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Bronchiolitis obliterans syndrome (BOS) is the most morbid form of chronic graft-versus-host disease (cGVHD) after hematopoietic cell transplantation (HCT). Progressive airway fibrosis leads to a five-year survival of 40%. Treatment options for BOS are limited. A single arm, 52-week, Phase I study of pirfenidone was conducted. The primary outcome was tolerability defined as maintaining the recommended dose of pirfenidone (2403mg/day) without a dose reduction totaling more than 21 days, due to adverse events (AEs) or severe AEs (SAEs). Secondary outcomes included pulmonary function tests (PFTs) and patient reported outcomes (PROs). Among 22 participants treated for 1-year, 13 (59%) tolerated the recommended dose, with an average daily tolerated dose of 2325.6 mg/day. Twenty-two SAEs were observed, with 90.9% related to infections, none were attributed to pirfenidone. There was an increase in the average percent predicted forced expiratory volume in 1 second (FEV(1)%) of 7 percentage points annually and improvements in PROs related to symptoms of cGVHD. In this Phase I study, treatment with pirfenidone was safe. The stabilization in PFTs and improvements in PROs suggest the potential of pirfenidone for BOS treatment and support the value of a randomized controlled trial to evaluate the efficacy of pirfenidone in BOS after HCT. CLINICAL TRIAL REGISTRATION: The study is registered in ClinicalTrials.gov (NCT03315741).

Nikkomycin Z (nikZ) is a chitin synthase inhibitor. Efficacy against Coccidioides has been demonstrated in animal models of pulmonary or brain infection. Its short half-life in mice and in humans would necessitate divided daily dosing. We assayed nikZ efficacy in disseminated coccidioidomycosis (in a reduction of CFU design) and whether sustained release might be useful. Mice were challenged intravenously with low or high arthroconidial inocula. Fluconazole, clinically the most commonly used anticoccidioidal drug, was compared (gavage) at high dose to a dose range of nikZ administered intraperitoneally or, to mimic sustained release, administered continuously in drinking water. Therapy was given for 5 days. In vitro, both fluconazole and nikZ inhibited the isolate studied; nikZ was fungicidal. Oral nikZ therapy gave similar results to intraperitoneal nikZ and sterilized infection in most animals after low-inoculum challenge. In both challenges, oral nikZ produced greater reduction of CFU in organs (lung, liver, and spleen) than fluconazole. Oral nikZ doses of ≥200 mg/kg of body weight/day were particularly effective in all organs and were well tolerated. This efficacy occurred even though, after severe challenge, mice had reduced water intake, resulting in ingesting less than the desired dose, particularly initially after infection. This study shows, for the first time, efficacy of nikZ against disseminated coccidioidomycosis. Efficacy was shown after challenges producing different levels of severity of disease. This study also suggests the likely benefits of developing an extended release formulation supplying continuous systemic concentrations of nikZ.

The apelinergic system is widely expressed and acts through autocrine and paracrine signaling to exert protective effects, including vasodilatory, metabolic, and inotropic effects on the cardiovascular (CV) system. The apelin pathway’s dominant physiological role has delineated therapeutic implications for coronary artery disease, heart failure (HF), aortic aneurysm, pulmonary arterial hypertension (PAH), and transplant vasculopathy. Apelin peptides interact with the renin–angiotensin system (RAS) by promoting angiotensin converting enzyme 2 (ACE2) transcription leading to increased ACE2 protein and activity while also antagonizing the effects of angiotensin II (Ang II). Apelin modulation of the RAS by increasing ACE2 action is limited due to its rapid degradation by proteases, including ACE2, neprilysin (NEP), and kallikrein. Apelin peptides are hence tightly regulated in a negative feedback manner by ACE2. Plasma apelin levels are suppressed in pathological conditions, but its diagnostic and prognostic utility requires further clinical exploration. Enhancing the beneficial actions of apelin peptides and ACE2 axes while complementing existing pharmacological blockade of detrimental pathways is an exciting pathway for developing new therapies. In this review, we highlight the interaction between the apelin and ACE2 systems, discuss their pathophysiological roles and potential for treating a wide array of CV diseases (CVDs).

