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.

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.

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.

Cytotoxic effects of Aeromonas hydrophila culture supernatant on peripheral blood leukocytes of Nile tilapia (Oreochromis niloticus): Possible presence of a secreted cytotoxic lectin.

Number of exotoxins like haemolysin, leukocidin, aerolysin etc. were reported from Aeromonas hydrophila. In this study, we report the haemolytic and cytotoxic effect of A. hydrophila culture supernatant (CS) that is specifically inhibited by lactose and also by serum and mucus of Nile tilapia (Oreochromis niloticus). Hence, we assume the presence of a secreted lectin in the CS. CS is toxic to peripheral blood leukocytes (PBL) of O. niloticus as revealed by MTT assay and by flow cytometry. DNA laddering assay indicates that CS causes necrosis to PBL. As a result of necrosis, CS treated PBL showed increased production of reactive oxygen species as indicated by nitroblue tetrazolium and 2',7' -dichlorofluorescin diacetate assays. CS treated PBL showed reduced mRNA expression of TNF-α and IFN-γ genes. When CS was subjected to polyacrylamide gel electrophoresis, it showed a single band corresponding to the molecular weight of 45 kDa. However, upon concentrating the CS by ultrafiltration, many bands were visualized. Further studies at molecular level are required to unravel this macromolecular-leukocyte interaction which would ultimately benefit the aquaculture industry.

Chenodeoxycholic acid attenuates ovalbumin-induced airway inflammation in murine model of asthma by inhibiting the T(H)2 cytokines.

Asthma is a complex highly prevalent airway disease that is a major public health problem for which current treatment options are inadequate. Recently, farnesoid X receptor (FXR) has been shown to exert anti-inflammatory actions in various disease conditions, but there have been no reported investigations of Chenodeoxycholic acid (CDCA), a natural FXR agonist, in allergic airway inflammation. To test the CDCA effectiveness in airway inflammation, ovalbumin (OVA)-induced acute murine asthma model was established. We found that lung tissue express FXR and CDCA administration reduced the severity of the murine allergic airway disease as assessed by pathological and molecular markers associated with the disease. CDCA treatment resulted in fewer infiltrations of cells into the airspace and peribronchial areas, and decreased goblet cell hyperplasia, mucus secretion and serum IgE levels which was increased in mice with OVA-induced allergic asthma. The CDCA treatment further blocked the secretion of TH2 cytokines (IL-4, IL-5 and IL-13) and proinflammatory cytokine TNF-α indicate that the FXR and its agonists may have potential for treating allergic asthma.

Increased yield of high purity recombinant human brain natriuretic peptide by acid hydrolysis of short fusion partner in Escherichia coli.

Recombinant human B-type natriuretic peptide (rhBNP) is a 32-amino acid peptide used to treat congestive heart failure. In this paper, we report a method for the increased production of rhBNP in Escherichia coli with high purity. hBNP was cloned with a short growth hormone fusion partner coupled with a unique acid-labile dipeptide linker to cleave the fusion protein to release the rhBNP. The recombinant fusion protein was expressed as an inclusion body (IB) and the fermentation process was optimized to produce on large scale. The IBs were recovered by cell lysis, and the pure IBs were directly treated with diluted acid to get the target peptide from the fusion protein and the resultant peptide was purified by reversed phase chromatography. The final purity of the rhBNP was more than 99% with yield of 50mg per liter of culture, which is ten times higher than the previous reports. The purified rhBNP exhibited specific biological activity similar to the standard peptide in producing cyclic-guanosine monophosphate.

Role of farnesoid X receptor in inflammation and resolution.

OBJECTIVE: The aim of this paper is to review the developments of farnesoid X receptor (FXR) biology, its ligands, and various functions, in particular we discuss the anti-inflammatory and anti-fibrotic role in chronic inflammatory diseases. INTRODUCTION: FXR is a ligand-dependent transcription factor belonging to the nuclear hormone receptor superfamily. The accrued data have shown that the FXR plays important roles not only in bile acid, lipid metabolism, and carbohydrate homeostasis, but also in inflammatory responses. The anti-inflammatory and anti-fibrotic effects of FXR on chronic inflammatory diseases are not well documented. METHODS: A literature survey was performed using PubMed database search to gather complete information regarding FXR and its role in inflammation. RESULTS AND DISCUSSION: FXR is highly expressed in liver, intestine, kidney and adrenals, but with lower expression in fat tissue, heart and recently it has been found to express in lungs too. Primary bile acids, cholic acid and chenodeoxycholic acid are the natural endogenous ligands for FXR. GW4064 and 6α-ethyl-chenodeoxycholic acid are the synthetic high-affinity agonists. An exhaustive literature survey revealed that FXR acts as a key metabolic regulator and potential drug target for many metabolic syndromes that include chronic inflammatory diseases.

Recombinant approach for the production of HIV fusion inhibitor Enfuvirtide using Escherichia coli.

The use of antiretroviral drugs is gaining importance in the recent past for the treatment of human immunodeficiency virus infection. Enfuvirtide (T20) is one of the fusion inhibitors, inhibits the fusion between the virus and healthy target CD4 cells. The treatment with T20 involves very high therapeutic dose. In addition to its high dose, production of T20 by synthetic methods is expensive and cumbersome. We report an alternative recombinant approach for the production of the T20 peptide through a novel short fusion-tag expression system. This expression system consists of the hydrophobic region of growth hormone (GH) as the fusion tag, a factor Xa cleavage site upstream to the T20. The fusion protein was expressed in Escherichia coli as inclusion bodies. We also report here, a simple and an efficient down-stream strategy for the purification of recombinant T20 peptide (rT20). Our study is the first to demonstrate a novel approach using GH fusion tag, ensured the peptide stability, for the production of rT20 which yields more than 250mg/L with 98% purity. The biological activity of the rT20 is comparable to its synthetic counterpart. Thus, this novel approach could be an alternate method of choice for production of therapeutically important small peptides.

Gene fragment polymerization for increased yield of recombinant HIV fusion inhibitor enfuvirtide. [corrected].

Fuzeon (Enfuvirtide, T20) is the first fusion inhibitor approved by the FDA of the USA for the treatment of HIV/AIDS in combination with other anti-retroviral drugs. Enfuvirtide is a synthetic peptide that blocks the entry of HIV into healthy host CD4 cells, which requires very high (90 mg twice daily) therapeutic doses. To increase the yield of Enfuvirtide, a gene polymerization strategy was introduced and recombinant T20 (rT20) was expressed in Escherichia coli as a five copy repeat polypeptide with a histidine-tag. The five copy rT20 was purified by Ni-affinity chromatography and cleaved to single rT20 units by cyanogen bromide. Finally, single rT20 units were purified by reversed phase chromatography giving a yield (400 mg/l) with a purity >95 %, which exhibited specific biological activity similar to Fuzeon.

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.

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.

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.

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.

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.

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.

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.

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.

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.