Current Drug Targets - Volume 21, Issue 13, 2020

The detection of the Programmed Death Ligand 1 (PD-L1) protein by immunohistochemistry is currently the only approved test predictive of response to drugs targeting the PD1/PDL1 axis. The role of this test is debated since several reagents have been used as companion diagnostics for different drugs on diverse immunostaining platforms. In addition, different scoring systems for PD-L1 immunohistochemistry have been applied in the registration studies regarding single drugs. This review deals with the various issues that are related to the immunohistochemical test for PD-L1. We discuss currently unsolved problems such as the advantages and the flaws of PD-L1 immunohistochemistry; the choice of the best reagents and the best scoring system. Finally, we review the current experiences on the role of immunohistochemistry for PD-L1 in clinical trials with immune checkpoint inhibitors.

The immune system is important to control tumor development and progression in humans. However, tumor cells and cells of the tumor microenvironment can induce immune escape mechanisms including activation of immune checkpoints such as PD-1/PD-L1. Based on this knowledge, new immune therapies, including PD-1 and PD-L1 inhibition, have been developed and are already recommended as a standard treatment in metastatic bladder and kidney cancer patients. In addition to its role as a therapeutic target, PD-L1 seems to be a prognostic parameter although data are controversial. Only little is known about signaling pathways inducing PD-L1 expression in tumor cells on one hand and about its functional role for tumor cells itself. However, the understanding of the complex biological function of PD-L1 will improve therapeutic options in urological malignancies. This review is giving an overview of the current knowledge concerning the PD-1/PD-L1 axis in urological tumors including bladder, kidney, prostate, testicular and penile cancer.

Wound research is an evolving science trying to unfold the complex untold mechanisms behind the wound healing cascade. In particular, interest is growing regarding the role of microorganisms in both acute and chronic wound healing. Microbial burden plays an important role in the persistence of chronic wounds, ultimately resulting in delayed wound healing. It is therefore important for clinicians to understand the evolution of infection science and its various etiologies. Therefore, to understand the role of bacterial biofilm in chronic wound pathogenesis, various in vitro and in vivo models are required to investigate biofilms in wound-like settings. Infection models should be refined comprising an important signet of biofilms. These models are eminent for translational research to obtain data for designing an improved wound care formulation. However, all the existing models possess limitations and do not fit properly in the model frame for developing wound care agents. Among various impediments, one of the major drawbacks of such models is that the wound they possess does not mimic the wound a human develops. Therefore, a novel wound infection model is required which can imitate the human wounds. This review article mainly discusses various in vitro and in vivo models showing microbial colonization, their advantages and challenges. Apart from these models, there are also present ex vivo wound infection models, but this review mainly focused on various in vitro and in vivo models available for studying wound infection in controlled conditions. This information might be useful in designing an ideal wound infection model for developing an effective wound healing formulation.

Background: The ubiquitin-proteasome pathway is crucial for all cellular processes and is, therefore, a critical target for the investigation and development of novel strategies for cancer treatment. In addition, approximately 30% of newly synthesized proteins never attain their final conformations due to translational errors or defects in post-translational modifications; therefore, they are also rapidly eliminated by the ubiquitin-proteasome pathway. Objective: Here, an effort was made to outline the recent findings deciphering the new molecular mechanisms involved in the regulation of ubiquitin-proteasome pathway as well as the resistance mechanisms developed against proteasome inhibitors in cell culture experiments and in the clinical trials. Results: Since cancer cells have higher proliferation rates and are more prone to translational errors, they require the ubiquitin-proteasome pathway for selective advantage and sustained proliferation. Therefore, drugs targeting the ubiquitin-proteasome pathway are promising agents for the treatment of both hematological and solid cancers. Conclusion: A number of proteasome inhibitors are approved and used for the treatment of advanced and relapsed multiple myeloma. Unfortunately, drug resistance mechanisms may develop very fast within days of the start of the proteasome inhibitor-treatment either due to the inherent or acquired resistance mechanisms under selective drug pressure. However, a comprehensive understanding of the mechanisms leading to the proteasome inhibitor-resistance will eventually help the design and development of novel strategies involving new drugs and/or drug combinations for the treatment of a number of cancers.

Iron, which is described as the most basic component found in nature, is hard to be assimilated by microorganisms. It has become increasingly complicated to obtain iron from nature as iron (II) in the presence of oxygen oxidized to press (III) oxide and hydroxide, becoming unsolvable at neutral pH. Microorganisms appeared to produce organic molecules known as siderophores in order to overcome this condition. Siderophore's essential function is to connect with iron (II) and make it dissolvable and enable cell absorption. These siderophores, apart from iron particles, have the ability to chelate various other metal particles that have collocated away to focus the use of siderophores on wound care items. There is a severe clash between the host and the bacterial pathogens during infection. By producing siderophores, small ferric iron-binding molecules, microorganisms obtain iron. In response, host immune cells produce lipocalin 2 to prevent bacterial reuptake of siderophores loaded with iron. Some bacteria are thought to produce lipocalin 2-resistant siderophores to counter this risk. The aim of this article is to discuss the recently described roles and applications of bacterial siderophore.