Airways of immunocompromised patients, or individuals with cystic fibrosis (CF), are common ground for Pseudomonas aeruginosa and Aspergillus fumigatus infections. Hence, in such a microenvironment both pathogens compete for resources. While under limiting iron conditions the siderophore pyoverdine is the most effective antifungal P. aeruginosa product, we now provide evidence that under nonlimiting iron conditions P. aeruginosa supernatants lack pyoverdine but still possess considerable antifungal activity. Spectrometric analyses of P. aeruginosa supernatants revealed the presence of phenazines, such as pyocyanin, only under nonlimiting iron conditions. Supernatants of quorum sensing mutants of strain PA14, defective in phenazine production, as well as supernatants of the P. aeruginosa strain PAO1, lacked pyocyanin, and were less inhibitory toward A. fumigatus biofilms under nonlimiting iron conditions. When blood as a natural source of iron was present during P. aeruginosa supernatant production, pyoverdine was absent, and phenazines, including pyocyanin, appeared, resulting in an antifungal effect on A. fumigatus biofilms. Pure pyocyanin reduced A. fumigatus biofilm metabolism. In summary, P. aeruginosa has mechanisms to compete with A. fumigatus under limiting and non-limiting iron conditions, and can switch from iron-denial-based to toxin-based antifungal activity. This has implications for the evolution of the microbiome in clinical settings where the two pathogens co-exist. Important differences in the iron response of P. aeruginosa laboratory strains PA14 and PAO1 were also uncovered. Lay summary P. aeruginosa (Pa) and A. fumigatus (Af) form biofilms in lungs of persons with cystic fibrosis and interact via virulence factors. Pa inhibits Af via different factors, depending on the availability of iron from blood. Low iron favors the use of pyoverdine, high iron the use of the toxin pyocyanin.

Pseudomonas aeruginosa is one of the most prominent opportunistic bacteria in airways of cystic fibrosis patients and in immunocompromised patients. These bacteria share the same polymicrobial niche with other microbes, such as the opportunistic fungus Aspergillus fumigatus. Their inter-kingdom interactions and diverse exchange of secreted metabolites are responsible for how they both fare in competition for ecological niches. The outcomes of their contests likely determine persistent damage and degeneration of lung function. With a myriad of virulence factors and metabolites of promising antifungal activity, P. aeruginosa products or their derivatives may prove useful in prophylaxis and therapy against A. fumigatus. Quorum sensing underlies the primary virulence strategy of P. aeruginosa, which serves as cell–cell communication and ultimately leads to the production of multiple virulence factors. Understanding the quorum-sensing-related pathogenic mechanisms of P. aeruginosa is a first step for understanding intermicrobial competition. In this review, we provide a basic overview of some of the central virulence factors of P. aeruginosa that are regulated by quorum-sensing response pathways and briefly discuss the hitherto known antifungal properties of these virulence factors. This review also addresses the role of the bacterial secretion machinery regarding virulence factor secretion and maintenance of cell–cell communication.

Parkinson's disease (PD) is the second most common neurodegenerative disorders throughout the world. In order to search for PD biomarkers, we performed a system-level study of RNA-Seq data from PD brain and blood samples. Differentially expressed miRs of RNA-Seq data were subjected to generate the Co-expression networks. Three highly co-expressed clusters were identified based on their correlation coefficient values and fold change ratio. SM2miR drugs of the miRs contained in the three highly co-expressed clusters were identified, and drugs common among these clusters were selected. Co-expressed miRs not previously known to be associated with PD were identified from both the samples. Functional enrichment analyses of these miR targets were done, and the pathways common and unique to both the samples were identified. Thus, our study presents a comparative analysis of miRs, their associated pathways, and drugs from brain and blood samples of PD that may help in system level understanding of this disease. miRs identified from our study may serve as biomarkers for PD.

Protein-protein interaction domain, PDZ, plays a critical role in efficient synaptic transmission in brain. Dysfunction of synaptic transmission is thought to be the underlying basis of many neuropsychiatric and neurodegenerative disorders including Alzheimer's disease (AD). In this study, Glutamate Receptor Interacting Protein1 (GRIP1) was identified as one of the most important differentially expressed, topologically significant proteins in the protein-protein interaction network. To date, very few studies have analyzed the detailed structural basis of PDZ-mediated protein interaction of GRIP1. In order to gain better understanding of structural and dynamic basis of these interactions, we employed molecular dynamics (MD) simulations of GRIP1-PDZ6 dimer bound with Liprin-alpha and GRIP1-PDZ6 dimer alone each with 100 ns simulations. The analyses of MD simulations of Liprin-alpha bound GRIP1-PDZ6 dimer show considerable conformational differences than that of peptide-free dimer in terms of SASA, hydrogen bonding patterns, and along principal component 1 (PC1). Our study also furnishes insight into the structural attunement of the PDZ6 domains of Liprin-alpha bound GRIP1 that is attributed by significant shift of the Liprin-alpha recognition helix in the simulated peptide-bound dimer compared to the crystal structure and simulated peptide-free dimer. It is evident that PDZ6 domains of peptide-bound dimer show differential movements along PC1 than that of peptide-free dimers. Thus, Liprin-alpha also serves an important role in conferring conformational changes along the dimeric interface of the peptide-bound dimer. Results reported here provide information that may lead to novel therapeutic approaches in AD.

