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Toxins Aug 2023T-2 toxin and selenium deficiency are considered important etiologies of Kashin-Beck disease (KBD), although the exact mechanism is still unclear. To identify...
T-2 toxin and selenium deficiency are considered important etiologies of Kashin-Beck disease (KBD), although the exact mechanism is still unclear. To identify differentially expressed microRNAs (DE-miRNAs) in the articular cartilage of rats exposed to T-2 toxin and selenomethionine (SeMet) supplementation, thirty-six 4-week-old Sprague Dawley rats were divided into a control group (gavaged with 4% anhydrous ethanol), a T-2 group (gavaged with 100 ng/g·bw/day T-2 toxin), and a T-2 + SeMet group (gavaged with 100 ng/g·bw/day T-2 toxin and 0.5 mg/kg·bw/day SeMet), respectively. Toluidine blue staining was performed to detect the pathological changes of articular cartilage. Three rats per group were randomly selected for high-throughput sequencing of articular cartilage. Target genes of DE-miRNAs were predicted using miRanda and RNAhybrid databases, and the Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway were enriched. The network map of miRNA-target genes was constructed using Cytoscape software. The expression profiles of miRNAs associated with KBD were obtained from the Gene Expression Omnibus database. Additionally, the DE-miRNAs were selected for real-time quantitative PCR (RT-qPCR) verification. Toluidine blue staining demonstrated that T-2 toxin damaged articular cartilage and SeMet effectively alleviated articular cartilage lesions. A total of 50 DE-miRNAs (28 upregulated and 22 downregulated) in the T-2 group vs. the control group, 18 DE-miRNAs (6 upregulated and 12 downregulated) in the T-2 + SeMet group vs. the control group, and 25 DE-miRNAs (5 upregulated and 20 downregulated) in the T-2 + SeMet group vs. the T-2 group were identified. Enrichment analysis showed the target genes of DE-miRNAs were associated with apoptosis, and in the MAPK and TGF-β signaling pathways in the T-2 group vs. the control group. However, the pathway of apoptosis was not significant in the T-2 + SeMet group vs. the control group. These results indicated that T-2 toxin induced apoptosis, whereas SeMet supplementation antagonized apoptosis. Apoptosis and autophagy occurred simultaneously in the T-2 + SeMet group vs. T-2 group, and autophagy may inhibit apoptosis to protect cartilage. Compared with the GSE186593 dataset, the evidence of miR-133a-3p involved in apoptosis was more abundant. The results of RT-qPCR validation were consistent with RNA sequencing results. Our findings suggested that apoptosis was involved in articular cartilage lesions induced by T-2 toxin, whereas SeMet supplementation antagonized apoptosis, and that miR-133a-3p most probably played a central role in the apoptosis process.
Topics: Rats; Animals; Cartilage, Articular; T-2 Toxin; Selenomethionine; Tolonium Chloride; Rats, Sprague-Dawley; Kashin-Beck Disease; MicroRNAs
PubMed: 37624253
DOI: 10.3390/toxins15080496 -
Indian Journal of Pathology &... 2023The Fine needle aspiration cytology (FNAC) is considered as a valuable and distinguished diagnostic test in the initial assessment of the patients presenting with a mass...
BACKGROUND
The Fine needle aspiration cytology (FNAC) is considered as a valuable and distinguished diagnostic test in the initial assessment of the patients presenting with a mass in the head and neck region or when a recurrence is suspected after previous treatment.
AIMS
This study was therefore designed to elucidate the efficacy of FNAC as an alternate diagnostic tool to histopathology in head and neck swellings and evaluation of staining efficacy of PAP and MGG stain over Haematoxylin and eosin (H and E) in routine cytopathological smears.
SETTINGS AND DESIGN
The study was conducted in the Department of Oral and Maxillofacial Pathology, where FNAC samples were collected from 150 patients with head and neck swellings.
MATERIALS AND METHODS
All the slides were stained with H and E, Papanicolaou (PAP), and May Grunewald Giemsa (MGG) stains. The cytopathological diagnosis was compared with histopathological diagnosis based on H and E stained sections obtained from paraffin-embedded formalin-fixed biopsy specimen of benign and malignant neoplasms.
