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Translational Psychiatry Oct 2023Paternal abuse of drugs, such as methamphetamine (METH), elevates the risk of developing addiction in subsequent generations, however, its underlying molecular mechanism...
Paternal abuse of drugs, such as methamphetamine (METH), elevates the risk of developing addiction in subsequent generations, however, its underlying molecular mechanism remains poorly understood. Male adult mice (F0) were exposed to METH for 30 days, followed by mating with naïve female mice to create the first-generation mice (F1). When growing to adulthood, F1 were subjected to conditioned place preference (CPP) test. Subthreshold dose of METH (sd-METH), insufficient to induce CPP normally, were used in F1. Selective antagonist (betaxolol) for β1-adrenergic receptor (ADRB1) or its knocking-down virus were administrated into mPFC to regulate ADRB1 function and expression on CaMKII-positive neurons. METH-sired male F1 acquired sd-METH-induced CPP, indicating that paternal METH exposure induce higher sensitivity to METH in male F1. Compared with saline (SAL)-sired male F1, CaMKII-positive neuronal activity was normal without sd-METH, but strongly evoked after sd-METH treatment in METH-sired male F1 during adulthood. METH-sired male F1 had higher ADRB1 levels without sd-METH, which was kept at higher levels after sd-METH treatment in mPFC. Either inhibiting ADRB1 function with betaxolol, or knocking-down ADRB1 level on CaMKII-positive neurons (ADRB1) with virus transfection efficiently suppressed sd-METH -evoked mPFC activation, and ultimately blocked sd-METH-induced CPP in METH-sired male F1. In the process, the p-ERK1/2 and ΔFosB may be potential subsequent signals of mPFC ADRB1. The mPFC ADRB1 mediates paternal METH exposure-induced higher sensitivity to drug addiction in male offspring, raising a promising pharmacological target for predicting or treating transgenerational addiction.
Topics: Male; Female; Mice; Animals; Methamphetamine; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Betaxolol; Phosphorylation; Central Nervous System Stimulants
PubMed: 37857642
DOI: 10.1038/s41398-023-02624-x -
International Journal of Molecular... Aug 2023With significant human and economic losses, increasing bacterial resistance is a serious global threat to human life. Due to their high efficacy, broad spectrum, and...
With significant human and economic losses, increasing bacterial resistance is a serious global threat to human life. Due to their high efficacy, broad spectrum, and cost-effectiveness, beta-lactams are widely used in the clinical management of bacterial infection. The emergence and wide spread of New Delhi metallo-β-lactamase (NDM-1), which can effectively inactivate β-lactams, has posed a challenge in the design of effective new antimicrobial treatments. Medicine repurposing is now an important tool in the development of new alternative medicines. We present a known glaucoma therapeutic, betaxolol (BET), which with a 50% inhibitory concentration (IC) of 19.3 ± 0.9 μM significantly inhibits the hydrolytic activity of the NDM-1 enzyme and may represent a potential NDM-1 enzyme inhibitor. BET combined with meropenem (MEM) showed bactericidal synergism in vitro. The efficacy of BET was further evaluated against systemic bacterial infections in BALB/c mice. The results showed that BET+MEM decreased the numbers of leukocytes and inflammatory factors in peripheral blood, as well as the organ bacterial load and pathological damage. Molecular docking and kinetic simulations showed that BET can form hydrogen bonds and hydrophobic interactions directly with key amino acid residues in the NDM-1 active site. Thus, we demonstrated that BET inhibited NDM-1 by competitively binding to it and that it can be developed in combination with MEM as a new therapy for the management of infections caused by medicine-resistant bacteria.
Topics: Humans; Animals; Mice; Meropenem; Betaxolol; Escherichia coli; Molecular Docking Simulation; Anti-Inflammatory Agents
PubMed: 37686201
DOI: 10.3390/ijms241713399 -
American Journal of Ophthalmology Aug 2023To compare long-term visual outcomes in the 2 arms of the Early Manifest Glaucoma Trial (EMGT) and determine if delayed treatment was associated with a penalty in terms... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
To compare long-term visual outcomes in the 2 arms of the Early Manifest Glaucoma Trial (EMGT) and determine if delayed treatment was associated with a penalty in terms of visual function.
DESIGN
Long-term follow-up of a prospective, randomized controlled clinical trial.
METHODS
EMGT was carried out at 2 centers in Sweden; 255 subjects with newly detected, untreated glaucoma were randomized to immediate treatment with topical betaxolol and argon laser trabeculoplasty or to no initial treatment as long as no progression was detected. Subjects were followed prospectively with standard automated perimetry, visual acuity measurements, and tonometry for up to 21 years. Outcomes included vision impairment (VI), the perimetric mean deviation (MD) index and rate of progression, and visual acuity.
