Virtual population pharmacokinetic using physiologically based pharmacokinetic model for evaluating bioequivalence of oral lacidipine formulations in dogs

The aim of the present study was to investigate virtual population pharmacokinetic using physiologically based pharmacokinetic(PBPK) model for evaluating bioequivalence of oral lacidipine formulations in dogs. The dissolution behaviors of three lacidipine formulations including one commercial product and two self-made amorphous solid dispersions(ASDs)capsules were determined in 0.07% Tween 80 media. A randomized 3-period crossover design in 6 healthy beagle dogs after oral administration of the three formulations at a single dose of 4 mg was conducted. The PBPK modeling was utilized for the virtual bioequivalence study.In vitro dissolution experiment showed that the dissolution behaviors of lacidipine amorphous solid dispersions(ASDs) capsules, which was respectively prepared by HPMC-E5 or Soluplus, as polymer displayed similar curves compared with the reference formulation in 0.07% Tween 80 media. In vivo pharmacokinetics experiments showed that three formulations had comparable maximum plasma drug concentration(Cmax), and the time(Tmax) to reach Cmax of lacidipine tablet, which was prepared by Soluplus, as polymer was slower than other two formulations in consistency with the in vitro dissolution rate. The 90% confidence interval(CI) for the Cmax, AUC0–24 h and AUC0–∞ of the ratio of the test drug to the reference drug exceeded the acceptable bioequivalence(BE) limits(0.80–1.25). However, the 90% CI of the AUC0–24 h, AUC0–∞ and Cmax of the ratio of test to reference drug were within the BE limit,calculated using PBPK modeling when the virtual subjects reached 24 dogs. The results all demonstrated that virtual bioequivalence study can overcome the inequivalence caused by inter-subject variability of the 6 beagle dogs involved in in vivo experiments.

Combination of a biopharmaceutic classification system and physiologically based pharmacokinetic models to predict absorption properties of baicalein in vitro and in vivo

Objective: To determine the in vitro and in vivo absorption properties of active ingredients of the Chinese medicine, baicalein, to enrich mechanistic understanding of oral drug absorption.Methods: The Biopharmaceutic Classification System(BCS) category was determined using equilibrium solubility, intrinsic dissolution rate, and intestinal permeability to evaluate intestinal absorption mechanisms of baicalein in rats in vitro. Physiologically based pharmacokinetic(PBPK) model commercial software GastroPlus~(TM) was used to predict oral absorption of baicalein in vivo.Results: Based on equilibrium solubility, intrinsic dissolution rate, and permeability values of main absorptive segments in the duodenum, jejunum, and ileum, baicalein was classified as a drug with low solubility and high permeability. Intestinal perfusion with venous sampling(IPVS) revealed that baicalein was extensively metabolized in the body, which corresponded to the low bioavailability predicted by the PBPK model. Further, the PBPK model predicted the key indicators of BCS, leading to reclassification as BCS-II. Predicted values of peak plasma concentration of the drug(C_(max)) and area under the curve(AUC)fell within two times of the error of the measured results, highlighting the superior prediction of absorption of baicalein in rats, beagles, and humans. The PBPK model supported in vitro and in vivo evidence and provided excellent prediction for this BCS class II drug.Conclusion: BCS and PBPK are complementary methods that enable comprehensive research of BCS parameters, intestinal absorption rate, metabolism, prediction of human absorption fraction and bioavailability, simulation of PK, and drug absorption in various intestinal segments across species. This combined approach may facilitate a more comprehensive and accurate analysis of the absorption characteristics of active ingredients of Chinese medicine from in vitro and in vivo perspectives.

RESEARCH ON THE ESTIMATE OF SAFETY AND TOXICITY OF P-NITROPHENOL SODIUM WITHA PHYSIOLOGICALLY BASED PHARMACOKINETICS MODEL

The safety and toxicity of chemicals given first to animals and finally to humans are generally estimated with a method of safe coefficient, which is scientifically a way lack of grounds. To make a change of the old method, we designed a Physiologically Based Pharmacokinetics Medel for the estimate of safety and toxicity of chemicais. As an example,p-nitrophenol sodium (PNP-Na) is used in the research work. Studies of the PNP-Na pharmacokinetics in bodies of rat as well as humans are made, and possibilities of making use of the Model in the estimate of safety and toxicity of chemicals are discussed.

