Cytotoxicity and genotoxicity of tributyltin in the early embryonic chick, Gallus gallus domesticus.

Tributyltin (TBT) is used in many commercial applications, including pesticides and antifouling paints, due to its biocidal properties. We examined the cytotoxicity and genotoxicity of TBT in the early chick embryo (Gallus gallus domesticus). Chick embryos (11 days) were treated with various doses of TBT to measure LD50 values for 24, 48, and 72 h exposures, which were determined to be 110, 54, and 18 µg/egg, respectively. The embryos were exposed to sub-lethal doses of TBT for evaluation of cytotoxicity and genotoxicity. An increase in the incidence of micronuclei (MN) was observed but it was not statistically significant. Induction of other nuclear abnormalities (ONA) after 72 h TBT exposure was significant. A significant increase in comet assay tail DNA content was also detected in TBT-exposed embryos. Cytotoxicity was also evidenced by alteration in the polychromatic erythrocytes (PCE) to normochromatic erythrocytes (NCE) ratio and by an increase in the erythroblast population in treated organisms. The cytotoxicity and genotoxicity of TBT may have long-term complications in later stages of the life cycle.

Progress of Photocapacitors.

In response to the current trend of miniaturization of electronic devices and sensors, the complementary coupling of high-efficiency energy conversion and low-loss energy storage technologies has given rise to the development of photocapacitors (PCs), which combine energy conversion and storage in a single device. Photovoltaic systems integrated with supercapacitors offer unique light conversion and storage capabilities, resulting in improved overall efficiency over the past decade. Consequently, researchers have explored a wide range of device combinations, materials, and characterization techniques. This review provides a comprehensive overview of photocapacitors, including their configurations, operating mechanisms, manufacturing techniques, and materials, with a focus on emerging applications in small wireless devices, Internet of Things (IoT), and Internet of Everything (IoE). Furthermore, we highlight the importance of cutting-edge materials such as metal-organic frameworks (MOFs) and organic materials for supercapacitors, as well as novel materials in photovoltaics, in advancing PCs for a carbon-free, sustainable society. We also evaluate the potential development, prospects, and application scenarios of this emerging area of research.

Areca nut and smokeless tobacco exposure induces micronucleus, other nuclear abnormalities and cytotoxicity in early chick embryo.

Areca nut (AN) and smokeless tobacco (SLT) are indiscriminately consumed among the populations of Southeast and South Asian countries, even by women during the gestational period. This study aimed to investigate the genotoxic and cytotoxic potentials of AN and Sadagura (SG), a unique homemade SLT preparation, alone and in combination in early chick embryos. Fertile white leghorn chicken eggs were randomly divided into five treatment groups: vehicle control, positive control (Mitomycin C, 20 µg/egg), AN, SG, and AN+SG. AN, SG, and AN+SG were given at dosages of 0.125, 0.25, and 0.5 mg/egg. The hen's egg test for micronucleus induction (HET-MN) was performed in chick embryos to evaluate the genotoxic potential of the test agents. Furthermore, the cytotoxic potential was assessed by studying erythroblast cell populations and the polychromatic erythrocytes (PCEs) to normochromatic erythrocytes (NCEs) ratio. Our results indicated a significant increase (p < .001) in MN frequency and other nuclear abnormalities, suggesting the potential of AN and SG to cause genotoxicity. Also, AN and SG exposure alone and in combination considerably altered the erythroblast cell population (%) and the PCE to NCE ratio in all the treatment periods. Our findings established the genotoxic and cytotoxic potential of both AN and SG alone and in combination during early embryonic development in the chick embryo.

NiMoO4@NiMnCo2O4 Heterostructure: A Poly(3,4-propylenedioxythiophene) Composite-Based Supercapacitor Powers an Electrochromic Device.

