Saroglitazar is noninferior to fenofibrate in reducing triglyceride levels in hypertriglyceridemic patients in a randomized clinical trial

Saroglitazar, being a dual PPAR-α/γ agonist, has shown beneficial effect in diabetic dyslipidemia and hypertriglyceridemia. Fibrates are commonly used to treat severe hypertriglyceridemia. However, the effect of saroglitazar in patients with moderate to severe hypertriglyceridemia was not evaluated. We conducted a study to compare the efficacy and safety of saroglitazar (4 mg) with fenofibrate (160 mg) in patients with moderate to severe hypertriglyceridemia. This was a multicenter, randomized, double-blinded, double-dummy, active-control, and noninferiority trial in adult patients with fasting triglyceride (TG) levels of 500–1,500 mg/dl. The patients were randomized in a 1:1 ratio to receive daily dose of saroglitazar or fenofibrate for 12 weeks. The primary efficacy end point was the percent change in TG levels at week 12 relative to baseline. The study comprised of 41 patients in the saroglitazar group and 41 patients in the fenofibrate group. We found that the percent reduction from baseline in TG levels at week 12 was significantly higher in the saroglitazar group (least square mean = ?55.3%; SE = 4.9) compared with the fenofibrate group (least square mean = ?41.1%; SE = 4.9; P = 0.048). Overall, 37 treatment-emergent adverse events (AEs) were reported in 24 patients (saroglitazar: 13; fenofibrate: 11). No serious AEs were reported, and no patient discontinued the study because of AEs. We conclude that saroglitazar (4 mg) is noninferior to fenofibrate (160 mg) in reducing TG levels after 12 weeks of treatment, was safe, and well tolerated.     

Phosphorelays Provide Tunable Signal Processing Capabilities for the Cell

Achieving a complete understanding of cellular signal transduction requires deciphering the relation between structural and biochemical features of a signaling system and the shape of the signal-response relationship it embeds. Using explicit analytical expressions and numerical simulations, we present here this relation for four-layered phosphorelays, which are signaling systems that are ubiquitous in prokaryotes and also found in lower eukaryotes and plants. We derive an analytical expression that relates the shape of the signal-response relationship in a relay to the kinetic rates of forward, reverse phosphorylation and hydrolysis reactions. This reveals a set of mathematical conditions which, when satisfied, dictate the shape of the signal-response relationship. We find that a specific topology also observed in nature can satisfy these conditions in such a way to allow plasticity among hyperbolic and sigmoidal signal-response relationships. Particularly, the shape of the signal-response relationship of this relay topology can be tuned by altering kinetic rates and total protein levels at different parts of the relay. These findings provide an important step towards predicting response dynamics of phosphorelays, and the nature of subsequent physiological responses that they mediate, solely from topological features and few composite measurements; measuring the ratio of reverse and forward phosphorylation rate constants could be sufficient to determine the shape of the signal-response relationship the relay exhibits. Furthermore, they highlight the potential ways in which selective pressures on signal processing could have played a role in the evolution of the observed structural and biochemical characteristic in phosphorelays.     

Nitrogen fixation ability explains leaf chemistry and arbuscular mycorrhizal responses to fertilization

Atmospheric nitrogen (N) and phosphorus (P) deposition rates are predicted to drastically increase in the coming decades. The ecosystem level consequences of these increases will depend on how plant tissue nutrient concentrations, stoichiometry and investment in nutrient uptake mechanisms such as arbuscular mycorrhizal fungi (AMF) change in response to increased nutrient availability, and how responses differ between plant functional types. Using a factorial nutrient addition experiment with seedlings of multiple N-fixing and non-N-fixing tree species, we examined whether leaf chemistry and AMF responses differ between these dominant woody plant functional groups of tropical savanna and dry forest ecosystems. We found that N-fixers have remarkably stable foliar chemistry that stays constant with external input of nutrients. Non-N-fixers responded to N and N + P addition by increasing both concentrations and total amounts of foliar N, but showed a corresponding decrease in P concentrations while total amounts of foliar P stayed constant, suggesting a ‘dilution’ of tissue P with increased N availability. Non-N-fixers also showed an increase in N:P ratios with N and N + P addition, probably driven by both an increase in N and a decrease in P concentrations. AMF colonization decreased with N + P addition in non-N-fixers and increased with N and N + P addition in N-fixers, suggesting differences in their nutrient acquisition roles in the two plant functional groups. Our results suggest that N-fixers and non-N-fixers can differ significantly in their responses to N and P deposition, with potential consequences for future nutrient and carbon cycling in savanna and dry forest ecosystems.     

