Possible cerebroprotective effect of citronellal: molecular docking, MD simulation and in vivo investigations.

This study focused on molecular docking, dynamic simulation, and in vivo approaches to examine the molecular interactions between citronellal (CT) and neurotoxic proteins. In silico studies of CT were performed using proteins involved in the pathophysiology of stroke, such as interleukin-6 (IL-6), interleukin-12 (IL-12), TNF-α, and nitric oxide synthase (NOS), to determine the binding affinity based on their interactions. The docking results of CT revealed that, among the targets, NOS had a better binding energy of -6.4 Kcal/mol. NOS showed good hydrophobic interactions: TYR A, 347; VAL A, 352; PRO A, 350; TYR A, 373 amino acids. Interactions with IL-6, TNF-α, and IL-12 resulted in lower binding affinities of -3.7, -3.9 and -3.1 Kcal/mol. Based on molecular dynamics simulations of 100 ns, the binding affinity of CT (-66.782 ± 7.309 kJ/mol) was well complemented, and NOS stability at the docked site was confirmed. In in vivo studies, cerebral stroke was induced by occlusion of the bilateral common carotid arteries for 30 min and reperfusion for 4 h. CT treatment protected the brain by decreasing cerebral infarction size, increasing GSH(p < 0.001***), decreasing MPO (p < 0.001***), MDA (p < 0.001***), NO production (p < 0.01**), and AChE (p < 0.001***) compared to stroke rats. Histopathological examination revealed that CT treatment reduced the severity of cerebral damage. The investigation concluded that CT strongly binds to NOS, as observed in molecular docking and dynamic simulation studies, which are involved in nitric oxide production, leading to cerebral damage, and CT treatment reduces NO production and oxidative stress parameters, and increases antioxidants via inhibition of NOS function.Communicated by Ramaswamy H. Sarma.

A-Kinase Anchor Protein 1 deficiency causes mitochondrial dysfunction in mouse model of hyperoxia induced acute lung injury.

Background: Critically ill patients on supplemental oxygen therapy eventually develop acute lung injury (ALI). Reactive oxygen species (ROS) produced during ALI perturbs the mitochondrial dynamics resulting in cellular damage. Genetic deletion of the mitochondrial A-kinase anchoring protein 1 (Akap1) in mice resulted in mitochondrial damage, Endoplasmic reticulum (ER) stress, increased expression of mitophagy proteins and pro-inflammatory cytokines, exacerbating hyperoxia-induced Acute Lung Injury (HALI). Objective: Despite a strong causal link between mitochondrial dysfunction and HALI, the mechanisms governing the disease progression at the transcriptome level is unknown. Methods: In this study, RNA sequencing (RNA-seq) analysis was carried out using the lungs of Akap1 knockout (Akap1 -/-) mice exposed to normoxia or 48 h of hyperoxia followed by quantitative real time PCR and Ingenuity pathway analysis (IPA). Western blot analysis assessed mitochondrial dysfunction, OXPHOS complex (I-V), apoptosis and antioxidant proteins. Mitochondrial enzymatic assays was used to measure the aconitase, fumarase, citrate synthase activities in isolated mitochondria from Akap1 -/- vs. Wt mice exposed to hyperoxia. Results: Transcriptome analysis of Akap1 -/- exposed to hyperoxia reveals increases in transcripts encoding electron transport chain (ETC) and tricarboxylic acid cycle (TCA) proteins. Ingenuity pathway analysis (IPA) shows enrichment of mitochondrial dysfunction and oxidative phosphorylation in Akap1 -/- mice. Loss of AKAP1, coupled with oxidant injury, significantly decreases the activities of TCA enzymes. Mechanistically, a significant loss of dynamin-related protein 1 (Drp1) phosphorylation at the protein kinase A (PKA) site Serine 637 (Ser637), decreases in Akt phosphorylation at Serine 437 (Ser47) and increase in the expression of pro-apoptotic protein Bax indicate mitochondrial dysfunction. Heme oxygenase-1 (HO-1) levels significantly increased in CD68 positive alveolar macrophages in Akap1 -/- lungs, suggesting a strong antioxidant response to hyperoxia. Conclusion: Overall these results suggest that AKAP1 overexpression and modulation of Drp1 phosphorylation at Ser637 is an important therapeutic strategy for acute lung injury.