The hierarchical heterostructure of NiMoO4@NiMnCo2O4 (NMO@NMCO) with furry structures of NMCO juxtaposed with NMO nanowires are endowed with multiple electrochemically active and accessible sites for ion storage, thus delivering an ultrahigh specific capacitance of 2706 F g-1, nearly two-fold times greater than that of sole NMCO. Electrodeposition of an overlayer of a highly robust and electrically conducting polymer, poly(3,4-propylenedioxythiophene) (PProDOT), not only improves the energy storage performance but also assists the binary oxide cathode in retaining its structural integrity during redox cycling. Coupling with an anode of porous flaky carbon (FC) derived from groundnut shells results in an asymmetric supercapacitor of FC//PProDOT@NiMoO4@NiMnCo2O4, which delivers an outstanding capacitance of 552 F g-1, energy and power density ranges of 172-40 Wh kg-1 and 0.75-10 kW kg-1, respectively, and a remarkable cycle life of 50 000 cycles, with ∼97.8% capacitance retention, over an operational voltage window of 1.5 V. From an application perspective, the charged supercapacitor was connected to a complementary coloring reversible electrochromic device (ECD) of Prussian blue//PProDOT, and the ECD state transformed from a pale-blue to a deep blue hue, thus signaling the efficient utilization of energy stored in the supercapacitor. The energy-saving attribute of the ECD was realized in terms of an integrated visible-light modulation of 39% that accompanied the optical transition. Deployment of low-cost devices at homes and commercial spaces, capable of storing and saving energy, is the way forward, and this is one significant step in this direction.

Consumption pattern and genotoxic potential of various smokeless tobacco products in Assam, India: A public health concern.

Smokeless tobacco (SLT) consumption is presumed to be one of the major causes of high incidence of oral cancer in India. The present study aimed to document various types of SLT products consumed and their potential impact on the genome instability on the population from Assam state in Northeast India. A cross-sectional study (n = 5000) showed that 60.56 % of the study population consumed at least one of the three forms (sadagura, zarda and khaini) of SLT of which 52.0 % were only sadagura users. Genotoxicity assessment using buccal cytome assay in 240 age and sex matched volunteers revealed that except for zarda, other forms of SLT induced significantly higher incidence micronuclei in the buccal epithelial cells compared to the control individuals. Similar effects were also observed in other cytome parameters related to cell proliferation, cytokinesis defects and cell death. Significantly higher incidence of micronucleus was observed among sadagura and khaini users in lymphocyte cytokinesis-blocked micronucleus assay. The addition of lime in sadagura increased the pH and anion levels which possibly result in higher absorption and may lead to the development of cellular anomalies.

Development and evaluation of a gold nanoparticle based Lateral Flow assay (LFA) strip test for detection of Brucella spp.

The widely used serodiagnostic test (RBPT, CFT, I-ELISA and FPA) for diagnosis of brucellosis cannot detect vertically infected or carrier animals that are seronegative, a persistent source of infection to other susceptible animals in the herd. For reducing transmission of disease within the herd, these animals must be detected using a rapid, sensitive, user friendly penside diagnostic test. In the present study, Lateral Flow immunoassay (LFA) strip test was developed for detection of Brucellaspp. from clinical samples (bovine aborted foetal stomach contents). The LFA strip was fabricated by printing anti-Brucella polyclonal antibodies (PAb) and anti-bovine antibodies IgG on test and control line, respectively. For conjugation, colloidal gold nanoparticles (30 nm GNP, Sigma, USA) were conjugated with anti-brucella PAb. The LFA strip test was able to detect 107 cfu/ml B.abortus S99 inactivated organism in PBS and it did not exhibit any cross reactivity with selected non Brucella pathogens. To further validate, 115 clinical specimens were tested using LFA strip test. The relative sensitivity (DSn) and relative specificity (DSp) of LFA strip test was determined by ROC curve analysis using PCR and culture method as reference standard. DSn and DSp of LFA strip test was observed as 78.57% (95%CI: 49.2-95.3); 93.07% (95%CI: 86.2-97.2) and 80.0% (95%CI:51.9-95.7); 94.0% (95%CI:0.795-0.925) using culture and PCR as reference diagnostic tests, respectively. It may be concluded that, the LFA strip test can be used as a rapid penside diagnostic test for screening of brucellosis. To the best of our knowledge, this is the first report on development of GNP based LFA strip test for detection of Brucella spp. from bovine aborted fetal content samples.