Physiologically based microenvironment for in vitro neural differentiation of adipose-derived stem cells

The limited capacity of nervous system to promote a spontaneous regeneration and the high rate of neurodegenerative diseases appearance are keys factors that stimulate researches both for defining the molecular mechanisms of pathophysiology and for evaluating putative strategies to induce neural tissue regeneration. In this latter aspect, the application of stem cells seems to be a promising approach, even if the control of their differentiation and the maintaining of a safe state of proliferation should be troubled. Here, we focus on adipose tissue-derived stem cells and we seek out the recent advances on the promotion of their neural differentiation, performing a critical integration of the basic biology and physiology of adipose tissuederived stem cells with the functional modifications that the biophysical, biomechanical and biochemical microenvironment induces to cell phenotype. The pre-clinical studies showed that the neural differentiation by cell stimulation with growth factors benefits from the integration with biomaterials and biophysical interaction like microgravity. All these elements have been reported as furnisher of microenvironments with desirable biological, physical and mechanical properties. A critical review of current knowledge is here proposed, underscoring that a real advance toward a stable, safe and controllable adipose stem cells clinical application will derive from a synergic multidisciplinary approach that involves material engineer, basic cell biology, cell and tissue physiology.

Minimum Attenuation of Physiologically-Patterned, 1 µTesla Magnetic Fields through Simulated Skull and Cerebral Space

To answer the queries concerning penetrability of ~1 μT, physiologically patterned, time-varying magnetic fields through the cranium, the proportions of attenuation through thicknesses and densities of ~3 times that of the human skull were measured directly. There was no reduction in the intensity of the magnetic field when two 2 cm thick dried pine boards (4.3 × 103 kg·m-3) were placed between the pairs of solenoids separated by the approximate width of the skull. Although volumes of water containing intracellular concentrations of ions did not attenuate the field intensity, placement of 290 cm2 of 2 mm sheets of duct metal reduced the amplitude by 25%. Spectra comparisons showed a clear congruence in profiles between direct measurement of the applied field and the original computer-generated pattern. These results indicate there is little validity to claims that weak, time-varying magnetic fields applied in this manner are eliminated or significantly attenuated by the human skull.

Benchmark Dose for Dioxin Based on Gestational Diabetes Mellitus Using Coexposure Statistical Methods and an Optimized Physiologically Based Toxicokinetic Model

Dioxins are ubiquitous endocrine-disrupting substances,but determining the effects and benchmark doses in situations of coexposure is highly challenging.The objective of this study was to assess the relationship between dioxin andgestational diabetes mellitus(GDM),calculate the benchmark dose(BMD)of dioxin in coexposure scenarios,and derive a daily exposure threshold using an optimized physiologically based toxicokinetic(PBTK)model.Based on a nested casecontrol study including 77 cases with GDM and 154 controls,serum levels of 29 dioxin-like compounds(DLCs)along with 10 perfluoroalkyl acids(PFAAs),seven polybrominated diphenyl ethers(PBDEs),and five non-dioxin-like polychlorinated biphenyls(ndl-PCBs)were measured at 9−16 weeks of gestation.Bayesian machine kernel regression(BKMR)was employed to identify significant chemicals,and probit and logistic models were used to calculate BMD adjusted for significant chemicals.A physiologically based toxicokinetic(PBTK)model was optimized using polyfluorinated dibenzo-p-dioxins and dibenzofurans(PFDD/Fs)data by the Bayesian−Monte Carlo Markov chain method and was used to determine the daily dietary exposure threshold.The median serum level of total dioxin toxic equivalent(TEQ)was 7.72 pg TEQ/g fat.Logistic regression analysis revealed that individuals in the fifth quantile of total TEQ level had significantly higher odds of developing GDM compared to those in the first quantile(OR,8.87;95%CI 3.19,27.58).The BKMR analysis identified dioxin TEQ and BDE-153 as the compounds with the greatest influence.The binary logistic and probit models showed that the BMD10(benchmark dose corresponding to a 10%extra risk)and BMDL_(10)(lower bound on the BMD_(10))were 3.71 and 3.46 pg TEQ/g fat,respectively,when accounting for coexposure to BDE-153 up to the 80%level.Using the optimized PBTK model and modifying factor,it was estimated that daily exposure should be below 4.34 pg TEQ kg^(−1)bw week^(−1)in order to not reach a harmful serum concentration for GDM.Further studies should utilize coexposure statistical methods and physiologically based pharmacokinetic(PBTK)models in reference dose calculation.

