Role of the redox state of the Pirin-bound cofactor on interaction with the master regulators of inflammation and other pathways.

Persistent cellular stress induced perpetuation and uncontrolled amplification of inflammatory response results in a shift from tissue repair toward collateral damage, significant alterations of tissue functions, and derangements of homeostasis which in turn can lead to a large number of acute and chronic pathological conditions, such as chronic heart failure, atherosclerosis, myocardial infarction, neurodegenerative diseases, diabetes, rheumatoid arthritis, and cancer. Keeping the vital role of balanced inflammation in maintaining tissue integrity in mind, the way to combating inflammatory diseases may be through identification and characterization of mediators of inflammation that can be targeted without hampering normal body function. Pirin (PIR) is a non-heme iron containing protein having two different conformations depending on the oxidation state of the iron. Through exploration of the Pirin interactome and using molecular docking approaches, we identified that the Fe2+-bound Pirin directly interacts with BCL3, NFKBIA, NFIX and SMAD9 with more resemblance to the native binding pose and higher affinity than the Fe3+-bound form. In addition, Pirin appears to have a function in the regulation of inflammation, the transition between the canonical and non-canonical NF-κB pathways, and the remodeling of the actin cytoskeleton. Moreover, Pirin signaling appears to have a critical role in tumor invasion and metastasis, as well as metabolic and neuro-pathological complications. There are regulatory variants in PIR that can influence expression of not only PIR but also other genes, including VEGFD and ACE2. Disparity exists between South Asian and European populations in the frequencies of variant alleles at some of these regulatory loci that may lead to differential occurrence of Pirin-mediated pathogenic conditions.

The pectinolytic activity of Burkholderia cepacia and its application in the bioscouring of cotton knit fabric.

BACKGROUND: Enzymatic catalysis in different industrial applications is often preferred over chemical methods due to various advantages, such as higher specificity, greater efficiency, and less environmental footprint. Pectinases are a group of enzymes that catalyze the degradation of pectic compounds, the key components of plant middle lamella and the primary cell wall. Pectinases have found applications in multiple industrial processes, including cotton bioscouring, fruit juice extraction and its clarification, plant fiber degumming, paper making, plant biomass liquefaction, and saccharification, among others. The purpose of this study was to taxonomically characterize a bacterial species exhibiting pectinolytic activities and assess its pectinolytic activity qualitatively and quantitatively, as well as test its bioscouring potential. RESULTS: Here, we report that Burkholderia cepacia, a previously unknown species with pectinolytic activity, exerts such activity comparable to commercially used pectinase enzymes in the textile industry, but requires less temperature for activity. CONCLUSION: Quantitative evaluation of enzyme activity indicates the potential of the bacterial species for use in the bioscouring of cotton knit fabric.

Disease-associated metabolic pathways affected by heavy metals and metalloid.

Increased exposure to environmental heavy metals and metalloids and their associated toxicities has become a major threat to human health. Hence, the association of these metals and metalloids with chronic, age-related metabolic disorders has gained much interest. The underlying molecular mechanisms that mediate these effects are often complex and incompletely understood. In this review, we summarize the currently known disease-associated metabolic and signaling pathways that are altered following different heavy metals and metalloids exposure, alongside a brief summary of the mechanisms of their impacts. The main focus of this study is to explore how these affected pathways are associated with chronic multifactorial diseases including diabetes, cardiovascular diseases, cancer, neurodegeneration, inflammation, and allergic responses upon exposure to arsenic (As), cadmium (Cd), chromium (Cr), iron (Fe), mercury (Hg), nickel (Ni), and vanadium (V). Although there is considerable overlap among the different heavy metals and metalloids-affected cellular pathways, these affect distinct metabolic pathways as well. The common pathways may be explored further to find common targets for treatment of the associated pathologic conditions.

A comprehensive in silico exploration of the impacts of missense variants on two different conformations of human pirin protein.