STATISTICAL ANALYSIS USED
The resulting data were analyzed using SPSS software version 19. Differences between the variables were analyzed using Pearson Chi-square test and Kruskal-Wallis test wherever applicable.
RESULTS
The FNAC as a diagnostic tool has sensitivity of 84.8%, 72.72%, and 78.78%, specificity of 62.5%, 75%, and 75%, and accuracy of 80.48%, 73.14%, and 78.04% in H and E, MGG, and PAP stain, respectively. PAP stain was the most efficient stain when all qualitative parameters are taken into consideration with maximum sensitivity and specificity for achieving definitive cytodiagnosis.
CONCLUSIONS
The FNAC is an inexpensive and minimally invasive technique to diagnose different types of head and neck swellings and complement histopathological diagnosis.
Topics: Humans; Coloring Agents; Pathology, Oral; Staining and Labeling; Neck; Cytological Techniques; Azure Stains; Hematoxylin
PubMed: 37530331
DOI: 10.4103/ijpm.ijpm_1254_21 -
Redox Biology Jul 2024Inflammation and subsequent mitochondrial dysfunction and cell death worsen outcomes after revascularization in ischemic stroke. Receptor-interacting protein kinase 1...
Modulation of NLRP3 inflammasome-related-inflammation via RIPK1/RIPK3-DRP1 or HIF-1α signaling by phenothiazine in hypothermic and normothermic neuroprotection after acute ischemic stroke.
BACKGROUND
Inflammation and subsequent mitochondrial dysfunction and cell death worsen outcomes after revascularization in ischemic stroke. Receptor-interacting protein kinase 1 (RIPK1) activated dynamin-related protein 1 (DRP1) in a NLRPyrin domain containing 3 (NLRP3) inflammasome-dependent fashion and Hypoxia-Inducible Factor (HIF)-1α play key roles in the process. This study determined how phenothiazine drugs (chlorpromazine and promethazine (C + P)) with the hypothermic and normothermic modality impacts the RIPK1/RIPK3-DRP1 and HIF-1α pathways in providing neuroprotection.
METHODS
A total of 150 adult male Sprague-Dawley rats were subjected to 2 h middle cerebral artery occlusion (MCAO) followed by 24 h reperfusion. 8 mg/kg of C + P was administered at onset of reperfusion. Infarct volumes, mRNA and protein expressions of HIF-1α, RIPK1, RIPK3, DRP-1, NLRP3-inflammation and cytochrome c-apoptosis were assessed. Apoptotic cell death, infiltration of neutrophils and macrophages, and mitochondrial function were evaluated. Interaction between RIPK1/RIPK3 and HIF-1α/NLRP3 were determined. In SH-SY5Y cells subjected to oxygen/glucose deprivation (OGD), the normothermic effect of C + P on inflammation and apoptosis were examined.
RESULTS
C + P significantly reduced infarct volumes, mitochondrial dysfunction (ATP and ROS concentration, citrate synthase and ATPase activity), inflammation and apoptosis with and without induced hypothermia. Overexpression of RIPK1, RIPK3, DRP-1, NLRP3-inflammasome and cytochrome c-apoptosis were all significantly reduced by C + P at 33 °C and the RIPK1 inhibitor (Nec1s), suggesting hypothermic effect of C + P via RIPK1/RIPK3-DRP1pathway. When body temperature was maintained at 37 °C, C + P and HIF-1α inhibitor (YC-1) reduced HIF-1α expression, leading to reduction in mitochondrial dysfunction, NLRP3 inflammasome and cytochrome c-apoptosis, as well as the interaction of HIF-1α and NLRP3. These were also evidenced in vitro, indicating a normothermic effect of C + P via HIF-1α.
CONCLUSION
Hypothermic and normothermic neuroprotection of C + P involve different pathways. The normothermic effect was mediated by HIF-1α, while hypothermic effect was via RIPK1/RIPK3-DRP1 signaling. This provides a theoretical basis for future precise exploration of hypothermic and normothermic neuroprotection.
