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The aim of the present study was to establish the potential of rifampicin loaded phospholipid lipospheres carrier for pulmonary application. Lipospheres were prepared with rifampicin and phospholipid in the ratio of 1:1 using spray drying method. Further, lipospheres were evaluated for flow properties and surface area measurement. The formulated lipospheres were evaluated in vitro for aerodynamic characterization and in vivo for lung pharmacokinetics and biodistribution studies in Sprague Dawley rats. Powder flow properties finding suggested the free flowing nature of the lipospheres. In-vitro aerosol performance study indicated more than 80 ± 5% of the emitted dose (ED) and 77.61 ± 3% fine particles fraction (FPF). Mass median aerodynamic diameter (MMAD) and geometric standard deviation (GSD) were found to be 2.72 ± 0.13 μm and 3.28 ± 0.12, respectively. In-vitro aerosol performance study revealed the higher deposition at 3, 4 and 5 stages which simulates the trachea-primary bronchus, secondary and terminal bronchus of the human lung, respectively. The drug concentration from nebulized lipospheres in the non-targeted tissues was lesser than from rifampicin-aqueous solution. The pulmonary pharmacokinetic study demonstrated improved bioavailability, longer residence of drug in the lung and targeting factor of 8.03 for lipospheres as compared to rifampicin-aqueous solution. Thus, the results of the study demonstrated the potential of rifampicin lipospheres formulation would be of use as an alternative to existing oral therapy. [ABSTRACT FROM AUTHOR]

In the present study, tamoxifen-phospholipid complex (TMX-PLC) was developed and evaluated for its impact on solubility and bioavailability of tamoxifen. TMX-PLC was prepared by solvent evaporation method and characterized. FTIR revealed the disappearance of the characteristic peaks of TMX in the complex, which can be due to weakening, removal or shielding by the phospholipid molecule. This phenomenon could be due to packing of TMX in the hydrophobic cavity of phospholipid and being held by van der Waals forces and hydrophobic interactions. This observation was confirmed by DSC and PXRD. TMX-PLC exhibited increased solubility, dissolution rate with decreased distribution coefficient indicating its increased hydrophilicity. Oral bioavailability of TMX and TMX-PLC were evaluated in Sprague-Dawley (SD) rats. TMX-PLC exhibited considerable enhancement in the bioavailability with an increase in C max (0.85 vs. 0.40 μg/mL), t 1/2 (22.47 vs. 13.93 h), and AUC 0–∞ (15.29 vs. 8.62 μg h/mL) with 212.25% relative bioavailability. This enhancement can be attributed to the improvement of the aqueous solubility of the complex and a probable decrease in its extent of intestinal and hepatic metabolism. Thus, phospholipid complexation holds a promising potential for increasing oral bioavailability of TMX. [ABSTRACT FROM AUTHOR]

Abstract: To enhance the oral bioavailability of rifampicin (RMP), the newly emerging phospholipid complexation technique was employed. Rifampicin–phospholipid complex (RMP-PC) was prepared by solvent-evaporation method. Infrared spectroscopy (IR), differential scanning calorimetry (DSC), scanning electron microscopy (SEM), powder X-ray diffraction (PXRD) and hot stage microscopy (HSM) analysis were employed to confirm the formation of phospholipid complex. The results reveal hydrogen bond formation and electrostatic interaction between RMP and phospholipid molecule play an important role in the formation of RMP-PC without the formation of a new compound. In comparison with the physical mixture and RMP, solubility studies indicated an enhancement in the aqueous solubility of RMP-PC. Stability studies of RMP-PC in presence of isoniazid showed a remarkable improvement of the stability of the phospholipid complex in comparison to free RMP. Oral bioavailability of RMP-PC was evaluated in Sprague-Dawley (SD) rats and plasma rifampicin estimated by LCMS. RMP-PC exhibited higher peak plasma concentration (54.3 vs. 48.5μg/mL), increased AUC0–∞ (472.4 vs. 147.71 5.812±0.49μgh/mL), increased T1/2 (8.3 vs. 1.5h) when compared to free RMP implying improved bioavailability of the drug. This enhancement can be attributed to the improvement of the aqueous solubility of rifampicin–phospholipid complex. Hence, phospholipid complexation holds a promising potential for increasing oral bioavailability of poorly water soluble drugs. [Copyright &y& Elsevier]

