Cell cycle checkpoint control in response to DNA damage by environmental stresses.

Being sessile organisms, plants are ubiquitously exposed to stresses that can affect the DNA replication process or cause DNA damage. To cope with these problems, plants utilize DNA damage response (DDR) pathways, consisting of both highly conserved and plant-specific elements. As a part of this DDR, cell cycle checkpoint control mechanisms either pause the cell cycle, to allow DNA repair, or lead cells into differentiation or programmed cell death, to prevent the transmission of DNA errors in the organism through mitosis or to its offspring via meiosis. The two major DDR cell cycle checkpoints control either the replication process or the G2/M transition. The latter is largely overseen by the plant-specific SOG1 transcription factor, which drives the activity of cyclin-dependent kinase inhibitors and MYB3R proteins, which are rate limiting for the G2/M transition. By contrast, the replication checkpoint is controlled by different players, including the conserved kinase WEE1 and likely the transcriptional repressor RBR1. These checkpoint mechanisms are called upon during developmental processes, in retrograde signaling pathways, and in response to biotic and abiotic stresses, including metal toxicity, cold, salinity, and phosphate deficiency. Additionally, the recent expansion of research from Arabidopsis to other model plants has revealed species-specific aspects of the DDR. Overall, it is becoming evidently clear that the DNA damage checkpoint mechanisms represent an important aspect of the adaptation of plants to a changing environment, hence gaining more knowledge about this topic might be helpful to increase the resilience of plants to climate change.

A multifaceted module of BRI1 ETHYLMETHANE SULFONATE SUPRESSOR1 (BES1)-MYB88 in growth and stress tolerance of apple.

The R2R3 transcription factor MdMYB88 has previously been reported to function in biotic and abiotic stress responses. Here, we identify BRI1 ETHYLMETHANE SULFONATE SUPRESSOR1 (MdBES1), a vital component of brassinosteroid (BR) signaling in apple (Malus × domestica) that directly binds to the MdMYB88 promoter, regulating the expression of MdMYB88 in a dynamic and multifaceted mode. MdBES1 positively regulated expression of MdMYB88 under cold stress and pathogen attack, but negatively regulated its expression under control and drought conditions. Consistently, MdBES1 was a positive regulator for cold tolerance and disease resistance in apple, but a negative regulator for drought tolerance. In addition, MdMYB88 participated in BR biosynthesis by directly regulating the BR biosynthetic genes DE ETIOLATED 2 (MdDET2), DWARF 4 (MdDWF4), and BRASSINOSTEROID 6 OXIDASE 2 (MdBR6OX2). Applying exogenous BR partially rescued the erect leaf and dwarf phenotypes, as well as defects in stress tolerance in MdMYB88/124 RNAi plants. Moreover, knockdown of MdMYB88 in MdBES1 overexpression (OE) plants decreased resistance to a pathogen and C-REPEAT BINDING FACTOR1 expression, whereas overexpressing MdMYB88 in MdBES1 OE plants increased expression of SQUAMOSA PROMOTER BINDING PROTEIN-LIKE 3 （MdSPL3） and BR biosynthetic genes, suggesting that MdMYB88 contributes to MdBES1 function during BR biosynthesis and the stress response. Taken together, our results reveal multifaceted regulation of MdBES1 on MdMYB88 in BR biosynthesis and stress tolerance.

Physiologically Based Pharmacokinetic/Pharmacodynamic Modeling to Support Waivers of In Vivo Clinical Studies: Current Status, Challenges, and Opportunities.

Physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) modeling has been extensively applied to quantitatively translate invitro data, predict the invivo performance, and ultimately support waivers of invivo clinical studies. In the area of biopharmaceutics and within the context of model-informed drug discovery and development (MID3), there is a rapidly growing interest in applying verified and validated mechanistic PBPK models to waive invivo clinical studies. However, the regulatory acceptance of PBPK analyses for biopharmaceutics and oral drug absorption applications, which is also referred to variously as "PBPK absorption modeling" [Zhang et al. CPT: Pharmacometrics Syst. Pharmacol. 2017, 6, 492], "physiologically based absorption modeling", or "physiologically based biopharmaceutics modeling" (PBBM), remains rather low [Kesisoglou et al. J. Pharm. Sci. 2016, 105, 2723] [Heimbach et al. AAPS J. 2019, 21, 29]. Despite considerable progress in the understanding of gastrointestinal (GI) physiology, invitro biopharmaceutic and in silico tools, PBPK models for oral absorption often suffer from an incomplete understanding of the physiology, overparameterization, and insufficient model validation and/or platform verification, all of which can represent limitations to their translatability and predictive performance. The complex interactions of drug substances and (bioenabling) formulations with the highly dynamic and heterogeneous environment of the GI tract in different age, ethnic, and genetic groups as well as disease states have not been yet fully elucidated, and they deserve further research. Along with advancements in the understanding of GI physiology and refinement of current or development of fully mechanistic in silico tools, we strongly believe that harmonization, interdisciplinary interaction, and enhancement of the translational link between invitro, in silico, and invivo will determine the future of PBBM. This Perspective provides an overview of the current status of PBBM, reflects on challenges and knowledge gaps, and discusses future opportunities around PBPK/PD models for oral absorption of small and large molecules to waive invivo clinical studies.

Protective effects of Lactobacillus plantarum strain P1 against toxicity of the environmental oestrogen di-n-butyl phthalate in rats.

Phthalates are contaminants widely distributed in the food-chain, and they are considered as important environmental oestrogens in our lives. In the present study, eight strains of lactic acid bacteria were isolated for their ability to adsorb di-n-butyl-phthalate (DBP), and one of the strains, Lactobacillus plantarum strain P1, was selected for more detailed analyses of its phthalate adsorption capacity in vitro. This study also evaluated the in vivo protective effects of strain P1 against DBP toxicity in rats. Sixteen rats were divided into four groups, and animals received by oral gavage every other day for a period of one month saline with or without strain P1 at 2×1011 cfu/kg followed by maize oil with or without DBP (50 mg/kg). Strain P1 could adsorb more DBP than saline alone, and the concentration of mono-n-butyl phthalate in urine was decreased in animals receiving P1. Furthermore, oestrogenic effects of the different treatments were assessed through counting of sperm and observation of testis, and strain P1 could protect the sexual organs of male rats. Our results suggested that P1 is effective against phthalate toxicity due to its ability to adsorb DBP in vivo and could be considered as a new dietary therapeutic strategy against environmental phtalate toxicity.

Pulmonary drug absorption and systemic exposure in human: Predictions using physiologically based biopharmaceutics modeling.

Systemic exposure of inhaled drugs is used to estimate the local lung exposure and assess systemic side effects for drugs with local pharmacological targets. Predicting systemic exposure is therefore central for successful development of drugs intended to be inhaled. Currently, these predictions are based mainly on data from in vitro experiments, but the accuracy of these predictions might be improved if they were based on data with higher physiological relevance. In this study, systemic exposure was simulated by applying biopharmaceutics input parameters from isolated perfused rat lung (IPL) data to a lung model developed in MoBi® as an extension to the full physiologically-based pharmacokinetic (PBPK) model in PK-Sim®. These simulations were performed for a set of APIs with a variety of physicochemical properties and formulation types. Simulations based on rat IPL data were also compared to simulations based on in vitro data. The predictive performances of the simulations were evaluated by comparing simulated plasma concentration-time profiles to clinical observations after pulmonary administration. Simulations using IPL-based input parameters predicted systemic exposure well, with predicted AUCs within two-fold of the observed value for nine out of ten drug compounds/formulations, and predicted Cmax values within two-fold for eight out of ten drug compounds/formulations. Simulations using input parameters based on IPL data performed generally better than simulations based on in vitro input parameters. These results suggest that the developed model in combination with IPL data can be used to predict human lung absorption for compounds with different physicochemical properties and types of inhalation formulations.

