TOXICOLOGICAL AND BEHAVIOR ANALYSES OF A FOLIOSE LICHEN PARMOTREMA TINCTORUM (DELISE EX NYL.) HALE EXTRACT USING ZEBRAFISH (DANIO RERIO) MODEL

Objective: The objective of the study was to evaluate the toxicity and behavior analysis with the extract of foliose lichen Parmotrema tinctorum against the adult zebrafish. Methods: The zebrafishes were exposed to different concentrations of P. tinctorum extract such as 50, 100, and 200 mg/ml for 7 days of exposure, in which the mortality and behavioral responses of zebrafishes were recorded. The standard histopathological examination was conducted with the lichen extracts of P. tinctorum. Results: The results revealed that P. tinctorum extract did not show any prominent behavior abnormalities in zebrafishes even at a high concentration of 200 mg/ml. The extract was found to have dose-dependent toxic to zebrafish and the number of neutrophil cells in the muscle bundles reduced at a high concentration. The results of the inflammatory marker gene expression using polymerase chain reaction results suggested that the dose-dependent suppression of tumor necrosis factor gene by the P. tinctorum lichen extract. Conclusion: Overall, concluded that the extract might contain anti-inflammatory induction properties and further tests are required to prove apoptosis and anticancer activity using other in vivo or in vitro techniques.

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Are synapses targets of nanoparticles?

Biochemical Society Transactions ◽

10.1042/bst0380536 ◽

2010 ◽

Vol 38 (2) ◽

pp. 536-538 ◽

Cited By ~ 13

Author(s):

Sergei V. Fedorovich ◽

Alexandra V. Alekseenko ◽

Tatyana V. Waseem

Keyword(s):

Neuronal Damage ◽

Glutamate Uptake ◽

Oxygen Species ◽

Glutamatergic Neurotransmission ◽

High Concentration ◽

Dose Dependent Fashion ◽

Dichlorofluorescein Diacetate ◽

Dose Dependent

The last few years have been marked by real breakthroughs in the field of nanotechnology. Application of nanoparticles was proposed for diagnosis and treatment of different central nervous system diseases. Exposure to nanoparticles in vivo increases the risk of onset of neurodegenerative diseases and nanoparticles are apparently able to kill neurons in vitro. We suggested that presynaptic terminals of neurons are another target for nanoparticles, beyond the already established microglial cells. Ferritin was chosen as a prototypic nanoparticle model. We found that even a high concentration of ferritin, 800 μg/ml, was not able to induce spontaneous release of [14C]glutamate. In contrast, [14C]glutamate uptake was inhibited by ferritin in a dose-dependent fashion. As a next step, the influence of ferritin on the formation of reactive oxygen species was monitored using the fluorescent dye DCFH-DA (2′,7′-dichlorofluorescein diacetate). It was shown that ferritin leads to a dose-dependent formation of free radicals. We found that the ferritin-mediated changes in glutamatergic neurotransmission at presynaptic endings can result in neuronal damage and finally neurodegeneration.

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Differences in in vitro microglial accumulation of the energy metabolism tracers [18F]FDG and [18F]BCPP-EF during LPS- and IL4 stimulation

Scientific Reports ◽

10.1038/s41598-021-92436-0 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Chie Suzuki ◽

Sarina Han ◽

Gandhervin Kesavamoorthy ◽

Mutsumi Kosugi ◽

Kaori Araki ◽

...

Keyword(s):

Gene Expression ◽

Inflammatory Marker ◽

Marker Gene ◽

Microglial Cells ◽

Interleukin 4 ◽

Expression Of Genes ◽

Positron Emission ◽

Insight Into

AbstractThe positron emission tomography probes 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) and 2-tert-butyl-4-chloro-5-{6-[2-(2-[18F]fluoroethoxy)-ethoxy]-pyridin-3-ylmethoxy}-2H-pyridazin-3-one ([18F]BCPP-EF) are designed to evaluate glycolysis and oxidative phosphorylation, respectively, and are both used to estimate neuronal activity. However, previous studies have shown a discrepancy in these probes’ accumulation in the compromised region, possibly due to the presence of activated microglia acting like deleterious or neuroprotective phenotypes. Hence, we evaluated lipopolysaccharide (LPS)- and interleukin 4 (IL4)-stimulated microglial uptake of [14C]2DG and [18F]BCPP-EF to give a new insight into the hypothesis that different uptake of [18F]FDG and [18F]BCPP-EF can be ascribed to the different metabolic pathways activated during microglial activation. LPS or IL4 stimulation increased the proinflammatory or anti-inflammatory marker gene expression in microglial cells. In LPS-stimulated cells, [14C]2DG uptake and glycolysis related gene expression were elevated, and [18F]BCPP-EF uptake was reduced. In IL4-stimulated cells, [18F]BCPP-EF uptake was increased, and [14C]2DG uptake was decreased. The expression of genes involved in glycolysis and mitochondrial complex I subunits was not changed by IL4 stimulation. The uptake of [14C]2DG and [18F]BCPP-EF differs in LPS- and IL4-stimulated polarized microglial cells. The present results suggest that the in vivo accumulation of metabolic tracers [18F]FDG and [18F]BCPP-EF can be influenced by the different aspects of neuroinflammation.