Rheumatoid arthritis (RA) related autoimmunity is developed at mucosal sites due to the interplay between genetic risk factors and environmental triggers. The pre-RA phase that leads to anti-citrullinated protein antibodies, rheumatoid factor, and other autoantibodies spread in the systemic circulation may not affect articular tissue for years until a mysterious second hit triggers the localization of RA-related autoimmunity in joints. Several players in the joint microenvironment mediate the synovial innate and adaptive immunological processes, eventually leading to clinical synovitis. There still exists a gap in the early phase of RA pathogenesis, i.e. , the progression of diseases from the systemic circulation to joints. The lack of better understanding of these events results in the inability to answer questions about why only after a certain point of time the disease appears in joints and why in some cases, it simply remains latent and doesn't affect joints at all. In the current review, we focused on the immunomodulatory and regenerative role of mesenchymal stem cells and associated exosomes in RA pathology. We also highlighted the age-related dysregulations in activities of mesenchymal stem cells and how that might trigger homing of systemic autoimmunity to joints. [Display omitted] [ABSTRACT FROM AUTHOR]

The aim of the study was to investigate the impact of erlotinib sulfobutyl ether beta-cyclodextrin complex (ERL-SBE-β-CD) on ERL dissolution rate and oral bioavailability. Preliminary comparative phase solubility study indicated ERL exhibited maximum solubility in SBE-β-CD solution. Optimal experimental design confirmed freeze drying of SBE-β-CD:ERL in 1:1.05 molar ratio as the optimum method. Differential scanning calorimetry (DSC), Fourier transformation infrared spectroscopy (FT-IR), powder X-ray diffractometry (PXRD), proton nuclear magnetic resonance ( 1 H NMR) and two-dimensional rotating-frame Overhauser effect spectroscopy (2D ROESY NMR) confirmed the inclusion complexation. The in silico computational study, employed to analyze the comparative interactions of ERL with SBE-β-CD and β-CD, indicated ease of ERL-SBE-β-CD complexation. In vitro dissolution and in vivo bioavailability studies further confirmed the ERL-SBE-β-CD as a valuable approach to enhance ERL oral bioavailability with 3.6-fold increase in relative oral bioavailability with higher C max (134.29 ± 36.51 vs. 42.36 ± 1.75 μg/ml) and AUC 0–∞ (2103.47 ± 156.75 vs. 580.43 ± 71.91 μg/ml h) over the free drug. The complex exhibited 3.2-fold increase in C max with 5.4-fold decrease in T max (0.5 ± 0.2 vs. 2.7 ± 0.8 h) in comparison to pure ERL. Thus, ERL-SBE-β-CD complexation exhibits a potential to enhance oral bioavailability of ERL leading to reduce dose and dose-related side effects. [ABSTRACT FROM AUTHOR]

• Non additive effects(NAEs) are more pronounced at later stages of decomposition. • Chemically heterogeneous mixtures observe greater values for interaction effect. • Chemical diversity influence non additive effects more than single trait diversity. • Interaction effect values increase with increase in species richness. Biodiversity loss may seriously impact some of the major ecological functions like primary productivity, nutrient cycling and decomposition. Decomposition is a fundamental ecosystem process regulating nutrient mineralization, microbial community composition and structure, carbon sequestration in the soil. Therefore it is important to find out the link between biodiversity and decomposition dynamic which is of key interest recently among ecologists, hence we took up eleven combinations of leaf litter mixtures of four multipurpose tree species commonly occurring together in western Himalayas to find out the direction, magnitude and drivers of litter mixing effect. We found positive non significant effect of litter diversity for all mixtures except two which showed antagonistic effects after three months of decomposition. But we found positive non additive effects (NAE)/interaction effects for all litter mixtures at later stage of decomposition i.e. after nine months. The strength of litter mixing effect varied from 5.45% to 14.75% among litter mixtures. The interaction effects are observed to be greater for those litter mixtures which are more heterogeneous with respect to initial nitrogen, and phosphorus content. However the effect of chemical diversity is more marked on interaction effect/ NAE than variation in single trait(N or P content) as revealed by R2 value (coefficient of determination). Interaction effect values increased with increase in percent of fast decomposing species in the litter mixture but rate of increase decreased when the mixtures move towards homogeneity. Interaction effect also increased with increase in species richness significantly up to three species, thereafter the increase is non significant. Our results indicate that tree diversity alters decomposition dynamics of component species in the mixture. Chemical diversity is more important factor in determining non additive effect rather than taxonomic diversity of a mixture. [ABSTRACT FROM AUTHOR]