Drugs in pregnancy: Pharmacologic and physiologic changes that affect clinical care.

Pharmacologic interventions play a major role in obstetrical care throughout pregnancy, labor and delivery and the postpartum. Traditionally, obstetrical providers have utilized standard dosing regimens developed for non-obstetrical indications based on pharmacokinetic knowledge from studies in men or non-pregnant women. With the recognition of pregnancy as a special pharmacokinetic population in the late 1990s, investigators have begun to study drug disposition in this unique patient dyad. Many of the basic physiologic changes that occur during pregnancy have significant impact on drug absorption, distribution and clearance. Activity of Phase I and Phase II drug metabolizing enzymes are differentially altered by pregnancy, resulting in drug concentrations sufficiently different for some medications that efficacy or toxicity is affected. Placental transporters play a major dynamic role in determining fetal drug exposure. In the past two decades, we have begun to expand our understanding of obstetrical pharmacology; however, to truly optimize pharmacologic care of our pregnant patients and their developing fetus, additional research is critically needed.

Pharmacokinetic changes post-bariatric surgery: A scoping review.

Bariatric surgeries induce structural changes that can alter the absorption of drugs in patients already at risk of polypharmacy. This scoping review aimed to explore pharmacokinetic changes of orally administered drugs in patients post-bariatric surgery, and assess the quality and level of bias. Electronic databases were searched for articles relating to bariatric surgery and pharmacokinetics published between 1998 and 2019. Pre-post studies reporting on pharmacokinetic parameters were included, and the Newcastle-Ottawa Scale was used to assess risk-of-bias. A total of 21 studies were included in this review, and changes in absorption were reported in all included studies across 29 drugs. In 11 studies, this change was reported as statistically significant (p<.05), while six reported a nonsignificant change. More drugs exhibited a shorter Tmax and higher Cmax after surgery than otherwise, however changes in AUC were variable. Four studies were assessed as having fair quality while the remainder of the included studies were of good quality and low risk-of-bias. Bariatric surgery alters the absorption of drugs and several mechanisms are implicated to be responsible. Short and long-term monitoring is recommended in patients post-surgery for clinical changes in response to medications. Future research with a higher number of participants and greater control of variables, such as concurrent medications, malabsorptive disorders, and body composition should be considered.

Pharmacokinetic studies in pregnancy.

The effects of the many biochemical and physiologic changes of pregnancy on the dose-response relationship of drugs administered to pregnant women are poorly understood. The dose-response relationship is affected by pharmacokinetics, or what the body does to a drug, and pharmacodynamics, or what a drug does to the body. Insights into the potential effects of the changes of pregnancy on one aspect of the dose-response relationship of a drug can be obtained by studying the pharmacokinetics of the drug in the various stages of pregnancy and the postpartum period. There are several available approaches to studying pharmacokinetic changes in pregnancy. Single trough screening studies can provide qualitative estimates of elimination clearance, which with the dosing rate determines the steady-state drug concentration, throughout pregnancy and into the postpartum period. Population pharmacokinetic studies such as two stage pharmacokinetic studies and studies using a nonlinear mixed effects pharmacokinetic modeling approach can characterize pharmacokinetic changes more rigorously.

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Concentration Levels, Biological Enrichment Capacities and Potential Health Risk Assessment of Trace Elements in Eichhornia crassipes from Honghu Lake, China.