Pseudomonas aeruginosa is one of the most prominent opportunistic bacteria in airways of cystic fibrosis patients and in immunocompromised patients. These bacteria share the same polymicrobial niche with other microbes, such as the opportunistic fungus Aspergillus fumigatus. Their inter-kingdom interactions and diverse exchange of secreted metabolites are responsible for how they both fare in competition for ecological niches. The outcomes of their contests likely determine persistent damage and degeneration of lung function. With a myriad of virulence factors and metabolites of promising antifungal activity, P. aeruginosa products or their derivatives may prove useful in prophylaxis and therapy against A. fumigatus. Quorum sensing underlies the primary virulence strategy of P. aeruginosa, which serves as cell–cell communication and ultimately leads to the production of multiple virulence factors. Understanding the quorum-sensing-related pathogenic mechanisms of P. aeruginosa is a first step for understanding intermicrobial competition. In this review, we provide a basic overview of some of the central virulence factors of P. aeruginosa that are regulated by quorum-sensing response pathways and briefly discuss the hitherto known antifungal properties of these virulence factors. This review also addresses the role of the bacterial secretion machinery regarding virulence factor secretion and maintenance of cell–cell communication.

BACKGROUND Epigenetics has emerged as an important field in drug discovery. Alzheimer's disease (AD), the leading neurodegenerative disorder throughout the world, is shown to have an epigenetic basis. Currently, there are very few effective epigenetic drugs available for AD. OBJECTIVE In this work, for the first time we have proposed 14 AD repositioning epigenetic drugs and identified their targets from extensive human interactome. METHODS Interacting partners of the AD epigenetic proteins were identified from the extensive human interactome to construct Epigenetic Protein-Protein Interaction Network (EP-PPIN). Epigenetic Drug-Target Network (EP-DTN) was constructed with the drugs associated with the proteins of EP-PPIN. Regulation of non-coding RNAs associated with the target proteins of these drugs was also studied. AD related target proteins, epigenetic targets, enriched pathways, and functional categories of the proposed repositioning drugs were also studied. RESULTS The proposed 14 AD epigenetic repositioning drugs have overlapping targets and miRs with known AD epigenetic targets and miRs. Furthermore, several shared functional categories and enriched pathways were obtained for these drugs with FDA approved epigenetic drugs and known AD drugs. CONCLUSIONS The findings of our work might provide insight into future AD epigenetic-therapeutics.

Parkinson's Disease (PD) is one of the most prevailing neurodegenerative disorders. Novel computational approaches are required to find new ways of using the existing drugs or drug repositioning, as currently there exists no cure for PD. We proposed a new bidirectional drug repositioning method that consists of Top-down and Bottom-up approaches and finally gives information about significant repositioning drug candidates. This method takes into account of the topological significance of drugs in the tripartite Indication-drug-target network (IDTN) as well the significance of their targets in the PD-specific protein-protein interaction network (PPIN). 9 non-Parkinsonian drugs have been proposed as the significant repositioning candidates for PD. In order to find out the efficiency of the repositioning candidates we introduced a parameter called the On-target ratio (OTR). The average OTR value of final repositioning candidates has been found to be higher than that of known PD specific drugs.

Topological properties of the hub genes obtained from the turquoise module. (DOCX 11Â kb)

FatiGO analysis of the turquoise module. S1A - Highly Significant KEGG pathways associated with the turquoise module. S1B - Highly Significant GO Biological Process associated with the turquoise module. (DOCX 12 kb)

Background Alzheimera#039;s disease (AD) is the most prevalent neurodegenerative disease throughout the world. Most of the clinical symptoms of AD appear at a very later stage, therefore, the identification of disease markers is essential which can help proper detection of AD at an earlier stage and slow down its progression. Studies have implicated that epigenetic biomarkers, such as DNA methylation, histone modification and non coding RNA mediated regulation serve crucial roles in several disease progression including AD. Objective The aim of our study was to identify the topologically significant AD-related proteins from experimentally validated human protein-protein interaction database, HPRD (interactome) and find out novel epigenetic biomarkers. Method In this computational work, we constructed AD specific diseasome from AD genelist and interactome. Using this diseasome we screened the interactome with the help of novel parameters namely degree band and similarity index and identified AD related proteins. Regulatory network involving AD related proteins, not previously known to be associated with AD was constructed. Several network motifs and epigenetic modification patterns of regulators of these motifs were studied. Result Our study identified computationally predicted 22 epigenetic genes and 11 epigenetic miRs, not previously known to be associated with AD, from the network motifs. Most of these genes and miRs show brain specific expression. Further study on the epigenetic modification patterns of these regulators regarding histone modification, CpG island and lncRNAs strengthened their association in AD. Conclusion Computationally predicted genes and miRs identified in our study might provide insight into new epigenetic AD therapeutic targets.

Background Parkinson's Disease (PD) is a progressive neurologic disorder that affects movement and balance. Recent studies have revealed the importance of microRNA (miR) in PD. However, the detailed role of miR and its regulation by Transcription Factor (TF) remain unexplored. In this work for the first time we have studied TF-miR-mRNA regulatory network as well as miR co-expression network in PD. Result We compared the 204 differentially expressed miRs from microarray data with 73 PD related miRs obtained from literature, Human MicroRNA Disease Database and found a significant overlap of 47 PD related miRs (p-value