Code inside the codon: The role of synonymous mutations in regulating splicing machinery and its impact on disease.

In eukaryotes, precise pre-mRNA processing, including alternative splicing, is essential to carry out the intricate protein translation process. Both point mutations (that alter the translated protein sequence) and synonymous mutations (that do not alter the translated protein sequence) are capable of affecting the splicing process. Synonymous mutations are known to affect gene expression via altering mRNA stability, mRNA secondary structure, splicing processes, and translational kinetics. In higher eukaryotes, precise splicing is regulated by three weakly conserved cis-elements, 5' and 3' splice sites and the branch site. Many other cis-acting elements (exonic/intronic splicing enhancers and silencers) and trans-acting splicing factors (serine and arginine-rich proteins and heterogeneous nuclear ribonucleoproteins) have also been found to enhance or suppress the splicing process. The appearance of synonymous mutations in cis-acting elements can alter the splicing process by changing the binding pattern of splicing factors to exonic splicing enhancers or silencer motifs. This results in exon skipping, intron retention, and various other forms of alternative splicing, eventually leading to the emergence of a wide range of diseases. The focus of this review is to elucidate the role of synonymous mutations and their impact on abnormal splicing mechanisms. Further, this study highlights the function of synonymous mutation in mediating abnormal splicing in cancer and development of X-linked, and autosomal inherited diseases.

Aberrant Expression of ACO1 in Vasculatures Parallels Progression of Idiopathic Pulmonary Fibrosis.

Rationale: Idiopathic pulmonary fibrosis (IPF) is characterized by mitochondrial dysfunction. However, details about the non-mitochondrial enzymes that sustain the proliferative nature of IPF are unclear. Aconitases are a family of enzymes that sustain metabolism inside and outside mitochondria. It is hypothesized that aconitase 1 (ACO1) plays an important role in the pathogenesis of IPF given that ACO1 represents an important metabolic hub in the cytoplasm. Objectives: To determine if ACO1 expression in IPF lungs shows specific patterns that may be important in the pathogenesis of IPF. To determine the similarities and differences in ACO1 expression in IPF, bleomycin-treated, and aging lungs. Methods: ACO1 expression in IPF lungs were characterized and compared to non-IPF controls by western blotting, immunostaining, and enzymatic activity assay. ACO1-expressing cell types were identified by multicolor immunostaining. Using similar methods, the expression profiles of ACO1 in IPF lungs versus bleomycin-treated and aged mice were investigated. Measurements and main results: Lower lobes of IPF lungs, unlike non-IPF controls, exhibit significantly high levels of ACO1. Most of the signals colocalize with von Willebrand factor (vWF), a lineage marker for vascular endothelial cells. Bleomycin-treated lungs also show high ACO1 expressions. However, most of the signals colocalize with E-cadherin and/or prosurfactant protein C, representative epithelial cell markers, in remodeled areas. Conclusions: A characteristic ACO1 expression profile observed in IPF vasculatures may be a promising diagnostic target. It also may give clues as to how de novo angiogenesis contributes to the irreversible nature of IPF.

Nitrated fatty acid, 10-nitrooleate protects against hyperoxia-induced acute lung injury in mice.