This study investigated the concentrations of Zn, Cu, Cr, Pb, As and Cd in different tissues of E. crassipes from Honghu Lake. The total concentrations of trace elements in E. crassipes were observed in descending order: Zn (111.6162) > Cu (15.7494) > Cr (7.0466) > Pb (5.6251) > As (3.6831) > Cd (0.1941) mg/kg. The order of the bioconcentration factor (BCF) measured in E. crassipes was Zn > As > Cr > Cu > Pb > Cd > 1, indicating that E. crassipes possessed a strong biological enrichment ability to accumulate a variety of trace elements. The translocation factor (TF) values decreased in the order of Cu > Zn > Cr > As > Pb > Cd, all of which were lower than 1, which showed that the absorption of the trace elements by E. crassipes was mainly accomplished in the roots. Moreover, the health risk assessments showed that the carcinogenic and noncarcinogenic risks of the edible parts of E. crassipes were 26.1 and 4.6 times higher than the maximum acceptable value recommended by the USEPA for adults and children of approximately 39.2- and 6.9-fold, respectively. Children were more sensitive than adults. The main trace elements that led to noncarcinogenic risks were As, Cr and Cu, while Cr and As led to carcinogenic risks. The results of the Pearson correlation showed positive correlations with the concentrations of Zn, Cr and As between E. crassipes and the water as well as negative correlations of the contents of all six trace elements between E. crassipes and the sediment.

Simultaneous Analysis of Dissolution and Permeation Profiles of Nanosized and Microsized Formulations of Indomethacin Using the In Vitro Dissolution Absorption System 2.

The in vitro dissolution absorption system 2 (IDAS2), a recent invention comprised a conventional dissolution vessel containing 2 permeation chambers with Caco-2 cell monolayers mounted with their apical side facing the dissolution media, permits simultaneous measurement of dissolution and permeation of drugs from intact clinical dosage forms. The objectives of this study were (1) to assess the utility of IDAS2 in the determination of the effect of particle size on in vitro performance of indomethacin and (2) to find out whether the behavior in IDAS2 of 2 indomethacin products differing in particle size is correlated with their in vivo behavior. Indomethacin dissolution and permeation across Caco-2 cell monolayers were simultaneously measured in IDAS2; the dissolution and permeation profiles were simultaneously modeled using a simple two-compartment model. Compared to microsized indomethacin, the nanosized formulation increased the dissolution rate constant by fivefold, whereas moderately increasing the permeation rate constant and the kinetic solubility. As a result, the drug amount permeated across the Caco-2 cell monolayers doubled in the nanosized versus microsized formulation. The in vitro results showed a good correlation with in vivo human oral pharmacokinetic parameters, thus emphasizing the physiological relevance of IDAS2 data in predicting in vivo absorption.

Tumor Drug Penetration Measurements Could Be the Neglected Piece of the Personalized Cancer Treatment Puzzle.

Precision medicine aims to use patient genomic, epigenomic, specific drug dose, and other data to define disease patterns that may potentially lead to an improved treatment outcome. Personalized dosing regimens based on tumor drug penetration can play a critical role in this approach. State-of-the-art techniques to measure tumor drug penetration focus on systemic exposure, tissue penetration, cellular or molecular engagement, and expression of pharmacological activity. Using in silico methods, this information can be integrated to bridge the gap between the therapeutic regimen and the pharmacological link with clinical outcome. These methodologies are described, and challenges ahead are discussed. Supported by many examples, this review shows how the combination of these techniques provides enhanced patient-specific information on drug accessibility at the tumor tissue level, target binding, and downstream pharmacology. Our vision of how to apply tumor drug penetration measurements offers a roadmap for the clinical implementation of precision dosing.

Gene Modification of Transforming Growth Factor ß (TGF-ß) and Interleukin 10 (IL-10) in Suppressing Mt Sonicate Induced Osteoclast Formation and Bone Absorption.