A Review on Role of Arecoline and Its Metabolites in the Molecular Pathogenesis of Oral Lesions with an Insight into Current Status of Its Metabolomics.

Areca nut consumption is a popular habit in Southeast Asian countries. One of the important biologically active alkaloids of areca nut is arecoline, which plays a role in mediating the development of several pathologies of the primary exposure site, the oral cavity. Studies on the metabolism of arecoline revealed the formation of several metabolites which themselves might be toxic. Moreover, polymorphisms in genes encoding enzymes involved in the metabolism of arecoline might predispose an organism towards the development of oral cancer. The present review tries to accumulate all the relevant existing literature and then elucidate the molecular mechanism by which arecoline plays a role in the development of oral submucous fibrosis and oral cancer. Existing information regarding arecoline metabolism, enzymes involved in the metabolic process and biological effects of the metabolites of arecoline have also been compiled and compared to study the toxicity of metabolites with its parent compound arecoline and whether they play any role in the pathogenesis of oral cancer mediated by areca nut consumption. A repertoire of molecular targets has come up in the discussion whose expression profile is perturbed by arecoline. Construction of induction cascade from existing literature has given an idea about the process of molecular pathogenesis. The summarized and analysed data can help to determine the molecular mechanism and drug targets, which in turn could be helpful in the prevention or treatment of these pathological conditions. It also brings into light areas where further research needs to be directed.

A poly(3,4-propylenedioxythiophene)/carbon micro-sphere-bismuth nanoflake composite and multifunctional Co-doped graphene for a benchmark photo-supercapacitor.

Efficient storage of sunlight in the form of charge is accomplished by designing and implementing a photo-supercapacitor (PSC) with a novel, cost-effective architecture. Sulfur (S)- and nitrogen (N)-doped graphene particles (SNGPs) are incorporated in a TiO2/CdS photoanode. The beneficial effects of SNGPs such as the high electrical conductance promoting fast electron transfer to TiO2, a suitably positioned conduction band that maximizes charge separation, and its' ability to absorb red photons translate into a power conversion efficiency of 9.4%, for the champion cell. A new composite of poly(3,4-propylenedioxythiophene)/carbon micro-sphere-bismuth nanoflakes (PProDOT/CMS-BiNF) is integrated with the photoanode to yield the PSC. The photocurrent produced under 1 sun irradiance is directed to the supercapacitor, wherein, the synergy between the faradaic and electrical double layer charge accumulation mechanisms of PProDOT and CMS-BiNF bestows storage parameters of an areal capacitance of 104.6 mF cm-2, and energy and power densities of 9 µW h cm-2 and 0.026 mW cm-2. An overall photo-conversion and storage efficiency of 6.8% and an energy storage efficiency of 72% exhibited by the PSC are much superior to those delivered by a majority of the PSCs reported in the literature on the otherwise highly efficient perovskite solar cell or the expensive Ru dye based solar cells.

Bifunctional Photo-Supercapacitor with a New Architecture Converts and Stores Solar Energy as Charge.