Topics: Animals; Receptor-Interacting Protein Serine-Threonine Kinases; NLR Family, Pyrin Domain-Containing 3 Protein; Rats; Ischemic Stroke; Hypoxia-Inducible Factor 1, alpha Subunit; Male; Signal Transduction; Inflammasomes; Dynamins; Rats, Sprague-Dawley; Phenothiazines; Inflammation; Neuroprotection; Humans; Disease Models, Animal; Hypothermia, Induced
PubMed: 38692093
DOI: 10.1016/j.redox.2024.103169 -
Indian Journal of Cancer 2023Diagnostic adjuncts such as toluidine blue have been investigated as screening tools that improve visual examination of potentially malignant disorders (PMD) and oral...
BACKGROUND
Diagnostic adjuncts such as toluidine blue have been investigated as screening tools that improve visual examination of potentially malignant disorders (PMD) and oral cancer. Acetic acid has been reported to be of value in the early detection of cervical cancers. This study assessed the utility of 5% acetic acid as a diagnostic adjunct in oral PMD and compared the accuracy of acetic acid with toluidine blue in the detection of dysplastic PMD and high-risk lesions.
MATERIALS AND METHODS
This cross-sectional study was conducted at a dental hospital in a rural setting. Thirty-one patients with oral PMD formed the study group. Five percent acetic acid was applied to the lesions, followed by toluidine blue application and biopsy. Sensitivity, specificity, and positive and negative predictive values were computed considering true positives as stain uptake in dysplastic and high-risk PMD.
RESULTS
The sensitivity, specificity, and positive and negative predictive values of acetic acid for identifying dysplastic or malignant lesions were 100%, 13.3%, 51.2%, and 100%, respectively, and that for toluidine blue were 75%, 100%, 100%, and 78.9%, respectively. The corresponding values for identifying high-risk PMD (lesions with moderate and severe dysplasia) using acetic acid were 100%, 9.1%, 25.9%, and 100%, respectively, and for toluidine blue were 85.7%, 81.8%, 60%, and 94.7%, respectively.
CONCLUSION
The utility of acetic acid in detecting dysplasia and high-risk PMD is severely limited due to its poor specificity. Compared with acetic acid, toluidine blue is a superior screening tool.
Topics: Humans; Tolonium Chloride; Acetic Acid; Cross-Sectional Studies; Precancerous Conditions; Mouth Diseases
PubMed: 36861696
DOI: 10.4103/ijc.IJC_42_21 -
Advanced Science (Weinheim,... Apr 2024Tumors often overexpress glucose-regulated proteins, and agents that interfere with the production or activity of these proteins may represent novel cancer treatments....
Tumors often overexpress glucose-regulated proteins, and agents that interfere with the production or activity of these proteins may represent novel cancer treatments. The chlorpromazine derivative JX57 exhibits promising effects against endometrial cancer with minimal extrapyramidal side effects; however, its mechanisms of action are currently unknown. Here, glucose-regulated protein 75 kD (GRP75) is identified as a direct target of JX57 using activity-based protein profiling and loss-of-function experiments. The findings show that GRP75 is necessary for the biological activity of JX57, as JX57 exhibits moderate anticancer properties in GRP75-deficient cancer cells, both in vitro and in vivo. High GRP75 expression is correlated with poor differentiation and poor survival in patients with endometrial cancer, whereas the knockdown of GRP75 can significantly suppress tumor growth. Mechanistically, the direct binding of JX57 to GRP75 impairs the structure of the mitochondria-associated endoplasmic reticulum membrane and disrupts the endoplasmic reticulum-mitochondrial calcium homeostasis, resulting in a mitochondrial energy crisis and AMP-activated protein kinase activation. Taken together, these findings highlight GRP75 as a potential prognostic biomarker and direct therapeutic target in endometrial cancer and suggest that the chlorpromazine derivative JX57 can potentially be a new therapeutic option for endometrial cancer.
Topics: Female; Humans; AMP-Activated Protein Kinases; Chlorpromazine; Endometrial Neoplasms; HSP70 Heat-Shock Proteins; Membrane Proteins; Mitochondria
PubMed: 38342610
DOI: 10.1002/advs.202304203 -
International Journal of Molecular... Nov 2023The use of a combination of nanoparticles as antimicrobial agents can be one strategy to overcome the tendency of microbes to become resistant to antibiotic action....
