scholarly journals Development of an LDL Receptor-Targeted Peptide Susceptible to Facilitate the Brain Access of Diagnostic or Therapeutic Agents

Biology ◽  
2020 ◽  
Vol 9 (7) ◽  
pp. 161
Author(s):  
Séverine André ◽  
Lionel Larbanoix ◽  
Sébastien Verteneuil ◽  
Dimitri Stanicki ◽  
Denis Nonclercq ◽  
...  
Keyword(s):  
Ldl Receptor ◽  
Density Lipoprotein ◽  
Therapeutic Agents ◽  
In Vivo Studies ◽  
Phage Display Technology ◽  
Brain Penetration ◽  
Wide Range ◽  
The Brain

Blood-brain barrier (BBB) crossing and brain penetration are really challenging for the delivery of therapeutic agents and imaging probes. The development of new crossing strategies is needed, and a wide range of approaches (invasive or not) have been proposed so far. The receptor-mediated transcytosis is an attractive mechanism, allowing the non-invasive penetration of the BBB. Among available targets, the low-density lipoprotein (LDL) receptor (LDLR) shows favorable characteristics mainly because of the lysosome-bypassed pathway of LDL delivery to the brain, allowing an intact discharge of the carried ligand to the brain targets. The phage display technology was employed to identify a dodecapeptide targeted to the extracellular domain of LDLR (ED-LDLR). This peptide was able to bind the ED-LDLR in the presence of natural ligands and dissociated at acidic pH and in the absence of calcium, in a similar manner as the LDL. In vitro, our peptide was endocytosed by endothelial cells through the caveolae-dependent pathway, proper to the LDLR route in BBB, suggesting the prevention of its lysosomal degradation. The in vivo studies performed by magnetic resonance imaging and fluorescent lifetime imaging suggested the brain penetration of this ED-LDLR-targeted peptide.

Electromagnetic field in Alzheimer’s disease: a literature review of recent preclinical and clinical studies

2020 ◽  
Vol 17 ◽  
Author(s):  
Reem Habib Mohamad Ali Ahmad ◽  
Marc Fakhoury ◽  
Nada Lawand
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurodegenerative Disorder ◽  
In Vivo Studies ◽  
Key Factors ◽  
Potential Benefits ◽  
Preclinical And Clinical Studies ◽  
The Brain

: Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by the progressive loss of neurons leading to cognitive and memory decay. The main signs of AD include the irregular extracellular accumulation of amyloidbeta (Aβ) protein in the brain and the hyper-phosphorylation of tau protein inside neurons. Changes in Aβ expression or aggregation are considered key factors in the pathophysiology of sporadic and early-onset AD and correlate with the cognitive decline seen in patients with AD. Despite decades of research, current approaches in the treatment of AD are only symptomatic in nature and are not effective in slowing or reversing the course of the disease. Encouragingly, recent evidence revealed that exposure to electromagnetic fields (EMF) can delay the development of AD and improve memory. This review paper discusses findings from in vitro and in vivo studies that investigate the link between EMF and AD at the cellular and behavioural level, and highlights the potential benefits of EMF as an innovative approach for the treatment of AD.

Phytochemistry and Pharmacology of the Genus Pedicularis Used in Traditional Chinese Medicine

2014 ◽  
Vol 42 (05) ◽  
pp. 1071-1098 ◽  
Author(s):  
Mao-Xing Li ◽  
Xi-Rui He ◽  
Rui Tao ◽  
Xinyuan Cao
Keyword(s):  
Chinese Medicine ◽  
Traditional Chinese Medicine ◽  
Chemical Constituents ◽  
Iridoid Glycosides ◽  
In Vivo Studies ◽  
Chemical Components ◽  
Wide Range ◽  
Phenylpropanoid Glycosides

In the present review, the literature data on the chemical constituents and biological investigations of the genus Pedicularis are summarized. Some species of Pedicularis have been widely applied in traditional Chinese medicine. A wide range of chemical components including iridoid glycosides, phenylpropanoid glycosides (PhGs), lignans glycosides, flavonoids, alkaloids and other compounds have been isolated and identified from the genus Pedicularis. In vitro and in vivo studies indicated some monomer compounds and extracts from the genus Pedicularis have been found to possess antitumor, hepatoprotective, anti-oxidative, antihaemolysis, antibacterial activity, fatigue relief of skeletal muscle, nootropic effect and other activities.