Photo-supercapacitors (PSCs) combine functions of energy harvesting and storage in a single device, and in this study, a new architecture for a PSC is designed and implemented. Cadmium sulfide (CdS) quantum dots/hibiscus (hb) dye co-sensitized TiO2 is used as the solar cell. Poly(3,4-ethylenedioxypyrrole) (PEDOP)@manganese dioxide (MnO2) is employed as the counter electrode (CE) for the solar cell and also as the electrodes for the symmetric supercapacitor. The two ends of a long flat current collector support two spatially separated PEDOP@MnO2 coatings, which serve as the CEs for the TiO2/hb/CdS photoanode and yet another PEDOP@MnO2 electrode in sandwich configurations. In this cell, under 1 sun (100 mW cm-2) illumination, the TiO2/hb/CdS photoanode undergoes charge separation and by channeling the photocurrent to the PEDOP@MnO2 electrodes, the symmetric cell part is charged to a voltage of 0.72 V. The PSC delivers a specific capacitance of 183 F g-1, an energy density of 13.2 Wh kg-1, and a power density of 360 W kg-1 at a discharge current density of 1 A g-1. During the self-discharge process, PEDOP@MnO2-based PSC retains a voltage of 0.72 V up to 500 s and maintains a stable voltage of 0.5 V thereafter. The TiO2/hb/CdS photoanode with the PEDOP@MnO2 CE in an aqueous polysulfide-silica gel electrolyte delivers a power conversion efficiency of 6.11%. This demonstration of a novel PSC opens up opportunities to develop new architectures for efficiently combining energy conversion and storage.

Draft genome sequence of field isolate Brucella melitensis strain 2007BM/1 from India.

OBJECTIVES: Brucellosis is among one of the most widespread important global zoonotic diseases that is endemic in many parts of India. Brucella melitensis is supposed to be the most pathogenic species for humans. Here we report the draft genome sequence of B. melitensis strain 2007BM/1 isolated from a human in India. METHODS: Genomic DNA was extracted from Brucella culture and was sequenced using an Illumina MiSeq platform. The generated reads were assembled using three de novo assemblers and the draft genome was annotated. RESULTS: This monoisolate, with a genome length of 3268756bp, was found to be resistant to azithromycin and trimethoprim/sulfamethoxazole but susceptible to tetracycline, ofloxacin, rifampicin, ciprofloxacin and doxycycline. The presence of virulence genes in the strain was identified. CONCLUSIONS: The results obtained will help in understanding drug resistance mechanisms and virulence factors in highly zoonotic B. melitensis and suggest the need for judicious use of antibiotics in livestock health and management practices.

Dual function of molybdenum sulfide/C-cloth in enhancing the performance of fullerene nanosheets based solar cell and supercapacitor.

Quantum dot solar cells (QDSCs) with hexagonal fullerene nanosheets (C60-NS) embedded in a titanium oxide/cadmium sulfide (TiO2/CdS) photoanode coupled with a carbon-cloth (C-cloth) coated with molybdenum sulfide (MoS2) counter electrode (CE) are studied for the first time. C60-NS due to a favorable work function of 4.57 eV and a conductance of 1.44 µS, enable faster electron injection from the conduction band of cadmium sulfide to the current collector, in contrast to the bulk fullerene based TiO2/CdS solar cell. The champion cell with the TiO2/C60-NS/CdS photoanode and a MoS2/C-cloth CE exhibits a high power conversion efficiency of 5.6%, greater by ∼14% relative to its' analogue cell with bulk fullerene. A large area cell of 1 cm2 dimensions with TiO2/C60-NS/CdS gives a PCE of 2.9%. The effect of MoS2 in improving the efficiency of the cell with a TiO2/C60-NS/CdS photoanode is realized in terms of enhanced electrocatalytic activity for polysulfide reduction, and lower charge transfer resistance at the polysulfide/CE interface compared to a cell with the same photoanode but having pristine carbon-cloth as the CE. The ability of MoS2 for catalyzing the oxidized polysulfide species at the CE and C60-NS for improving the charge collection at the photoanode serve as indicators for their wider utilization in solar cells. It also serves as a good supercapacitor material. A MoS2/C-cloth based symmetric cell exhibits a specific capacitance of 645 F g-1 at 2 A g-1, which shows its' potential for energy storage as well. By integrating the QDSC and the supercapacitor, the resulting integrated device acquires a photovoltage of 0.7 V, under 1 sun illumination.

Molecular Characterization and Antioxidant Potential of Three Wild Culinary-Medicinal Mushrooms from Tripura, Northeast India.