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Soluble Thrombomodulin Purified from Human Urine Exhibits a Potent Anticoagulant Effect In Vitro and In Vivo

Thrombosis and Haemostasis ◽

10.1055/s-0038-1653872 ◽

1995 ◽

Vol 73 (05) ◽

pp. 805-811 ◽

Cited By ~ 12

Author(s):

Yasuo Takahashi ◽

Yoshitaka Hosaka ◽

Hiromi Niina ◽

Katsuaki Nagasawa ◽

Masaaki Naotsuka ◽

...

Keyword(s):

Human Urine ◽

Specific Activity ◽

Anticoagulant Activity ◽

Rabbit Lung ◽

Soluble Thrombomodulin ◽

Molecular Weights ◽

Dose Dependent Fashion ◽

Dose Dependent

SummaryWe examined the anticoagulant activity of two major molecules of soluble thrombomodulin purified from human urine. The apparent molecular weights of these urinary thrombomodulins (UTMs) were 72,000 and 79,000, respectively. Both UTMs showed more potent cofactor activity for protein C activation [specific activity >5,000 thrombomodulin units (TMU)/mg] than human placental thrombomodulin (2,180 TMU/mg) and rabbit lung thrombomodulin (1,980 TMU/mg). The UTMs prolonged thrombin-induced fibrinogen clotting time (>1 TMU/ml), APTT (>5 TMU/ml), TT (>5 TMU/ml) and PT (>40 TMU/ml) in a dose-dependent fashion. These effects appeared in the concentration range of soluble thrombomodulins present in human plasma and urine. In the rat DIC model induced by thromboplastin, administration of UTMs by infusion (300-3,000 TMU/kg) restored the hematological abnormalities derived from DIC in a dose-dependent fashion. These results demonstrate that UTMs exhibit potent anticoagulant and antithrombotic activities, and could play a physiologically important role in microcirculation.

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Vasorelaxant and Antihypertensive Effects of Mentha pulegium L. in Rats: An in vitro and in vivo Approach

Endocrine Metabolic & Immune Disorders - Drug Targets ◽

10.2174/1871530320666200909093908 ◽

2020 ◽

Vol 20 ◽

Author(s):

Mohammed Ajebli ◽

Mohamed Eddouks

Keyword(s):

Blood Pressure ◽

Acute Experiment ◽

Antihypertensive Activity ◽

Mentha Pulegium ◽

In Vitro Experiment ◽

Arterial Blood ◽

Dose Dependent ◽

Ca2 Channels

Aims and objective: The aim of the study was to investigate the effect of aqueous aerial part extract of Mentha pulegium L. (Pennyrile) (MPAE) on arterial pressure parameters in rats. Background: Mentha pulegium is a medicinal plant used to treat hypertension in Morocco. Material and methods: In the current study, MPAE was prepared and its antihypertensive activity was pharmacologically investigated. L-NAME-hypertensive and normotensive rats have received orally MPAE (180 and 300 mg/kg) during six hours for the acute experiment and during seven days for the sub-chronic treatment. Thereafter, systolic, diastolic, mean arterial blood pressure and heart rate were evaluated. While, in the in vitro experiment, isolated denuded and intact thoracic aortic rings were suspended in a tissue bath system and the tension changes were recorded. Results: A fall in blood pressure was observed in L-NAME-induced hypertensive treated with MPAE. The extract also produced a dose-dependent relaxation of aorta pre-contracted with NE and KCl. The study showed that the vasorelaxant ability of MPAE seems to be exerted through the blockage of extracellular Ca2+ entry. Conclusion: The results demonstrate that the extract of pennyrile exhibits antihypertensive activity. In addition, the effect may be, at least in part, due to dilation of blood vessels via blockage of Ca2+ channels.