BACKGROUND Osteoarticular tuberculosis is an osteolytic lesion caused by Mycobacterium tuberculosis (MTB). Inflammatory factors such as TNF-α play a critical role in anti-tuberculosis immunity by regulating osteoblast and osteoclast functions. Both TGF-ß and IL-10 have immune suppression effects to downregulate secretion and release of inflammatory factors, such as TNF-α, that play roles in regulating osteoblast and osteoclast functions. This study thus investigated the effects of osteoclast with modified TGF-ß and IL-10 gene expression on MTB-induced osteoclast formation and bone absorption. MATERIAL AND METHODS Bone marrow mononuclear cells were induced to differentiate into osteoblasts and osteoclasts in vitro to generate a co-culture system. MTB powder lysed by ultrasound (Mt sonicate) were added in gradients to observe osteoblast formation and osteoclast absorption. Cell apoptosis was measured by flow cytometry, while ELISA was used assess TNF-α, TGF-ß, and IL-10. Viral vectors carrying TGF-ß or IL-10 gene were used to transfect osteoclasts, followed by ELISA assay. Bone absorption and osteoblast apoptosis were compared among groups. RESULTS Mt sonicate significantly facilitated osteoclast formation and bone formation. It upregulated contents of TNF-α, TGF-ß, and IL-10, induced osteoblast apoptosis, enhanced RANKL expression in osteoblasts, and decreased OPG expression. Overexpression of TGF-ß and/or IL-10 significantly decreased its upregulation effect on TNF-α by Mt sonicate, and hindered Mt sonicate-induced osteoblast apoptosis, osteoclast formation, and bone absorption. CONCLUSIONS Overexpression of TGF-ß and IL-10 significantly inhibits TMB-induced TNF-α synthesis and release, suppresses osteoblast apoptosis, and hinders osteoclast formation and bone absorption.

Physiologically Based Absorption Modeling of Salts of Weak Bases Based on Data in Hypochlorhydric and Achlorhydric Biorelevant Media.

Physiologically based absorption modeling has been attracting increased attention to study the interactions of weakly basic drug compounds with acid-reducing agents like proton-pump inhibitors and H2 blockers. Recently, standardized gastric and intestinal biorelevant media to simulate the achlorhydric and hypochlorhydric stomach were proposed and solubility and dissolution data for two model compounds were generated. In the current manuscript, for the first time, we report the utility of these recently proposed biorelevant media as input into physiologically based absorption modeling. Where needed, data collected with the biorelevant gastrointestinal transfer (BioGIT) system were used for informing the simulations in regard to the precipitation kinetics. Using two model compounds, a HCl salt and a semi-fumarate co-crystal which as expected dissolve to a greater extent in these media (and in gastric and intestinal human aspirates) compared to what the pH-solubility profile of the free form would suggest, we demonstrate successful description of the plasma concentration profiles and correctly predicted the lack of significant interaction after administration with pantoprazole or famotidine, respectively. Thus, the data reported in this manuscript represent an initial step towards defining biorelevant input for such simulations on interactions with acid-reducing agents.

Timing and placement of cattle manure and/or gliricidia affects cotton and sunflower nutrient accumulation and biomass productivity.

Organic fertilizers are a viable alternative to increase oilseed productivity in family agriculture systems. The study aimed to evaluate the effects of timing and placement of cattle manure and/or gliricidia (Gliricidia sepium Jacq. Walp) prunings on cotton (Gossipium hirsutum L.) and sunflower (Helianthus annuus L.) nutrient accumulation and biomass productivity. Experiments were carried out in 2010 and 2011 in Taperoá, Paraíba, Brazil. The organic fertilization treatments were: GI - gliricidia incorporated before planting; GS - gliricidia applied on surface 45 days after planting (DAP); MI + GI - manure and gliricidia incorporated before planting; MI + GS - manure incorporated before planting and gliricídia applied on the surface 45 DAP; MI - manure incorporated before planting; and T - with no organic fertilization. In 2010, treatment MI + GS increased N, P, and K accumulation in cotton (12 and 7 kg ha-1) as well as in sunflower (20 and 29 kg ha-1). In 2011, GI and GS treatments resulted in higher N, P, K accumulations in both crops. The highest cotton productivity in 2010 was obtained with MI + GS treatment (198 kg ha-1) and in 2011 with GS treatment (594 kg ha-1). For sunflower, MI + GS treatment yielded the highest productivity in 2010 (466 kg ha-1) and GI treatment in 2011 (3542 kg ha-1). GI and MI + GS treatments increased total biomass productivity for cotton and sunflower. The treatment that combined both cattle manure incorporated into the soil before planting and gliricidia applied on the surface 45 days after planting was the most viable management strategy.

