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Sabah Ansar,1 Saad M Alshehri,2 Manal Abudawood,1 Sherifa S Hamed,3,4 Tansir Ahamad2 1Clinical Laboratory Sciences, Applied Medical Science, King Saud University, Riyadh, Saudi Arabia; 2Department of Chemistry, College of Science, King Saud University, Riyadh, Saudi Arabia; 3Zoology Department, College of Science, King Saud University, Riyadh, Saudi Arabia; 4Zoology Department, Faculty of Science, University of Alexandria, Moharram Bey, Alexandria, Egypt Abstract: Silver nanoparticles (AgNPs) have attracted the most interest in terms of their potential biomedical and industrial applications. However, these nanoparticles have shown their toxic behavior toward environment, living tissues, and organisms. Selenium (Se), an essential trace element, is necessary for various metabolic processes, including protection against ­oxidative stress and immune function. The present study was undertaken to evaluate the effect of Se against AgNP-induced hepatic oxidative stress. AgNPs were synthesized and then prepared nanoparticles were characterized using various analytical techniques such as UV-visible spectroscopy, X-ray diffraction, and transmission electron microscopy. Rats were administered AgNPs intraperitoneally (5 mg/kg/day) and Se (0.2 mg/kg) was given by gavage. AgNP administration induced hepatic damage as indicated by the serum marker enzymes with reduction in levels of glutathione, and decrease in activities of SOD, CAT, and GSH-peroxidase (P

Ansar S, Alshehri SM, Abudawood M, Hamed SS, Ahamad T. Antioxidant and hepatoprotective role of sele-nium against silver nanoparticles. Int J Nanomedicine. 2017;12:7789–7797. On page 7796, the Acknowledgment is incorrect, it should have been: The authors extend their appreciation to the Deanship of Scientific Research, King Saud University, for funding this work through the Undergraduate Student Research Support Program. Read the original article.

On April 3, 2023, the FDA granted accelerated approval to enfortumab vedotin-ejfv (EV) plus pembrolizumab for treatment of patients with locally advanced or metastatic urothelial carcinoma who are ineligible for cisplatin-containing chemotherapy. Substantial evidence of effectiveness was obtained from EV-103/KEYNOTE-869 (NCT03288545), a multicohort study. Across cohorts, a total of 121 patients received EV 1.25 mg/kg (maximum of 125 mg) intravenously on days 1 and 8 of a 21-day cycle plus pembrolizumab 200 mg intravenously on day 1 of each 21-day cycle until disease progression or unacceptable toxicity. The major efficacy outcome measures were objective response rate (ORR) and duration of response (DoR), determined by blinded independent central review using RECIST v1.1. The confirmed ORR in 121 patients was 68% (95% confidence interval, 59-76), including 12% with complete responses. The median DoR for the 82 responders was 22 months (range: 1+ to 46+). The safety profile of the combination comprised adverse reactions expected to occur with the corresponding monotherapies, but with overall increased frequency of adverse reactions, including skin toxicity, pneumonitis, and peripheral neuropathy. The article summarizes the data and the FDA thought process supporting accelerated approval of EV + pembrolizumab, as well as additional exploratory analyses conducted by the FDA., (©2024 American Association for Cancer Research.)

On November 14, 2022, the FDA granted accelerated approval to mirvetuximab soravtansine-gynx for treatment of adult patients with folate receptor-α (FRα)-positive, platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer who have received one to three prior systemic therapies. The VENTANA FOLR1 (FOLR-2.1) RxDx Assay was approved as a companion diagnostic device to select patients for this indication. Approval was based on Study 0417 (SORAYA, NCT04296890), a single-arm, multicenter trial. In 104 patients with measurable disease who received mirvetuximab soravtansine-gynx, the overall response rate was 31.7% [95% confidence interval (CI), 22.9-41.6] with a median duration of response of 6.9 months (95% CI, 5.6-9.7). Ocular toxicity was included as a Boxed Warning in the U.S. Prescribing Information (USPI) to alert providers of the risks of developing severe ocular toxicity including vision impairment and corneal disorders. Pneumonitis and peripheral neuropathy were additional important safety risks included as Warnings and Precautions in the USPI. This is the first approval of a targeted therapy for FRα-positive, platinum-resistant ovarian cancer and the first antibody-drug conjugate approved for ovarian cancer. This article summarizes the favorable benefit-risk assessment leading to FDA's approval of mirvetuximab soravtansine-gynx., (©2023 American Association for Cancer Research.)