RESULTS
At study end, percentages of eyes with VI or blindness were slightly higher in the treated group than in the untreated control group, 12.1% vs 11.0%, and 9.4.% vs 6.1% respectively, as were subjects with VI in at least one eye, 19.5% vs 18.7%. The differences were not statistically significant, nor were cumulative incidences of VI in at least one eye. The control group had more field loss than the treatment group, with median MD in the worse eye of -14.73 dB vs -12.85 dB, and rate of progression of -0.74 vs -0.60 dB/y, which was not statistically significant. Differences in visual acuity were minimal.
CONCLUSIONS
Delaying treatment did not result in serious penalties. VI occurred at similar proportions in both treatment arms with a slight preponderance in the treatment group, whereas visual field damage was slightly higher in the control group.
Topics: Humans; Glaucoma, Open-Angle; Intraocular Pressure; Prospective Studies; Time-to-Treatment; Glaucoma; Visual Field Tests; Disease Progression; Follow-Up Studies; Vision Disorders
PubMed: 37142174
DOI: 10.1016/j.ajo.2023.04.010 -
International Journal of Molecular... Mar 2023Uveal melanoma (UM) is the most common primary cancer of the eye in adults. A new systemic therapy is needed to reduce the high metastasis and mortality rate. As...
Uveal melanoma (UM) is the most common primary cancer of the eye in adults. A new systemic therapy is needed to reduce the high metastasis and mortality rate. As β-blockers are known to have anti-tumor effects on various cancer entities, this study focuses on investigating the effect of β1-selective blockers atenolol, celiprolol, bisoprolol, metoprolol, esmolol, betaxolol, and in particular, nebivolol on UM. The study was performed on 3D tumor spheroids as well as 2D cell cultures, testing tumor viability, morphological changes, long-term survival, and apoptosis. Flow cytometry revealed the presence of all three β-adrenoceptors with a dominance of β2-receptors on cell surfaces. Among the blockers tested, solely nebivolol concentration-dependently decreased viability and altered 3D tumor spheroid structure. Nebivolol blocked the repopulation of cells spreading from 3D tumor spheroids, indicating a tumor control potential at a concentration of ≥20 µM. Mechanistically, nebivolol induced ATP depletion and caspase-3/7 activity, indicating that mitochondria-dependent signaling is involved. D-nebivolol or nebivolol combined with the β2-antagonist ICI 118.551 displayed the highest anti-tumor effects, suggesting a contribution of both β1- and β2-receptors. Thus, the present study reveals the tumor control potential of nebivolol in UM, which may offer a perspective for co-adjuvant therapy to reduce recurrence or metastasis.
Topics: Adult; Humans; Nebivolol; Ethanolamines; Benzopyrans; Adrenergic beta-Antagonists; Melanoma; Receptors, Adrenergic, beta
PubMed: 36982966
DOI: 10.3390/ijms24065894 -
Drug Delivery Dec 2023Recently, various novel drug delivery systems have been developed to overcome ocular barriers in order to improve drug efficacy. We have previously reported that...
Physicochemical properties and micro-interaction between micro-nanoparticles and anterior corneal multilayer biological interface film for improving drug delivery efficacy: the transformation of tear film turnover mode.
Recently, various novel drug delivery systems have been developed to overcome ocular barriers in order to improve drug efficacy. We have previously reported that montmorillonite (MT) microspheres (MPs) and solid lipid nanoparticles (SLNs) loaded with the anti-glaucoma drug betaxolol hydrochloride (BHC) exhibited sustained drug release and thus intraocular pressure (IOP) lowering effects. Here, we investigated the effect of physicochemical particle parameters on the micro-interactions with tear film mucins and corneal epithelial cells. Results showed that the MT-BHC SLNs and MT-BHC MPs eye drops significantly prolonged the precorneal retention time due to their higher viscosity and lower surface tension and contact angle compared with the BHC solution, with MT-BHC MPs exhibiting the longest retention due to their stronger hydrophobic surface. The cumulative release of MT-BHC SLNs and MT-BHC MPs was up to 87.78% and 80.43% after 12 h, respectively. Tear elimination pharmacokinetics study further confirmed that the prolonged precorneal retention time of the formulations was due to the micro-interaction between the positively charged formulations and the negatively charged tear film mucins. Moreover, the area under the IOP reduction curve (AUC) of MT-BHC SLNs and MT-BHC MPs was 1.4 and 2.5 times that of the BHC solution. Accordingly, the MT-BHC MPs also exhibit the most consistent and long-lasting IOP-lowering effect. Ocular irritation experiments showed no significant toxicity of either. Taken together, MT MPs may have the potential for more effective glaucoma treatment.
Topics: Drug Delivery Systems; Eye; Betaxolol; Bentonite; Drug Liberation
PubMed: 36866574
DOI: 10.1080/10717544.2023.2184312 -
International Journal of Nanomedicine 2022Glaucoma is a chronic disease that requires long-term adherence to treatment. Topical application of conventional eye drops results in substantial drug loss due to rapid...
INTRODUCTION
Glaucoma is a chronic disease that requires long-term adherence to treatment. Topical application of conventional eye drops results in substantial drug loss due to rapid tear turnover, with poor drug bioavailability being a major challenge for efficient glaucoma treatment. We aimed to prepare the anti-glaucoma drug betaxolol hydrochloride (BH) as a novel nano-delivery system that prolonged the retention time at the ocular surface and improved bioavailability.
