Aberrant Expression of FGFRL1 in Esophageal Cancer and Its Regulation by miR-107.

BACKGROUND: Fibroblast growth factor receptors are growth factor receptor tyrosine kinases, exerting their roles in embryogenesis, tissue homeostasis, and development of cancer. However, little is known about the expression and function of FGFRL1 in esophageal cancer (EC). METHODS: We systematically evaluated the expression of FGFRL1 in TCGA and GETex datasets followed by expression analysis in EC cell lines and clinical specimens using immunofluorescence (IF) and immunohistochemistry (IHC) respectively. RESULTS: GEPIA analysis on TCGA and GETex datasets identified significant upregulation of FGFRL1 in EC patients (n=182) compared to normal controls (n=286, p<0.05). IHC analysis showed significantly higher FGFRL1 expression in EC tissues as compared to the distant matched non-malignant tissues (p<0.001).  Immunoflourescence in EC cells suggested increased expression of FGFRL1 from WDSCC (KYSE30) to MDSCC (KYSE140) and finally to PDSCC (KYSE410). In-silico tools predicted miR-107 as most significant miRNA regulating FGFRL1 expression. qRT-PCR revealed miR-107 expression to be significantly and inversely correlated with FGFRL1 expression in 73% (22/30) EC tissues (p=0.015) and over-expression of miR-107 resulted in significantly decreased expression of FGFRL1 at mRNA (fold change=0.11, p=0.0016) as well as protein level in miR-107 versus NC treated cells. Luciferase reporter assay using FGFRL1-3'UTR further confirmed it to be a direct target of miR-107. CONCLUSION: Our results herein document clinical as well as functional relevance of FGFRL1 in EC and its regulation by miR-107.

Different Efflux Pump Systems in Acinetobacter baumannii and Their Role in Multidrug Resistance.

Several infections, such as pneumonia, urinary tract infections (UTIs), as well as bloodstream, skin, and soft tissue infections, are caused by Acinetobacter baumannii, a nosocomial pathogen and Gram-negative coccobacillus. Due to its resistance to a variety of medications, multidrug therapy, and occasionally pan therapies, this bacterium is a huge public health concern. Drug resistance is a big worry not only in A. baumannii, but it is also a major challenge in many other diseases. Antibiotic resistance, biofilm development, and genetic alterations are all linked to variables like the efflux pump. Efflux pumps are transport proteins involved in the extrusion of hazardous substrates from within cells into the external environment (including nearly all types of therapeutically relevant antibiotics). Both Gram-positive and Gram-negative bacteria, as well as eukaryotic organisms, contain these proteins. Efflux pumps may be specialized for a single substrate or can transport a variety of structurally dissimilar molecules (including antibiotics of many classes); these pumps have been linked to multiple drug resistance (MDR). There are five primary families of efflux transporters in the prokaryotic kingdom: MF (major facilitator), MATE (multidrug and toxic efflux), RND (resistance-nodulation-division), SMR (small multidrug resistance), and ABC (ATP-binding cassette). The efflux pumps and their types as well as the mechanisms of an efflux pump involved in multidrug resistance in bacteria have been discussed here. The main focus is on the variety of efflux pumps commonly found in A. baumannii, along with their mechanism by which they make this bacteria drug resistant. The efflux-pump-inhibitor-based strategies that are significant in targeting efflux pumps in A. baumannii have also been discussed. The connection of biofilm and bacteriophage with the efflux pump can prove as an efficient strategy for targeting efflux-pump-based resistance in A. baumannii.

Interaction of RecA mediated SOS response with bacterial persistence, biofilm formation, and host response.

Antibiotics have a primary mode of actions, and most of them have a common secondary mode of action via reactive species (ROS and RNS) mediated DNA damage. Bacteria have been able to tolerate this DNA damage by SOS (Save-Our-Soul) response. RecA is the universal essential key protein of the DNA damage mediated SOS repair in various bacteria including ESKAPE pathogens. In addition, antibiotics also triggers activation of various other bacterial mechanisms such as biofilm formation, host dependent responses, persister subpopulation formation. These supporting the survival of bacteria in unfriendly natural conditions i.e. antibiotic presence. This review highlights the detailed mechanism of RecA mediated SOS response as well as role of RecA-LexA interaction in SOS response. The review also focuses on inter-connection between DNA damage repair pathway (like SOS response) with other survival mechanisms of bacteria such as host mediated RecA induction, persister-SOS interplay, and biofilm-SOS interplay. This understanding of inter-connection of SOS response with different other survival mechanisms will prove beneficial in targeting the SOS response for prevention and development of therapeutics against recalcitrant bacterial infections. The review also covers the significance of RecA as a promising potent therapeutic target for hindering bacterial SOS response in prevailing successful treatments of bacterial infections and enhancing the conventional antibiotic efficiency.

Antipersister strategies against stress induced bacterial persistence.

The increase in antibiotic non-responsive bacteria is the leading concern in current research oriented to eliminate pathogens. Nowadays, the excess use of antibiotics without specifically understanding the potentiality of killing pathogens and bacterial survival patterns has helped bacteria emerge indefatigably. Bacteria use various mechanisms such as resistance, persistence, and tolerance to ensure survival. Among these, persistence is a mechanism by which bacteria reside in their dormant state, bypassing the effects of treatments, making it crucial for bacterial survival. Persistent bacterial cells arise from the normal bacterial population as a slow-growing subset of bacteria with no metabolic flux. This behavior renders it to survive for a longer duration and at higher concentrations of antibiotics. They are one of the underlying causes of recurrence of bacterial infections. The present article explains the detailed molecular mechanisms and strategies of bacterial persistence, including the toxin-antitoxin modules, DNA damage, the formation of inactive ribosomal complexes, (p)ppGpp network, antibiotic-induced persistence, which are triggered by drug-induced stress. The article also comprehensively covers the epigenetic memory of persistence in bacteria, and anti-persistent therapeutics like antimicrobial molecules, synthetic peptides, acyldepsipeptide antibiotics, and endolysin therapy to reduce persister cell formation and control their frequency. These strategies could be utilized in combating the pathogenic bacteria undergoing persistence.

Therapeutic strategies against potential antibiofilm targets of multidrug-resistant Acinetobacter baumannii.

Acinetobacter baumannii is the causative agent of various hospital-acquired infections. Biofilm formation is one of the various antimicrobial resistance (AMR) strategies and is associated with high mortality and morbidity. Hence, it is essential to review the potential antibiofilm targets in A. baumannii and come up with different strategies to combat these potential targets. This review covers different pathways involved in the regulation of biofilm formation in A. baumannii like quorum sensing (QS), cyclic-di-GMP signaling, two-component system (TCS), outer-membrane protein (ompA), and biofilm-associated protein (BAP). A newly discovered mechanism of electrical signaling-mediated biofilm formation and contact-dependent biofilm modulation has also been discussed. As biofilm formation and its maintenance in A. baumannii is facilitated by these potential targets, the detailed study of these targets and pathways can bring light to different therapeutic strategies such as anti-biofilm peptides, natural and synthetic molecule inhibitors, QS molecule degrading enzymes, and other strategies. These strategies may help in suppressing the lethality of biofilm-mediated infections. Targeting essential proteins/targets which are crucial for biofilm formation and regulation may render new therapeutic strategies that can aid in combating biofilm, thus reducing the recalcitrant infections and morbidity associated with the biofilm of A. baumannii.