Current Drug Targets - Volume 22, Issue 2, 2021

Skin cancer remains a major cause of mortality worldwide. It can be divided into melanoma and non-melanoma cancer, which comprise mainly squamous cell carcinoma and basal cell carcinoma. Although conventional therapies have ameliorated the management of skin cancer, the search for chemopreventive compounds is still the most effective and safer strategy to treat cancer. Nowadays, chemoprevention is recognized as a novel approach to prevent or inhibit carcinogenesis steps with the use of natural products. Crude extracts of plants and isolated phytocompounds are considered chemopreventive agents since they harbor anti-inflammatory, antioxidant and anti-oncogenic properties against many types of diseases and cancers. In this review, we will discuss the therapeutic effect and preventive potential of selected medicinal plants used as crude extracts or as phytocompounds against melanoma and non-melanoma cutaneous cancers.

Five programmed death-1/programmed death-ligand 1 (PD-L1) inhibitors are currently approved for the treatment of locally advanced or metastatic urothelial carcinoma of the bladder and the upper urinary tract. Following the FDA and EMA restrictions of first-line treatment with Atezolizumab and Pembrolizumab in platinum-ineligible patients, immunohistochemical PD-L1 testing is now required. Several emerging issues on antibodies, test platforms and scoring algorithms have raised concerns about the comparability and interchangeability between these assays. In this review, we have focused on the interchangeability of the used algorithms and assays for PD-L1 testing in urothelial carcinoma, on the predictive reliability of PD-L1 testing in urothelial carcinoma and the potential of other new and upcoming biomarkers.

Epilepsy is one of the most common serious neurological disorders, affecting over 70 million people worldwide. For the treatment of epilepsy, antiepileptic drugs (AEDs) and surgeries are widely used. However, drug resistance and adverse effects indicate the need to develop targeted AEDs based on further exploration of the epileptogenic mechanism. Currently, many efforts have been made to elucidate the neuroinflammation theory in epileptogenesis, which may show potential in the treatment of epilepsy. In this respect, an important target protein, high mobility group box 1 (HMGB1), has received increased attention and has been developed rapidly. HMGB1 is expressed in various eukaryotic cells and localized in the cell nucleus. When HMGB1 is released by injuries or diseases, it participates in inflammation. Recent studies suggest that HMGB1 via Toll-like receptor (TLR) pathways can trigger inflammatory responses and play an important role in epilepsy. In addition, studies of HMGB1 have shown its potential in the treatment of epilepsy. Herein, the authors analyzed the experimental and clinical evidence of the HMGB1-TLR pathway in epilepsy to summarize the theory of epileptogenesis and provide insights into antiepileptic therapy in this novel field.

Extracellular vesicles (EVs) of endocytic origin are known as exosomes. These vesicles are released by cells and are found in biofluids, such as saliva, urine, and plasma. These vesicles are made up of small RNA, DNA, proteins, and play a vital role in many physiological processes. In the central nervous system (CNS), they participate in various physiological processes such as stress of nerve cells, communication between the cells, synaptic plasticity, and neurogenesis. The role of exosomes in depression needs to be explored further. It is known that exosomes can cross the blood brain barrier (BBB), which is made up of glial cells astrocytes. One of the advantages of these vesicles is that they are able to transfer macromolecules like DNA, protein, mRNAs, and miRNAs to recipient cells. This review focuses on the potential role of exosomes in depression and their utilization as a treatment option or diagnostic tool of depression.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has spread worldwide and caused widespread devastation. In the absence of definitive therapy, symptomatic management remains the standard of care. Repurposing of many existing drugs, including several anti-viral drugs, is being attempted to tackle the COVID-19 pandemic. However, most of them have failed to show significant benefit in clinical trials. An attractive approach may be to target host proteases involved in SARS-CoV-2 pathogenesis. The priming of the spike (S) protein of the virus by proteolytic cleavage by the transmembrane serine protease-2 (TMPRSS2) is necessary for the fusion of the virus to the host cell after it binds to its receptor angiotensin converting enzyme-2 (ACE2). There are other proteases with varying spatiotemporal locations that may be important for viral entry and subsequent replication inside the cells, and these include trypsin, furin and cathepsins. In this report, we have discussed the tentative therapeutic role of inhibitors of TMPRSS2, cathepsin, trypsin, furin, plasmin, factor X and elastase in infection caused by SARS-CoV-2. Both available evidence, as well as hypotheses, are discussed, with emphasis on drugs which are approved for other indications such as bromhexine, ammonium chloride, nafamostat, camostat, tranexamic acid, epsilon amino-caproic acid, chloroquine, ulinastatin, aprotinin and anticoagulant drugs. Simultaneously, novel compounds being tested and problems with using these agents are also discussed.