The aim of this study was to characterize 3 wild culinary-medicinal mushrooms using molecular tools and to analyze their antioxidant activity. Antioxidant properties were studied by evaluating free radical scavenging, reducing power, and chelating effect. The mushrooms were identified as Lentinus squarrosulus, L. tuber-regium, and Macrocybe gigantean by amplifying internal transcribed spacer regions of ribosomal DNA. The results demonstrated that the methanolic extract of M. gigantean has the highest free radical scavenging effect and chelating effect, whereas the methanolic extract of L. squarrosulus has the highest reducing power. The highest total phenol content and the most ascorbic acid were found in the M. gigantean extracts. Among the 3 mushroom extracts, M. gigantean displayed the most potent antioxidant activity. Molecular characterization using the nuclear ribosomal internal transcribed spacer region as a universal DNA marker was an effective tool in the identification and phylogenetic analysis of the studied mushrooms. The study also indicated that these wild macrofungi are rich sources of natural antioxidants.

Lead-Sulfide-Selenide Quantum Dots and Gold-Copper Alloy Nanoparticles Augment the Light-Harvesting Ability of Solar Cells.

Lead-sulfide-selenide (PbSSe) quantum dots (QDs) and gold-copper (AuCu) alloy nanoparticles (NPs) were incorporated into a cadmium sulfide (CdS)/titanium oxide (TiO2 ) photoanode for the first time to achieve enhanced conversion of solar energy into electricity. PbSSe QDs with a band gap of 1.02 eV extend the light-harvesting range of the photoanode from the visible region to the near-infrared region. The conduction band (CB) edge of the PbSSe QDs is wedged between the CBs of TiO2 and CdS; this additional level coupled with the good electrical conductivity of the dots facilitate charge transport and collection, and a high power conversion efficiency (PCE) of 4.44 % is achieved for the champion cell with the TiO2 /PbSSe/CdS electrode. Upon including AuCu alloy NPs in the QD-sensitized electrodes, light absorption is enhance by plasmonic and light-scattering effects and also by the injection of hot electrons to the CBs of the QDs. Comparison of the incident photon-to-current conversion efficiency enhancement factors in addition to fluorescence decay and impedance studies reveal that the PbSSe QDs and AuCu alloy NPs promote charge injection to the current collector and increase the photogenerated charges produced, which thus enables the TiO2 /PbSSe/CdS/AuCu cell to deliver the highest PCE of 5.26 % among all the various photoanode compositions used.

Development of carrier-based formulation of root endophyte Piriformospora indica and its evaluation on Phaseolus vulgaris L.

Endophytic fungi are plant beneficial rhizospheric microorganisms often applied as bioinoculants for enhanced and disease-free crop production. The objectives of the present work were to develop a carrier-based formulation of root endophyte Piriformospora indica as a bioinoculant. Powder formulation of four different carrier materials viz., talcum powder, clay, sawdust and bioboost (organic supplement) were evaluated and a talc-based formulation was optimized for a longer shelf life with respect to microbial concentration, storage temperature and biological activity. Finally the effect of optimized talc formulation on plant productivity was determined. The application dosages were optimized by studies on plant growth parameters of Phaseolus vulgaris L. plants under green house conditions. Five percent formulation (w/w) of talcum powder was observed to be the most stable at 30 °C with 10(8) CFU g(-1) and effective for a storage period of 6 months. The application of this optimized formulation resulted in increase of growth parameters of P. vulgaris L. and better adaptation of plants under green house conditions.

In vitro plant development and root colonization of Coleus forskohlii by Piriformospora indica.

The present study was conducted for optimization of in vitro substrates under aseptic conditions for interaction of Piriformospora indica with the medicinal plant Coleus forskohlii. It aims to test the effects of different substrates on P. indica colonization as well as growth parameters of the in vitro raised C. forskohlii. Interaction of in vitro C. forskohlii with root endophyte P. indica under aseptic condition resulted in increase in growth parameters in fungus colonized plants. It was observed that P. indica promoted the plant's growth in all irrespective of substrates used for co-culture study. The growth was found inferior in liquid compared to semisolid medium as well as there was problem of hyperhydricity in liquid medium. P. indica treated in vitro plantlets were better adapted for establishment under green house compared to the non treated plants due to fungal intervention.