Guggulsterone, a farnesoid X receptor antagonist lowers plasma trimethylamine-N-oxide levels: An evidence from in vitro and in vivo studies

2018 ◽  
Vol 38 (3) ◽  
pp. 356-370 ◽  
Author(s):  
A Gautam ◽  
YN Paudel ◽  
SAZ Abidin ◽  
U Bhandari
Keyword(s):  
Hepatic Injury ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Farnesoid X Receptor ◽  
Lipoprotein Cholesterol ◽  
In Vivo Studies ◽  
Low Density Lipoprotein Cholesterol ◽  
Pro Inflammatory Cytokines

The current study investigated the role of guggulsterone (GS), a farnesoid X receptor antagonist, in the choline metabolism and its trimethylamine (TMA)/flavin monooxygenases/trimethylamine- N-oxide (TMAO) inhibiting potential in a series of in vitro and in vivo studies as determined by high-performance liquid chromatography (HPLC), mass spectroscopy (MS), and liquid chromatography (LC)-MS techniques. Atherosclerosis (AS) was successfully induced in a group of experimental animals fed with 2% choline diet for 6 weeks. Serum lipid profiles such as total cholesterol, triglycerides, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and very low-density lipoprotein cholesterol were measured. Pro-inflammatory cytokines levels, markers for a hepatic injury, and oxidative stress markers were assessed. Interestingly, GS reduced the level of TMA/TMAO in both in vitro and in vivo studies as demonstrated by the peaks obtained from HPLC, MS, and LC–MS. Furthermore, GS exhibited cardioprotective and antihyperlipidemic effects as evidenced by the attenuation of levels of several serum lipid profiles and different atherogenic risk predictor indexes. GS also prevented hepatic injury by successfully restoring the levels of hepatic injury biomarkers to normal. Similarly, GS inhibited the production of pro-inflammatory cytokines levels, as well as GS, enhanced antioxidant capacity, and reduced lipid peroxidation. Histopathological study of aortic sections demonstrated that GS maintained the normal architecture in AS-induced rats. On the basis of results obtained from current investigation, we suggest that GS might have a great therapeutic potential for the treatment of AS.

scholarly journals Boosting GSH Using the Co-Drug Approach: I-152, a Conjugate of N-acetyl-cysteine and β-mercaptoethylamine

Nutrients ◽  
2019 ◽  
Vol 11 (6) ◽  
pp. 1291 ◽  
Author(s):  
Rita Crinelli ◽  
Carolina Zara ◽  
Michaël Smietana ◽  
Michele Retini ◽  
Mauro Magnani ◽  
...  
Keyword(s):  
Cell Cultures ◽  
In Vivo Studies ◽  
In Vivo Metabolism ◽  
Pharmacokinetic Properties ◽  
Immunomodulatory Properties ◽  
Acetyl Cysteine ◽  
High Doses ◽  
The Brain

Glutathione (GSH) has poor pharmacokinetic properties; thus, several derivatives and biosynthetic precursors have been proposed as GSH-boosting drugs. I-152 is a conjugate of N-acetyl-cysteine (NAC) and S-acetyl-β-mercaptoethylamine (SMEA) designed to release the parent drugs (i.e., NAC and β-mercaptoethylamine or cysteamine, MEA). NAC is a precursor of L-cysteine, while MEA is an aminothiol able to increase GSH content; thus, I-152 represents the very first attempt to combine two pro-GSH molecules. In this review, the in-vitro and in-vivo metabolism, pro-GSH activity and antiviral and immunomodulatory properties of I-152 are discussed. Under physiological GSH conditions, low I-152 doses increase cellular GSH content; by contrast, high doses cause GSH depletion but yield a high content of NAC, MEA and I-152, which can be used to resynthesize GSH. Preliminary in-vivo studies suggest that the molecule reaches mouse organs, including the brain, where its metabolites, NAC and MEA, are detected. In cell cultures, I-152 replenishes experimentally depleted GSH levels. Moreover, administration of I-152 to C57BL/6 mice infected with the retroviral complex LP-BM5 is effective in contrasting virus-induced GSH depletion, exerting at the same time antiviral and immunomodulatory functions. I-152 acts as a pro-GSH agent; however, GSH derivatives and NAC cannot completely replicate its effects. The co-delivery of different thiol species may lead to unpredictable outcomes, which warrant further investigation.

scholarly journals Evidence for the role of high density lipoproteins in mediating the antioxidant effect of estrogens

2000 ◽  
pp. 79-83 ◽  
Author(s):  
W Abplanalp ◽  
MD Scheiber ◽  
K Moon ◽  
B Kessel ◽  
JH Liu ◽  
...  
Keyword(s):  
Density Lipoprotein ◽  
Antioxidant Effect ◽  
High Density ◽  
In Vivo Studies ◽  
Ldl Oxidation ◽  
High Density Lipoproteins ◽  
Oh Groups

