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Drug Delivery Dec 2024Glaucoma is the leading cause of blindness worldwide. However, its surgical treatment, in particular via trabeculectomy, can be complicated by fibrosis. In current...
Glaucoma is the leading cause of blindness worldwide. However, its surgical treatment, in particular via trabeculectomy, can be complicated by fibrosis. In current clinical practice, application of the drug, Mitomycin C, prevents or delays fibrosis, but can lead to additional side effects, such as bleb leakage and hypotony. Previous drug screening and testing has identified the known antibiotic, josamycin, as a possible alternative antifibrotic medication with potentially fewer side effects. However, a suitable ocular delivery mechanism for the hydrophobic drug to the surgical site does not yet exist. Therefore, the focus of this paper is the development of an implantable drug delivery system for sustained delivery of josamycin after glaucoma surgery based on crosslinked γ-cyclodextrin. γ-Cyclodextrin is a commonly used solubilizer which was shown to complex with josamycin, drastically increasing the drug's solubility in aqueous solutions. A simple γ-cyclodextrin crosslinking method produced biocompatible hydrogels well-suited for implantation. The crosslinked γ - cyclodextrin retained the ability to form complexes with josamycin, resulting in a 4-fold higher drug loading efficiency when compared to linear dextran hydrogels, and prolonged drug release over 4 days.
Topics: Hydrogels; Delayed-Action Preparations; gamma-Cyclodextrins; Solubility; Drug Liberation; Drug Delivery Systems; Glaucoma; Anti-Bacterial Agents; Drug Carriers; Animals; Humans; Cross-Linking Reagents
PubMed: 38899440
DOI: 10.1080/10717544.2024.2361168 -
International Journal of Ophthalmology 2024
PubMed: 38895670
DOI: 10.18240/ijo.2024.06.25 -
Journal of Clinical Medicine May 2024The purpose of this study is to investigate outcomes of visual acuity (VA) and intraocular pressure (IOP) in proliferative diabetic retinopathy (PDR)-associated...
The purpose of this study is to investigate outcomes of visual acuity (VA) and intraocular pressure (IOP) in proliferative diabetic retinopathy (PDR)-associated neovascular glaucoma (NVG) in Japanese patients treated with surgical therapies without the use of glaucoma drainage devices. A retrospective analysis of medical records was conducted for 31 consecutive PDR-associated NVG patients who underwent surgical treatments in our institution between 2013 and 2022. Patient demographics, clinical characteristics, VA, and IOP were recorded at the first and last visits, and surgical procedures, including pars plana vitrectomy with extensive panretinal and ciliary photocoagulation (PPV-PRCP), diode laser trans-scleral cyclophotocoagulation (DCPC), and trabeculectomy with mitomycin C (TLE-MMC), with or without a prior intravitreal bevacizumab (IVB) injection, were reviewed. Of the thirty-one PDR patients with NVG, two patients received PPV-PRCP or DCPC alone (6.5%), respectively, three patients received TLE-MMC alone (9.7%), two patients received TLE-MMC after IVB (6.5%), six patients received PPV-PRCP and TLE-MMC (19.4%), seven patients received PPV-PRCP and TLE-MMC after IVB (22.6%), five patients received PPV-PRCP and DCPC and TLE-MMC (16.1%), and four patients received PPV-PRCP and DCPC and TLE-MMC after IVB (12.9%). The VA of two patients (6.5%) deteriorated to no light perception. In all patients, the mean logMAR VA was 1.28 ± 1.05 at the first visit and remained at 1.26 ± 1.08 at the last visit, with no significant change; the mean IOP was 33.0 ± 15.2 mmHg at the initial visit and decreased significantly to 14.0 ± 7.4 mmHg at the last visit. The number of eyes with IOP ≥ 21 decreased from twenty-eight (90.3%) to three (9.7%). Although IOP in patients with IOP > 30 mmHg at the initial visit reduced to a level comparable to that of patients with IOP ≤ 30 mmHg, the IOP > 30 mmHg group received IVB more frequently and had significantly higher logMAR VA at the last visit compared to the IOP ≤ 30 mmHg group. Hypotony (<6 mmHg) was observed in four eyes (12.9%). In PDR patients with NVG, various combinations of PPV-PRCP, DCPC, and TLE-MMC after adjunctive IVB without the use of glaucoma drainage devices lowered IOP sufficiently; for these patients, neovascular regression was observed, with no further deterioration of VA. However, surgical procedures should be performed for PDR patients with NVG before visual impairment occurs. On the other hand, approximately less than 15% of patients developed blindness or low IOP.