Lyotropic Liquid Crystalline Nanoparticles of Amphotericin B: Implication of Phytantriol and Glyceryl Monooleate on Bioavailability Enhancement

Implication of different dietary specific lipids such as phytantriol (PT) and glyceryl monooleate (GMO) on enhancing the oral bioavailability of amphotericin B (AmB) was examined. Liquid crystalline nanoparticles (LCNPs) were prepared using hydrotrope method, followed by in vitro characterization, Caco-2 cell monolayer uptake, and in vivo pharmacokinetic and toxicity evaluation. Optimized AmB-LCNPs displayed small particle size (<?210 nm) with a narrow distribution (~?0.2), sustained drug release and high gastrointestinal stability, and reduced hemolytic toxicity. PLCNPs presented slower release, i.e., ~?80% as compared to ~?90% release in case of GLCNPs after 120 h. Significantly higher uptake in Caco-2 monolayer substantiated the role of LCNPs in increasing the intestinal permeability followed by increased drug titer in plasma. Pharmacokinetic studies demonstrated potential of PT in enhancing the bioavailability (approximately sixfold) w.r.t. of its native counterpart with reduced nephrotoxicity as presented by reduced nephrotoxicity biomarkers and histology studies. These studies established usefulness of PLCNPs over GLCNPs and plain drug. It can be concluded that acid-resistant lipid, PT, can be utilized efficiently as an alternate lipid for the preparation of LCNPs to enhance bioavailability and to reduce nephrotoxicity of the drug as compared to other frequently used lipid, i.e., GMO.     

Regulation of miR-34 Family in Neuronal Development

Differentiation of neural stem cells (NSC’s) to mature and functional neurons requires coordinated expression of mRNA, microRNAs (miRNAs) and regulatory proteins. Our earlier unbiased miRNA profiling studies have identified miR-200, miR-34 and miR-221/222 as maximally up-regulated miRNA families in differentiating PC12 cells and demonstrated the capability of miR-200 family in inducing neuronal differentiation (J. Neurochem, 2015, 133, 640–652). In present study, we have investigated role of miR-34 family in neuronal differentiation and identified P53 as mediator of nerve growth factor (NGF) induced miR-34a expression in differentiating PC12 cells. Our studies have shown that NGF induced miR-34a, arrests proliferating PC12 cells to G1 phase, which is pre-requisite for neuronal differentiation. Our studies have also shown that increased expression of miR-34a controls the P53 level in differentiated PC12 cells in feedback inhibition manner, which probably prevents differentiated cells from P53 induced apoptosis. Expression profiling of miR-34 family in different neuronal, non-neuronal and developing cells have identified differentiated and aged brain cells as richest source of miR-34, which also indicates that higher expression of miR-34 family helps in maintaining the mature neurons in non-proliferative stage. In conclusion, our studies have shown that miR-34 is brain enriched miRNA family, which up-regulates with neuronal maturation and brain ageing and co-operative regulation of P53 and miR-34a helps in neuronal differentiation by arresting cells in G1 phase.     

Application of photographic capture–recapture modelling to estimate demographic parameters for male Asian elephants

In addition to the threats of habitat loss and degradation, adult males of the Asian elephant Elephas maximus also face greater threats from ivory poaching and conflict with humans. To understand the impact of these threats, conservationists need robust estimates of abundance and vital rates specifically for the adult male segment of elephant populations. By integrating the identification of individual male elephants in a population from distinct morphology and natural markings, with modern capture–recapture (CR) sampling designs, it is possible to estimate various demographic parameters that are otherwise difficult to obtain from this long-lived and wide-ranging megaherbivore. In this study, we developed systematic individual identification protocols and integrated them into CR sampling designs to obtain capture histories and thereby estimate the abundance of adult bull elephants in a globally important population in southern India. We validated these estimates against those obtained from an independent method combining line-transect density estimates with age–sex composition data for elephants. The sampled population was open to gains and losses between sampling occasions. The abundance of adult males in the 176 km² study area was (SÊ ) = 134(14.20) and they comprised 14% (±1%) of the total elephant population. Time-specific abundance estimates for each sampling occasion showed a distinct increase in adult male numbers over the sampling period, explained by seasonal patterns of local migration. CR-based estimates for adult male abundance closely matched estimates from distance-based methods. Thus, while providing abundance data of comparable rigour and precision, photographic CR methods permit estimation of demographic parameters for the Asian elephant that are both urgently needed and difficult to obtain.     