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Anti-tumor activity of a novel proteasome inhibitor D395 against multiple myeloma and its lower cardiotoxicity compared with carfilzomib

Cell Death and Disease ◽

10.1038/s41419-021-03701-z ◽

2021 ◽

Vol 12 (5) ◽

Author(s):

Xuxing Shen ◽

Chao Wu ◽

Meng Lei ◽

Qing Yan ◽

Haoyang Zhang ◽

...

Keyword(s):

Multiple Myeloma ◽

Proteasome Inhibitor ◽

Osteoclast Differentiation ◽

Dependent Manner ◽

Serum Enzyme ◽

Herg Channels ◽

Anti Tumor Activity ◽

Dose Dependent

AbstractCarfilzomib, a second-generation proteasome inhibitor, has significantly improved the survival rate of multiple myeloma (MM) patients, but its clinical application is still restricted by drug resistance and cardiotoxicity. Here, we identified a novel proteasome inhibitor, D395, and assessed its efficacy in treating MM as well as its cardiotoxicity at the preclinical level. The activities of purified and intracellular proteasomes were measured to determine the effect of D395 on the proteasome. CCK-8 and flow cytometry experiments were designed to evaluate the effects of D395 on cell growth and apoptosis. The effects of D395 and carfilzomib on serum enzyme activity, echocardiography features, cardiomyocyte morphology, and hERG channels were also compared. In our study, D395 was highly cytotoxic to MM cell lines and primary MM cells but not normal cells, and it was well tolerated in vivo. Similar to carfilzomib, D395 inhibited osteoclast differentiation in a dose-dependent manner. In particular, D395 exhibited lower cardiotoxicity than carfilzomib in all experiments. In conclusion, D395 is a novel irreversible proteasome inhibitor that has remarkable anti-MM activity and mild cardiotoxicity in vitro and in vivo.

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Current Knowledge on Functionality and Potential Therapeutic Uses of Donkey Milk

Animals ◽

10.3390/ani11051382 ◽

2021 ◽

Vol 11 (5) ◽

pp. 1382

Author(s):

Mina Martini ◽

Iolanda Altomonte ◽

Domenico Tricò ◽

Riccardo Lapenta ◽

Federica Salari

Keyword(s):

Animal Models ◽

Randomized Clinical Trials ◽

Current Knowledge ◽

Saturated Fatty Acids ◽

Cow Milk ◽

Donkey Milk ◽

Alpha Linolenic Acid ◽

High Concentration

The increase of knowledge on the composition of donkey milk has revealed marked similarities to human milk, which led to a growing number of investigations focused on testing the potential effects of donkey milk in vitro and in vivo. This paper examines the scientific evidence regarding the beneficial effects of donkey milk on human health. Most clinical studies report a tolerability of donkey milk in 82.6–98.5% of infants with cow milk protein allergies. The average protein content of donkey milk is about 18 g/L. Caseins, which are main allergenic components of milk, are less represented compared to cow milk (56% of the total protein in donkey vs. 80% in cow milk). Donkey milk is well accepted by children due to its high concentration of lactose (about 60 g/L). Immunomodulatory properties have been reported in one study in humans and in several animal models. Donkey milk also seems to modulate the intestinal microbiota, enhance antioxidant defense mechanisms and detoxifying enzymes activities, reduce hyperglycemia and normalize dyslipidemia. Donkey milk has lower calorie and fat content compared with other milks used in human nutrition (fat ranges from 0.20% to 1.7%) and a more favourable fatty acid profile, being low in saturated fatty acids (3.02 g/L) and high in alpha-linolenic acid (about 7.25 g/100 g of fat). Until now, the beneficial properties of donkey milk have been mostly related to whey proteins, among which β-lactoglobulin is the most represented (6.06 g/L), followed by α-lactalbumin (about 2 g/L) and lysozyme (1.07 g/L). So far, the health functionality of donkey milk has been tested almost exclusively on animal models. Furthermore, in vitro studies have described inhibitory action against bacteria, viruses, and fungi. From the literature review emerges the need for new randomized clinical trials on humans to provide stronger evidence of the potential beneficial health effects of donkey milk, which could lead to new applications as an adjuvant in the treatment of cardiometabolic diseases, malnutrition, and aging.

