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Molecular Neurobiology Jun 2024Alzheimer's Disease is a degenerative neurological condition which leads to a decline in memory and cognitive function. Chlorogenic Acid (CGA) presents properties...
Alzheimer's Disease is a degenerative neurological condition which leads to a decline in memory and cognitive function. Chlorogenic Acid (CGA) presents properties including neuroprotective, antioxidant and anti-inflammatory. The aim of this study was to examine the impact of CGA on cognitive impairments, neuroinflammation and neuronal damage in mice submitted to an experimental model of Sporadic Alzheimer Disease (SAD) induced by intracerebroventricular administration of streptozotocin (ICV-STZ). Male Swiss mice received bilateral ICV-STZ injections (3 mg/Kg) on days 1 and 3. The treatment with CGA (5 mg/Kg, orally) or vehicle (water, orally), was initiated and continued for 26 days, starting 2 h after the second induction procedure. At first, there was no change in serum glucose levels after SAD induction. ICV-STZ induces impairments in aversive, recognition, and spatial memory, while CGA treatment significantly alleviated these memory deficits. Furthermore, locomotor activity, working memory, and anxiety-related activities remained unaffected by the treatments. CGA treatment protects against ICV-STZ-induced increase in the nitrite/nitrate and TBARS levels. ICV-STZ induced a reduction in viable cells, depletion of BDNF, and triggered astrogliosis and microgliosis in the cortex and hippocampus. Treatment with CGA preserves viable cell count in the prefrontal cortex, CA1, and CA3 regions of the hippocampus. Additionally, it prevented BDNF depletion in the prefrontal cortex and hippocampus (CA1, CA3, and DG regions), and mitigated astrogliosis and microgliosis in the prefrontal cortex and hippocampus (CA1, CA3, and DG regions). These findings indicate the neuroprotective effects of CGA, underscoring their potential as therapeutic agents or adjuncts in the treatment of SAD.
PubMed: 38898198
DOI: 10.1007/s12035-024-04299-x -
International Journal of Toxicology Jun 2024The subchronic toxicity and toxicokinetics of a combination of rabeprazole sodium and sodium bicarbonate were investigated in dogs by daily oral administration for 13...
The subchronic toxicity and toxicokinetics of a combination of rabeprazole sodium and sodium bicarbonate were investigated in dogs by daily oral administration for 13 consecutive weeks with a 4-week recovery period. The dose groups consisted of control (vehicles), (5 + 200), (10 + 400), and (20 + 800) mg/kg of rabeprazole sodium + sodium bicarbonate, 20 mg/kg of rabeprazole sodium only, and 800 mg/kg of sodium bicarbonate only. Esophageal ulceration accompanied by inflammation was observed in only one animal in the male (20 + 800) mg/kg rabeprazole sodium + sodium bicarbonate group. However, the severity of the ulceration was moderate, and the site of occurrence was focally extensive; thus, it was assumed to be a treatment-related effect of rabeprazole sodium + sodium bicarbonate. In the toxicokinetics component of this study, systemic exposure to rabeprazole sodium (AUC and C at Day 91) was greater in males than females, suggesting sex differences. AUC and C at Day 91 were increased compared to those on Day 1 in a dose-dependent manner. A delayed T and no drug accumulation were observed after repeated dosage. In conclusion, we suggest under the conditions of this study that the no-observed-adverse-effect level (NOAEL) of the combination of rabeprazole sodium + sodium bicarbonate in male and female dogs is (10 + 400) and (20 + 800) mg/kg, respectively.
PubMed: 38897632
DOI: 10.1177/10915818241261631 -
Journal of Pharmaceutical Sciences Jun 2024Since eyedrops have conventionally been formulated in aqueous vehicles, ocular pharmacokinetic studies are generally performed using aqueous buffers to identify...
Since eyedrops have conventionally been formulated in aqueous vehicles, ocular pharmacokinetic studies are generally performed using aqueous buffers to identify physicochemical properties of the drug and the vehicles that influence drug absorption. In recent years, biocompatible lipophilic vehicles are increasingly finding application in ocular drug delivery; however, the mechanism of drug penetration from these non-aqueous vehicles is poorly understood. This study aims to compare ocular penetration of the model lipophilic drug curcumin when incorporated into lipophilic vehicles. To elucidate whether intrinsic solubility in the lipophilic vehicle influences ocular penetration, a curcumin solution and suspension were prepared in medium chain triglycerides (MCT) and squalane, respectively. Ocular penetration and distribution of curcumin from both vehicles was compared and evaluated qualitatively and quantitatively ex vivo. Significantly greater and faster penetration was observed from the squalane suspension than from the MCT solution in all ocular tissues. Our results suggest that the ability of lipophilic drugs to partition out of lipophilic vehicles and into cell membranes, rather than their intrinsic solubility in the lipophilic vehicle, determines the rate and extent of their ocular penetration.
