bluuebunny/crossref_metadata_2025_split huggingface dataset:
Oral biopharmaceutics tools: recent progress from partnership through the Pharmaceutical Education and Research with Regulatory Links collaboration
Authors: O’Dwyer Patrick J , Box Karl J , Dressman Jennifer , Griffin Brendan T , Henze Laura J , Litou Chara , Pentafragka Christina , Statelova Marina , Vertzoni Maria , Reppas Christos 
Published: January 2021

Abstract

Objectives
To summarise key contributions of the Pharmaceutical Education and Research with Regulatory Links (PEARRL) project (2016–2020) to the optimisation of existing and the development of new biopharmaceutics tools for evaluating the in vivo performance of oral drug products during the development of new drugs and at the regulatory level.

Key findings
Optimised biopharmaceutics tools: Based on new clinical data, the composition of biorelevant media for simulating the fed state conditions in the stomach was simplified. Strategies on how to incorporate biorelevant in vitro data of bio-enabling drug products into physiologically based pharmacokinetic (PBPK) modelling were proposed. Novel in vitro biopharmaceutics tools: Small-scale two-stage biphasic dissolution and dissolution-permeation setups were developed to facilitate understanding of the supersaturation effects and precipitation risks of orally administered drugs. A porcine fasted state simulated intestinal fluid was developed to improve predictions and interpretation of preclinical results using in vitro dissolution studies. Based on new clinical data, recommendations on the design of in vitro methodologies for evaluating the GI drug transfer process in the fed state were suggested. The optimized design of in vivo studies for investigating food effects: A food effect study protocol in the pig model was established which successfully predicted the food-dependent bioavailability of two model compounds. The effect of simulated infant fed state conditions in healthy adults on the oral absorption of model drugs was evaluated versus the fasted state and the fed state conditions, as defined by regulatory agencies for adults. Using PBPK modelling, the extrapolated fasted and infant fed conditions data appeared to be more useful to describe early drug exposure in infants, while extrapolation of data collected under fed state conditions, as defined by regulators for adults, failed to capture in vivo infant drug absorption.

Summary
Substantial progress has been made in developing an advanced suite of biopharmaceutics tools for streamlining drug formulation screening and supporting regulatory applications. These advances in biopharmaceutics were achieved through networking opportunities and research collaborations provided under the H2020 funded PEARRL project.
Isoliquiritigenin attenuates inflammation and modulates Nrf2/caspase-3 signalling in STZ-induced aortic injury
Authors: Alzahrani Sharifa , Said Eman , Ajwah Sadeem M , Alsharif Sumayyah Y , El-Bayoumi Khaled S , Zaitone Sawsan A , Qushawy Mona , Elsherbiny Nehal M 
Published: January 2021

Abstract

Objectives
The current study provides evidence on the ameliorative impact of Isoliquiritigenin (ISL), a natural bioflavonoid isolated from licorice roots against diabetes mellitus (DM)-induced aortic injury in rats.

Methods
DM was induced in male Sprague–Dawley rats by single I.P. injection of STZ (50 mg/kg). ISL was administrated daily (20 mg/kg, orally) for 8 wks.

Key findings
Diabetic group showed a significant aortic injury with evidence of atherosclerotic lesions development. Daily ISL (20 mg/kg, orally) administration for 8 wks significantly restored aortic oxidative/antioxidative stress homeostasis via modulating NrF-2/Keap-1/HO-1. Moreover, ISL treatment restored aortic levels of IL-10 and dampened aortic levels of IL-6 and TNF-α. Caspase-3 expression significantly declined as well. Further, ISL treatment successfully suppressed aortic endothelin-1 (ET-1) expression and restored NO contents, eNOS immunostaining paralleled with retraction in atherosclerotic lesions development, and lipid deposition with histopathological architectural preservation and restoration of almost normal aortic thickness.

Conclusion
ISL can be proposed to be an effective protective therapy to prevent progression of DM-induced vascular injury and to preserve aortic integrity.
Anti-inflammatory effect of Adelia ricinella L. aerial parts
Authors: Berenguer-Rivas Clara Azalea , Escalona-Arranz Julio César , Llauradó-Maury Gabriel , Van der Auwera Anastasia , Piazza Stefano , Méndez-Rodríguez Daniel , Foubert Kenn , Cos Paul , Pieters Luc 
Published: January 2021

Abstract

Objective
To investigate the main chemical components and the anti-inflammatory activity of extracts of Adelia ricinella L. aerial parts.