PubMed: 38892963
DOI: 10.3390/jcm13113252 -
Frontiers in Oncology 2024Mitomycin-C (MMC) chemotherapy is a well-established anti-cancer treatment for non-muscle-invasive bladder cancer (NMIBC). However, despite comprehensive biological...
Mitomycin-C (MMC) chemotherapy is a well-established anti-cancer treatment for non-muscle-invasive bladder cancer (NMIBC). However, despite comprehensive biological research, the complete mechanism of action and an ideal regimen of MMC have not been elucidated. In this study, we present a theoretical investigation of NMIBC growth and its treatment by continuous administration of MMC chemotherapy. Using temporal ordinary differential equations (ODEs) to describe cell populations and drug molecules, we formulated the first mathematical model of tumor-immune interactions in the treatment of MMC for NMIBC, based on biological sources. Several hypothetical scenarios for NMIBC under the assumption that tumor size correlates with cell count are presented, depicting the evolution of tumors classified as small, medium, and large. These scenarios align qualitatively with clinical observations of lower recurrence rates for tumor size ≤ 30[mm] with MMC treatment, demonstrating that cure appears up to a theoretical [mm] tumor size threshold, given specific parameters within a feasible biological range. The unique use of mole units allows to introduce a new method for theoretical pre-treatment assessments by determining MMC drug doses required for a cure. In this way, our approach provides initial steps toward personalized MMC chemotherapy for NMIBC patients, offering the possibility of new insights and potentially holding the key to unlocking some of its mysteries.
PubMed: 38884094
DOI: 10.3389/fonc.2024.1352065 -
Microbial Cell Factories Jun 2024Bacterial infections and the rising antimicrobial resistance pose a significant threat to public health. Pseudomonas aeruginosa produces bacteriocins like pyocins,...
INTRODUCTION
Bacterial infections and the rising antimicrobial resistance pose a significant threat to public health. Pseudomonas aeruginosa produces bacteriocins like pyocins, especially S-type pyocins, which are promising for biological applications. This research focuses on clinical P. aeruginosa isolates to assess their bacteriocin production, inhibitory spectrum, chemical structure, antibacterial agents, and preservative potential.
METHODS
The identification of P. aeruginosa was conducted through both phenotypic and molecular approaches. The inhibitory spectrum and antibacterial potential of the isolates were assessed. The kinetics of antibacterial peptide production were investigated, and the activity of bacteriocin was quantified in arbitrary units (AU ml). Physico-chemical characterization of the antibacterial peptides was performed. Molecular weight estimation was carried out using SDS-PAGE. qRT-PCR analysis was employed to validate the expression of the selected candidate gene.
RESULT
The antibacterial activity of P. aeruginosa was attributed to the secretion of bacteriocin compounds, which belong to the S-type pyocin family. The use of mitomycin C led to a significant 65.74% increase in pyocin production by these isolates. These S-type pyocins exhibited the ability to inhibit the growth of both Gram-negative (P. mirabilis and P. vulgaris) and Gram-positive (S. aureus, S. epidermidis, E. hirae, S. pyogenes, and S. mutans) bacteria. The molecular weight of S-type pyocin was 66 kDa, and its gene expression was confirmed through qRT-PCR.
CONCLUSION
These findings suggest that S-type pyocin hold significant potential as therapeutic agents against pathogenic strains. The Physico-chemical resistance of S-type pyocin underscores its potential for broad applications in the pharmaceutical, hygiene, and food industries.
Topics: Pseudomonas aeruginosa; Anti-Bacterial Agents; Bacteriocins; Microbial Sensitivity Tests; Pyocins; Humans; Pseudomonas Infections
PubMed: 38872163
DOI: 10.1186/s12934-024-02450-w -
BioRxiv : the Preprint Server For... May 2024During HTLV-1 infection, the virus integrates into the host cell genome as a provirus with a single CCCTC binding protein (CTCF) binding site (vCTCF-BS), which acts as...