The antioxidant and anti-inflammatory effects of electrophilic nitrated fatty acid (NFA); 10-nitrooleate, have been reported. The present study investigated whether 10-nitrooleate has a protective role against hyperoxic-induced acute lung injury (HALI). Using a C57BL/6 mice model of HALI, we investigated the protective effect of 10-nitrooleate. C57BL/6 mice were administered with NFA intratracheally, exposed to hyperoxia for 48 h to induce HALI, and kept at room air for 24 h. Bronchoalveolar lavage (BAL) fluid and lung samples were collected after 24 h of post hyperoxia to analyze markers associated with HALI. Intratracheal (IT) and intraperitoneal (IP) administration of NFA notably attenuated hyperoxia-induced infiltration of inflammatory cells, alveolar-capillary leakage, upregulation of proinflammatory cytokine levels (IL-6 and TNFα) into the BAL fluid, and resolution of inflammation in the lung. Western blot analyses showed that 10-nitrooleate reduced the expression of the inflammatory transcription factor NFκB p65 subunit and increased antioxidant proteins HO-1 and NQO1 expression in the lung tissues compared to vehicle-treated animals. Moreover, 10-nitrooleate reversed the hyperoxia-induced expression of mitophagy-associated markers (PINK1 and p62/SQSTM1), thereby protecting the HALI/ acute respiratory distress syndrome (ARDS). IT and IP delivery of 10-nitrooleate reduces hyperoxia-induced ALI/ARDS by regulating the antioxidant pathways and restoring the mitochondrial homeostasis by regulating mitophagy. It is suggested that NFAs can be further evaluated as supplementary therapy for critically ill patients like COVID-19/ARDS.

Mitochondrial Protein Akap1 Deletion Exacerbates Endoplasmic Reticulum Stress in Mice Exposed to Hyperoxia.

Acute lung injury (ALI) and its severe manifestation, acute respiratory distress syndrome (ARDS), are treated with high concentrations of supplementary oxygen. However, prolonged exposure to high oxygen concentrations stimulates the production of reactive oxygen species (ROS), which damages the mitochondria and accumulates misfolded proteins in the endoplasmic reticulum (ER). The mitochondrial protein A-kinase anchoring protein 1 (Akap1) is critical for mitochondrial homeostasis. It is known that Akap1 deficiency results in heart damage, neuronal development impairment, and mitochondrial malfunction in preclinical studies. Our laboratory recently revealed that deleting Akap1 increases the severity of hyperoxia-induced ALI in mice. To assess the role of Akap1 deletion in ER stress in lung injury, wild-type and Akap1 -/- mice were exposed to hyperoxia for 48 h. This study indicates that Akap1 -/- mice exposed to hyperoxia undergo ER stress, which is associated with an increased expression of BiP, JNK phosphorylation, eIF2α phosphorylation, ER stress-induced cell death, and autophagy. This work demonstrates that deleting Akap1 results in increased ER stress in the lungs of mice and that hyperoxia exacerbates ER stress-related consequences.

Potential therapeutic interventions of plant-derived isoflavones against acute lung injury.

Acute lung injury (ALI) is a life-threatening syndrome that possibly leads to high morbidity and mortality as no therapy exists. Several natural ingredients with negligible adverse effects have recently been investigated to possibly inhibit the inflammatory pathways associated with ALI at the molecular level. Isoflavones, as phytoestrogenic compounds, are naturally occurring bioactive compounds that represent the most abundant category of plant polyphenols (Leguminosae family). A broad range of therapeutic activities of isoflavones, including antioxidants, chemopreventive, anti-inflammatory, antiallergic and antibacterial potentials, have been extensively documented in the literature. Our review exclusively focuses on the possible anti-inflammatory, antioxidant role of botanicals'-derived isoflavones against ALI and their immunomodulatory effect in experimentally induced ALI. Despite the limited scope covering their molecular mechanisms, isoflavones substantially contributed to protecting from ALI via inhibiting toll-like receptor 4 (TLR4)/Myd88/NF-κB pathway and subsequent cytokines, chemokines, and adherent proteins. Nonetheless, future research is suggested to fill the gap in elucidating the protective roles of isoflavones to alleviate ALI concerning antioxidant potentials, inhibition of the inflammatory pathways, and associated molecular mechanisms.

Lytic Bacteriophages Against Bacterial Biofilms Formed by Multidrug-Resistant Pseudomonas aeruginosa, Escherichia coli, Klebsiella pneumoniae, and Staphylococcus aureus Isolated from Burn Wounds.