PubMed: 38897564
DOI: 10.1016/j.xphs.2024.06.011 -
Molecules (Basel, Switzerland) May 2024Radiotherapy is an essential component of the treatment regimens for many cancer patients. Despite recent technological advancements to improve dose delivery techniques,... (Review)
Review
Radiotherapy is an essential component of the treatment regimens for many cancer patients. Despite recent technological advancements to improve dose delivery techniques, the dose escalation required to enhance tumor control is limited due to the inevitable toxicity to the surrounding healthy tissue. Therefore, the local enhancement of dosing in tumor sites can provide the necessary means to improve the treatment modality. In recent years, the emergence of nanotechnology has facilitated a unique opportunity to increase the efficacy of radiotherapy treatment. The application of high-atomic-number (Z) nanoparticles (NPs) can augment the effects of radiotherapy by increasing the sensitivity of cells to radiation. High-Z NPs can inherently act as radiosensitizers as well as serve as targeted delivery vehicles for radiosensitizing agents. In this work, the therapeutic benefits of high-Z NPs as radiosensitizers, such as their tumor-targeting capabilities and their mechanisms of sensitization, are discussed. Preclinical data supporting their application in radiotherapy treatment as well as the status of their clinical translation will be presented.
Topics: Humans; Radiation-Sensitizing Agents; Neoplasms; Nanoparticles; Animals; Radiotherapy
PubMed: 38893315
DOI: 10.3390/molecules29112438 -
Nutrients May 2024Autism spectrum disorder (ASD) is a neurodevelopmental disorder identified by impairments in common social interactions and repetitive behaviors. In ASD patients,...
Autism spectrum disorder (ASD) is a neurodevelopmental disorder identified by impairments in common social interactions and repetitive behaviors. In ASD patients, substantial morphological alterations have been observed in the hippocampus, which represents an important region for the development of social skills. Melatonin, commonly found in many foods and plants, is also produced by the pineal gland. This indolamine, known to regulate the circadian rhythm, shows antioxidant and anti-inflammatory properties. We therefore hypothesized that melatonin may reduce oxidative stress and inflammation in the hippocampus of ASD patients. We explored our hypothesis using the BTBR mouse, a well-regarded murine transgenic model for ASD. Immediately after weaning, male BTBR and C57BL/6 mice underwent an 8-week treatment with melatonin or vehicle. Later, through immunohistochemistry and the immunoblotting analysis of the hippocampus, we evaluated the overall expression and cellular localization of Nrf2 and SOD1, two enzymes involved in the oxidative stress response. Similarly, we evaluated NLRP3 and NFkB, two mediators of inflammation, and GAD67, an enzyme responsible for the synthesis of GABA. Ultimately, we addressed melatonin's potential to regulate iron metabolism through a DAB-enhanced Perls reaction assay. Results showed melatonin's potential for modulating the analyzed markers in BTBR mice, suggesting a potential neuroprotective effect in ASD patients.
Topics: Animals; Melatonin; Hippocampus; Male; Neuroprotective Agents; Mice; Mice, Inbred C57BL; Oxidative Stress; Disease Models, Animal; Autism Spectrum Disorder; Antioxidants; Mice, Transgenic; NF-E2-Related Factor 2; Inflammation
PubMed: 38892585
DOI: 10.3390/nu16111652 -
International Journal of Molecular... Jun 2024The biological activities and related mechanisms of curcumin, a major polyphenolic compound in turmeric, the rhizome of , have been extensively investigated. Due to its...