During HTLV-1 infection, the virus integrates into the host cell genome as a provirus with a single CCCTC binding protein (CTCF) binding site (vCTCF-BS), which acts as an insulator between transcriptionally active and inactive regions. Previous studies have shown that the vCTCF-BS is important for maintenance of chromatin structure, regulation of viral expression, and DNA and histone methylation. Here, we show that the vCTCF-BS also regulates viral infection and pathogenesis in a humanized (Hu) mouse model of adult T-cell leukemia/lymphoma. Three cell lines were used to initiate infection of the Hu-mice, i) HTLV-1-WT which carries an intact HTLV-1 provirus genome, ii) HTLV-1-CTCF, which contains a provirus with a mutated vCTCF-BS which abolishes CTCF binding, and a stop codon immediate upstream of the mutated vCTCF-BS which deletes the last 23 amino acids of p12, and iii) HTLV-1-p12stop that contains the intact vCTCF-BS, but retains the same stop codon in p12 as in the HTLV-1-CTCF cell line. Hu-mice were infected with mitomycin treated or irradiated HTLV-1 producing cell lines. There was a delay in pathogenicity when Hu-mice were infected with the CTCF virus compared to mice infected with either p12 stop or WT virus. Proviral load (PVL), spleen weights, and CD4 T cell counts were significantly lower in HTLV-1-CTCF infected mice compared to HTLV-1-p12stop infected mice. Furthermore, we found a direct correlation between the PVL in peripheral blood and death of HTLV-1-CTCF infected mice. In cell lines, we found that the vCTCF-BS regulates Tax expression in a time-dependent manner. The scRNAseq analysis of splenocytes from infected mice suggests that the vCTCF-BS plays an important role in activation and expansion of T lymphocytes . Overall, these findings indicate that the vCTCF-BS regulates Tax expression, proviral load, and HTLV pathogenicity .
PubMed: 38853836
DOI: 10.1101/2024.05.28.596170 -
PloS One 2024The FA/BRCA pathway safeguards DNA replication by repairing interstrand crosslinks (ICL) and maintaining replication fork stability. Chromatin structure, which is in...
The FA/BRCA pathway safeguards DNA replication by repairing interstrand crosslinks (ICL) and maintaining replication fork stability. Chromatin structure, which is in part regulated by histones posttranslational modifications (PTMs), has a role in maintaining genomic integrity through stabilization of the DNA replication fork and promotion of DNA repair. An appropriate balance of PTMs, especially acetylation of histones H4 in nascent chromatin, is required to preserve a stable DNA replication fork. To evaluate the acetylation status of histone H4 at the replication fork of FANCA deficient cells, we compared histone acetylation status at the DNA replication fork of isogenic FANCA deficient and FANCA proficient cell lines by using accelerated native immunoprecipitation of nascent DNA (aniPOND) and in situ protein interactions in the replication fork (SIRF) assays. We found basal hypoacetylation of multiple residues of histone H4 in FA replication forks, together with increased levels of Histone Deacetylase 1 (HDAC1). Interestingly, high-dose short-term treatment with mitomycin C (MMC) had no effect over H4 acetylation abundance at the replication fork. However, chemical inhibition of histone deacetylases (HDAC) with Suberoylanilide hydroxamic acid (SAHA) induced acetylation of the FANCA deficient DNA replication forks to levels comparable to their isogenic control counterparts. This forced permanence of acetylation impacted FA cells homeostasis by inducing DNA damage and promoting G2 cell cycle arrest. Altogether, this caused reduced RAD51 foci formation and increased markers of replication stress, including phospho-RPA-S33. Hypoacetylation of the FANCA deficient replication fork, is part of the cellular phenotype, the perturbation of this feature by agents that prevent deacetylation, such as SAHA, have a deleterious effect over the delicate equilibrium they have reached to perdure despite a defective FA/BRCA pathway.
Topics: Histones; Humans; DNA Replication; Acetylation; DNA Damage; Fanconi Anemia Complementation Group A Protein; Mitomycin; Histone Deacetylase Inhibitors; Vorinostat; Hydroxamic Acids
PubMed: 38820384
DOI: 10.1371/journal.pone.0298032 -
International Journal For Parasitology.... May 2024Plasmodium falciparum aminoacyl tRNA synthetases (PfaaRSs) are potent antimalarial targets essential for proteome fidelity and overall parasite survival in every stage...