Methods
Three extracts obtained by soxhlet extraction and ethanol/water mixtures were evaluated in their chemical composition by UPLC-DAD-MS/MS. The in vitro anti-inflammatory activity of the prepared extracts was assessed through three different assays: COX-1 and COX-2 enzymatic inhibition, cell-based COX assays on RAW264.7 macrophages (ATCC) measuring the COX-2 protein expression by Western blot and the measurement of the PGE2 concentration in the supernatants of the culture medium. Also was determinate the effect of the three extracts on the RAW 264.7 cell viability.

Key findings
Few differences in the phytochemical profile were found between the three prepared extracts, identifying a blend of thirteen flavonoids derived from luteolin and apigenin, with orientin as main constituent. Plant extracts (alcoholic and aqueous) did not affect the macrophage cell viability (IC50 &gt; 256 μg/ml) and significantly reduced COX-1 and COX-2 enzyme activities. Additionally, COX-2 expression and PGE2 release were suppressed after 24 h of LPS stimulation and treatment with plant extracts (8–64 µg/ml).

Conclusions
A. ricinella extracts showed the ability to reduce the inflammatory effect exerted by LPS in murine macrophages. However, further studies should confirm their anti-inflammatory activity.
Fluvastatin protects neuronal cells from hydrogen peroxide-induced toxicity with decreasing oxidative damage and increasing PI3K/Akt/mTOR signalling
Authors: Wang Miaoxia , Wang Jia , Liu Meirong , Chen Gang 
Published: January 2021

Abstract

Background
Statins, the most effective lipoprotein–cholesterol lowering drugs, are widely used for patients with cardiovascular disease. The pleiotropic effects of statins have been recently gained attention for their both beneficial and deleterious effects on neurons. We investigated the effects and molecular mechanisms of fluvastatin at clinically relevant concentrations on neuronal cells after induction of oxidative stress.

Materials and methods
Both SH-SY5Y, a representative cell line for in vitro neurone model, and human primary neuronal cells were applied. Cellular and biochemical assays were used to investigate the effects of fluvastatin in neurone cells.

Results
Fluvastatin significantly restored H2O2-induced neuronal death in a dose-dependent manner (P &lt; 0.05) and reversed H2O2-induced oxidative stress and damage via restoring mitochondrial function in neuronal cells (P &lt; 0.05). Although fluvastatin inhibited prenylation in neuronal cells, the protective effects of fluvastatin against H2O2-induced neuronal cytotoxicity are not associated with prenylation inhibition or AMPK activation. In contrast, PI3K/Akt/mTOR activation mediated fluvastatin’s neuroprotective activity (P &lt; 0.05).

Conclusions
Our work demonstrates the beneficial effects of fluvastatin in neuronal cells under pathological conditions, and, furthermore, this is via prenylation-independent activation of PI3K/Akt/mTOR pathway. Our data highlights the functional significance of the PI3K/Akt/mTOR pathway in neuronal cells in response to oxidative stress.
Identification of human uridine diphosphate-glucuronosyltransferase isoforms responsible for the glucuronidation of 10,11-dihydro-10-hydroxy-carbazepine
Authors: Huang Kai , Que Linling , Ding Ying , Chu Nannan , Qian Zhenzhong , Qin Wei , Chen Yuanxing , Zhang Jisheng , He Qing 
Published: January 2021

Abstract

Objectives
To determine the kinetics of the formation of 10,11-dihydro-10-hydroxy-carbazepine (MHD)-O-glucuronide in human liver microsomes (HLMs), human intestine microsomes (HIMs), human kidney microsomes (HKMs) and recombinant human UDP-glucuronosyltransferase (UGTs), and identify the primary UGT isoforms catalyzing the glucuronidation of MHD.

Methods
The kinetics of the glucuronidation of MHD was determined in HLMs, HIMs as well as HKMs. Screening assays with 13 recombinant human UGTs, inhibition studies and correlation analysis were performed to identify the main UGTs involved in the glucuronidation of MHD.

Key findings
MHD-O-glucuronide was formed in HLMs, HIMs as well as HKMs, HLMs showed the highest intrinsic clearance of MHD. Among 13 recombinant human UGTs, UGT2B7 and UGT1A9 were identified to be the principal UGT isoforms mediating the glucuronidation of MHD, while UGT1A4 played a partial role. In addition, inhibition studies and correlation analysis further confirmed that UGT2B7 and UGT1A9 participated in the formation of MHD-O-glucuronide.