On August 13, 2021, the FDA approved belzutifan (WELIREG, Merck), a first-in-class hypoxia-inducible factor (HIF) inhibitor for adult patients with von Hippel-Lindau (VHL) disease who require therapy for associated renal cell carcinoma (RCC), central nervous system (CNS) hemangioblastomas, or pancreatic neuroendocrine tumors (pNET), not requiring immediate surgery. The FDA granted approval based on the clinically meaningful effects on overall response rate (ORR) observed in patients enrolled in Study MK-6482-004. All 61 patients had VHL-associated RCC; some also had CNS hemangioblastomas and/or pNET. For VHL disease-associated RCC, ORR was 49% [95% confidence interval (CI), 36-62], median duration of response (DoR) was not reached, 56% of responders had DoR ≥12 months, and median time to response was 8 months. Twenty-four patients had measurable CNS hemangioblastomas with an ORR of 63% (95% CI, 41-81), and 12 patients had measurable pNET with an ORR of 83% (95% CI, 52-98). For these tumors, median DoR was not reached, with 73% and 50% of patients having response durations ≥12 months for CNS hemangioblastomas and pNET, respectively. The most common adverse reactions, including laboratory abnormalities, reported in ≥20% were anemia, fatigue, increased creatinine, headache, dizziness, increased glucose, and nausea. Belzutifan can render some hormonal contraceptives ineffective and can cause embryo-fetal harm during pregnancy. This article summarizes the data and the FDA thought process supporting traditional approval of belzutifan for this indication., (©2022 American Association for Cancer Research.)

On June 15, 2020, the FDA granted accelerated approval to lurbinectedin for the treatment of adult patients with metastatic small cell lung cancer (SCLC) with disease progression on or after platinum-based chemotherapy. Approval was granted on the basis of the clinically meaningful effects on overall response rate (ORR) and duration of response (DOR), and the safety profile observed in a multicenter, open-label, multicohort clinical trial (PM1183-B-005-14, NCT02454972), referred to as Study B-005, in patients with advanced solid tumors. The trial included a cohort of 105 patients with metastatic SCLC who had disease progression on or after platinum-based chemotherapy. The confirmed ORR determined by investigator assessment using RECIST 1.1 in the approved SCLC patient population was 35% [95% confidence interval (CI): 26-45], with a median DOR of 5.3 (95% CI: 4.1-6.4) months. The drug label includes warnings and precautions for myelosuppression, hepatotoxicity, and embryo-fetal toxicity. This is the first drug approved by the FDA in over 20 years in the second line for patients with metastatic SCLC. Importantly, this approval includes an indication for patients who have platinum-resistant disease, representing an area of particular unmet need., (©2020 American Association for Cancer Research.)

On April 22, 2020, the FDA granted accelerated approval to sacituzumab govitecan-hziy (TRODELVY; Immunomedics, Inc.) for the treatment of patients with metastatic triple-negative breast cancer (mTNBC) who have received at least two prior therapies for metastatic disease. Approval was based on data from the IMMU-132-01 trial, a single-arm, multicohort, multicenter, phase I/II trial of sacituzumab govitecan. The assessment of efficacy was based on 108 patients with mTNBC who had previously received at least two prior lines of therapy in the metastatic setting and who received sacituzumab govitecan 10 mg/kg i.v. The assessment of safety was based on 408 patients with advanced solid tumors who had received sacituzumab govitecan at doses up to 10 mg/kg i.v. The primary efficacy endpoint was investigator-assessed objective response rate (ORR) and duration of response (DoR) was a key secondary endpoint. The ORR was 33.3% [36/108; 95% confidence interval (CI), 24.6-43.1], and median DoR among responders was 7.7 months (95% CI, 4.9-10.8). The most common adverse reactions occurring in ≥25% of patients were nausea, neutropenia, diarrhea, fatigue, anemia, vomiting, alopecia, constipation, rash, decreased appetite, and abdominal pain. This article summarizes the FDA review process and data supporting the approval of sacituzumab govitecan., (©2020 American Association for Cancer Research.)