Plasmodium falciparum aminoacyl tRNA synthetases (PfaaRSs) are potent antimalarial targets essential for proteome fidelity and overall parasite survival in every stage of the parasite's life cycle. So far, some of these proteins have been singly targeted yielding inhibitor compounds that have been limited by incidences of resistance which can be overcome via pan-inhibition strategies. Hence, herein, for the first time, we report the identification and in vitro antiplasmodial validation of Mitomycin (MMC) as a probable pan-inhibitor of class 1a (arginyl(A)-, cysteinyl(C), isoleucyl(I)-, leucyl(L), methionyl(M), and valyl(V)-) PfaaRSs which hypothetically may underlie its previously reported activity on the ribosomal RNA to inhibit protein translation and biosynthesis. We combined multiple in silico structure-based discovery strategies that first helped identify functional and druggable sites that were preferentially targeted by the compound in each of the plasmodial proteins: Ins1-Ins2 domain in Pf-ARS; anticodon binding domain in Pf-CRS; CP1-editing domain in Pf-IRS and Pf-MRS; C-terminal domain in Pf-LRS; and CP-core region in Pf-VRS. Molecular dynamics studies further revealed that MMC allosterically induced changes in the global structures of each protein. Likewise, prominent structural perturbations were caused by the compound across the functional domains of the proteins. More so, MMC induced systematic alterations in the binding of the catalytic nucleotide and amino acid substrates which culminated in the loss of key interactions with key active site residues and ultimate reduction in the nucleotide-binding affinities across all proteins, as deduced from the binding energy calculations. These altogether confirmed that MMC uniformly disrupted the structure of the target proteins and essential substrates. Further, MMC demonstrated IC < 5 μM against the Dd2 and 3D7 strains of parasite making it a good starting point for malarial drug development. We believe that findings from our study will be important in the current search for highly effective multi-stage antimalarial drugs.
PubMed: 38805932
DOI: 10.1016/j.ijpddr.2024.100548 -
Cureus Apr 2024We present the case of a 27-year-old male who presented to our ophthalmology outpatient clinic with a pigmented lesion on the conjunctiva of his right eye. There was no...
We present the case of a 27-year-old male who presented to our ophthalmology outpatient clinic with a pigmented lesion on the conjunctiva of his right eye. There was no history of ocular trauma or familial ocular complaints, and a thorough evaluation revealed the patient's seropositive status for HIV for the past eight years. The presentation resembled a conjunctival pigmentary lesion, with typical features of ocular surface squamous neoplasia (OSSN) being absent and a demographic incongruent with typical OSSN cases as OSSN typically affects the elderly population. Given the patient's HIV status and the lesion's recent increase in size, a more aggressive treatment approach was warranted. Mass excisional biopsy surgery confirmed conjunctival intraepithelial neoplasia with one positive margin. Adjuvant treatment with mitomycin eye drops (0.04%) resulted in no lesion recurrence at the one-month follow-up. Conjunctival intraepithelial neoplasia can mimic pigmentary lesions in young HIV-positive patients with obvious signs of OSSN being absent. In such cases, the history of seropositivity should be sufficient to suspect it as OSSN and aggressive management measures should be adopted to get best possible outcomes.
PubMed: 38800191
DOI: 10.7759/cureus.58953 -
Journal of Personalized Medicine May 2024Chronic tympanic membrane perforation represents a prevalent otological condition, necessitating a reliable animal model for the validation and safety assessment of...
Chronic tympanic membrane perforation represents a prevalent otological condition, necessitating a reliable animal model for the validation and safety assessment of surgical techniques and materials employed in myringoplasty. This prospective study involved the establishment of chronic tympanic membrane perforation animal models in 16 chinchillas. A thermic myringotomy was conducted on the right ear (study group), followed by cold instrument myringotomy, coupled with the topical application of mitomycin C and dexamethasone solution on the left ear (control group). Results revealed that tympanic membrane perforations in the study group persisted for a minimum of 4 weeks in 93.7% of cases and extended to 12 weeks in 62.5% of the cases. In contrast, all tympanic membrane perforations in the control group were present at 4 weeks, with only 37.5% persisting after 12 weeks, although statistical tests did not find significant differences between the two groups (chi-square: -value = 0.157, Kruskal-Wallis: -value = 0.093, Mann-Whitney: -value = 0.121). The thermic myringotomy employed to induce chronic tympanic membrane perforation in animals demonstrated efficiency and sustainability. This model, characterized by stability and reproducibility, holds promise for future experimental applications in the field.
PubMed: 38793095
DOI: 10.3390/jpm14050513