Background: Use of bacteriophages as antibiofilm agents to tackle multidrug-resistant bacteria has gained importance in recent years. Materials and Methods: In this study, biofilm formation by Staphylococcus aureus, Pseudomona aeruginosa, Klebsiella pneumoniae, and Escherichia coli under different growth conditions was studied. Furthermore, the ability of bacteriophages to inhibit biofilm formation was analyzed. Results: Under dynamic growth condition, wherein the medium is renewed for every 12 h, the amount of biomass produced and log10 colony-forming unit counts of all bacterial species studied was highest when compared with other growth conditions tested. Biomass of biofilms produced was drastically reduced when incubated for 2 or 4 h with bacteriophages vB_SAnS_SADP1, vB_PAnP_PADP4, vB_KPnM_KPDP1, and vB_ECnM_ECDP3. Scanning electron microscopy and confocal laser scanning microscopy analyses indicated that the reduction in biomass was due to the lytic action of the bacteriophages. Conclusions: Results of our study reinforce the concept of developing bacteriophages as alternatives to antibiotics to treat bacterial infections.

An Overview on COVID-19 Pandemic: from Discovery to Treatment.

Recently, novel coronavirus infection (COVID-19) emerged in Wuhan, China has been declared as pandemic by WHO. Until now, no evidence is documented regarding its wild animal reservoir or intermediary host, but, human-to-human transmission, asymptomatic carriers were very much observed. The number of confirmed cases and death toll have been increased almost all over the world indicating its potential threat to public health. Though the phylogenetic analysis shows some similarity of SARS-CoV2 to bat betacoronaviruses, it exhibited significant variation in S1 domain of spike protein from bat-derived viruses. S1 domain plays an important role in receptor binding and it can be a target for the development of therapeutics and vaccines. In this review, we have discussed the updates on transmission, diagnosis, genome analysis and comparison, treatment options and clinical trials of COVID-19.

Electrophilic nitrated fatty acids are potential therapeutic candidates for inflammatory and fibrotic lung diseases.

Several types of exposures can cause acute or chronic inflammatory reactions in the lungs often leading to asthma, pulmonary fibrosis, chronic obstructive pulmonary disease (COPD), acute lung injury, lung cancer, and other deleterious health outcomes. Current therapy, with inhaled or oral glucocorticoids, successfully targets inflammation but also produces adverse effects that limit their enthusiastic use. Accordingly, the need remains for interventions that are safer and more effective. Nitrated fatty acids (NFAs) are highly electrophilic and are produced endogenously by non-enzymatic reactions of nitric oxide with conjugated unsaturated fatty acids. The literature indicates that NFAs are detected in humans at the nanomolar range and are produced more robustly under inflammatory conditions. Recent studies on novel NFAs report antiinflammatory, antioxidant, and antifibrotic effects, while also acting as partial agonists of peroxisome proliferator-activated receptor-gamma (PPAR-γ). Furthermore, these functions of NFAs occur via reversible electrophilic alkylation of cysteine residues and regulation of antiinflammatory, antioxidant signaling through modulation of transcription factors, including nuclear factor E2-related factor 2 (Nrf2), PPAR-γ, and NF-κB. Here, we review and update the role of NFA signaling mechanisms and their therapeutic potential in various lung diseases. As NFAs display strong electrophilic interaction with multimechanistic pathways, they can be considered promising drug candidates for challenging lung diseases.

Alda-1 Attenuates Hyperoxia-Induced Acute Lung Injury in Mice.