Exogenous melatonin improves cotton yield under drought stress by enhancing root development and reducing root damage

The exogenous application of melatonin by the root drenching method is an effective way to improve crop drought resistance.However,the optimal concentration of melatonin by root drenching and the physiological mechanisms underlying melatonin-induced drought tolerance in cotton(Gossypium hirsutum L.)roots remain elusive.This study determined the optimal concentration of melatonin by root drenching and explored the protective effects of melatonin on cotton roots.The results showed that 50μmol L-1 melatonin was optimal and significantly mitigated the inhibitory effect of drought on cotton seedling growth.Exogenous melatonin promoted root development in drought-stressed cotton plants by remarkably increasing the root length,projected area,surface area,volume,diameter,and biomass.Melatonin also mitigated the drought-weakened photosynthetic capacity of cotton and regulated the endogenous hormone contents by regulating the relative expression levels of hormone-synthesis genes under drought stress.Melatonin-treated cotton seedlings maintained optimal enzymatic and non-enzymatic antioxidant capacities,and produced relatively lower levels of reactive oxygen species and malondialdehyde,thus reducing the drought stress damage to cotton roots(such as mitochondrial damage).Moreover,melatonin alleviated the yield and fiber length declines caused by drought stress.Taken together,these findings show that root drenching with exogenous melatonin increases the cotton yield by enhancing root development and reducing the root damage induced by drought stress.In summary,these results provide a foundation for the application of melatonin in the field by the root drenching method.

Nacre-inspired MXene-based film for highly sensitive piezoresistive sensing over a broad sensing range

As the main component of wearable electronic equipment,flexible pressure sensors have attracted wide attention due to their excellent sensitivity and their promise with respect to applications in health monitoring,electronic skin,and human-computer interactions.However,it remains a significant challenge to achieve epidermal sensing over a wide sensing range,with short response/recovery time and featuring seamless conformability to the skin simultaneously.This is critical since the capture of minute electrophysiological signals is important for health care applications.In this paper,we report the preparation of a nacre-like MXene/sodium carboxymethyl cellulose(CMC)nanocomposite film with a“brick-and-mortar”interior structure using a vacuum-induced self-assembly strategy.The synergistic behavior of the MXene“brick”and flexible CMC“mortar”contributes to attenuating interlamellar self-stacking and creates numerous variable conductive pathways on the sensing film.This resulted in a high sensitivity over a broad pressure range(i.e.,0.03-22.37 kPa:162.13 kPa^(-1);22.37-135.71 kPa:127.88 kPa^(-1);135.71-286.49 kPa:100.58 kPa^(-1)).This sensor also has a low detection limit(0.85 Pa),short response/recovery time(8.58 ms/34.34 ms),and good stability(2000 cycles).Furthermore,we deployed pressure sensors to distinguish among tiny particles,various physiological signals of the human body,space arrays,robot motion monitoring,and other related applications to demonstrate their feasibility for a variety of health and motion monitoring use cases.

