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Molecular Pain Jun 2024Pain and anxiety are two common and undertreated non-motor symptoms in Parkinson's disease (PD), which affect the life quality of PD patients, and the underlying...
Pain and anxiety are two common and undertreated non-motor symptoms in Parkinson's disease (PD), which affect the life quality of PD patients, and the underlying mechanisms remain unclear. As an important subtype of adenylyl cyclases (ACs), adenylyl cyclase subtype 1 (AC1) is critical for the induction of cortical long-term potentiation (LTP) and injury induced synaptic potentiation in the cortical areas including anterior cingulate cortex (ACC) and insular cortex (IC). Genetic deletion of AC1 or pharmacological inhibition of AC1 improved chronic pain and anxiety in different animal models. In this study, we proved the motor deficit, pain, and anxiety symptoms of PD in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice model. As a lead candidate AC1 inhibitor, oral administration (1 dose and 7 doses) of NB001 (20 and 40 mg/kg) showed significant analgesic effect in MPTP-treated mice, and the anxiety behavior was also reduced (40 mg/kg). By using genetic knockout mice, we found that AC1 knockout mice showed reduced pain and anxiety symptoms after MPTP administration, but not AC8 knockout mice. In summary, genetic deletion of AC1 or pharmacological inhibition of AC1 improved pain and anxiety symptoms in PD model mice, but didn't affect motor function. These results suggest that NB001 is a potential drug for the treatment of pain and anxiety symptoms in PD patients by inhibiting AC1 target.
PubMed: 38912637
DOI: 10.1177/17448069241266683 -
Frontiers in Microbiology 2024Lowing blood lipid levels with probiotics has good application prospects. This study aimed to isolate probiotics with hypolipidemic efficacy from homemade na dish and...
Lowing blood lipid levels with probiotics has good application prospects. This study aimed to isolate probiotics with hypolipidemic efficacy from homemade na dish and investigate their mechanism of action. experiments were conducted to determine the cholesterol-lowering ability of five isolates, with results showing that N4 exhibited a high cholesterol-lowering rate of 50.27% and significant resistance to acid (87%), bile salt (51.97%), and pepsin (88.28%) in simulated gastrointestinal fluids, indicating promising application prospects for the use of probiotics in lowering blood lipids. The findings from the experiment demonstrated that the administration of N4 effectively attenuated lipid droplet accumulation and inflammatory cell infiltration in the body weight and liver of hyperlipidemic rats, leading to restoration of liver tissue morphology and structure, as well as improvement in lipid and liver biochemical parameters. 16S analysis indicated that the oral administration of N4 led to significant alterations in the relative abundance of various genera, including , , , and , in the gut microbiota of hyperlipidemia rats. Additionally, fecal metabolomic analysis identified a total of 78 metabolites following N4 intervention, with carboxylic acids and their derivatives being the predominant compounds detected. The transcriptomic analysis revealed 156 genes with differential expression following N4 intervention, leading to the identification of 171 metabolic pathways through Kyoto Encyclopedia of Genes and Genomes enrichment analysis. Notably, the glutathione metabolism pathway, PPAR signaling pathway, and bile secretion pathway emerged as the primary enrichment pathways. The findings from a comprehensive multi-omics analysis indicate that N4 influences lipid metabolism and diminishes lipid levels in hyperlipidemic rats through modulation of fumaric acid and γ-aminobutyric acid concentrations, as well as glutathione and other metabolic pathways in the intestinal tract, derived from both the gut microbiota and the host liver. This research offers valuable insights into the therapeutic potential of probiotics for managing lipid metabolism disorders and their utilization in the development of functional foods.
PubMed: 38912346
DOI: 10.3389/fmicb.2024.1390293 -
ACS Nanoscience Au Jun 2024Activating the glucagon-like peptide-1 (GLP-1) receptor by oral nucleic acid delivery would be a promising treatment strategy against hyperglycemia due to its various...