The root endophyte fungus Piriformospora indica leads to early flowering, higher biomass and altered secondary metabolites of the medicinal plant, Coleus forskohlii.

This study was undertaken to investigate the influence of plant probiotic fungus Piriformospora indica on the medicinal plant C. forskohlii. Interaction of the C. forskohlii with the root endophyte P. indica under field conditions, results in an overall increase in aerial biomass, chlorophyll contents and phosphorus acquisition. The fungus also promoted inflorescence development, consequently the amount of p-cymene in the inflorescence increased. Growth of the root thickness was reduced in P. indica treated plants as they became fibrous, but developed more lateral roots. Because of the smaller root biomass, the content of forskolin was decreased. The symbiotic interaction of C. forskohlii with P. indica under field conditions promoted biomass production of the aerial parts of the plant including flower development. The plant aerial parts are important source of metabolites for medicinal application. Therefore we suggest that the use of the root endophyte fungus P. indica in sustainable agriculture will enhance the medicinally important chemical production.

Thyroid transcription factor-1 (TTF-1) gene: identification of ZBP-89, Sp1, and TTF-1 sites in the promoter and regulation by TNF-α in lung epithelial cells.

Thyroid transcription factor-1 (TTF-1/Nkx2.1/TITF1) is a homeodomain-containing transcription factor essential for the morphogenesis and differentiation of the lung. In the lung, TTF-1 controls the expression of surfactant proteins that are essential for lung stability and lung host defense. In this study, we identified functionally important transcription factor binding sites in the TTF-1 proximal promoter and studied tumor necrosis factor-α (TNF-α) regulation of TTF-1 expression. TNF-α, a proinflammatory cytokine, has been implicated in the pathogenesis of acute respiratory distress syndrome (ARDS) and inhibits surfactant protein levels. Deletion analysis of TTF-1 5'-flanking DNA indicated that the TTF-1 proximal promoter retained high-level activity. Electrophoretic mobility shift assay, chromatin immunoprecipitation, and mutational analysis experiments identified functional ZBP-89, Sp1, Sp3, and TTF-1 sites in the TTF-1 proximal promoter. TNF-α inhibited TTF-1 protein levels in H441 and primary alveolar type II cells. TNF-α inhibited TTF-1 gene transcription and promoter activity, indicating that transcriptional mechanisms play important roles in the inhibition of TTF-1 levels. TNF-α inhibited TTF-1 but not Sp1 or hepatocyte nuclear factor-3 DNA binding to TTF-1 promoter. Transactivation experiments in A549 cells indicated that TNF-α inhibited TTF-1 promoter activation by exogenous Sp1 and TTF-1 without altering their levels, suggesting inhibition of transcriptional activities of these proteins. TNF-α inhibition of TTF-1 expression was associated with increased threonine, but not serine, phosphorylation of Sp1. Because TTF-1 serves as a positive regulator for surfactant protein gene expression, TNF-α inhibition of TTF-1 expression could have important implications for the reduction of surfactant protein levels in diseases such as ARDS.

Transcriptional regulation of SP-B gene expression by nitric oxide in H441 lung epithelial cells.