Schizophrenia is one of the most debilitating mental disorders around the world. It is characterized by neuroanatomical or biochemical changes. The role of the fibroblast growth factors (FGFs) system in schizophrenia has received considerable attention in recent years. Various changes in the gene expression and/or level of FGFs have been implicated in the etiology, symptoms and progression of schizophrenia. For example, studies have substantiated an interaction between FGFs and the signaling pathway of dopamine receptors. To understand the role of this system in schizophrenia, the databases of Open Access Journals, Web of Science, PubMed (NLM), LISTA (EBSCO), and Google Scholar with keywords including fibroblast growth factors, dopamine, schizophrenia, psychosis, along with neurotrophic were searched. In conclusion, the FGF family represent molecular candidates as new drug targets and treatment targets for schizophrenia.

Fluoroquinolones are one of the world’s most valuable and popularly used categories of antimicrobial agents. This paper attempts to review the substantial progress of fluoroquinolones from their discovery to black box warning. Antibiotic drug choice will remain difficult in the presence of increasing resistance, but the introduction of fluoroquinolones has created a new and exciting era in antimicrobial treatment. These are a synthetic heterogeneous group of compounds used in both hospital and community practices to treat numerous severe infections. The era of quinolone antibiotics began with the serendipitous discovery of the quinolone prototype in 1962. The chronological development of fluoroquinolone reported that nalidixic acid was the first quinolone that gained popular choice for the treatment of urinary tract infection. The subsequent agents like levofloxacin, ofloxacin, norfloxacin, gatifloxacin, moxifloxacin, clinafloxacin, sparfloxacin, and ciprofloxacin were derived through side chain and nuclear manipulation from basic pharmacophore. The fluoroquinolone motifs have been found as a milestone, effective in certain infections that are respiratory tract infection, urinary tract infection, bone disorders, meningococcal and mycobacterial infections, sexually transmitted diseases, skin infections, etc. Fluoroquinolones are first entirely man-made antibiotics that exhibit antibacterial activity through the inhibition of topoisomerase II, topoisomerase IV and deoxyribonucleic acid gyrase, which is vital for chromosome replication and function. The post-marketing surveillance pointed out the favorable side effects associated with fluoroquinolones such as phototoxicity, QT interval prolongation and anaphylaxis. The discovery, development and clinical use of fluoroquinolone antibiotics in the last century contributed to a decline in morbidity and mortality rates.

Defects in brain functions associated with aging and neurodegenerative diseases benefit insignificantly from existing options, suggesting that there is a lack of understanding of pathological mechanisms. Alzheimer’s disease (AD) is such a nearly untreatable, allied to age neurological deterioration for which only the symptomatic cure is available and the agents able to mould progression of the disease, is still far away. The altered expression of phosphodiesterases (PDE) and deregulated cyclic nucleotide signaling in AD has provoked a new thought of targeting cyclic nucleotide signaling in AD. Targeting cyclic nucleotides as an intracellular messenger seems to be a viable approach for certain biological processes in the brain and controlling substantial. Whereas, the synthesis, execution, and/or degradation of cyclic nucleotides has been closely linked to cognitive deficits. In relation to cognition, the cyclic nucleotides (cAMP and cGMP) have an imperative execution in different phases of memory, including gene transcription, neurogenesis, neuronal circuitry, synaptic plasticity and neuronal survival, etc. AD is witnessed by impairments of these basic processes underlying cognition, suggesting a crucial role of cAMP/cGMP signaling in AD populations. Phosphodiesterase inhibitors are the exclusive set of enzymes to facilitate hydrolysis and degradation of cAMP and cGMP thereby, maintains their optimum levels initiating it as an interesting target to explore. The present work reviews a neuroprotective and substantial influence of PDE inhibition on physiological status, pathological progression and neurobiological markers of AD in consonance with the intensities of cAMP and cGMP.

Berberine (Brb) is one of the well-known naturally occurring compounds exclusively found in Berberis vulgaris and other members of this family, such as Berberis aristata, Berberis aroatica, and Berberis aquifolium. This plant-derived natural compound has a variety of therapeutic impacts, including anti-oxidant, anti-inflammatory, anti-diabetic, and anti-tumor. Multiple studies have demonstrated that Brb has great anti-inflammatory activity and is capable of reducing the levels of proinflammatory cytokines, while it enhances the concentrations of anti-inflammatory cytokines, making it suitable for the treatment of inflammatory disorders. Colitis is an inflammatory bowel disease with chronic nature. Several factors are involved in the development of colitis and it appears that inflammation and oxidative stress are the most important ones. With respect to the anti-inflammatory and antioxidant effects of Brb, its administration seems to be beneficial in the treatment of colitis. In the present review, the protective effects of Brb in colitis treatment and its impact on molecular pathways are discussed.