Enhancing the Therapeutic Efficacy of GLP-1 for Hyperglycemia Treatment: Overcoming Barriers of Oral Gene Therapy with Taurocholic Acid-Conjugated Protamine Sulfate and Calcium Phosphate.
Activating the glucagon-like peptide-1 (GLP-1) receptor by oral nucleic acid delivery would be a promising treatment strategy against hyperglycemia due to its various therapeutic actions. However, GLP-1 receptor agonists are effective only in subcutaneous injections because they face multiple barriers due to harsh gastrointestinal tract (GIT) conditions before reaching the site of action. The apical sodium bile acid transporter (ASBT) pathway at the intestinal site could be an attractive target to overcome the problem. Herein, we used our previously established multimodal carrier system utilizing bile salt, protamine sulfate, and calcium phosphate as excipients (PTCA) and the GLP-1 gene as an active ingredient (GENE) to test the effects of different formulation doses against diabetes and obesity. The carrier system demonstrated the ability to protect the GLP-1 model gene encoded within the plasmid at the GIT and transport it ASBT at the target site. A single oral dose, regardless of quantity, showed the generation of GLP-1 and insulin from the body and maintained the normoglycemic condition by improving insulin sensitivity and blood sugar tolerance for a prolonged period. This oral gene therapy approach shows significantly higher therapeutic efficacy in preclinical studies than currently available US Food and Drug Administration-approved GLP-1 receptor agonists such as semaglutide and liraglutide. Also, a single oral dose of GENE/PTCA is more effective than 20 insulin injections. Our study suggests that oral GENE/PTCA formulation could be a promising alternative to injection-based therapeutics for diabetics, which is effective in long-term treatment and has been found to be highly safe in all aspects of toxicology.
PubMed: 38912289
DOI: 10.1021/acsnanoscienceau.3c00035 -
Biomedical Reports Aug 2024At low medically-relevant concentrations, ozone serves as an oxidant with a wide spectrum of antimicrobial activity and the ability to promote healing and reduce... (Review)
Review
At low medically-relevant concentrations, ozone serves as an oxidant with a wide spectrum of antimicrobial activity and the ability to promote healing and reduce inflammation. Despite providing therapeutic benefits in a range of diseases, certain adverse effects and contraindications of ozone treatment must be considered. These are primarily related to toxicity from inhalation and systemic types of administration and can be avoided by following relevant guidelines and recommendations. Ozone therapy has been implemented in a number of fields of dentistry and the most commonly used formulations for the oral cavity are gaseous ozone, ozonized water and ozonized oil. The biological mechanisms underlying the molecular effects of ozone have been increasingly reported, but currently remain largely unknown. The aim of the present review was to provide an overview of the mechanisms involved in ozone interaction with dental tissues. The present review focused on relevant evidence regarding the effect of ozone on dental tissues, including periodontal structures, dental cells, enamel and dentine, considering studies in addition to animal and human studies. A variety of biological mechanisms acting through multiple biochemical target pathways were reported to be responsible for the therapeutic effects of ozone. The main beneficial effects of ozone occurred in the following domains: antimicrobial activity, remineralization and microstructural changes of hard dental tissues, immunomodulation and biostimulation of dental and periodontal cells. Additional research could provide further insights into the use of ozone, increase its use for broader clinical applications and assist in the selection of targeted protocols.
PubMed: 38912169
DOI: 10.3892/br.2024.1803 -
International Journal of Tryptophan... 2024Alterations in the composition of the gut microbiota may be causally associated with several brain diseases. Indole-3-propionic acid (IPrA) is a tryptophan-derived...