Acute lung injury (ALI), a milder form of acute respiratory distress syndrome (ARDS), is a leading cause of mortality in older adults with an increasing prevalence. Oxygen therapy, is a common treatment for ALI, involving exposure to a high concentration of oxygen. Unfortunately, hyperoxia induces the formation of reactive oxygen species which can cause an increase in 4-HNE (4-hydroxy 2 nonenal), a toxic byproduct of lipid peroxidation. Mitochondrial aldehyde dehydrogenase 2 (ALDH2) serves as an endogenous shield against oxidative stress-mediated damage by clearing 4-HNE. Alda-1 [(N-(1, 3 benzodioxol-5-ylmethyl)-2, 6- dichloro-benzamide)], a small molecular activator of ALDH2, protects against reactive oxygen species-mediated oxidative stress by promoting ALDH2 activity. As a result, Alda-1 shields against ischemic reperfusion injury, heart failure, stroke, and myocardial infarction. However, the mechanisms of Alda-1 in hyperoxia-induced ALI remains unclear. C57BL/6 mice implanted with Alzet pumps received Alda-1 in a sustained fashion while being exposed to hyperoxia for 48 h. The mice displayed suppressed immune cell infiltration, decreased protein leakage and alveolar permeability compared to controls. Mechanistic analysis shows that mice pretreated with Alda-1 also experience decreased oxidative stress and enhanced levels of p-Akt and mTOR pathway associated proteins. These results show that continuous delivery of Alda-1 protects against hyperoxia-induced lung injury in mice.

Alda-1 attenuates hyperoxia-induced mitochondrial dysfunction in lung vascular endothelial cells.

Acute lung injury (ALI) is a major cause of morbidity and mortality worldwide, especially in aged populations. Mitochondrial damage is one of the key features of ALI. Hyperoxia-induced lung injury model in mice has been widely used for ALI study because it features many ALI phenotypes including, but not limited to, mitochondrial and vascular endothelial cell damage. Recently, accumulating evidence has shown that mitochondrial aldehyde dehydrogenase 2 (ALDH2) has a protective effect against oxidative stress mediated cell damage in epithelial cells. However, it is not known whether ALDH2 protects against oxidative stress in vascular endothelial cells. In this current study, we attempted to find the capacity of Alda-1 [(N-(1,3benzodioxol-5-ylmethyl)-2,6- dichloro-benzamide), an ALDH2 activator] to protect against oxidative stress in human microvascular endothelial cells (HMVEC). HMVEC pretreated with Alda-1 prior to hyperoxic exposure vs non-treated controls showed i) lower 4-hydroxynonenal (4-HNE) levels, ii) significantly decreased expressions of Bax and Cytochrome C, iii) partially restored activity and expression of ALDH2 and iv) significantly improved mitochondrial membrane potential. These results suggest that ALDH2 protein in lung vascular endothelial cells is a promising therapeutic target for the treatment of ALI and that Alda-1 is a potential treatment option.

The nitrated fatty acid, 10-nitrooleate inhibits the neutrophil chemotaxis via peroxisome proliferator-activated receptor gamma in CLP-induced sepsis in mice.

The inhibition of polymorphonuclear neutrophils' (PMNs) migration to the source of injury is among the most prominent aspects of immunosuppression following sepsis, although the precise mechanisms involved remain unclear and multifaceted. Increasing evidence connects this immunosuppression to nitric oxide (NO), as NO production is a classic feature of inflammation probably through neutrophil activation and migration. Nitrated fatty acids (NFA) such as 10-nitrooleate (OA-NO2), nitrolinoleic acid etc. produced endogenously by the non-enzymatic reaction of NO with unsaturated fatty acids, are found to be potent activators of the transcription factor, peroxisome proliferator-activated receptor gamma (PPARγ). Upregulation of PPARγ during immunosuppression and the subsequent inhibition of neutrophil migration in sepsis have been reported. However, the interplay of OA-NO2, NO and PPARγ in polymicrobial-induced immunosuppression has not been established. Hence to understand this, we have studied the role of OA-NO2 in blood PMNs migration, the effects of iNOS inhibitor on PMNs migration and PPARγ activity in cecal ligation and puncture (CLP)-induced sepsis in mice. We found increased expression of PPARγ and its DNA-binding activity in the lungs and blood PMNs from CLP mice. CLP or OA-NO2 treatment inhibited PMNs' migration in response to fMLP stimulation. Pharmacological inhibition of iNOS resulted in decreased PPARγ DNA-binding activity with a concomitant increase in the migration of PMNs to the site of infection. OA-NO2 treatment also inhibited the production of inflammatory cytokines (TNFα and IL-1ß) secretion from PMNs stimulated with lipopolysaccharide. We have also established that, OA-NO2 mediated inhibition of PMNs migration in vivo and ex vivo are regulated through PPARγ-dependent pathway. This study further highlights the fact that the activation of PPARγ by the NFA has a pivotal role in PMNs' migration and immunosuppression.