Background: The portunid crab Charybdis hellerii is an economically critical aquatic species in the Mediterranean region. Several investigators have reported scanning electron microscopy (SEM) observations on some crustacean's eggs' morphology. Going through the previous studies, knowledge regarding the morphology of C. hellerii . vitellogenic oocytes and spawned egg membranes are not available., Aims and Objectives: In the present study, an attempt has been made to describe the morphology and the structure of the membranes of vitellogenic oocytes and the newly spawned eggs to provide necessary information for further studies on the reproductive and evolutionary biology of the crab C. hellerii ., Materials and Methods: Samples of ripe pinkish orange ovaries of non-ovigarous females and the spawned incubated eggs of ovigerous females with orange and grey spawns were processed for scanning electron microscopy. The prepared samples were examined in a Zeiss DSM 940 scanning electron microscope., Results: The present SEM study revealed that, vitellogenic oocytes are highly packed with yolk inclusions, which appear to be embedded in a definite acellular matrix and surrounded by a distinct chorion, which is pierced by several pores. The follicle cells appear polygonal in shape and interconnected through thin lateral projections and strongly associated with vitellogenic oocytes. The brooded fertilized eggs are attached through a marked stalk (funiculus) and surrounded by three distinct envelopes, which showed specific ornamentations and variations in their surface topography. The outer envelope coarsely wrinkled, while the middle envelope showed finely wrinkled ornamentation, and the inner envelope appeared with its characteristic spongy, porous appearance., Conclusions: This study denotes a significant difference between mature vitellogenic oocytes inside the ripe ovary and the spawned ova. The differences have been shown in the structure and external ornamentation of their surrounding membranes. Unlike the vitellogenic oocytes, the spawned ova were surrounded by three distinct layers, which are differ in their surface architecture. Such membrane architecture is species specific characteristic and has been thought to be an adaptive feature for brooded fertilized eggs to survive from stressful environmental conditions., Competing Interests: There are no conflicts of interest., (Copyright: © 2021 Journal of Microscopy and Ultrastructure.)

Objectives: This study aims to explore the perceptions of different stakeholders about the privatisation of the Saudi health care system., Methods: Using a qualitative case study design, we interviewed 21 administrators and clinical staff of a public hospital in the Eastern Province of the KSA and analysed all official documents relevant to this study. The analysis followed a thematic approach to provide an in-depth interpretation of the data., Results: Our analysis generated three main themes. The first was pertinent to the changes in the governance structure, with gradually increased autonomy from the government. The second reflected the necessity to introduce accountability within hospitals. The third described the cooperative relationship among the E1-Cluster hospitals as well as its competitive relationship with the private sector., Conclusion: Our study demonstrates the interplay between newly introduced concepts of autonomy and accountability within the Saudi health care system. The findings of this study and their implications for research, practice, and policy are elaborated. Such an understanding is essential to improve the implementation process of privatisation and to recognise new dynamics that are shaping the health care system. The study contributes to the current scarce literature on health care reforms in KSA by reporting perceptions and experiences of key stakeholders., (© 2020 The Authors.)