Alterations in the composition of the gut microbiota may be causally associated with several brain diseases. Indole-3-propionic acid (IPrA) is a tryptophan-derived metabolite, which is produced by intestinal commensal microbes, rapidly enters the circulation, and crosses the blood-brain barrier. IPrA has neuroprotective properties, which have been attributed to its antioxidant and bioenergetic effects. Here, we evaluate an alternative and/or complementary mechanism, linking IPrA to kynurenic acid (KYNA), another neuroprotective tryptophan metabolite. Adult Sprague-Dawley rats received an oral dose of IPrA (200 mg/kg), and both IPrA and KYNA were measured in plasma and frontal cortex 90 minutes, 6 or 24 hours later. IPrA and KYNA levels increased after 90 minutes and 6 hours (brain IPrA: ~56- and ~7-fold; brain KYNA: ~4- and ~3-fold, respectively). In vivo microdialysis, performed in the medial prefrontal cortex and in the striatum, revealed increased KYNA levels (~2.5-fold) following the administration of IPrA (200 mg/kg, p.o), but IPrA failed to affect extracellular KYNA when applied locally. Finally, treatment with 100 or 350 mg IPrA, provided daily to the animals in the chow for a week, resulted in several-fold increases of IPrA and KYNA levels in both plasma and brain. These results suggest that exogenously supplied IPrA may provide a novel strategy to affect the function of KYNA in the mammalian brain.
PubMed: 38911967
DOI: 10.1177/11786469241262876 -
Drug, Healthcare and Patient Safety 2024The manifestation and spread of neuroinvasive circulating vaccine-derived polioviruses (cVDPVs) across several countries, which led to the emergency use of the novel...
BACKGROUND
The manifestation and spread of neuroinvasive circulating vaccine-derived polioviruses (cVDPVs) across several countries, which led to the emergency use of the novel oral polio vaccine type 2 (nOPV2), raised concerns about adverse events following immunization (AEFI) surveillance. We assessed the attributes of AEFI with nOPV2 and examined stakeholder experiences and challenges in AEFI surveillance in Sierra Leone.
METHODS
Using a mixed method approach, we retrospectively reviewed passive data collected during a 2021 immunization campaign, and conducted semi-structured, interviews with vaccinators, district AEFI focal persons, and key stakeholders at the national Expanded Program on Immunization and the National Medicines Regulatory Authority. AEFI were categorized using the Medical Dictionary for Regulatory Activities (MedDRA) Preferred Terms (PTs) and System Organ Class (SOC). Outcomes were stratified as recovered or not, with preventability and causality assessed using the Schumock and Thornton and World Health Organization (WHO) algorithms, respectively.
RESULTS
A total of 528 suspected AEFI were documented, predominantly affecting children aged 28 days to 23 months (63.3%). Most reported AEFI were administration site conditions and general disorders, with pyrexia being the predominant PT. Of 80 serious cases, 78 recovered, with 74 having an inconsistent causal relationship with the vaccine. Most serious cases (78) were deemed non-preventable, with only two being probably preventable. AEFI reporting was not routinely carried out across the group of people interviewed. AEFI reporting was not consistently performed, with discrepancies in defining reportable events and confusion over responsibility. Challenges with the open data kit (ODK) platform were noted, along with perceived inadequacies in training.
CONCLUSION
While the nOPV2 is relatively new, the majority of AEFI were not serious, and most serious cases were not causally linked to the vaccine. Participants exhibited variations in experience and awareness of AEFI reporting.
PubMed: 38911456
DOI: 10.2147/DHPS.S466039 -
Iranian Journal of Basic Medical... 2024The present study aimed to explore the mechanisms underlying the potency of the renoprotective effect of the EtOAc fraction of (EALD) (Plumbaginaceae) against...
OBJECTIVES
The present study aimed to explore the mechanisms underlying the potency of the renoprotective effect of the EtOAc fraction of (EALD) (Plumbaginaceae) against cyclosporine A (CsA), in comparison to vitamin E (Vit. E).
MATERIALS AND METHODS
In the experiment, a model of CsA-induced nephrotoxicity was established by dosing male Wistar rats with 25 mg/kg, for 14 days. The protective effect of EALD was investigated through pretreatment of rats with a dose of 200 mg/kg for 14 days, compared to the oral administration of Vit. E at 100 mg/kg. Renal function and markers of oxidative stress were then assessed. Furthermore, a complementary study was carried out to evaluate CsA-induced endoplasmic reticulum stress (ERS) and inflammation on cell culture (3T3 cells and MCT cells) using western blot and quantitative RT-PCR..