Altered expression of p63 isoforms and expansion of p63- and club cell secretory protein-positive epithelial cells in the lung as novel features of aging.

Aging is a key contributor for subclinical progression of late-onset lung diseases. Basal, club, and type II alveolar epithelial cells (AECs) are lung epithelial progenitors whose capacities of differentiation are extensively studied. The timely transition of these cells in response to environmental changes helps maintain the intricate organization of lung structure. However, it remains unclear how aging affects their behavior. This paper demonstrates that the protein expression profiles of a type II AEC marker, prosurfactant protein C (pro-SPC), and a basal cell marker, p63, are altered in the lungs of 14-mo-old versus 7- to 9-wk-old mice. Expression of NH2-terminal-truncated forms of p63 (ΔNp63), a basal cell marker, and claudin-10, a club cell marker, in cytoplasmic extracts of lungs of 14-mo-old mice was upregulated. In contrast, nuclear expression of full-length forms of p63 (TAp63) decreases with age. These alterations in protein expression profiles coincide with dramatic changes in lung functions including compliance. Whole tissue lysates of middle-aged versus aged rhesus monkey lungs display similar age-associated alterations in pro-SPC expression. An age-associated decrease of TAp63 in nuclear lysates was observed in aged monkey group. Moreover, the lungs of 14-mo-old versus 7- to 9-wk-old mice display a wider spreading of ΔNp63-positive CCSP-positive bronchiolar epithelial cells. This expansion did not involve upregulation of Ki67, a representative proliferation marker. Collectively, it is postulated that 1) this expansion is secondary to a transition of progenitor cells committed to club cells from ΔNp63-negative to ΔNp63-positive status, and 2) high levels of cytoplasmic ΔNp63 expression trigger club cell migration.

Akap1 genetic deletion increases the severity of hyperoxia-induced acute lung injury in mice.

Critically ill patients are commonly treated with high levels of oxygen, hyperoxia, for prolonged periods of time. Unfortunately, extended exposure to hyperoxia can exacerbate respiratory failure and lead to a high mortality rate. Mitochondrial A-kinase anchoring protein (Akap) has been shown to regulate mitochondrial function. It has been reported that, under hypoxic conditions, Akap121 undergoes proteolytic degradation and promotes cardiac injury. However, the role of Akap1 in hyperoxia-induced acute lung injury (ALI) is largely unknown. To address this gap in our understanding of Akap1, we exposed wild-type ( wt) and Akap1-/- mice to 100% oxygen for 48 h, a time point associated with lung damage in the murine model of ALI. We found that under hyperoxia, Akap1-/- mice display increased levels of proinflammatory cytokines, immune cell infiltration, and protein leakage in lungs, as well as increased alveolar capillary permeability compared with wt controls. Further analysis revealed that Akap1 deletion enhances lung NF-κB p65 activity as assessed by immunoblotting and DNA-binding assay and mitochondrial autophagy-related markers, PINK1 and Parkin. Ultrastructural analysis using electron microscopy revealed that Akap1 deletion was associated with remarkably aberrant mitochondria and lamellar bodies in type II alveolar epithelial cells. Taken together, these results demonstrate that Akap1 genetic deletion increases the severity of hyperoxia-induced acute lung injury in mice.

Expression, purification and biological characterisation of recombinant human irisin (12.5 kDa).