Effects of Maillard reaction and its product AGEs on aging and age-related diseases

Maillard reaction(MR)is a non-enzymatic browning reaction commonly seen in food processing,which occurs between reducing sugars and compounds with amino groups.Despite certain advantages based on Maillard reaction products(MRPs)found in some food for health and storage application have appeared,however,the MR occurring in human physiological environment can produce advanced glycation end products(AGEs)by non-enzymatic modification of macromolecules such as proteins,lipids and nucleic acid,which could change the structure and functional activity of the molecules themselves.In this review,we take AGEs as our main object,on the one hand,discuss physiologic aging,that is,age-dependent covalent cross-linking and modification of proteins such as collagen that occur in eyes and skin containing connective tissue.On the other hand,pathological aging associated with autoimmune and inflammatory diseases,neurodegenerative diseases,diabetes and diabetic nephropathy,cardiovascular diseases and bone degenerative diseases have been mainly proposed.Based on the series of adverse effects of accelerated aging and disease pathologies caused by MRPs,the possible harm caused by some MR can be slowed down or inhibited by artificial drug intervention,dietary pattern and lifestyle control.It also stimulates people's curiosity to continue to explore the potential link between the MR and human aging and health,which should be paid more attention to for the development of life sciences.

Determination of the Bioaccessibility of Cadmium in Golden Thread by Physiologically Based Extraction Test Digestion Using the in vitro/Caco2 Cell Model and Subsequent Risk Assessment

Background:The ingestion of golden thread contaminated with heavy metals through the food chain leads to detrimental effects to human health.During digestion,not all of the heavy metals could be released to the gastrointestinal tract and readily to be absorbed by human body.Thus,bioaccessibility is an important issue in health risk assessments.Aims and Objectives:The aims and objectives of this study were to investigate the bioaccessibility of Cd in golden thread and assess the associated health risks based on the exposure to bioaccessible Cd.Materials and Methods:Inductively coupled plasma mass spectrometry(ICP-MS)has been applied to determine the Cd content in golden thread.Physiologically based extraction test(PBET)digestion was performed in the in vitro/Caco2 cell model to investigate the bioaccessibility of Cd in golden thread.Furthermore,the target hazard quotient(THQ)was used to assess the risks of the total and the bioaccessible content of Cd in golden thread.Results:The results revealed that the total Cd content in six batches of golden thread ranged from 3.203 to 5.723 mg/kg.After uptake by Caco2 cells,the bioaccessibility of Cd ranged from 42.36%to 59.73%.The results of the risk assessment indicated that prior to uptake by Caco2 cells,the THQ values of Cd for all batches of golden thread were greater than 1.However,after uptake by Caco2 cells,the THQ values of Cd in all samples were less than 1,thus suggesting that the risks were at a safe level.Conclusion:This study was the first to perform health risk assessment with bioaccessible heavy metals present in traditional Chinese medicine by PBET digestion using an in vitro/Caco2 cell model,thus enabling us to obtain more accurate and objective results while allowing us to avoid unnecessary government intervention and to establish more reasonable limit standards for heavy metals.

Genome-wide association study dissecting drought resistance-associated loci based on physiological traits in common bean

Genetic improvement of drought resistance is one of the main breeding goals for common bean,so molecular markers must be identified to facilitate drought resistance breeding.In this study,we evaluated the proline,trehalose,raffinose,and stachyose contents of 210 common bean accessions under two watering conditions and found large variations in all four.The coefficients of variation ranged from 21.21%for proline content to 78.69%for stachyose content under well-watered conditions,and from 20.11%for proline content to 50.08%for trehalose content under drought stress.According to our genome-wide association analysis,32 quantitative trait loci were associated with drought resistance,seven of which overlapped with known loci.Four hotspot regions were identified at Pv01,Pv07 and Pv11.A set of candidate genes was identified,including genes encoding MYB,bZIP,bHLH,ERF,and protein kinases.Among these genes,Phvul.001G189400,Phvul.007G273000 and Phvul.008G270500 were annotated as bZIP,ERF and WRKY,respectively.These genes are reportedly involved in drought stress responses in Arabidopsis thaliana and were induced by drought stress in common bean.Significant SNPs in six candidate gene regions formed different haplotypes,and phenotypic analysis revealed significant differences among the haplotypes.These results provide new insight into the genetic basis of drought resistance in common bean and reveal candidate genes and superior natural variations that will be useful for improving common bean.

Corrigendum:Disentangling brain PrPC proteoforms and their roles in physiology and disease

In the article titled“Disentangling brain PrPC proteoforms and their roles in physiology and disease”,published on pages 963-965,Issue 5,Volume 19 of Neural Regeneration Research(Vanni and Romolo,2024;doi:10.4103/1673-5374.385302),the name of the second author appears incorrectly.The correct name is Romolo Nonno.