The development of modified-release (MR) drug products aims to address a clinical need such as improving patient compliance. There are multiple pathways and development strategies for the registration and approval of MR products. The development strategy of an MR product is usually dependent on the availability and pharmacokinetic/pharmacodynamics (PK/PD) characteristics of the reference drug product, that is, an immediate-release (IR) product or a reference MR. Compared with a reference IR product, an MR product is likely to have a different PK profile over the least common dosing time due to unequal dosing intervals. In case of differences in PK profiles between the MR product and the reference product, confirmatory efficacy and safety studies may be needed to support registration. In some cases, however, a thorough clinical PK/PD characterization may provide sufficient basis to support the approval of the proposed MR product without the need for additional safety and efficacy studies. This article summarizes the US Food and Drug Administration experience and the regulatory considerations supporting the approval of MR products in the past 6 years and discusses cases in which clinical pharmacology and PK/PD information were leveraged to support approval without the need for additional clinical studies. Details of all these cases are available in the public domain. In 2 cases a well-characterized exposure-response relationship provided sufficient justification that differences in the shape of the PK profiles were not clinically relevant. In the remaining 3 cases a thorough characterization of the PK profile along with a risk-based approach provided bases for approval., (Published 2020. This article is a U.S. Government work and is in the public domain in the USA.)

The human dentition is a typical diphyodont mammalian system with tooth replacement of most positions. However, after dental replacement and sequential molar development, the dental lamina undergoes apoptosis and fragments, leaving scattered epithelial units (dental lamina rests; DLRs). DLRs in adult humans are considered inactive epithelia, thought to possess limited capacity for further regeneration. However, we show that these tissues contain a small proportion of proliferating cells (assessed by both Ki67 and PCNA) but also express a number of common dental stem cell markers (Sox2, Bmi1, β-catenin and PH3) similar to that observed in many vertebrates that actively, and continuously regenerate their dentition. We compared these human tissues with the dental lamina of sharks that regenerate their dentition throughout life, providing evidence that human tissues have the capacity for further and undocumented regeneration. We also assessed cases of human ameloblastoma to characterise further the proliferative signature of dental lamina rests. Ameloblastomas are assumed to derive from aberrant lamina rests that undergo changes, which are not well understood, to form a benign tumour. We suggest that dental lamina rests can offer a potential source of important dental stem cells for future dental regenerative therapy. The combined developmental genetic data from the shark dental lamina and ameloblastoma may lead to the development of novel methods to utilise these rested populations of adult lamina stem cells for controlled tooth replacement in humans.

Context: Breast cancer is a leading cause of cancer fatalities among women worldwide. Of the more than 80% of patients who receive adjuvant chemotherapy, approximately 40% relapse. The majority of these patients die of disseminated metastatic disease, which emphasizes the need for new therapeutic strategies., Objective: The study intended to investigate the anticancer effects of oleuropein (OL) and doxorubicin (DOX) individually and in combination on breast tumor xenografts and also to evaluate the molecular pathways involved., Design: The research team designed in vivo (animal) and in vitro (cell culture) studies., Setting: The study was performed in the College of Science of King Saud University in the University Center for Women Students (Riyadh, Saudi Arabia)., Animals: The study involved 40 female, nude mice (BALB/c OlaHsd-foxn1)., Intervention: The mice were injected subcutaneously with MDA-MB-231 human breast cancer cells. After the growth of tumors, the animals were randomly divided into 4 groups to receive intraperitoneal injections: (1) group 1 (control group)-dimethyl sulfoxide, (2) group 2 (intervention group)-50 mg/kg of OL, (3) group 3 (intervention group)-2.5 mg/kg of DOX, and (4) group 4 (intervention group)-1.5 mg/kg of DOX, immediately followed by 50 mg/kg of OL. The OL was extracted from Manzanillo olive trees (Olea europaea) grown in Tabouk, Saudi Arabia., Outcome Measures: The measures included the isolation and primary culture of the tumor xenografts, apoptosis analysis by annexin V, cellular lysate preparation, and immunoblotting., Results: The volume of the tumor increased aggressively, reaching 173 mm3 in the control animals in a time-dependent manner. On the other hand, a sharp drop, to 48.7 mm3, in the volume of the tumor was observed with the 2 drugs combined, a more than 3-fold decrease. The effect was mediated through the induction of apoptosis via the mitochondrial pathway. The combined treatment downregulated the antiapoptosis and proproliferation protein, nuclear factor-kappa Β, and its main oncogenic target cyclin D1. Furthermore, it inhibited the expression of BCL-2 and survivin. This inhibition could explain the cooperative suppression of the proliferation of breast tumor xenografts and the induction of apoptosis by the combined effect of the compounds used., Conclusions: The key findings clearly indicate the synergistic efficacy of DOX with natural and nontoxic OL against breast tumor xenografts.