Fibronectin type III domain containing 5 (FNDC5) is a transmembrane protein. Upon cleavage, it yields a peptide called irisin that is supposedly bind to an unknown receptor and facilitates browning of white adipose tissue (WAT). Increased levels of irisin are associated with increased levels of energy expenditure markers PGC-1α, UCP-1, besides abundance of beige adipocytes in WAT. Though varied sizes of irisin were reported in humans and rodents it is not yet clear about the actual size of the irisin produced physiologically. Hence, we cloned and expressed human irisin (32-143 aa of FNDC5) in Escherichia coli based on the proposed cleavage site that yields 12.5 kDa peptide to study its antigenicity and other biological functions in vitro. We purified recombinant human irisin (rh-irisin) to 95% homogeneity with simple purification method with a yield of 25 mg/g wet cell pellet. rh-irisin has been detected by commercially available antibodies from different sources with similar antigenicity. Biological activity of the rh-irisin was confirmed by using 3T3-L1 pre-adipocyte differentiation by Oil red O staining. Further, rh-irisin treatment on pre-adipocytes showed increased expression of markers associated with energy expenditure. As it is involved in energy expenditure process, it could be considered as potential therapeutic option for various metabolic diseases.

Curcumin Nanotechnologies and Its Anticancer Activity.

Cancer is one of the leading causes of death worldwide. Curcumin is a well-established anticancer agent in vitro but its efficacy is yet to be proven in clinical trials. Poor bioavailability of curcumin is the principal reason behind the lack of efficiency of curcumin in clinical trials. Many studies prove that the bioavailability of curcumin can be improved by administering it through nanoparticle drug carriers. This review focuses on the efforts made in the field of nanotechnology to improve the bioavailability of curcumin. Nanotechnologies of curcumin come in various shapes and sizes. The simplest curcumin nanoparticle that increased the bioavailability of curcumin is the curcumin-metal complex. On the other hand, we have intricate thermoresponsive nanoparticles that can release curcumin upon stimulation (analogous to a remote control). Future research required for developing potent curcumin nanoparticles is also discussed.

The role of club cell phenoconversion and migration in idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is an age-related multifactorial disease featuring non-uniform lung fibrosis. The decisive cellular events at early stages of IPF are poorly understood. While the involvement of club cells in IPF pathogenesis is unclear, their migration has been associated with lung fibrosis. In this study, we labeled club cells immunohistochemically in IPF lungs using a club cell marker Claudin-10 (Cldn10), a unique protein based on the recent report which demonstrated that the appearance of Cldn10 in developing and repairing lungs precedes other club cell markers including club cell secretory protein (CCSP). Cldn10-positive cells in IPF lungs displayed marked pleomorphism and were found in varied arrangements, suggesting their phenoconversion. These results were corroborated by immunogold labeling for Cldn10. Further, immunohistochemical double-labeling for Cldn10 and α-smooth muscle actin (α-SMA) demonstrated that aberrant α-SMA signals are frequently encountered near disorganized Cldn10-positive cells in hyperplastic bronchiolar epithelium and thickened interstitium of IPF lungs. Collectively, these data indicate that club cells actively participate in the initiation and progression of IPF through phenoconversion involving the acquisition of proliferative and migratory abilities. Thus, our new findings open the possibility for club cell-targeted therapy to become a strategic option for the treatment of IPF.

Protein tyrosine phosphatase nonreceptor type 22 (PTPN22) gene polymorphism in pulmonary tuberculosis in the Indian population.

A variant of the protein tyrosine phosphatase nonreceptor type 22 (PTPN22) gene is known to be associated with susceptibility to autoimmune diseases and bacterial infections as it acts as an important regulator of T-cell activation. The objective of this study was to evaluate whether PTPN22-C1858T polymorphism is associated with the resistance to pulmonary tuberculosis (PTB). Single-nucleotide polymorphism of PTPN22-C1858T (rs2476601) was genotyped in 124 patients with PTB and 130 healthy controls from India using restriction fragment length polymorphism and direct sequencing of the amplified DNA. The frequencies of genotypes CC, CT, and TT were 100%, 0%, and 0%, respectively, in PTB; and 99.2%, 0.8% and 0%, respectively, in healthy control individuals. These values did not differ significantly between the patients and controls. The mutant allele C1858T was found to be a rare allele in Indian population.