Seed Storability in Rice: Physiological Foundations, Molecular Mechanisms, and Applications in Breeding

Long-term storage of crop seeds is critical for the conservation of germplasm resources, ensuring food supply, and supporting sustainable production. Rice, as a major food staple, has a substantial stock for consumption and production worldwide. However, its food value and seed viability tend to decline during storage. Understanding the physiological responses and molecular mechanisms of aging tolerance forms the basis for enhancing seed storability in rice. This review outlines the latest progress in influential factors, evaluation methods, and identification indices of seed storability. It also discusses the physiological consequences, molecular mechanisms, and strategies for breeding aging-tolerant rice in detail. Finally, it highlights challenges in seed storability research that require future attention. This review offers a theoretical foundation and research direction for uncovering the mechanisms behind seed storability and breeding aging-tolerant rice.

Estimation of the water productivity of different varieties of wheat and rice in the context of agronomic, physiological and nutritional attributes

Water shortage is a global concern, and it poses a particularly severe threat in Pakistan. It is estimated that over 60% of irrigation water is not efficiently applied or not efficiently utilized by crop depending upon genetic variability. The pot study was conducted to evaluate the water efficiency of various wheat varieties (Millat 2011, Galaxy 2013, Faisalabad 2008, and Gandum-1) and rice varieties (Punjab Basmati, Chenab Basmati, B-515, and PS-2) based on their photosynthetic efficiency and nutritional quality by measuring their protein and chlorophyll contents. The highest concentrations of protein and chlorophyll were observed in plants of both crops that were watered and cultivated with 50 mL of water. For wheat, the greatest leaf length (cm), net assimilation rate [g/(d∙m2)], and photosynthetic efficiency were achieved when 80 mL of water was applied. Similarly, rice varieties (Punjab Basmati, Chenab Basmati, B-515, and PS-2) exhibited the highest photosynthetic efficiency, leaf length, net assimilation rate, and chlorophyll content when grown with 80 mL of water. Therefore, a conservative cultivation of wheat and rice is possible by selecting efficient varieties and by improving the technological approach of water saving through irrigation level and wise scheduling. The judicious use of water not only limits losses but also improves productivity, particularly in scenarios of water scarcity.

Rice canopy temperature is affected by nitrogen fertilizer

Canopy temperature strongly influences crop yield formation and is closely related to plant physiological traits.However, the effects of nitrogen treatment on canopy temperature and rice growth have yet to be comprehensively examined. We conducted a two-year field experiment with three rice varieties(HD-5, NJ-9108, and YJ-805) and three nitrogen treatments(zero-N control(CK), 200 kg ha~(–1)(MN), and 300 kg ha~(–1)(HN)). We measured canopy temperature using a drone equipped with a high-precision camera at the six stages of the growth period. Generally,canopy temperature was significantly higher for CK than for MN and HN during the tillering, jointing, booting, and heading stages. The temperature was not significantly different among the nitrogen treatments between the milky and waxy stages. The canopy temperature of different rice varieties was found to follow the order: HD-5>NJ-9108>YJ-805, but the difference was not significant. The canopy temperature of rice was mainly related to plant traits, such as shoot fresh weight(correlation coefficient r=–0.895), plant water content(–0.912), net photosynthesis(–0.84), stomatal conductance(–0.91), transpiration rate(–0.90), and leaf stomatal area(–0.83). A structural equation model(SEM) showed that nitrogen fertilizer was an important factor affecting the rice canopy temperature.Our study revealed:(1) A suite of plant traits was associated with the nitrogen effects on canopy temperature,(2) the heading stage was the best time to observe rice canopy temperature, and(3) at that stage, canopy temperature was negatively correlated with rice yield, panicle number, and grain number per panicle. This study suggests that canopy temperature can be a convenient and accurate indicator of rice growth and yield prediction.