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Development of Triamcinolone Acetonide-Loaded Microemulsion as a Prospective Ophthalmic Delivery System for Treatment of Uveitis: In Vitro and In Vivo Evaluation

Pharmaceutics ◽

10.3390/pharmaceutics13040444 ◽

2021 ◽

Vol 13 (4) ◽

pp. 444

Author(s):

Alaa Mahran ◽

Sayed Ismail ◽

Ayat A. Allam

Keyword(s):

Triamcinolone Acetonide ◽

Delivery System ◽

Histopathological Examination ◽

Rabbit Model ◽

Subconjunctival Injection ◽

In Vivo Evaluation ◽

Ternary Phase Diagrams ◽

Ophthalmic Delivery

Treatment of uveitis (i.e., inflammation of the uvea) is challenging due to lack of convenient ophthalmic dosage forms. This work is aimed to determine the efficiency of triamcinolone acetonide (TA)-loaded microemulsion as an ophthalmic delivery system for the treatment of uveitis. Water titration method was used to construct different pseudo-ternary phase diagrams. Twelve microemulsion formulations were prepared using oleic acid, Cremophor EL, and propylene glycol. Among all tested formulations, Formulation F3, composed of oil: surfactant-co-surfactant (1:1): water (15:35:50% w/w, respectively), was found to be stable and showed acceptable pH, viscosity, conductivity, droplet size (211 ± 1.4 nm), and zeta potential (−25 ± 1.7 mV) and almost complete in vitro drug release within 24 h. The in vivo performance of the optimized formulation was evaluated in experimentally uveitis-induced rabbit model and compared with a commercial TA suspension (i.e., Kenacort®-A) either topically or by subconjunctival injection. Ocular inflammation was evaluated by clinical examination, white blood cell count, protein content measurement, and histopathological examination. The developed TA-loaded microemulsion showed superior therapeutic efficiency in the treatment of uveitis with high patient compliance compared to commercial suspension. Hence, it could be considered as a potential ocular treatment option in controlling of uveitis.

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In vitro and in vivo applications of Euphorbia wallichii shoot extract-mediated gold nanospheres

Green Processing and Synthesis ◽

10.1515/gps-2021-0013 ◽

2021 ◽

Vol 10 (1) ◽

pp. 101-111

Author(s):

Rehman Ullah ◽

Sumaira Shah ◽

Zahir Muhammad ◽

Sajjad Ali Shah ◽

Shah Faisal ◽

...

Keyword(s):

Gold Nanoparticles ◽

Muscular Contraction ◽

Surface Plasmon Resonance Peak ◽

Plasmon Resonance Peak ◽

Optical Absorption Peak ◽

Visible Spectra ◽

Scattering Spectra ◽

Dose Dependent

Abstract The current study was designed to investigate the potential of Euphorbia wallichii shoot extract for reducting Au3+ and stabilizing gold nanoparticles. UV-visible spectra of gold nanoparticles showed obvious surface plasmon resonance peak at 548 nm. Microscopy (SEM and TEM) showed spherical dimensions, and the energy dispersive X-ray spectra displayed the strongest optical absorption peak for gold (Au) at 2.1 keV. Dynamic light scattering spectra represent polydispersed mixture with particulate diameter of 2.5–103.2 nm. The IR spectra confirm the potential functional groups of shoot extract responsible for the reduction of Au3+ to gold nanoparticles which exhibit tremendous antibacterial potential of 76.31%, 68.47%, 79.85%, 48.10%, and 65.53% against Escherichia coli, Staphylococcus aureus, Bacillus pumilus, Pseudomonas aeruginosa, and Klebsiella pneumoniae, respectively. Gold nanoparticles showed markedly elevated fungicidal potency compared to the shoot extract alone against the tested fungal strains. IC50 for 2,2-diphenyl-1-picrylhydrazyl scavenging was 31.52, 18.29, and 15.32 µg/mL at 30, 60, and 90 min of reaction time, respectively. Both shoot extract and nanoparticles revealed 71% mortality at 100 µg/mL, with LD90 values of 310.56 µg/mL. Experimental mice acquired dose-dependent analgesia of 54.21%, 82.60%, and 86.53% when treated with gold nanoparticles at 50, 100, and 200 mg/kg bw. Inhibition of gastrointestinal muscular contraction was 21.16%, 30.49%, and 40.19% in mice feed with 50, 100, and 200 mg/kg bw, respectively.