We presented allele frequencies of 27 X-chromosomal short tandem repeats (DXS6807, DXS9902, DXS6795, DXS6810, DXS10076, DXS10077, DXS10078, DXS10162, DXS10163, DXS10164, DXS7132, DXS981, DXS6800, DXS6803, DXS6809, DXS6789, DXS6799, DXS7424, DXS101, DXS7133, GATA172D05, DXS10103, HPRTB, GATA31E08, DXS8377, DXS10147, and DXS7423) obtained from 352 unrelated individuals in Egypt. No deviation from Hardy-Weinberg equilibrium was detected. Two pairs of adjacent loci showed significant linkage disequilibrium. In the principal component analysis plot, the Egyptian data were located between Europe and sub-Saharan Africa, away from Asia., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Nanoparticles are widely utilized in many products such as cosmetics and sunscreens. The present study was undertaken to evaluate the effect of hesperidin (HSP) on nano zinc oxide particles (nZnO) induced oxidative stress in rat livers., Methods: Rats were randomly divided into 4 groups of 6 rats each and exposed to single administration of nZnO intraperitoneally (600 mg/kg bwt) and HSP (100 mg/kg bwt) by gavage. Group I served as the control; group II was given nZnO only; groups III received HSP only and group IV received nZnO 1 h after pretreatment with HSP for 7 days., Results: Compared to the controls, nZnO administration enhanced alanine aminotransferase (AST) and aspartate aminotransferase (ALT) levels (p < 0.05) with reduction in the levels of glutathione (GSH), catalase (CAT), glutathione peroxidase (GPx), superoxide dismutase (SOD) and increase in levels of malondialdehyde (MDA) while HSP attenuated nZnO-induced hepatotoxicity for above mentioned parameters., Conclusions: The induced toxicity in the liver was corrected by pretreatment with HSP. The findings of this study suggest that HSP pretreatment can potentially be used to prevent nZnO-induced biochemical alterations toxicity. Further, protection by HSP on biochemical results was confirmed by histopathological changes. The present study suggests that HSP can protect against nZnO-induced oxidative damage in the rat livers.

Nigella sativa is a well-known dietary antioxidant and a valuable inhibitor of clastogenesis and carcinogenesis. The purpose of the present work was to investigate the effects of N. sativa seeds against chromosomal aberrations in primary spermatocytes and early embryonic lethality induced by CCl 4 hepatotoxin in Swiss albino mice. One hundred male Swiss albino mice were randomly divided into five groups. Groups I, II, and III received only normal saline, olive oil, and aqueous suspension of N. sativa seeds (50 mg/kg b.w.), while groups IV and V were orally given CCl 4 dissolved in olive oil at a dose level of 1.9 (¼ LD 50 ) alone and with aqueous suspension of N. sativa seeds (50 mg/kg b.w.) alternately. Aqueous extract of N. sativa significantly reduced the elevated frequency of chromosomal aberrations induced by CCl 4 in mouse primary spermatocytes. For the male-dominant lethal test, four males from each group (control and experimental) were used and each male was mated for 13 days to two untreated virgin females. On days 14-16 after breeding, all the females were evaluated for incidence of pregnancy, live implants, and fetal deaths. Treatment with 1/4 LD 50 of CCl 4 induced positive dominant lethal mutation, reflecting a high rate of deformations in male germ cells. Interestingly, no dominant lethal mutations were recorded in females mated to male mice treated with CCl 4 plus N. sativa. Under the experimental conditions of this study, our results highlight the beneficial role of N. sativa against CCl 4 -induced mutagenicity.