Reduced blood flow (hypoxia) to the brain is thought to be the main cause of strokes because it deprives the brain of oxygen and nutrients. An increasing amount of evidence indicates that the Centella-Asiatica (HA-CA) hydroalcoholic extract has a variety of pharmacological benefits, such as antioxidant activity, neuroprotection, anti-inflammatory qualities, and angiogenesis promotion. Intermittent fasting (IF) has neurological benefits such as anti-inflammatory properties, neuroprotective effects, and the ability to enhance neuroplasticity. The current study evaluates the combined effect of IF (for 1, 6, and 12 days) along with HA-CA (daily up to 12 days) in adult zebrafish subjected to hypoxia every 5 min for 12 days followed by behavioral (novel tank and open-field tank test), biochemical (SOD, GSH-Px, and LPO), inflammatory (IL-10, IL-1β, and TNF-α), mitochondrial enzyme activities (Complex-I, II, and IV), signaling molecules (AMPK, MAPK, GSK-3β, Nrf2), and imaging/staining (H&E, TTC, and TEM) analysis. Results show that sub-acute hypoxia promotes the behavioral alterations, and production of radical species and alters the oxidative stress status in brain tissues of zebrafish, along with mitochondrial dysfunction, neuroinflammation, and alteration of signaling molecules. Nevertheless, HA-CA along with IF significantly ameliorates these defects in adult zebrafish as compared to their effects alone. Further, imaging analysis significantly provided evidence of infarct damage along with neuronal and mitochondrial damage which was significantly ameliorated by IF and HA- CA. The use of IF and HA-CA has been proven to enhance the physiological effects of hypoxia in all dimensions. A reduction in the supply of oxygen results in stroke through an elevation in oxidative stress, reactive oxygen species, mitochondrial dysfunction and inflammation. Elevated levels of ROS are accountable for the inhibition of AMPK following sub-acute term hypoxia, which is responsible for cell survival. Our treatment, namely IF and HA-CA, exhibit an effect and vice versa. [Display omitted] • Sub-acute hypoxia exposure produces alterations in zebrafish behavior, along with biological and cellular activity. • HA-CA and IF promote cell viability by regulating AMPK levels. • AMPK activation appears to improve mitochondrial enzyme activity, oxidative stress, and inflammation. • Elevated AMP to ATP ratio leads to AMPK activation, autophagy, and increased energy production in cerebral ischemia or hypoxia. [ABSTRACT FROM AUTHOR]