RESULTS
Pretreatment of rats with EALD significantly attenuated the elevated levels of renal dysfunction markers (BUN, creatinine) and suppressed malondialdehyde (MDA) levels; It also significantly regulated the changes in superoxide dismutase (SOD), reduced glutathione (GSH), glutathione peroxydase (GPx), and glutathione S-transferase (GST) levels as compared to Vit. E, demonstrating a more effective recovery in renal tissues. Treatment of cells with CsA was linked to the expression of ERS and inflammatory markers activating transcription factor (ATF4), inositol-requiring enzyme 1α (IRE1α), binding immunoglobulin protein (BiP), and monocyte chemoattractant protein-1 (MCP1). In contrast, pretreatment of cells with EALD resulted in a significant decrease in both ERS and inflammatory markers.
CONCLUSION
These findings indicate the renoprotective potential of , as it demonstrated the ability to ameliorate CsA-induced renal dysfunction through its distinctive antioxidant properties.
PubMed: 38911250
DOI: 10.22038/IJBMS.2024.77052.16661 -
Veterinary World May 2024Lincomycin is an antibiotic used in broiler farming and is commonly combined with other substances to achieve synergistic and complementary effects on the antibacterial...
BACKGROUND AND AIM
Lincomycin is an antibiotic used in broiler farming and is commonly combined with other substances to achieve synergistic and complementary effects on the antibacterial spectrum and mechanism. We developed a specific high-performance liquid chromatography (HPLC) method to measure lincomycin levels in broiler tissues. This study aimed to determine the lincomycin level in tissues and compare it with the minimum inhibitory concentration (MIC) and maximum residue limit (MRL) of certain pathogenic bacteria.
MATERIALS AND METHODS
Three groups of broiler chickens were involved in the study (n = 20 in each group): A control group without lincomycin treatment and two groups (each further divided into two sub-groups) that received oral lincomycin at a dose of 1 g/10 kg of body weight daily for 7 and 14 consecutive days. Tissue samples were collected from each group 1 day and 1 week after lincomycin administration (ALA). This study validated the development of a technique for analyzing drug level degradation in tissues using HPLC. Descriptive and statistical analyses were performed for drug levels to assess their therapeutic value and safety based on lincomycin MIC of certain pathogenic bacteria and MRL.
RESULTS
The method validation resulted in linear regression and coefficient of determination for tissues with r > 0.99, with a recovery rate of 90%-110%, precision as the coefficient of variation 15%, and specificity with no peak overlap for lincomycin. The limits of detection for the liver and kidney were 0.01 μg/g, 0.05 μg/g, and 0.1 μg/g for the breast muscle and all tissues. Administration of lincomycin for 7 and 14 days resulted in therapeutic value concentrations. Lincomycin levels in the liver and kidney of ALA exceeded the MRL, whereas breast muscles were below the MRL for a week of ALA treatment.
CONCLUSION
Administration of lincomycin for 7 and 14 consecutive days resulted in therapeutic value; however, after a week, most tissues showed high drug concentrations that exceeded the MRL. It is necessary to carefully consider the prolonged therapeutic dose of lincomycin in broilers. Antibiotic therapy must be guided in such a way as to protect the product from harmful residues.
PubMed: 38911093
DOI: 10.14202/vetworld.2024.1026-1034 -
Journal of Alzheimer's Disease Reports 2024Despite intense investigations, no effective treatment is yet available to reduce plaques and protect memory and learning in patients with Alzheimer's disease (AD), the...
Identification of Cinnamein, a Component of Balsam of Tolu/Peru, as a New Ligand of PPARα for Plaque Reduction and Memory Protection in a Mouse Model of Alzheimer's Disease.
BACKGROUND
Despite intense investigations, no effective treatment is yet available to reduce plaques and protect memory and learning in patients with Alzheimer's disease (AD), the most common neurodegenerative disorder. Therefore, it is important to identify a non-toxic, but effective, treatment option for AD.