Conclusions
MHD could be metabolized by UGTs in the liver, intestine and kidney, and the hepatic glucuronidation was the critical metabolic pathway. UGT2B7 and UGT1A9 were the primary UGT isoforms mediating the formation of MHD-O-glucuronide in the liver.
Pharmacokinetics-based chronoefficacy of Fuzi against chronic kidney disease
Authors: Yang Zemin , Lin Yanke , Su Chong , Wang Shuai , Gao Lu , Lin Jingpan , Wang Zhigang , Wu Baojian 
Published: January 2021

Abstract

Objectives
Identifying drugs with time-varying efficacy or toxicity, and understanding the underlying mechanisms would help to improve treatment efficacy and reduce adverse effects. In this study, we uncovered that the therapeutic effect of Fuzi (the lateral root of Aconitum carmichaelii Debeaux) depended on the dosing time in mice with adenine-induced chronic kidney disease (CKD).

Methods
The Fuzi efficacy was determined by biomarker measurements [i.e. plasma creatinine (CRE), blood urea nitrogen (BUN) and urinary N-acetyl-β-D-glucosaminidase (NAG)], as well as inflammation, fibrosis and histological analyses. Circadian regulation of Fuzi pharmacokinetics and efficacy was evaluated using brain and muscle Arnt-like protein-1 (Bmal1)-deficient (Bmal1−/−) mice.

Key findings
The Fuzi efficacy was higher when the drug was dosed at ZT10 and was lower when the drug was dosed at other times (ZT2, ZT6, ZT14, ZT18 and ZT22) according to measurements of plasma CRE, BUN and urinary NAG. Consistently, ZT10 (5 PM) dosing showed a stronger protective effect on the kidney (i.e. less extensive tubular injury) as compared to ZT22 (5 AM) dosing. This was supported by lower levels of inflammatory and fibrotic factors (IL-1β, IL-6, Tnf-α, Ccl2, Tgfb1 and Col1a1) at ZT10 than at ZT22. Pharmacokinetic analyses showed that the area under the curve (AUC) values (reflective of systemic exposure) and renal distribution of aconitine, hypaconitine and mesaconitine (three putative active constituents) for Fuzi dosing at ZT10 were significantly higher than those for herb dosing at ZT22, suggesting a role of circadian pharmacokinetics in Fuzi chronoefficacy. Drug efficacy studies confirmed that aconitine, hypaconitine and mesaconitine possessed a kidney-protecting effect. In addition, genetic knockout of Bmal1 in mice abolished the time-dependency of Fuzi pharmacokinetics and efficacy. This reinforced the existence of chronoefficacy for Fuzi and supported the role of circadian pharmacokinetics in Fuzi chronoefficacy.

Conclusions
The efficacy of Fuzi against CKD depends on the dosing time in mice, which is associated with circadian pharmacokinetics of the three main active constituents (i.e. aconitine, hypaconitine and mesaconitine). These findings highlight the relevance of dosing time in the therapeutic outcomes of herbal medicines.
An in vitro evaluation of antitumor activity of sirolimus-encapsulated liposomes in breast cancer cells
Authors: Nandi Uttom , Onyesom Ichioma , Douroumis Dennis 
Published: January 2021

Abstract

Objectives
Design and examine the effect of sirolimus-PEGylated (Stealth) liposomes for breast cancer treatment. In this study, we developed conventional and Stealth liposome nanoparticles comprising of distearoylphosphatidylcholine (DSPC) or dipalmitoyl-phosphatidylcholine (DPPC) and DSPE-MPEG-2000 lipids loaded with sirolimus as an anticancer agent. The effect of lipid grade, drug loading and incubation times were evaluated.

Methods
Particle size distribution, encapsulation efficiency of conventional and Stealth liposomes were studied followed by cytotoxicity evaluation. The cellular uptake and internal localisation of liposome formulations were investigated using confocal microscopy.

Key findings
The designed Stealth liposome formulations loaded with sirolimus demonstrated an effective in vitro anticancer therapy compared with conventional liposomes while the length of the acyl chain affected the cell viability. Anticancer activity was found to be related on the drug loading amounts and incubation times. Cell internalization was observed after 5 h while significant cellular uptake of liposome was detected after 24 h with liposome particles been located in the cytoplasm round the cell nucleus. Sirolimus Stealth liposomes induced cell apoptosis

Conclusions
The design and evaluation of sirolimus-loaded PEGylated liposome nanoparticles demonstrated their capacity as drug delivery carrier for the treatment of breast cancer tumours.
Novel therapeutic approaches for Parkinson’s disease by targeting brain cholesterol homeostasis
Authors: Pingale Tanvi Dayanand , Gupta Girdhari Lal 
Published: January 2021

Abstract

Objectives
Human brain is composed of 25% of the cholesterol & any dysfunction in brain cholesterol homeostasis contributes to neurodegenerative disorders such as Parkinson, Alzheimer’s, Huntington’s disease, etc. A growing literature indicates that alteration in neurotransmission & brain cholesterol metabolism takes place in the early stage of the disease. The current paper summarizes the role of cholesterol & its homeostasis in the pathophysiology of Parkinson’s disease.