Background: Pirin, a member of the cupin superfamily, is an iron-binding non-heme protein. It acts as a coregulator of several transcription factors, especially the members of NFκB transcription factor family. Based on the redox state of its iron cofactor, it can assume two different conformations and thereby act as a redox sensor inside the nucleus. Previous studies suggested that pirin may be associated with cancer, inflammatory diseases as well as COVID-19 severities. Hence, it is important to explore the pathogenicity of its missense variants. In this study, we used a number of in silico tools to investigate the effects of missense variants of pirin on its structure, stability, metal cofactor binding affinity and interactions with partner proteins. In addition, we used protein dynamics simulation to elucidate the effects of selected variants on its dynamics. Furthermore, we calculated the frequencies of haplotypes containing pirin missense variants across five major super-populations (African, Admixed American, East Asian, European and South Asian). Results: Among a total of 153 missense variants of pirin, 45 were uniformly predicted to be pathogenic. Of these, seven variants can be considered for further experimental studies. Variants R59P and L116P were predicted to significantly destabilize and damage pirin structure, substantially reduce its affinity to its binding partners and alter pirin residue fluctuation profile via changing the flexibility of several key residues. Additionally, variants R59Q, F78V, G98D, V151D and L220P were found to impact pirin structure and function in multiple ways. As no haplotype was identified to be harboring more than one missense variant, further interrogation of the individual effects of these seven missense variants is highly recommended. Conclusions: Pirin is involved in the transcriptional regulation of several genes and can play an important role in inflammatory responses. The variants predicted to be pathogenic in this study may thus contribute to a better understanding of the underlying molecular mechanisms of various inflammatory diseases. Future studies should be focused on clarifying if any of these variants can be used as disease biomarkers. Supplementary Information: The online version contains supplementary material available at 10.1186/s42269-022-00917-7.

Effects of arsenic and heavy metals on metabolic pathways in cells of human origin: Similarities and differences.

Various anthropogenic and natural events over the years have gradually increased human exposure to various heavy metals. Several of these heavy metals including cadmium, mercury, nickel, chromium, and the metalloid arsenic among others, have created major public health concerns for their high level of toxicities. Identification of the general as well as the differentially affected cellular metabolic pathways will help understanding the molecular mechanism of different heavy metal-induced toxicities. In this study, we analyzed 25 paired (control vs. treated) transcriptomic datasets derived following treatment of various human cells with different heavy metals and metalloid (arsenic, cadmium, chromium, iron, mercury, nickel and vanadium) to identify the affected metabolic pathways. The effects of these metals on metabolic pathways depend not only on the metals per se, but also on the nature of the treated cells. Tissue of origin, therefore, must be considered while assessing the effects of any particular heavy metal or metalloid. Among the metals and metalloid, arsenic appears to have relatively more pleiotropic influences on cellular metabolic pathways including those known to have association with diabetes. Although only two stem cell derived datasets are included in the current study, effects of heavy metals on these cells appear to be different from other mature cells of similar tissue origin. This study provides useful information about different heavy metal affected pathways, which may be useful in further exploration using wet-lab based techniques.

Disparities in COVID-19 severities and casualties across ethnic groups around the globe and patterns of ACE2 and PIR variants.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) mediated Coronavirus disease-19 (COVID-19) has affected millions of individuals around all corners of the globe. Symptoms and severities of infection with this highly contagious virus vary among individuals and there is disparity in the number of COVID-19-related casualties across different ethnic groups. The primary receptor for SARS-CoV-2 entry into the host cells is angiotensin-converting enzyme 2 (ACE2). Certain variants of ACE2 are known to be associated with COVID-19 comorbidities such as hypertension, cardiovascular complications, diabetes, chronic lung disease, etc. In this study, we looked into the geographic distribution of disease-associated variants of ACE2 as well as closely located PIR gene to explore any possible correlation with the disparities in COVID-19 severities and casualties across ethnic groups. Frequencies of the ACE2 variants associated with COVID-19 comorbidities are higher in the European and the admixed American populations. These variants are also present with stronger pairwise linkage disequilibrium (LD) in the European and the admixed American populations. On the other hand, the variants with protective role are more prevalent in the East and the South Asian populations. Strong pairwise LD exists among the activity modifying (modifier) variants of the PIR and ACE2 genes only in the European super-population. Absence of these PIR variants in the South Asian population may contribute to the overall lower COVID-19 case fatality rates (CFR) despite the dense population in this region.

Common genetic variants and pathways in diabetes and associated complications and vulnerability of populations with different ethnic origins.

Diabetes mellitus is a complex and heterogeneous metabolic disorder which is often pre- or post-existent with complications such as cardiovascular disease, hypertension, inflammation, chronic kidney disease, diabetic retino- and nephropathies. However, the frequencies of these co-morbidities vary among individuals and across populations. It is, therefore, not unlikely that certain genetic variants might commonly contribute to these conditions. Here, we identified four single nucleotide polymorphisms (rs5186, rs1800795, rs1799983 and rs1800629 in AGTR1, IL6, NOS3 and TNFA genes, respectively) to be commonly associated with each of these conditions. We explored their possible interplay in diabetes and associated complications. The variant allele and haplotype frequencies at these polymorphic loci vary among different super-populations (African, European, admixed Americans, South and East Asians). The variant alleles are particularly highly prevalent in different European and admixed American populations. Differential distribution of these variants in different ethnic groups suggests that certain drugs might be more effective in selective populations rather than all. Therefore, population specific genetic architectures should be considered before considering a drug for these conditions.