An experiment was conducted for evaluating the performance of 149 elite Indian and Australian germplasm lines under normal and waterlogged soil conditions over two years (2014–15 and 2015–16), revealed significant differences for all the studied traits under waterlogged as well as under normal soil conditions. Waterlogging adversely affected thousand kernel weight, tillers per meter, biological yield and grain yield. The three morphological traits namely; biological yield, tillers per meter and plant height significantly contributed towards waterlogging tolerance. The geometric mean productivity (GMP), harmonic mean (HM), stress tolerance index (STI), mean productivity (MP) and mean relative performance (MRP), were significantly and positively correlated with grain yield under waterlogged (Ys) as well as under normal soil conditions (Yp). Whereas, yield stability index (YSI) was found positively correlated with grain yield only under waterlogged soil conditions (Ys) in both years as well as over the years. Besides, GMP, HM, MP, MRP and STI were also significantly correlated with each other in individual year as well as across years, indicating thereby that any one of these parameters might be used as an alternative option to each other for selecting high yielding genotypes under both the conditions (waterlogging and normal). The promising lines identified based on GMP, STI, MP, HM and MRP could also be rated as tolerant being high yielding particularly for waterlogging condition. The two parameters (YSI and reduction percentage) identified as effective selection indices clearly discriminated the per se performance of genotypes based on stable performance under waterlogged conditions, and thus these could be used an indicative approach of germplasm lines possessing waterlogging tolerance genes. The correlation values also supported results and indicated strong association of biological yield with yield stability index. The germplasm lines namely; UP 2584, TINCURRIN, SSD-C2-172, SSD-C2-151, SSD-C2 204, SSD-C2 140, RW 3684, NW 4098, KRL 105, K 307, HD 3086, HD 2329, DUCULA 4 and CUNDERIN were identified to be capable of producing highest biomass and also higher values for YSI among all lines taken for this study. Based on both YSI and biological yield, lines CUNDERIN, DUCULA 4, HD 3086, KRL 105 and RW 3684 were identified to as tolerant and could be utilized as potential donor for increasing waterlogging tolerance of future wheat genotypes. Our research findings also imply that tolerant lines eventually would lead to higher productivity under stress situations, where heavy rainfall and stagnation of water for a prolonged period adversely affect the wheat crop. The results of the present study based on field screening technique and the selection criteria based upon indices will be rewarding for increasing grain yield of wheat under such harsh environments. [ABSTRACT FROM AUTHOR]

The present study was envisaged to evaluate the effect of erlotinib β-cyclodextrin nanosponge (ERL-NS) on the solubility, dissolution, in vitro cytotoxicity and oral bioavailability of erlotinib (ERL). Preliminary studies were conducted to select the optimized stoichiometry concentration of ERL and NS. The drug nanosponge complex comprising of 1:4 proportions of ERL and NS was prepared by freeze drying. ERL-NS formed nanoparticles of 372 ± 31 nm size with narrow size distribution (0.21 ± 0.07 PDI) and high zeta potential (−32.07 ± 4.58 mV). The complexation phenomenon was confirmed by DSC, SEM, PXRD, FTIR, and TEM studies. In vitro dissolution studies revealed an increased dissolution rate (2-folds) with an enhanced dissolution efficiency of the nanosponge complex in comparison to pure drug. In vitro cytotoxicity study and apoptosis assay in pancreatic cell lines (MIA PaCa-2 and PANC-1) indicates the increased toxicity of ERL-NS. Both, quantitative and qualitative cell uptake studies unveiled the higher uptake efficiency of ERL-NS than free drug. ERL-NS showed enhanced oral bioavailability with 1.8-fold higher C max (78.98 ± 6.2 vs. 42.36 ± 1.75 μg/ml), and ∼2-fold AUC 0−∞ (1079.95 ± 41.38 vs. 580.43 ± 71.91), in comparison to pure ERL. Therefore, we conclude that the formation of a complex of nanosponge with ERL is a successful approach to increase its solubility, dissolution and oral bioavailability which may ultimately result in reduction in dose and dose related side-effects. [ABSTRACT FROM AUTHOR]

The high prevalence of neurodegenerative diseases has become a major public health challenge and is associated with a tremendous burden on individuals, society and federal governments worldwide. Protein misfolding and aggregation are the major pathological hallmarks of several neurodegenerative disorders. The cells have evolved several regulatory mechanisms to deal with aberrant protein folding, namely the classical ubiquitin pathway, where ubiquitination of protein aggregates marks their degradation via lysosome and the novel autophagy or mitophagy pathways. Autophagy is a catabolic process in eukaryotic cells that allows the lysosome to recycle the cell's own contents, such as organelles and proteins, known as autophagic cargo. Their most significant role is to keep cells alive in distressed situations. Mitophagy is also crucial for reducing abnormal protein aggregation and increasing organelle clearance and partly accounts for maintaining cellular homeostasis. Furthermore, substantial data indicate that any disruption in these homeostatic mechanisms leads to the emergence of several age-associated metabolic and neurodegenerative diseases. So, targeting autophagy and mitophagy might be a potential therapeutic strategy for a variety of health conditions. [Display omitted] [ABSTRACT FROM AUTHOR]