Key findings
Literature findings suggest the possible role of lipids such as oxysterols, lipoproteins, etc. in Parkinson’s disease pathophysiology. Cholesterol performs a diverse role in the brain but any deviation in its levels leads to neurodegeneration. Dysregulation of lipid caused by oxidative stress & inflammation leads to α-synuclein trafficking which contributes to Parkinson’s disease progression. Also, α-synuclein by binding to membrane lipid forms lipid-protein complex & results in its aggregation. Different targets such as Phospholipase A2, Stearoyl-CoA desaturase enzyme, proprotein convertase subtilisin/kexin type 9, etc. have been identified as a potential novel approach for Parkinson’s disease treatment.

Summary
In the current review, we have discussed the possible molecular role of cholesterol homeostasis in Parkinson’s disease progression. We also identified potential therapeutic targets that need to be evaluated clinically for the development of Parkinson’s treatment.
Silencing of SNHG6 alleviates hypoxia/reoxygenation-induced cardiomyocyte apoptosis by modulating miR-135a-5p/HIF1AN to activate Shh/Gli1 signalling pathway
Authors: Lang Zhibin , Fan Xiaozhen , Lin Hongqi , Qiu Lin , Zhang Jiaqiang , Gao Chuanyu 
Published: January 2021

Abstract

Objectives
To examine the effects of small nucleolar RNA host gene 6 (SNHG6) on apoptosis during myocardial ischemic/reperfusion (I/R) injury and its potential molecular mechanisms.

Methods
In vitro model of I/R was built through exposing mouse HL-1 cardiomyocytes to hypoxia/reoxygenation (H/R) treatment. Quantitative real-time polymerase chain reaction assays were performed to determine gene expression. Cell Counting Kit-8, flow cytometric and western blot assays were conducted to detect cell viability, apoptosis and protein expression. Lactate dehydrogenase (LDH) activity was examined by a commercial detection kit. Dual-luciferase gene reporter and RNA immunoprecipitation experiments were applied for determining the interaction between the molecules.

Key findings
SNHG6 expression was increased in H/R-challenged cardiomyocytes. Depletion of SNHG6 protected against H/R-induced cardiomyocytes apoptosis. SNHG6 could sponge miR-135a-5p to inhibit its expression. Down-regulation of miR-135a-5p reversed the anti-apoptotic effect caused by SNHG6 knockdown in H/R-induced cardiomyocytes. Hypoxia inducible factor 1 subunit alpha inhibitor (HIF1AN) was identified as a direct target of miR-135a-5p, and knockdown of HIF1AN relieved H/R-induced cardiomyocytes apoptosis. Silencing of SNHG6 activated Shh/Gli1 signalling pathway by regulating miR-135a-5p/HIF1AN. Furthermore, inactivation of Shh/Gli signalling abolished the anti-apoptotic effects of SNHG6 knockdown in H/R-induced cardiomyocytes.

Conclusions
SNHG6 serves as a sponge for miR-135a-5p to promote HIF1AN expression and inactivate Shh/Gli1 signalling, eventually aggravating H/R-induced apoptosis in cardiomyocytes.
Study of the cardioprotective effects of crocin on Human Cardiac Myocyte cells and reduction of oxidative stress produced by aluminum phosphide poisoning
Authors: Naddafi Mastoureh , Eghbal Mohammad Ali , Ghazi-Khansari Mahmoud , Sattari Mohammad Reza , Azarmi Yadollah 
Published: January 2021

Abstract

Objectives
The effects of Crocin as a cardioprotective material against Aluminum phosphide poisoning by reducing the oxidative stress is investigated.

Methods
The level of biomarkers of oxidative stress (Catalase, Superoxide dismutase, Malondialdehyde and Protein carbonyl) were measured in the cell culture model on Human Cardiac Myocyte cells to detect the protective effect of crocin. Initially, to define the pure impact of aluminum phosphide poison and crocin on the heart cells, their effects on the biomarkers quantity in cell line were measured, separately, using the standard related kits. Later the effect of crocin with different concentration as a treatment on the oxidative stress biomarkers of the poisoned heart cells were monitored. Note that in pre-treatment case, the crocin was initially added to the cells before poisoning them. Data were analyzed using the analysis of variance method.