Estrogens possess strong antioxidant effects in vitro, but in vivo studies in humans have yielded conflicting results. Little is known regarding factors that mediate the antioxidant effect of estrogens in vivo. In this study the potential role of high density lipoprotein (HDL) was examined. The antioxidant effect of estradiol-17beta (E2) added to low density lipoprotein (LDL) was lost after dialysis. In contrast, the antioxidant effect of E2 added to HDL was conserved after dialysis, suggesting that E2 was bound to HDL. Binding of E2 to LDL increased after esterification (especially to long chain fatty acids). In the presence of HDL, an increased amount of E2 was transferred to LDL. E2-17 ester was as potent as E2 in preventing LDL oxidation in vitro, but 3,17-diesters were not as effective (E2=E2-17 ester>E2-3 ester>E2-3,17 diester). This was also supported by experiments which showed that estrogens with masked 3-OH groups were not effective as antioxidants. These studies provide evidence that HDL could facilitate the antioxidant effect of E2 through initial association, esterification and eventual transfer of E2 esters to LDL. Therefore it is critical that HDL peroxidation parameters be evaluated in subjects receiving estrogen replacement therapy.

scholarly journals Nutraceutical Activity in Osteoarthritis Biology: A Focus on the Nutrigenomic Role

Cells ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 1232
Author(s):  
Stefania D’Adamo ◽  
Silvia Cetrullo ◽  
Veronica Panichi ◽  
Erminia Mariani ◽  
Flavio Flamigni ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Antioxidant Activities ◽  
Synergistic Effects ◽  
National Health System ◽  
Bioactive Molecules ◽  
Joint Disease ◽  
In Vivo Studies ◽  
Wide Range

Osteoarthritis (OA) is a disease associated to age or conditions that precipitate aging of articular cartilage, a post-mitotic tissue that remains functional until the failure of major homeostatic mechanisms. OA severely impacts the national health system costs and patients’ quality of life because of pain and disability. It is a whole-joint disease sustained by inflammatory and oxidative signaling pathways and marked epigenetic changes responsible for catabolism of the cartilage extracellular matrix. OA usually progresses until its severity requires joint arthroplasty. To delay this progression and to improve symptoms, a wide range of naturally derived compounds have been proposed and are summarized in this review. Preclinical in vitro and in vivo studies have provided proof of principle that many of these nutraceuticals are able to exert pleiotropic and synergistic effects and effectively counteract OA pathogenesis by exerting both anti-inflammatory and antioxidant activities and by tuning major OA-related signaling pathways. The latter are the basis for the nutrigenomic role played by some of these compounds, given the marked changes in the transcriptome, miRNome, and methylome. Ongoing and future clinical trials will hopefully confirm the disease-modifying ability of these bioactive molecules in OA patients.

scholarly journals Pleiotropic Biological Effects of Dietary Phenolic Compounds and their Metabolites on Energy Metabolism, Inflammation and Aging

Molecules ◽  
2020 ◽  
Vol 25 (3) ◽  
pp. 596 ◽  
Author(s):  
María del Carmen Villegas-Aguilar ◽  
Álvaro Fernández-Ochoa ◽  
María de la Luz Cádiz-Gurrea ◽  
Sandra Pimentel-Moral ◽  
Jesús Lozano-Sánchez ◽  
...  
Keyword(s):  
Energy Metabolism ◽  
Phenolic Compounds ◽  
Molecular Mechanisms ◽  
Biological Effects ◽  
Biological Properties ◽  
In Vivo Studies ◽  
Wide Range ◽  
High Prevalence

Dietary phenolic compounds are considered as bioactive compounds that have effects in different chronic disorders related to oxidative stress, inflammation process, or aging. These compounds, coming from a wide range of natural sources, have shown a pleiotropic behavior on key proteins that act as regulators. In this sense, this review aims to compile information on the effect exerted by the phenolic compounds and their metabolites on the main metabolic pathways involved in energy metabolism, inflammatory response, aging and their relationship with the biological properties reported in high prevalence chronic diseases. Numerous in vitro and in vivo studies have demonstrated their pleiotropic molecular mechanisms of action and these findings raise the possibility that phenolic compounds have a wide variety of roles in different targets.

scholarly journals Stretchable multichannel antennas in soft wireless optoelectronic implants for optogenetics

2016 ◽  
Vol 113 (50) ◽  
pp. E8169-E8177 ◽  
Author(s):  
Sung Il Park ◽  
Gunchul Shin ◽  
Jordan G. McCall ◽  
Ream Al-Hasani ◽  
Aaron Norris ◽  
...  
Keyword(s):  
Radio Frequency ◽  
Antenna Arrays ◽  
Capacitive Coupling ◽  
Radio Frequency Power ◽  
In Vivo Studies ◽  
Active Motion ◽  
The Brain ◽  
Frequency Power