With this article, we would like to take the reader on a journey into the world of molecular medicine as it has evolved over the past decades, enabled by advances in genomics. These findings advanced both the development of prognostic parameters and the evolvement of therapy strategies. In this manuscript, we will present haematopoietic diseases as a prime example of this progress because they are relevant not only for their frequency but also for the evident diagnostic and therapeutic progress. The growing understanding of the underlying pathophysiology originates from the cellular pathology as it was described by, e.g., Rudolf Virchow (1821-1902). The identification of specific genomic changes in haematological malignancies and solid tumour diseases provided us with very sensitive tools for diagnostics and prediction of prognosis. Thus, it paved the way for individualized or personalized therapy. In particular, the rapid development of sequencing techniques for the human genome using Next Generation Sequencing (NGS) has contributed to this progress. Recently, artificial intelligence provided us with the tools to analyze the complex interactions of genomic alterations, course of the disease, and further factors of as yet unknown significance. With all these indisputable improvements, we should not neglect the holistic treatment mandate of personalized therapy, i.e., therapy appropriate to the individual. In this context, the treating physician should address relevant co-morbidities, the psychosocial embedding of the patient and his desire for treatment.

Background: The fibroblast growth factor (FGF) family is comprised of 23 highly regulated monomeric proteins that regulate a plethora of developmental and pathophysiological processes, including tissue repair, wound healing, angiogenesis, and embryonic development. Binding of FGF to fibroblast growth factor receptor (FGFR), a tyrosine kinase receptor, is facilitated by a glycosaminoglycan, heparin. Activated FGFRs phosphorylate the tyrosine kinase residues that mediate induction of downstream signaling pathways, such as RAS-MAPK, PI3K-AKT, PLCγ, and STAT. Dysregulation of the FGF/FGFR signaling occurs frequently in cancer due to gene amplification, FGF activating mutations, chromosomal rearrangements, integration, and oncogenic fusions. Aberrant FGFR signaling also affects organogenesis, embryonic development, tissue homeostasis, and has been associated with cell proliferation, angiogenesis, cancer, and other pathophysiological changes. Objective: This comprehensive review will discuss the biology, chemistry, and functions of FGFs, and its current applications toward wound healing, diabetes, repair and regeneration of tissues, and fatty liver diseases. In addition, specific aberrations in FGFR signaling and drugs that target FGFR and aid in mitigating various disorders, such as cancer, are also discussed in detail. Conclusion: Inhibitors of FGFR signaling are promising drugs in the treatment of several types of cancers. The clinical benefits of FGF/FGFR targeting therapies are impeded due to the activation of other RTK signaling mechanisms or due to the mutations that abolish the drug inhibitory activity on FGFR. Thus, the development of drugs with a different mechanism of action for FGF/FGFR targeting therapies is the recent focus of several preclinical and clinical studies.

Fibrotic strictures are one of the most severe complications of Crohn’s Disease (CD). They occur in about 50% of patients at five years and in 70% at ten years of the diagnosis. The only treatment available for symptomatic fibrotic strictures is surgical resection and endoscopic dilation. Both strategies are associated with a high rate of recurrence, and with multiple surgical resections, which pose the threat of surgical morbidity and short bowel syndrome. Therefore, it is crucial to identify, early, the patients more prone to develop intestinal fibrosis to intensify follow-ups, switch to more aggressive treatments, and suggest lifestyle modifications. Scarce data are available concerning biomarkers and genetic determinants to predict which patient will develop intestinal fibrosis. Biologic or clinical markers would be useful to determine this subgroup of CD patients and to predict the onset of intestinal fibrosis and, ideally, its severity. Furthermore, the identification of environmental risk factors may suggest lifestyle changes aimed at modifying the natural course, thus decreasing the risk of complicated CD. In this review, we will critically revise clinical, environmental, genetic, and serologic factors that have been associated with a complicated CD course with a particular focus on the fibrostenosing phenotype and their possible implications as predictive factors of intestinal fibrosis.