Zinc oxide nanoparticles (ZnONPs) are widely used in food packaging and may enter the body directly if exposed. Hereby, in this study, the oral administration was selected as the route of exposure for rats to nanoparticles and the effect of hesperidin (HSP, 100 mg/kg bwt) was evaluated on ZnONP (600 mg/kg bwt)-induced neurotoxicity in rats. ZnONPs were characterized using transmission electron microscopy. Neurotoxicity was observed as seen by elevation in serum inflammatory markers including tumor necrosis factor alpha (TNF-α), interleukin 1 (IL-1β), interleukin-6 (IL-6), C-reactive protein (CRP), and activities of catalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GR), and glutathione (GSH) content in rat brains. Pretreatment of rats with HSP in ZnONP-treated group elevated activities of antioxidant enzymes. HSP also caused decrease in TNF-α, IL-1β, IL-6, and CRP levels which was higher in the ZnONP-treated group. The results suggest that HSP augments antioxidant defense with anti-inflammatory response against ZnONP-induced neurotoxicity. The increased antioxidant enzymes enhance the antioxidant potential to reduce oxidative stress.

Background: Liver diseases are major global health problems. Ginseng extract has antioxidant, immune-modulatory and anti-inflammatory activities. This study investigated the effect of ginseng extract on carbon tetrachloride (CCl4)-induced liver fibrosis in rats., Methods: Male Wistar rats were divided into four groups: control group, ginseng group, CCl 4 group and CCl 4  + ginseng group. Liver injury was induced by the intraperitoneal (I.P) injection of 3 ml/kg CCl 4 (30% in olive oil) weekly for 8 weeks. The control group was I.P injected with olive oil. The expression of genes encoding transforming growth factor beta (TGF-β), type I TGF-β receptor (TβR-1), type II TGF-β receptor (TβR-II), mothers against decapentaplegic homolog 2 (Smad2), Smad3, Smad4, matrix metalloproteinase 2 (MMP2), MMP9, tissue inhibitor matrix metalloproteinase-1 (TIMP-1), Collagen 1a2 (Col1a2), Collagen 3a1 (Col3a1), interleukin-8 (IL-8) and interleukin -10 (IL-10) were measured by real-time PCR., Results: Treatment with ginseng extract decreased hepatic fat deposition and lowered hepatic reticular fiber accumulation compared with the CCl 4 group. The CCl 4 group showed a significant increase in hepatotoxicity biomarkers and up-regulation of the expression of genes encoding TGF-β, TβR-I, TβR-II, MMP2, MMP9, Smad-2,-3, -4, and IL-8 compared with the control group. However, CCl 4 administration resulted in the significant down-regulation of IL-10 mRNA expression compared with the control group. Interestingly, ginseng extract supplementation completely reversed the biochemical markers of hepatotoxicity and the gene expression alterations induced by CCl 4 ., Conclusion: ginseng extract had an anti-fibrosis effect via the regulation of the TGF-β1/Smad signaling pathway in the CCl 4 -induced liver fibrosis model. The major target was the inhibition of the expression of TGF-β1, Smad2, and Smad3.

Metal nanomaterials hold great potential and play an important role in consumer products. However, the increasing use of nanomaterials has raised concern over inadvertent exposure and potential risks for human health and the environment. Henceforth, in vivo testing of nanoparticles and protection against its toxicity is required. Using rat as an animal model, effect of sodium selenite (Se), an essential trace element, on rat testes exposed to silver nanoparticles (AgNPs) was evaluated. Male rats were treated with AgNPs (5 mg/kg/b.w) i/p or Se (0.2 mg/kg/b.w) by gavage. AgNP administration decreased Glutathione (GSH) levels and activities of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) and increased levels of malondialdehyde (MDA) and expression of interleukin-1 beta (IL-1β), IL-6, and tumor necrosis factor alpha (TNF-α). However, treatment with Se increased GSH levels and activities of SOD, CAT, and GPx compared with AgNP-treated group and decreased the level of MDA and inflammatory biomarkers significantly (p < 0.05) as compared with AgNP-treated group. Light microscopic analyses also revealed that AgNP induced histopathological changes in testes tissue. Further, protection by Se on biochemical results was confirmed by alleviation of the histopathological changes in the tissue. Results show the adverse effects of AgNPs on the male reproductive tract, particularly spermatogenesis, and suggest that Se possesses significant potential in reducing AgNP-induced testicular toxicity.