The biological activities and related mechanisms of curcumin, a major polyphenolic compound in turmeric, the rhizome of , have been extensively investigated. Due to its poor solubility in water, the analysis of curcumin's biological activities is limited in most aqueous experimental systems. In the present study, the effects of polyvinyl alcohol (PVA), a dietary-compatible vehicle, on the solubility, stability, cellular uptake, and bioactivities of curcumin were investigated. Curcumin solubility was improved significantly by PVA; the color intensity of curcumin aqueous solution in the presence of PVA increased concentration-dependently with its peak shift to a shorter wavelength. Improved suspension stability and photostability of curcumin in an aqueous solution were also observed in the presence of PVA, even at 62.5 μg/mL. The scavenging activities of curcumin against DPPH, ABTS, AAPH radicals, and nitric oxide were enhanced significantly in the presence of PVA. PVA at 250 μg/mL also significantly enhanced the cytotoxic activity of curcumin against both HCT 116 colon cancer and INT 407 (HeLa-derived) embryonic intestinal cells by reducing the IC from 16 to 11 μM and 25 to 15 μM, respectively. PVA improved the cellular uptake of curcumin in a concentration-dependent manner in INT 407 cells; it increased the cellular levels more effectively at lower curcumin treatment concentrations. The present results indicate that PVA improves the solubility and stability of curcumin, and changes in these chemical behaviors of curcumin in aqueous systems by PVA could enhance the bioavailability and pharmacological efficacy of curcumin.
Topics: Curcumin; Polyvinyl Alcohol; Humans; Solubility; Drug Stability; HCT116 Cells; HeLa Cells; Free Radical Scavengers; Cell Survival
PubMed: 38892468
DOI: 10.3390/ijms25116278 -
International Journal of Molecular... Jun 2024Neurotoxicity is a major obstacle in the effectiveness of Cisplatin in cancer chemotherapy. In this process, oxidative stress and inflammation are considered to be the...
Neurotoxicity is a major obstacle in the effectiveness of Cisplatin in cancer chemotherapy. In this process, oxidative stress and inflammation are considered to be the main mechanisms involved in brain and lung toxicity. The aim of the present work was to study the influence of the amount of protein on some oxidative parameters in the brain and lungs of rats treated with Cisplatin (CP) and N-Acetylcysteine (NAC) as neuroprotectors. Four groups of Wistar rats, each containing six animals, were fed with a protein diet at 7% for 15 days. Thereafter, the groups were given either a unique dose of CP 5 mg/kg or NAC 5 mg/kg as follows: group 1 (control), NaCl 0.9% vehicle; group 2, CP; group 3, NAC; and group 4, NAC + CP. The animals were sacrificed immediately after the treatments. Blood samples were collected upon sacrifice and used to measure blood triglycerides and glucose. The brain and lungs of each animal were obtained and used to assay lipid peroxidation (TBARS), glutathione (GSH), serotonin metabolite (5-HIAA), catalase, and the activity of Ca, and Mg ATPase using validated methods. TBARS, HO, and GSH were found to be significantly decreased in the cortex and cerebellum/medulla oblongata of the groups treated with CP and NAC. The total ATPase showed a significant increase in the lung and cerebellum/medulla oblongata, while 5-HIAA showed the same tendency in the cortex of the same group of animals. The increase in 5-HIAA and ATPase during NAC and CP administration resulted in brain protection. This effect could be even more powerful when membrane fluidity is increased, thus proving the efficacy of combined NAC and CP drug therapy, which appears to be a promising strategy for future chemotherapy in malnourished patients.
Topics: Animals; Cisplatin; Acetylcysteine; Rats; Rats, Wistar; Lung; Lipid Peroxidation; Oxidative Stress; Male; Cerebrum; Glutathione; Neuroprotective Agents; Antineoplastic Agents
PubMed: 38892427
DOI: 10.3390/ijms25116239 -
International Journal of Molecular... May 2024Astatine (At) is a cyclotron-produced alpha emitter with a physical half-life of 7.2 h. In our previous study, the At-labeled prostate-specific membrane antigen (PSMA)...
Astatine (At) is a cyclotron-produced alpha emitter with a physical half-life of 7.2 h. In our previous study, the At-labeled prostate-specific membrane antigen (PSMA) compound ([At]PSMA-5) exhibited excellent tumor growth suppression in a xenograft model. We conducted preclinical biodistribution and toxicity studies for the first-in-human clinical trial. [At]PSMA-5 was administered to both normal male ICR mice ( = 85) and cynomolgus monkeys ( = 2). The mice were divided into four groups for the toxicity study: 5 MBq/kg, 12 MBq/kg, 35 MBq/kg, and vehicle control, with follow-ups at 1 day ( = 10 per group) and 14 days ( = 5 per group). Monkeys were observed 24 h post-administration of [At]PSMA-5 (9 MBq/kg). Blood tests and histopathological examinations were performed at the end of the observation period. Blood tests in mice indicated no significant myelosuppression or renal dysfunction. However, the monkeys displayed mild leukopenia 24 h post-administration. Despite the high accumulation in the kidneys and thyroid, histological analysis revealed no abnormalities. On day 1, dose-dependent single-cell necrosis/apoptosis was observed in the salivary glands of mice and intestinal tracts of both mice and monkeys. Additionally, tingible body macrophages in the spleen and lymph nodes indicated phagocytosis of apoptotic B lymphocytes. Cortical lymphopenia (2/10) in the thymus and a decrease in the bone marrow cells (9/10) were observed in the 35 MBq/kg group in mice. These changes were transient, with no irreversible toxicity observed in mice 14 days post-administration. This study identified no severe toxicities associated with [At]PSMA-5, highlighting its potential as a next-generation targeted alpha therapy for prostate cancer. The sustainable production of At using a cyclotron supports its applicability for clinical use.