Optogenetic methods to modulate cells and signaling pathways via targeted expression and activation of light-sensitive proteins have greatly accelerated the process of mapping complex neural circuits and defining their roles in physiological and pathological contexts. Recently demonstrated technologies based on injectable, microscale inorganic light-emitting diodes (μ-ILEDs) with wireless control and power delivery strategies offer important functionality in such experiments, by eliminating the external tethers associated with traditional fiber optic approaches. Existing wireless μ-ILED embodiments allow, however, illumination only at a single targeted region of the brain with a single optical wavelength and over spatial ranges of operation that are constrained by the radio frequency power transmission hardware. Here we report stretchable, multiresonance antennas and battery-free schemes for multichannel wireless operation of independently addressable, multicolor μ-ILEDs with fully implantable, miniaturized platforms. This advance, as demonstrated through in vitro and in vivo studies using thin, mechanically soft systems that separately control as many as three different μ-ILEDs, relies on specially designed stretchable antennas in which parallel capacitive coupling circuits yield several independent, well-separated operating frequencies, as verified through experimental and modeling results. When used in combination with active motion-tracking antenna arrays, these devices enable multichannel optogenetic research on complex behavioral responses in groups of animals over large areas at low levels of radio frequency power (<1 W). Studies of the regions of the brain that are involved in sleep arousal (locus coeruleus) and preference/aversion (nucleus accumbens) demonstrate the unique capabilities of these technologies.

Inhibition of Human Lymphoma Cell Growth by the PKC-Beta Selective Inhibitor Enzastaurin (LY317615) in Combination with Multiple Therapeutic Agents.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1595-1595
Author(s):  
Randall M Rossi ◽  
Marlene Balys ◽  
Dean Franklin ◽  
Valerie Grose ◽  
Richard I Fisher ◽  
...  
Keyword(s):  
Single Agent ◽  
Large Cell ◽  
Therapeutic Agents ◽  
In Vivo Studies ◽  
Therapeutic Drugs ◽  
Potential Synergy ◽  
Size Growth ◽  
Reduce Tumor Growth

Abstract Previous studies in our lab have shown that the PKC-beta inhibitor, enzastaurin (LY317615), when used to treat a panel of human diffuse large cell lymphoma (DLCL) lines, was able to induce cell death in vitro and substantially reduce tumor growth in xenograft assays. These findings support the hypothesis that activation of PKC contributes to tumor cell survival and proliferation, which has been implicated in the pathogenesis of human B cell lymphomas. Specifically, PKC-beta activation is increased in tumor cells from patients with poor prognosis DLCL, suggesting that PKC-beta may be a target for therapeutic intervention. In the present study, we have explored the interaction of enzastaurin with a panel of well characterized therapeutic agents to evaluate whether its anti-tumor activity can potentially be enhanced. Drugs were chosen for analysis based either on known single agent activity in lymphoma, or by preclinical evaluation indicating potential synergy with enzastaurin. For in vitro culture assays (48–72 hr treatment), the addition of gemcitabine, rapamycin, or bortezomib, increased the cytotoxicity of enzastaurin from 2 to 7 fold. This effect was evident with multiple human DLCL cell lines, (OCI-Ly3, 7, 10, 19, and SUDHL-4, and 6), as well as two independent primary DLCL cultures. For in vivo studies, subcutaneous transplantation of the DLCL cell line OCI-Ly19, (previously engineered to express luciferase which allows for real time in vivo imaging), or a primary DLCL isolate, into immune deficient NOD/SCID mice formed reproducible tumors. Recipient animals were separated into uniform cohorts when the tumors were of &lt;=500 cubic mm in size. The animals were then simultaneously or sequentially treated with enzastaurin, (150 mg/kg b.i.d. via oral gavage) and a secondary drug, either gemcitabine, (2.5 or 5.0 mg/kg 1x/3 days IP), bortezomib, (0.4 mg/kg twice weekly IP), rapamycin, (1.0 mg/kg, daily IP), or rituxan, (5 mg/kg, weekly IP). Imaging and analysis of tumor volumes showed that addition of either rituxan or rapamycin provided no additional benefit in comparison to enzastaurin alone during the course of treatment. In contrast, the combination of either gemcitabine or bortezomib with enzastaurin demonstrated significantly reduced tumor volumes in comparison to enzastaurin alone (17% to 38% greater decrease with enzastaurin + gemcitabine, and 50% greater decrease in tumor volume with enzastaurin + bortezomib). These data suggest that the use of enzastaurin in combination with existing therapeutic drugs (gemcitabine or bortezomib) has the potential to limit tumor size/growth while lowering dose levels and thereby reducing potential side effects associated with traditional treatments.

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