The strawberry (Fragaria ananassa) has been extensively used to treat a wide range of ailments in many cultures. The present study was aimed at evaluating the hepatoprotective effect of strawberry juice on experimentally induced liver injury in rats. To this end, rats were introperitoneally injected with carbon tetrachloride (CCl4) with or without strawberry juice supplementation for 12 weeks and the hepatoprotective effect of strawberry was assessed by measuring serum liver enzyme markers, hepatic tissue redox status and apoptotic markers with various techniques including biochemistry, ELISA, quantitative PCR assays and histochemistry. The hepatoprotective effect of the strawberry was evident by preventing CCl4-induced increase in liver enzymes levels. Determination of oxidative balance showed that strawberry treatment significantly blunted CCl4-induced increase in oxidative stress markers and decrease in enzymatic and non-enzymatic molecules in hepatic tissue. Furthermore, strawberry supplementation enhanced the anti-apoptotic protein, Bcl-2, and restrained the pro-apoptotic proteins Bax and caspase-3 with a marked reduction in collagen areas in hepatic tissue. These findings demonstrated that strawberry (F. ananassa) juice possessed antioxidant, anti-apoptotic and anti-fibrotic properties, probably mediated by the presence of polyphenols and flavonoids compounds.

Drug interactions due to efflux transporters may result in one drug increasing or decreasing the systemic exposure of a second drug. The potential for in vivo drug interactions is estimated through in vitro cell assays. Variability in in vitro parameter determination (e.g., IC₅₀ values) among laboratories may lead to different conclusions in in vivo interaction predictions. The objective of this study was to investigate variability in in vitro inhibition potency determination that may be due to calculation methods. In a Caco-2 cell assay, the absorptive and secretive permeability of digoxin was measured in the presence of spironolactone, itraconazole and vardenafil. From the permeability data, the efflux ratio and net secretory flux where calculated for each inhibitor. IC₅₀ values were then calculated using a variety of equations and software programs. All three drugs decreased the secretory transport of digoxin in a concentration-dependent manner while increasing digoxin's absorption to a lesser extent. The resulting IC₅₀ values varied according to the parameter evaluated, whether percent inhibition or percent control was applied, and the computational IC₅₀ equation. This study has shown that multiple methods used to quantitate the inhibition of drug efflux in a cell assay can result in different IC₅₀ values. The variability in the results in this study points to a need to standardize any transporter assay and calculation methods within a laboratory and to validate the assay with a set of known inhibitors and non-inhibitors against a clinically relevant substrate.

Purpose: The standard of care for treating patients with pancreatic adenocarcinomas includes gemcitabine (2',2'-difluorodeoxycytidine). Gemcitabine primarily elicits its response by stalling the DNA replication forks of cells in the S phase of the cell cycle. To provide a quantitative framework for characterizing the cell cycle and apoptotic effects of gemcitabine, we developed a pharmacodynamic model in which the activation of cell cycle checkpoints or cell death is dependent on gemcitabine exposure., Methods: Three pancreatic adenocarcinoma cell lines (AsPC-1, BxPC-3, and MiaPaca-2) were exposed to varying concentrations (0-100,000 ng/mL) of gemcitabine over a period of 96 h in order to quantify proliferation kinetics and cell distributions among the cell cycle phases. The model assumes that the drug can inhibit cycle-phase transitioning in each of the 3 phases (G1, S, and G2/M) and can cause apoptosis of cells in G1 and G2/M phases. Fitting was performed using the ADAPT5 program., Results: The time course of gemcitabine effects was well described by the model, and parameters were estimated with good precision. Model predictions and experimental data show that gemcitabine induces cell cycle arrest in the S phase at low concentrations, whereas higher concentrations induce arrest in all cell cycle phases. Furthermore, apoptotic effects of gemcitabine appear to be minimal and take place at later time points., Conclusion: The pharmacodynamic model developed provides a quantitative, mechanistic interpretation of gemcitabine efficacy in 3 pancreatic cancer cell lines, and provides useful insights for rational selection of chemotherapeutic agents for combination therapy.