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Effect of Synchronous Versus Sequential Regimens on the Pharmacokinetics and Biodistribution of Regorafenib with Irradiation

Pharmaceutics ◽

10.3390/pharmaceutics13030386 ◽

2021 ◽

Vol 13 (3) ◽

pp. 386

Author(s):

Tung-Hu Tsai ◽

Yu-Jen Chen ◽

Li-Ying Wang ◽

Chen-Hsi Hsieh

Keyword(s):

Stereotactic Body Radiation Therapy ◽

In Vivo Studies ◽

Control Group ◽

High Dose ◽

Dependent Manner ◽

Hep G2 ◽

Time Curve ◽

Dose Dependent

This study was performed to evaluate the interaction between conventional or high-dose radiotherapy (RT) and the pharmacokinetics (PK) of regorafenib in concurrent or sequential regimens for the treatment of hepatocellular carcinoma. Concurrent and sequential in vitro and in vivo studies of irradiation and regorafenib were designed. The interactions of RT and regorafenib in vitro were examined in the human hepatoma Huh-7, HA22T and Hep G2 cell lines. The RT–PK phenomenon and biodistribution of regorafenib under RT were confirmed in a free-moving rat model. Regorafenib inhibited the viability of Huh-7 cells in a dose-dependent manner. Apoptosis in Huh-7 cells was enhanced by RT followed by regorafenib treatment. In the concurrent regimen, RT decreased the area under the concentration versus time curve (AUC)regorafenib by 74% (p = 0.001) in the RT2 Gy × 3 fraction (f’x) group and by 69% (p = 0.001) in the RT9 Gy × 3 f’x group. The AUCregorafenib was increased by 182.8% (p = 0.011) in the sequential RT2Gy × 1 f’x group and by 213.2% (p = 0.016) in the sequential RT9Gy × 1 f’x group. Both concurrent regimens, RT2Gy × 3 f’x and RT9Gy × 3 f’x, clearly decreased the biodistribution of regorafenib in the heart, liver, lung, spleen and kidneys, compared to the control (regorafenib × 3 d) group. The concurrent regimens, both RT2Gy × 3 f’x and RT9Gy × 3 f’x, significantly decreased the biodistribution of regorafenib, compared with the control group. The PK of regorafenib can be modulated both by off-target irradiation and stereotactic body radiation therapy (SBRT).

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An approach for the analysis of relapse and marrow reconstitution after autologous marrow transplantation using retrovirus-mediated gene transfer

Blood ◽

10.1182/blood.v79.10.2694.2694 ◽

1992 ◽

Vol 79 (10) ◽

pp. 2694-2700 ◽

Cited By ~ 1

Author(s):

DR Rill ◽

RC Moen ◽

M Buschle ◽

C Bartholomew ◽

NK Foreman ◽

...

Keyword(s):

Gene Transfer ◽

Marrow Transplantation ◽

Residual Disease ◽

Marker Gene ◽

Autologous Bone Marrow Transplantation ◽

Autologous Bone Marrow ◽

Disease Recurrence ◽

Malignant Cells

Abstract Autologous bone marrow transplantation (ABMT) is widely used as treatment for malignant disease. Although the major cause of treatment failure is relapse, it is unknown if this arises entirely because of residual disease in the patient or whether contaminating cells in the rescuing marrow contribute. Attempts to purge marrow of its putative residual malignant cells may delay hematopoietic reconstitution and are of uncertain efficacy. We now describe how retrovirus-mediated gene transfer may be used to elucidate the source of relapse after ABMT for acute myeloid leukemia and to evaluate the efficacy of purging. Clonogenic myeloid leukemic blast cells in patient marrow can be transduced with the NeoR gene-containing helper-free retrovirus, LNL6, with an efficacy of 0% to 23.5% (mean, 10.5%). Transduced colonies grow in selective media and the presence of the marker gene can be confirmed in individual malignant colonies by polymerase chain reaction. If such malignant cells remain in harvested “remission” marrow, they will therefore be marked after exposure to LNL6. Detection of the marker gene in the malignant cells present at any later relapse would be firm evidence that residual disease contributed to disease recurrence, and would permit rapid subsequent evaluation of purging techniques. The technique also marks normal marrow progenitors from patients with acute myeloblastic leukemia. These colony-forming cells can be detected in long-term marrow cultures at a frequency of 1% to 18% for up to 10 weeks after exposure to the vector. Animal models and analysis of probability tables both suggest that these levels of marking in vitro are sufficient to provide information about the mechanisms of relapse and the biology of marrow regeneration in vivo. These preclinical data form part of the basis for current clinical studies of gene transfer into marrow before ABMT.

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