Surfactant protein B (SP-B) is essential for the surface tension-lowering function of pulmonary surfactant. Surfactant dysfunction and reduced SP-B levels are associated with elevated nitric oxide (NO) in inflammatory lung diseases, such as acute respiratory distress syndrome. We previously found that NO donors decreased SP-B expression in H441 and MLE-12 lung epithelial cells by reducing SP-B promoter activity. In this study, we determined the roles of DNA elements and interacting transcription factors necessary for NO inhibition of SP-B promoter activity in H441 cells. We found that the NO donor diethylenetriamine-nitric oxide adduct (DETA-NO) decreased SP-B promoter thyroid transcription factor 1 (TTF-1), hepatocyte nuclear factor 3 (HNF-3), and Sp1 binding activities but increased activator protein 1 (AP-1) binding activity. DETA-NO decreased TTF-1, but not Sp1, levels, suggesting that reduced TTF-1 expression contributes to reduced TTF-1 binding activity. Lack of effect on Sp1 levels suggested that DETA-NO inhibits Sp1 binding activity per se. Overexpression of Sp1, but not TTF-1, blocked DETA-NO inhibition of SP-B promoter activity. DETA-NO inhibited SP-B promoter induction by exogenous TTF-1 without altering TTF-1 levels. DETA-NO decreased TTF-1 mRNA levels and gene transcription rate, indicating that DETA-NO inhibits TTF-1 expression at the transcriptional level. We conclude that NO inhibits SP-B promoter by decreasing TTF-1, Sp1, and HNF-3 binding activities and increasing AP-1 binding activity. NO inhibits TTF-1 levels and activity to decrease SP-B expression. NO inhibition of SP-B expression could be a mechanism by which surfactant dysfunction occurs in inflammatory lung diseases.

Advances in the treatment of heart failure with a preserved ejection fraction.

PURPOSE OF REVIEW: Heart failure with preserved ejection fraction (HF-PEF) occurs in approximately 50% of patients with heart failure (HF) and is associated with high morbidity and mortality. A recent study demonstrated that, although survival improved significantly over time among HF patients with reduced ejection fraction (EF), there was no such trend toward improvement among patients with HF-PEF. Therefore, there exists an urgent need to develop effective treatment strategies specifically for patients with HF-PEF. Recently completed and ongoing research in the treatment of HF-PEF is reviewed in this article. RECENT FINDINGS: The two large randomized clinical trials completed in HF-PEF patients did not achieve statistical significance in benefit of renin-angiotensin system blockade on their primary combined endpoints of morbidity and mortality. Both trials, however, suggested the benefit of the angiotensin receptor and angiotensin-converting enzyme blockade on HF hospitalization. In addition, no clear benefit of beta-blockers has been demonstrated specifically in patients with HF-PEF. SUMMARY: Current therapeutic recommendations for HF-PEF are aimed mostly at symptomatic management and treatment of concomitant comorbidities. Results of ongoing clinical trials further evaluating inhibition of the angiotensin and the aldosterone receptors as well as examining other novel therapeutic targets in HF-PEF are keenly awaited.

Proteasome dysfunction inhibits surfactant protein gene expression in lung epithelial cells: mechanism of inhibition of SP-B gene expression.

Surfactant proteins maintain lung function through their actions to reduce alveolar surface tension and control of innate immune responses in the lung. The ubiquitin proteasome pathway is responsible for the degradation of majority of intracellular proteins in eukaryotic cells, and proteasome dysfunction has been linked to the development of neurodegenerative, cardiac, and other diseases. Proteasome function is impaired in interstitial lung diseases associated with surfactant protein C (SP-C) mutation mapping to the BRICHOS domain located in the proSP-C protein. In this study we determined the effects of proteasome inhibition on surfactant protein expression in H441 and MLE-12 lung epithelial cells to understand the relationship between proteasome dysfunction and surfactant protein gene expression. Proteasome inhibitors lactacystin and MG132 reduced the levels of SP-A, SP-B, and SP-C mRNAs in a concentration-dependent manner in H441 and MLE-12 cells. In H441 cells, lactacystin and MG132 inhibition of SP-B mRNA was associated with similar decreases in SP-B protein, and the inhibition was due to inhibition of gene transcription. Proteasome inhibitors decreased thyroid transcription factor-1 (TTF-1)/Nkx2.1 DNA binding activity, and the reduced TTF-1 DNA binding activity was due to reduced expression levels of TTF-1 protein. These data indicated that the ubiquitin proteasome pathway is essential for the maintenance of surfactant protein gene expression and that disruption of this pathway inhibits surfactant protein gene expression via reduced expression of TTF-1 protein.