Context: Cancer is a serious clinical problem to the health care system. Anticancer drugs have been extracted from plants containing phenolic compounds. Leucenia species (Fabaceae) contain a variety of bioactive components of numerous biological and pharmacological properties., Objective: This study explored the constitutive polyphenols of Leucenia leucocephala Lam. growing in Egypt and evaluated the antioxidant and cytotoxic activity., Materials and Methods: Chemical structures of the isolated compounds from the leaves of L. leucocephala were established by spectral techniques (UV, (1)H, and (13)C NMR, MS)., Results: Chromatographic separation of 80% MeOH extract of the leaves of L. leucocephala have resulted in a novel flavonoid-galloyl glycoside [myricetin 3-O-(2',3'4'-tri-O-galloyl)-α-L-rhamnopyranoside] with three known polyphenolic compounds isolated for the first time from this species (apigenin 7-O-β-D-glucuronopyranoside methyl ester, luteolin 7-O-β-D-glucuronopyranoside methyl ester, and 1,3,6-tri-O-galloyl-β-D-glucopyranose) and seven known previously isolated compounds. Also, 80% methanol extract exhibited high antioxidant activity (SC(50) = 3.94 µg/ml), which is correlated with its phenolic content. The extract also showed cytotoxic activity against Hep G2 (IC(50) value 1.41 µg/ml) confirming its anticancer activity against hepatocellular carcinoma. Among the tested compounds (4-8) for antioxidant property, compound 7 was the most active compound (SC(50) = 2.49 µg/ml). Also compounds 7 and 8 exhibited high cytotoxic activity (IC(50) = 2.41 and 2.81 µg/ml, respectively)., Discussion and Conclusion: These findings demonstrate that the leaves of L. leucocephala contain a considerable amount of polyphenolic compounds with high antioxidant properties, thus it has great potential as a source for natural health products.

Concentration response experiments are utilized widely to characterize the response of tumor cell lines to chemotherapeutic drugs, but the assay methods are non-standardized and their analysis based on phenomenological equations. To provide a framework for better interpretation of these experiments, we have developed a mathematical model in which progression through the tumor cell cycle is inhibited by drug treatment via either cell cycle arrest or entrance into cell death pathways. By fitting concentration response data, preferably over a dynamic range, the contributions of these mechanisms can be delineated. The model was shown to fit well experimental data for three glioma cell lines treated with either carmustine or etoposide. In each cell line, the major mechanism of tumor cell inhibition was cell death for carmustine in contrast to cell cycle arrest for etoposide. The model also provides a possible interpretation for the acquired in vitro resistance of U87 cells to carmustine as an accelerated desensitization to cell killing effects. This approach will aid in understanding better the action of chemotherapeutic agents on tumor cells.

The present study was designed to investigate the neuropathological effect of the two carbamate pesticides: methomyl and methiocarb on the neurons of the buccal ganglia in the land snail Eobania vermiculata using topical application and baiting technique. Their in vivo effects on acetylcholinesterase (AChE, EC 3.1.1.7) activity were also investigated. Sublethal dose and concentration (1/4 LD(50) and 1/4 LC(50)) of both pesticides were used, and the experiment lasted for 14 days. Histopathological and ultrastuctural alterations in the buccal ganglia were more obvious after the baiting technique treatment than after the topical application method, and methomyl was found to be more toxic than methiocarb. These alterations included shrinkage of the perikarya of neurons, increased cytoplasmic basophilia, and extreme indentation of the plasma membrane. In addition, the nuclei appeared karyolitic, eccentric, and highly shrunken with an irregular nuclear envelope. The most outstanding symptom observed after topical application of methiocarb was a highly vacuolated cytoplasm with a peripheral increase in electron density associated with dense accumulations of free ribosomes. On the other hand, an increased number of lysosomes and autophagosomes were observed after topical application of methomyl. Mitochondrial damage, increased number of lipid droplets, and myelin figures were frequently observed in ganglia treated with either methomyl or methiocarb. Moreover, it was noticed that both compounds induced reductions in AChE activity. However, methomyl exhibited more potency in reducing AChE activity than methiocarb.