METHODS
We constructed multifunctional nanoparticles (MMt-BH-HA/CS-ED NPs) by ion cross-linking-solvent evaporation method. The particle size, zeta potential, encapsulation efficiency and drug loading of MMt-BH-HA/CS-ED NPs were physicochemically characterized. The structure of the preparations was characterized by microscopic techniques of SEM, TEM, XPS, XRD, FTIR and TGA, and evaluated for their in vitro release performance as well as adhesion properties. Its safety was investigated using irritation assays of hemolysis experiment, Draize test and histopathology examination. Precorneal retention was examined by in vivo fluorescence tracer method and pharmacokinetics in tear fluid was studied. A model of high IOP successfully induced by injection of compound carbomer solution was used to assess the IOP-lowering efficacy of the formulation, and it was proposed that micro-interactions between the formulation and the tear film would be used to analyze the behavior at the ocular surface.
RESULTS
The positively charged MMt-BH-HA/CS-ED NPs were successfully prepared with good two-step release properties, higher viscosity, and slower pre-corneal diffusion rate along with longer precorneal retention time compared to BH solution. The micro-interactions between nanoparticles and tear film converted the drug clearance from being controlled by fast aqueous layer turnover to slow mucin layer turnover, resulting in higher drug concentration on the ocular surface, providing more durable and stable IOP-lowering efficacy.
CONCLUSION
The novel multifunctional MMt-BH-HA/CS-ED NPs can effectively reduce IOP and are suitable for the treatment of chronic disease glaucoma.
Topics: Humans; Betaxolol; Intraocular Pressure; Nanoparticles; Glaucoma; Cornea; Particle Size; Drug Carriers
PubMed: 36506343
DOI: 10.2147/IJN.S382968 -
International Journal of Molecular... Nov 2022Glaucoma is a group of eye diseases consisting of optic nerve damage with corresponding loss of field vision and blindness. Hydrogen sulfide (HS) is a gaseous...
Glaucoma is a group of eye diseases consisting of optic nerve damage with corresponding loss of field vision and blindness. Hydrogen sulfide (HS) is a gaseous neurotransmitter implicated in various pathophysiological processes. It is involved in the pathological mechanism of glaucomatous neuropathy and exerts promising effects in the treatment of this disease. In this work, we designed and synthetized new molecular hybrids between antiglaucoma drugs and HS donors to combine the pharmacological effect of both moieties, providing a heightened therapy. Brinzolamide, betaxolol and brimonidine were linked to different HS donors. The HS-releasing properties of the new compounds were evaluated in a phosphate buffer solution by the amperometric approach, and evaluated in human primary corneal epithelial cells (HCEs) by spectrofluorometric measurements. Experimental data showed that compounds , and were the hybrids with the best properties, characterized by a significant and long-lasting production of the gasotransmitter both in the aqueous solution (in the presence of L-cysteine) and in the intracellular environment. Because, to date, the donation of HS by antiglaucoma HS donor hybrids using non-immortalized corneal cells has never been reported, these results pave the way to further investigation of the potential efficacy of the newly synthesized compounds.
Topics: Humans; Antiglaucoma Agents; Betaxolol; Gasotransmitters; Glaucoma; Hydrogen Sulfide
PubMed: 36430281
DOI: 10.3390/ijms232213804 -
Journal of Personalized Medicine Oct 2022Alzheimer's disease (AD) is a neurologic disorder causing brain atrophy and the death of brain cells. It is a progressive condition marked by cognitive and behavioral...
Alzheimer's disease (AD) is a neurologic disorder causing brain atrophy and the death of brain cells. It is a progressive condition marked by cognitive and behavioral impairment that significantly interferes with daily activities. AD symptoms develop gradually over many years and eventually become more severe, and no cure has been found yet to arrest this process. The present study is directed towards suggesting putative novel solutions and paradigms for fighting AD pathogenesis by exploiting new insights from network medicine and drug repurposing strategies. To identify new drug-AD associations, we exploited SAveRUNNER, a recently developed network-based algorithm for drug repurposing, which quantifies the vicinity of disease-associated genes to drug targets in the human interactome. We complemented the analysis with an in silico validation of the candidate compounds through a gene set enrichment analysis, aiming to determine if the modulation of the gene expression induced by the predicted drugs could be counteracted by the modulation elicited by the disease. We identified some interesting compounds belonging to the beta-blocker family, originally approved for treating hypertension, such as betaxolol, bisoprolol, and metoprolol, whose connection with a lower risk to develop Alzheimer's disease has already been observed. Moreover, our algorithm predicted multi-kinase inhibitors such as regorafenib, whose beneficial effects were recently investigated for neuroinflammation and AD pathology, and mTOR inhibitors such as sirolimus, whose modulation has been associated with AD.
PubMed: 36294870
DOI: 10.3390/jpm12101731