Electromechanics and Volume Dynamics in Nonexcitable Tissue Cells

Cell volume regulation is fundamentally important in phenomena such as cell growth, proliferation, tissue homeostasis, and embryogenesis. How the cell size is set, maintained, and changed over a cell’s lifetime is not well understood. In this work we focus on how the volume of nonexcitable tissue cells is coupled to the cell membrane electrical potential and the concentrations of membrane-permeable ions in the cell environment. Specifically, we demonstrate that a sudden cell depolarization using the whole-cell patch clamp results in a 50% increase in cell volume, whereas hyperpolarization results in a slight volume decrease. We find that cell volume can be partially controlled by changing the chloride or the sodium/potassium concentrations in the extracellular environment while maintaining a constant external osmotic pressure. Depletion of external chloride leads to a volume decrease in suspended HN31 cells. Introducing cells to a high-potassium solution causes volume increase up to 50%. Cell volume is also influenced by cortical tension: actin depolymerization leads to cell volume increase. We present an electrophysiology model of water dynamics driven by changes in membrane potential and the concentrations of permeable ions in the cells surrounding. The model quantitatively predicts that the cell volume is directly proportional to the intracellular protein content.     

Biosynthesis and therapeutic implications of iridoid glycosides from <Emphasis Type="Italic">Picrorhiza</Emphasis> genus: the road ahead

Picrorhiza genus is emerging as an important paradigm for herbal drug formulations due to its versatile iridoid glycosides exhibition and robustness in the treatment of diverse infections including hepatic amoebiasis, cancer, malaria, ulcerative colitis and cerebral ischemia reperfusion injury. Owing to the superiority of these bioactivities, iridoid glycosides from Picrorhiza have become a hot research area over the years. A metabolic pathway for the formation of iridoid glycosides has been proposed. However, some enzymes and genes of this route are still unidentified and demand the enumeration of facilitating pathways contributing to the biosynthesis of iridoid glycosides. This review summarizes the current knowledge of all naturally occurring iridoid glycosides from Picrorhiza, their biosynthesis and pharmacological capabilities which could provide the insight into metabolic regulation and the basis for the development of new drugs.     

A molecular insight into papaya leaf curl—a severe viral disease

Papaya leaf curl disease (PaLCuD) caused by papaya leaf curl virus (PaLCuV) not only affects yield but also plant growth and fruit size and quality of papaya and is one of the most damaging and economically important disease. Management of PaLCuV is a challenging task due to diversity of viral strains, the alternate hosts, and the genomic complexities of the viruses. Several management strategies currently used by plant virologists to broadly control or eliminate the viruses have been discussed. In the absence of such strategies in the case of PaLCuV at present, the few available options to control the disease include methods like removal of affected plants from the field, insecticide treatments against the insect vector (Bemisia tabaci), and gene-specific control through transgenic constructs. This review presents the current understanding of papaya leaf curl disease, genomic components including satellite DNA associated with the virus, wide host and vector range, and management of the disease and suggests possible generic resistance strategies.     

A novel role of BELL1-like homeobox genes, PENNYWISE and POUND-FOOLISH, in floral patterning

Flowers are determinate shoots comprised of perianth and reproductive organs displayed in a whorled phyllotactic pattern. Floral organ identity genes display region-specific expression patterns in the developing flower. In Arabidopsis, floral organ identity genes are activated by LEAFY (LFY), which functions with region-specific co-regulators, UNUSUAL FLORAL ORGANS (UFO) and WUSCHEL (WUS), to up-regulate homeotic genes in specific whorls of the flower. PENNYWISE (PNY) and POUND-FOOLISH (PNF) are redundant functioning BELL1-like homeodomain proteins that are expressed in shoot and floral meristems. During flower development, PNY functions with a co-repressor complex to down-regulate the homeotic gene, AGAMOUS (AG), in the outer whorls of the flower. However, the function of PNY as well as PNF in regulating floral organ identity in the central whorls of the flower is not known. In this report, we show that combining mutations in PNY and PNF enhance the floral patterning phenotypes of weak and strong alleles of lfy, indicating that these BELL1-like homeodomain proteins play a role in the specification of petals, stamens and carpels during flower development. Expression studies show that PNY and PNF positively regulate the homeotic genes, APETALA3 and AG, in the inner whorls of the flower. Moreover, PNY and PNF function in parallel with LFY, UFO and WUS to regulate homeotic gene expression. Since PNY and PNF interact with the KNOTTED1-like homeodomain proteins, SHOOTMERISTEMLESS (STM) and KNOTTED-LIKE from ARABIDOPSIS THALIANA2 (KNAT2) that regulate floral development, we propose that PNY/PNF-STM and PNY/PNF-KNAT2 complexes function in the inner whorls to regulate flower patterning events.