A Systematic Review and Meta-Analysis Reveals Altered Drug Pharmacokinetics in Humans During Acute Exposure to Terrestrial High Altitude-Clinical Justification for Dose Adjustment?

Bailey, Damian Miles, Benjamin S. Stacey, and Mark Gumbleton. A systematic review and meta-analysis reveals altered drug pharmacokinetics in humans during acute exposure to terrestrial high altitude-clinical justification for dose adjustment? High Alt Med Biol. 19:141-148, 2018. OBJECTIVE: While physiological responses during acute ascent to terrestrial high altitude (HA) have the potential to alter the pharmacokinetics (PKs) that define absorption and disposition of medicinal drugs, there have been no systematic reviews and meta-analyses performed to date. METHODS: We conducted a systematic literature search in June 2017 using NCBI PubMed, EMBASE, Web of Science, and Ovid MEDLINE databases to identify relevant observational studies. Studies were deemed eligible based on the following criteria: (1) participants: healthy, nonacclimatized male or female lowlanders (born and bred at sea level) and (2) environment: exposure to low altitude (LA, ≤600 m), followed by terrestrial high altitude (HA, ≤24 hours to ≥2500 m), the time course specifically selected to avoid interpretive complications associated with erythrocytosis. All PK parameters were standardized to be in the same units and the weighted standardized mean difference (SMD) calculated using a combination of fixed and random effects models with heterogeneity evaluated using χ2 and I2 statistics. RESULTS: Of 20,840 studies reviewed, 6 prospective cohort studies (n = 75) qualified for inclusion, with participants exposed to a mean altitude of 4025 (mean) ± 380 (SD) m. We observed increases for absorption half-life (SMD: 0.40, 95% CI: 0.01-0.80, p = 0.04], elimination half-life (SMD: 0.89, 95% CI: 0.30-1.48, p = 0.003), and erythrocyte binding (SMD: 0.52, 95% CI: 0.16-0.88, p = 0.004) and reduction in clearance (SMD: -0.56, 95% CI: -1.13 to 0.00, p = 0.05). CONCLUSIONS: Collectively, these findings reveal impairments in both oral absorption and corresponding clearance of the, although limited, sample of drugs at HA that may potentially require closer patient monitoring and dose adjustments to maintain therapeutic efficacy and avoid incidental toxicity.

Timing and placement of cattle manure and/or gliricidia affects cotton and sunflower nutrient accumulation and biomass productivity

ABSTRACT Organic fertilizers are a viable alternative to increase oilseed productivity in family agriculture systems. The study aimed to evaluate the effects of timing and placement of cattle manure and/or gliricidia (Gliricidia sepium Jacq. Walp) prunings on cotton (Gossipium hirsutum L.) and sunflower (Helianthus annuus L.) nutrient accumulation and biomass productivity. Experiments were carried out in 2010 and 2011 in Taperoá, Paraíba, Brazil. The organic fertilization treatments were: GI - gliricidia incorporated before planting; GS - gliricidia applied on surface 45 days after planting (DAP); MI + GI - manure and gliricidia incorporated before planting; MI + GS - manure incorporated before planting and gliricídia applied on the surface 45 DAP; MI - manure incorporated before planting; and T - with no organic fertilization. In 2010, treatment MI + GS increased N, P, and K accumulation in cotton (12 and 7 kg ha-1) as well as in sunflower (20 and 29 kg ha-1). In 2011, GI and GS treatments resulted in higher N, P, K accumulations in both crops. The highest cotton productivity in 2010 was obtained with MI + GS treatment (198 kg ha-1) and in 2011 with GS treatment (594 kg ha-1). For sunflower, MI + GS treatment yielded the highest productivity in 2010 (466 kg ha-1) and GI treatment in 2011 (3542 kg ha-1). GI and MI + GS treatments increased total biomass productivity for cotton and sunflower. The treatment that combined both cattle manure incorporated into the soil before planting and gliricidia applied on the surface 45 days after planting was the most viable management strategy.