Topics: Animals; Male; Prostatic Neoplasms; Mice; Tissue Distribution; Mice, Inbred ICR; Astatine; Alpha Particles; Humans; Macaca fascicularis; Glutamate Carboxypeptidase II; Radiopharmaceuticals
PubMed: 38891856
DOI: 10.3390/ijms25115667 -
International Journal of Molecular... May 2024Organophosphoate (OP) chemicals are known to inhibit the enzyme acetylcholinesterase (AChE). Studying OP poisoning is difficult because common small animal research...
Organophosphoate (OP) chemicals are known to inhibit the enzyme acetylcholinesterase (AChE). Studying OP poisoning is difficult because common small animal research models have serum carboxylesterase, which contributes to animals' resistance to OP poisoning. Historically, guinea pigs have been used for this research; however, a novel genetically modified mouse strain (KIKO) was developed with nonfunctional serum carboxylase (Es1 KO) and an altered acetylcholinesterase (AChE) gene, which expresses the amino acid sequence of the human form of the same protein (AChE KI). KIKO mice were injected with 1xLD of an OP nerve agent or vehicle control with or without atropine. After one to three minutes, animals were injected with 35 mg/kg of the currently fielded Reactivator countermeasure for OP poisoning. Postmortem brains were imaged on a Bruker RapifleX ToF/ToF instrument. Data confirmed the presence of increased acetylcholine in OP-exposed animals, regardless of treatment or atropine status. More interestingly, we detected a small amount of Reactivator within the brain of both exposed and unexposed animals; it is currently debated if reactivators can cross the blood-brain barrier. Further, we were able to simultaneously image acetylcholine, the primary affected neurotransmitter, as well as determine the location of both Reactivator and acetylcholine in the brain. This study, which utilized sensitive MALDI-MSI methods, characterized KIKO mice as a functional model for OP countermeasure development.
Topics: Animals; Organophosphate Poisoning; Mice; Disease Models, Animal; Humans; Acetylcholinesterase; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Atropine; Brain; Mice, Knockout; Cholinesterase Inhibitors; Acetylcholine
PubMed: 38891812
DOI: 10.3390/ijms25115624 -
Animals : An Open Access Journal From... Jun 2024is a heteroxenous nematode that infects the harderian gland and other ocular tissues in birds. High-intensity infections often cause damage to the infected tissues. Due...
is a heteroxenous nematode that infects the harderian gland and other ocular tissues in birds. High-intensity infections often cause damage to the infected tissues. Due to the nature of the infection sites, treatment of in these hosts can be difficult. Fenbendazole (FBZ) is a common anthelmintic used to treat birds for helminth infections; however, little information exists as to the efficacy of the drug on infections. The present study aims to estimate lethal concentrations of FBZ to . Adult were maintained in vitro and exposed to doses of 5, 50, 100, and 200 µM concentrations of FBZ and included both negative and vehicle controls. Exposure lasted 7.5 days and lethality was determined for each treatment. Negative and vehicle controls did not differ, and both had 75% survival at the end of the treatment period. The percentage survivorship in ascending order of concentration, corrected for the controls, was 66.67%, 44.44%, 33.33%, and 0%. LC, LC, and LC estimates were 7.5 ± 0.26, 49.1 ± 1.69, and 163.2 ± 5.63 µM, respectively. In the context of known pharmacokinetics of FBZ in birds, a single oral dose of FBZ can achieve exposure levels that are lethal to , but the drug does not stay in the system long enough. Thus, treatment of infections will require multiple oral doses over several days.
PubMed: 38891706
DOI: 10.3390/ani14111659