Key findings
Results showed that crocin treatment reduced the aluminum phosphide (AlP) poisoning effect significantly. The treatment resulted in substantial deviation in the biomarkers of oxidative stress at the pre- and post-treatment phases for all groups. The oxidative markers values of the poisoned cells were recovered by crocin treatment.

Conclusions
Crocin is proposed as a potentially powerful antioxidant to treat the cardiotoxicity caused by aluminum phosphide poisoning.
Ginsenoside Rg3 ameliorates acetaminophen-induced hepatotoxicity by suppressing inflammation and oxidative stress
Authors: Gao Yan , Yan Jiaqing , Li Juntong , Li Xun , Yang Songwei , Chen Naihong , Li Lin , Zhang Lan 
Published: January 2021

Abstract

Objectives
Improper usage of acetaminophen (APAP) leads to morbidity and also mortality secondary to liver damage. Ginseng could suppress APAP-induced hepatotoxicity and ginsenoside Rg3 is a kind of major component in ginseng against liver damage. Herein, we intended to estimate the beneficial function and molecular mechanism of Rg3 on APAP-caused hepatotoxicity and identified hepatoprotection.

Methods
A total of 50 C57BL/6J mice were divided into five random groups, and each contains 10 mice as the control, acetaminophen (350 mg/kg) and Rg3 (5, 10 and 20 mg/kg) + acetaminophen (350 mg/kg) groups. These mice were intragastric administration a single dose of acetaminophen by oral treatment behind pre-administered with several doses of ginsenoside Rg3 for six hours.

Key findings
According to our data, the injection of APAP (350 mg/kg) enhanced the basal levels of alanine aminotransferase, alkaline phosphatase, aspartate aminotransferase and lactic dehydrogenase. However, these abnormal added were alleviated by Rg3. Moreover, Rg3 treatment obviously relieved APAP-caused inflammation and oxidant in liver tissues. The depletion of glutathione, glutathione peroxidase, total antioxidant capacity and generation of malondialdehyde induced by APAP treatment were reduced by Rg3. By H&E staining, Rg3 effectively reduced APAP-caused apoptosis and inflammatory infiltration. Moreover, Rg3 attenuated APAP-caused hepatic damage in part by regulating the pro-inflammatory and anti-inflammatory cytokines. Moreover, we found that Rg3 could bind to NLRP3 suggesting the anti-inflammatory effects of Rg3 by molecular docking study.

Conclusions
In summary, Rg3 showed hepatic protective function in APAP-induced hepatotoxicity as evidenced by a reduction of the oxidant and the inflammatory reply, relieve of hepatocellular damage, showing potential in Rg3 as a potential therapeutic medicine to prevent hepatic injury.
A selanylimidazopyridine (3-SePh-IP) reverses the prodepressant- and anxiogenic-like effects of a high-fat/high-fructose diet in mice
Authors: Veloso Izolene Corrêa , Delanogare Eslen , Machado Adriano Emanuel , Braga Sara Pereira , Rosa Giovana Karoline , De Bem Andreza Fabro , Rafique Jamal , Saba Sumbal , da Trindade Roberth Nascimento , Galetto Fábio Zazyki , Moreira Eduardo Luiz Gasnhar 
Published: January 2021

Abstract

Objective
While chronic feeding with high-fat or high-sugar diets is known related to obesity and type 2 diabetes, later data have indicated that it is also related to depression and anxiety appearance. In this regard, multi-target drugs raise considerable interest as promising therapeutic solutions to complex diseases. Considering the pharmacological effects of the imidazopyridine-derivative moiety imidazo[1,2-a]pyridine and the organoselenium molecules, the combination of both could be a feasible strategy to develop efficient drugs to handle obesity and related comorbidities, for example dyslipidemia and mood disorders.

Methods
The antidepressant- and anxiolytic-like properties of a selanylimidazopyridine compound, 2-Phenyl-3-(phenylselanyl)imidazo[1,2-a]pyridine (3-SePh-IP), were evaluated on high-fat/high-fructose diet (HFFD)-fed female Swiss mice.

Key findings
Our results showed that a short-term HFFD (16 days) could promote a significant body weight gain, hypercholesterolemia, glucose intolerance, and anxiety- and depressive-like behaviour in mice. Concomitant treatment with 3-SePh-IP (10 mg/kg; i.p.) attenuated the HFFD-induced increase in cholesterol levels and blunted the anxiety- and depressive-like behaviour in mice.

Conclusions
3-SePh-IP holds multimodal pharmacological properties, which provide a rationale for further studies, for example to assess the underlying mechanisms linked to its anxiolytic- and antidepressive-like activities.