and radiopharmaceuticals for the treatment of metastatic bone pain and neuroendocrine and other malignant or non-malignant tumours. Today, the field of radionuclide therapy is enjoying an exciting phase and is poised for greater growth and development in the coming years. For example, in Asia, the high prevalence of thyroid and liver diseases has prompted many novel developments and clinical trials using targeted radionuclide therapy. This paper reviews the characteristics and clinical applications of the commonly available therapeutic radionuclides, as well as the problems and issues involved in translating novel radionuclides into clinical therapies.

Matched MeSH terms: Molecular Targeted Therapy/trends*
Translational genomics and recent advances in oral squamous cell carcinoma

Chai AWY, Lim KP, Cheong SC

Semin Cancer Biol, 2020 04;61:71-83.
PMID: 31542510 DOI: 10.1016/j.semcancer.2019.09.011

Oral squamous cell carcinomas (OSCC) are a heterogeneous group of cancers arising from the mucosal lining of the oral cavity. A majority of these cancers are associated with lifestyle risk habits including smoking, excessive alcohol consumption and betel quid chewing. Cetuximab, targeting the epidermal growth factor receptor was approved for the treatment of OSCC in 2006, and remains the only molecular targeted therapy available for OSCC. Here, we reviewed the current findings from genomic analyses of OSCC and discuss how these studies inform on the biological mechanisms underlying OSCC. Exome sequencing revealed that the significantly mutated genes are mainly tumour suppressors. Mutations in FAT1, CASP8, CDKN2A, and NOTCH1 are more frequently found in OSCC when compared to non-OSCC head and neck cancers and other squamous cell carcinomas, and HRAS and PIK3CA are the only significantly mutated oncogenes. The distribution of these mutations also differs in populations with distinct risk habits. Gene expression-based molecular classification showed that OSCC can be divided into distinct subtypes and these have a preferential response to different types of therapies, suggesting that these classifications could have clinical implications. More recently, with the approval of checkpoint inhibitors for the treatment of cancers including OSCC, genomics studies also dissected the genetic signatures of the immune compartment to delineate immune-active and -exhausted subtypes that could inform on the immune status of OSCC patients and guide the development of novel therapies to improve response to immunotherapy. Taken together, genomics studies are informing on the biology of both the epithelial and stromal compartments underlying OSCC development, and we discuss the opportunities and challenges in using these to derive clinical benefit for OSCC patients.

Matched MeSH terms: Molecular Targeted Therapy
Try to Remember: Interplay between Memory and Substance Use Disorder

Mohamed RMP, Kumar J, Yap E, Mohamed IN, Sidi H, Adam RL, et al.

Curr Drug Targets, 2019;20(2):158-165.
PMID: 28641520 DOI: 10.2174/1389450118666170622092824

Memories associated with substance use disorders, or substance-associated cues increase the likelihood of craving and relapse during abstinence. There is a growing consensus that manipulation of synaptic plasticity may reduce the strength of substance abuse-related memories. On the biological front, there are new insights that suggest memories associated with substance use disorder may follow unique neurobiological pathways that render them more accessible to pharmacological intervention. In parallel to this, research in neurochemistry has identified several potential candidate molecules that could influence the formation and maintenance of long-term memory. Drugs that target these molecules (blebbistatin, isradipine and zeta inhibitory peptide) have shown promise at the preclinical stage. In this review, we shall provide an overview of the evolving understanding on the biochemical mechanisms involved in memory formation and expound on the premise that substance use disorder is a learning disorder.

Matched MeSH terms: Molecular Targeted Therapy
Tumor regression and modulation of gene expression via tumor-targeted tocotrienol niosomes

Tan DM, Fu JY, Wong FS, Er HM, Chen YS, Nesaretnam K

Nanomedicine (Lond), 2017 Oct;12(20):2487-2502.
PMID: 28972460 DOI: 10.2217/nnm-2017-0182

AIM: To develop 6-O-palmitoyl-ascorbic acid-based niosomes targeted to transferrin receptor for intravenous administration of tocotrienols (T3) in breast cancer.
MATERIALS & METHODS: Niosomes were prepared using film hydration and ultrasonication methods. Transferrin was coupled to the surface of niosomes via chemical linker. Nanovesicles were characterized for size, zeta potential, morphology, stability and biological efficacy.
RESULTS: When evaluated in MDA-MB-231 cells, entrapment of T3 in niosomes caused 1.5-fold reduction in IC50 value compared with nonformulated T3. In vivo, the average tumor volume of mice treated with tumor-targeted niosomes was 12-fold lower than that of untreated group, accompanied by marked downregulation of three genes involved in metastasis.
CONCLUSION: Findings suggested that tumor-targeted niosomes served as promising delivery system for T3 in cancer therapy.

Matched MeSH terms: Molecular Targeted Therapy/methods
sFRP-mediated Wnt sequestration as a potential therapeutic target for Alzheimer's disease

Warrier S, Marimuthu R, Sekhar S, Bhuvanalakshmi G, Arfuso F, Das AK, et al.

Int J Biochem Cell Biol, 2016 06;75:104-11.
PMID: 27063405 DOI: 10.1016/j.biocel.2016.04.002

The extracellular ligand, Wnt, and its receptors are involved in sign al transduction and play an important role in axis formation and neural development. In neurodegenerative disorders such as Alzheimer's disease (AD), a decrease of the intracellular Wnt effector, β-catenin, has been linked to amyloid-β-peptide-induced neurotoxicity. Despite this knowledge, targeting Wnt inhibitors as potential biomarkers has not been explored, and harnessing Wnt activators as therapeutic candidates remains largely not investigated. A wide acting family of Wnt mediators, secreted frizzled-related proteins (sFRPs), has not been probed so far as molecular indicators of disease occurrence and progression of Alzheimer's. Unlike the effect of the Dickkopf (DKK) family of Wnt antagonists on AD, the sFRP molecules have a more pleiotropic impact on the Wnt signaling cascade and probably have a far-reaching involvement in neurodegeneration. The role of sFRPs has been poorly described in AD, and in this review, we analyze the present status of the role of sFRPs on neurodegeneration, their likely involvement, and potential implications in treatment modalities of AD. This information would provide valuable clues for the development of potential therapeutic targets for aberrant neurodegenerative disorders.

Matched MeSH terms: Molecular Targeted Therapy/methods*
Fulltext scFv antibody: principles and clinical application

Ahmad ZA, Yeap SK, Ali AM, Ho WY, Alitheen NB, Hamid M

Clin. Dev. Immunol., 2012;2012:980250.
PMID: 22474489 DOI: 10.1155/2012/980250

To date, generation of single-chain fragment variable (scFv) has become an established technique used to produce a completely functional antigen-binding fragment in bacterial systems. The advances in antibody engineering have now facilitated a more efficient and generally applicable method to produce Fv fragments. Basically, scFv antibodies produced from phage display can be genetically fused to the marker proteins, such as fluorescent proteins or alkaline phosphatase. These bifunctional proteins having both antigen-binding capacity and marker activity can be obtained from transformed bacteria and used for one-step immunodetection of biological agents. Alternatively, antibody fragments could also be applied in the construction of immunotoxins, therapeutic gene delivery, and anticancer intrabodies for therapeutic purposes. This paper provides an overview of the current studies on the principle, generation, and application of scFv. The potential of scFv in breast cancer research is also discussed in this paper.

Matched MeSH terms: Molecular Targeted Therapy