Biological,pathological,and multifaceted therapeutic functions of exosomes to target cancer

Exosomes,small tiny vesicle contains a large number of intracellular particles that employ to cause various diseases and prevent several pathological events as well in the human body.It is considered a“double-edged sword”,and depending on its biological source,the action of exosomes varies under physiological conditions.Also,the isolation and characterization of the exosomes should be performed accurately and the methodology also will vary depending on the exosome source.Moreover,the uptake of exosomes from the recipients’cells is a vital and initial step for all the physiological actions.There are different mechanisms present in the exosomes’cellular uptake to deliver their cargo to acceptor cells.Once the exosomal uptake takes place,it releases the intracellular particles that leads to activate the physiological response.Even though exosomes have lavish functions,there are some challenges associated with every step of their preparation to bring potential therapeutic efficacy.So,overcoming the pitfalls would give a desired quantity of exosomes with high purity.

Advances in Wireless,Batteryless,Implantable Electronics for Real‑Time,Continuous Physiological Monitoring

This review summarizes recent progress in developing wireless,batteryless,fully implantable biomedical devices for real-time continuous physiological signal monitoring,focusing on advancing human health care.Design considerations,such as biological constraints,energy sourcing,and wireless communication,are discussed in achieving the desired performance of the devices and enhanced interface with human tissues.In addition,we review the recent achievements in materials used for developing implantable systems,emphasizing their importance in achieving multi-functionalities,biocompatibility,and hemocompatibility.The wireless,batteryless devices offer minimally invasive device insertion to the body,enabling portable health monitoring and advanced disease diagnosis.Lastly,we summarize the most recent practical applications of advanced implantable devices for human health care,highlighting their potential for immediate commercialization and clinical uses.

Advances in Understanding Cadmium Stress and Breeding of Cadmium-Tolerant Crops

Cadmium(Cd) pollution has emerged as a critical global environmental concern, due to its significant toxicity, environmental persistence, and the pervasiveness of contamination. Significantly, the bioaccumulation of Cd in agricultural crops constitutes a primary vector for its entry into the human diet. This issue warrants urgent attention from both the scientific community and policymakers to develop and implement effective mitigation strategies. This review delves into the physiological impacts of Cd stress on plants, including the suppression of photosynthetic activity, amplification of oxidative stress, and disruptions in mineral nutrient homeostasis. Additionally, the resistance mechanisms deployed by plants in response to Cd stress have been explored, and the prospective contributions of molecular breeding strategies in augmenting crop tolerance to Cd and minimizing its bioaccumulation have been assessed. By integrating and analyzing these findings, we seek to inform future research trajectories and proffer strategic approaches to enhance agricultural sustainability, safeguard human health, and protect environmental integrity.

Plant aquaporins:Their roles beyond water transport

Compared to other organisms,plants have evolved a greater number of aquaporins with diverse substrates and functions to adapt to ever-changing environmental and internal stimuli for growth and development.Although aquaporins were initially identified as channels that allow water molecules to cross biological membranes,progress has been made in identifying various novel permeable substrates.Many studies have characterized the versatile physiological and biophysical functions of plant aquaporins.Here,we review the recent reports that highlight aquaporin-facilitated regulation of major physiological processes and stress tolerance throughout plant life cycles as well as the potential prospects and possibilities of applying aquaporins to improve agricultural productivity,food quality,environmental protection,and ecological conservation.

Physiology of medicinal and aromatic plants under drought stress

Drought poses a significant challenge,restricting the productivity of medicinal and aromatic plants.The strain induced by drought can impede vital processes like respiration and photosynthesis,affecting various aspects of plants’growth and metabolism.In response to this adversity,medicinal plants employ mechanisms such as morphological and structural adjustments,modulation of drought-resistant genes,and augmented synthesis of secondary metabolites and osmotic regulatory substances to alleviate the stress.Extreme water scarcity can lead to leaf wilting and may ultimately result in plant death.The cultivation and management of medicinal plants under stress conditions often differ from those of other crops.This is because the main goal with medicinal plants is not only to increase the yield of the above-ground parts but also to enhance the production of active ingredients such as essential oils.To elucidate these mechanisms of drought resistance in medicinal and aromatic plants,the current review provides a summary of recent literature encompassing studies on the morphology,physiology,and biochemistry of medicinal and aromatic plants under drought conditions.