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Gene Therapy and Small Molecules Used in the Treatment of Cystic Fibrosis
Published in Yashwant Pathak, Gene Delivery, 2022
Manish P. Patel, Uma G. Daryai, Mansi N. Athalye, Praful D. Bharadia, Jayvadan Patel
As the CFTR gene is responsible for secretion of bicarbonate and chloride, it works as a chloride-bicarbonate exchanger and is known to have an exchange of one chloride molecule for two bicarbonate molecules by the apical chloride-bicarbonate exchanger in the SLC26 family. In addition to direct conductance of ions through CFTR, local pH affects the proteins that act on different ion channels, and most specifically in the airways (Borowitz, 2015). Normal airway surface liquid (ASL) has a pH of around 7.0, with the bicarbonate concentration of 10 to 20 mMol. The literature describes the evidence that airway surface liquid pH is controlled by bicarbonate secretion via CFTR and other secreted proteins. Airways clearances are also affected by changes in pH, based on the observation that transient acidification of normal airway surface liquid increases the rate of airway surface liquid absorption by the epithelia, while alkalinization of airway surface liquid leads to a slowing of airway surface liquid absorption and transiently restores airway surface liquid height into the normal range. Thus an epithelial sodium channel (ENaC) plays a major role in ionic content and fluid on the airway epithelial surface (Borowitz, 2015). Prostasin, a membrane-anchored serine protease with a trypsin-like substrate specificity, is required to activate ENaC but is inactive below pH 7.0. Another regulatory protein is a short palate lung and nasal epithelial clone 1 (SPLUNC1, also known as BPIFA1) that has been shown to be a pH-sensitive regulator of ENaC that is not able to inhibit ENaC within the acidic cystic fibrosis airway environment (Garland et al., 2013). Hence, CFTR is responsible for controlling ENaC by regulating the local acid–base balance. Hence, both the gastrointestinal tract and airways are responsible for bicarbonate secretion, which regulates ionic content and fluid secretion on the epithelial surfaces (Borowitz, 2015). Although the ‘low volume’ hypothesis, (Boucher, 2007) suggests that decrease in the transepithelial chloride transport due to mutated CFTR and increase in transepithelial sodium absorption due to lack of CFTR-dependent inhibition of the epithelial sodium channel leads to an increase in water absorption into the tissue and, therefore, decreases airway surface liquid and mucociliary clearance (Uta Griesenbach, Pytel, and Alton, 2015). The work of chloride secretion is not only limited to CFTR—calcium-dependent chloride channels but it may also act as alternative channels if CFTR is non-functioning. There are at minimum two agents that stimulate this secretion, which are in clinical trials. Denufosol has been shown to stimulate chloride secretion (Accurso et al., 2008). The other drug is Lancovutide or Moli1901, which has been shown to improve Nasal Potential Difference (NPD) when applied to the nasal epithelium (Grasemann et al., 2007).
Current status of sperm functional genomics and its diagnostic potential of fertility in bovine (Bos taurus)
Published in Systems Biology in Reproductive Medicine, 2018
Sellappan Selvaraju, Sivashanmugam Parthipan, Lakshminarayana Somashekar, B. Krishnan Binsila, Atul P. Kolte, Arunachalam Arangasamy, Janivara Parameshwaraiah Ravindra, Stephen A. Krawetz
Microbiome and metagenomic evolutionary studies have emphasized the importance of microbial diversity in physiological function (Doyle et al. 2017). The semen-associated microbiome is highly diverse among individuals and may correlate with semen quality (Hou et al. 2013). It is likely a factor in male infertility (Wang et al. 2014) balanced by the antimicrobial activities of spermatozoa. This may be achieved through the use of the bactericidal/permeability-increasing protein (BPI), BPIFA2A, BPIFA2B, BPIFB1, BPIFB3, and BPIFA1 transcripts encoding the antimicrobial activity. A preliminary study from the ICAR-National Institute of Animal Nutrition and Physiology, Animal Physiology Division, Reproductive Physiology Laboratory has revealed that the level (reads per kilobase million, RPKM) of BPIFA2A, BPIFB1, and BPIFB5 is significantly (p < 0.05) different between high and low fertile bulls.
Microvesicles as promising biological tools for diagnosis and therapy
Published in Expert Review of Proteomics, 2018
Isabella Panfoli, Laura Santucci, Maurizio Bruschi, Andrea Petretto, Daniela Calzia, Luca A. Ramenghi, Gianmarco Ghiggeri, Giovanni Candiano
The first global 1-D SDS-PAGE and nano-LC-MS/MS proteomic analyses of highly purified MVs derived from human colorectal cancer (CRC) ascites identified a total of 846 MV’s proteins among which proteins promoting tumor progression as well as several potential diagnostic markers of CRC [47]. A systematic protein profiling of salivary MVs from normal subjects and lung cancer patients was conducted by LC-MS/MS-based label-free quantification. Out of 243 proteins as highlighted as dysregulated in the salivary MVs, 40 were found to originate from distal organ of lung cancer patients, 9 of which were lung-expressed proteins, suggesting that MV proteomic analysis is a promising tool for the noninvasive detection of lung cancer [48]. Among salivary MVs proteins, BPI fold-containing family A member 1 (BPIFA1, involved in the innate immunity responses) and Cornulin (CRNN, a survival factor involved in apoptosis) displayed significant difference between cancer group and controls. Interestingly, it was concluded that salivary MVs are a more specific source of lung cancer biomarkers [48].