OBJECTIVE
Cinnamein, a nontoxic compound, is naturally available in Balsam of Peru and Tolu Balsam. We examined whether cinnamein treatment could decrease plaques and improve cognitive functions in mouse model of AD.
METHODS
We employed analysis, time-resolved fluorescence energy transfer assay, thermal shift assay, primary neuron isolation, western blot, immunostaining, immunohistochemistry, Barnes maze, T maze, and open field behavior.
RESULTS
Oral administration of cinnamein led to significant reduction in amyloid-β plaque deposits in the brain and protection of spatial learning and memory in mice. Peroxisome proliferator-activated receptor alpha (PPARα), a nuclear hormone receptor, is involved in plaque lowering and increase in hippocampal plasticity. While investigating underlying mechanisms, we found that cinnamein served as a ligand of PPARα. Accordingly, oral cinnamein upregulated the level of PPARα, but not PPARβ, in the hippocampus, and remained unable to decrease plaques from the hippocampus and improve memory and learning in mice lacking PPARα. While A disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) is one of the drivers of nonamyloidogenic pathway, transcription factor EB (TFEB) is considered as the master regulator of autophagy. Cinnamein treatment was found to upregulate both ADAM10 and TFEB in the brain of mice via PPARα.
CONCLUSIONS
Our results suggest that this balsam component may have therapeutic importance in AD.
PubMed: 38910936
DOI: 10.3233/ADR-230179 -
Frontiers in Pharmacology 2024Artemisinin, artemether, artesunate, and dihydroartemisinin are renowned for their antimalarial potential. The current study aims to repurpose the above-mentioned...
Artemisinin, artemether, artesunate, and dihydroartemisinin are renowned for their antimalarial potential. The current study aims to repurpose the above-mentioned artemisinic compounds (ACs) by conducting an intercomparison to evaluate their antiinflammatory potential (AIP). In order to develop potential candidates for the evaluation of AIP of ACs (50 and 100 mg/kg BW), carbon tetrachloride (1ml/kg body weight (BW)) was administered intraperitoneally to BALB/c mice. Alterations in animal behavior were assessed weekly through tail suspension test, force swim test, open field test, Y-maze test, inverted screen analysis, and weight lifting test. Aberrations in hematological, serological, endogenous antioxidants, and oxidative stress marker profiles were assessed in all twelve groups. Histological alterations were read using hematoxylin and eosin staining. Levels of inflammatory markers including nuclear factor kappa B (NF-κB), tumor necrosis factor alpha (TNF-α), and nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3), were determined using immunohistochemical analysis (IHCA). Antioxidant markers i.e., nuclear factor erythroid-2-related factor (Nrf-2) and thioredoxin (TRX) were also quantified through IHCA. Comet assay was performed to quantify DNA damage. Oral administration of ACs to mice significantly alleviated the carbon tetrachloride induced inflammation in comparison with silymarin. Reduced levels of several inflammatory markers including nitric oxide, thiobarbituric acid reactive substances, interleukin-1 beta, NF-κB, TNF-α, and NLRP3, underscore the substantial AIP of ACs. IHCA depicted the revitalized percent relative expression of Nrf-2 and TRX in groups treated with ACs. Behavioral analysis revealed that ACs-treated groups significantly (p<0.05) attenuated the memory deficit, anxiety, and depressive-like behavior. Moreover, histopathological, hematological, serological, and endogenous antioxidant profiles indicated substantial AIP of ACs. Findings of comet assay further bolstered the compelling evidence as DNA damage was significantly (p<0.05) curbed down after ACs (100 mg/kg) treatment. All these outcomes implied that ACs exhibited AIP in a dose-dependent manner with maximal AIP imparted by artemisinin (100 mg/kg). This pre-clinical investigation avers the tremendous AIP of ACs targeting key molecular pathways. The current study divulges artemisinin as the most potent antiinflammatory agent among the tested compounds.
PubMed: 38910883
DOI: 10.3389/fphar.2024.1352827