The use of a combination of nanoparticles as antimicrobial agents can be one strategy to overcome the tendency of microbes to become resistant to antibiotic action. Also, the optimization of nano-photocatalysts to efficiently remove persistent pollutants from wastewater is a hot topic. In this study, two composites ZnO/Au (1% wt.) and ZnO/Ag (1% wt.) were synthesized by simple aqueous solution methods. The structure and morphology of the r nanocomposites were analyzed by structural and optical characterization methods. The formation of AuNPs and AgNPs in these experiments was also discussed. The antimicrobial properties of ZnO, ZnO/Au, and ZnO/Ag nanomaterials were investigated against Gram-negative bacteria () and Gram-positive bacteria (). The results showed an increase of 80% in the antimicrobial activity of ZnO/Au against compared with 30% in the case of ZnO/Ag. Similarly, in the case of the strain tests, ZnO/Au increased the antimicrobial activity by 55% and ZnO/Ag by 33%. The photocatalytic tests indicated an improvement in the photocatalytic degradation of methylene blue (MB) under UV irradiation using ZnO/Au and ZnO/Ag nanocomposites compared to bare ZnO. The photocatalytic degradation efficiency of ZnO after 60 min of UV irradiation was ∼83%, while the addition of AuNPs enhanced the degradation rate to ∼95% (ZP2), and AgNP presence enhanced the efficiency to ∼98%. The introduction of noble metallic nanoparticles into the ZnO matrix proved to be an effective strategy to increase their antimicrobial activity against and , and their photocatalytic activity was evaluated through the degradation of MB dye. Comparing the enhancing effects of Au and Ag, it was found that ZnO/Au was a better antimicrobial agent while ZnO/Ag was a more effective photocatalyst under UV irradiation.
Topics: Zinc Oxide; Staphylococcus aureus; Gold; Metal Nanoparticles; Anti-Bacterial Agents; Nanocomposites; Methylene Blue
PubMed: 38069261
DOI: 10.3390/ijms242316939 -
Molecular Diversity Apr 2024Phenoxazines have sparked a lot of interest owing to their numerous applications in material science, organic light-emitting diodes, photoredox catalyst, dye-sensitized... (Review)
Review
Phenoxazines have sparked a lot of interest owing to their numerous applications in material science, organic light-emitting diodes, photoredox catalyst, dye-sensitized solar cells and chemotherapy. Among other things, they have antioxidant, antidiabetic, antimalarial, anti-alzheimer, antiviral, anti-inflammatory and antibiotic properties. Actinomycin D, which contains a phenoxazine moiety, functions both as an antibiotic and anticancer agent. Several research groups have worked on various structural modifications over the years in order to develop new phenoxazines with improved properties. Both phenothiazines and phenoxazines have gained prominence in medicine as pharmacological lead structures from their traditional uses as dyes and pigments. Organoelectronics and material sciences have recently found these compounds and their derivatives to be quite useful. Due to this, organic synthesis has been used in an unprecedented amount of exploratory alteration of the parent structures in an effort to create novel derivatives with enhanced biological and material capabilities. As a result, it is critical to conduct more frequent reviews of the work done in this area. Various stages of the synthetic transformation of phenoxazine scaffolds have been depicted in this article. This article aims to provide a state of the art review for the better understanding of the phenoxazine derivatives highlighting the progress and prospects of the same in medicinal and material applications.
Topics: Oxazines; Humans; Animals
PubMed: 36757655
DOI: 10.1007/s11030-023-10619-5 -
Methylene blue as adjunctive therapy in septic shock: correct drug diluent derives optimal efficacy.Critical Care (London, England) Aug 2023
Topics: Humans; Methylene Blue; Shock, Septic; Dental Care; Patients
PubMed: 37644588
DOI: 10.1186/s13054-023-04615-2 -
Sensors (Basel, Switzerland) Nov 2023This paper describes the development of a simple voltammetric biosensor for the stereoselective discrimination of myo-inositol (myo-Ins) and D-chiro-inositol...
This paper describes the development of a simple voltammetric biosensor for the stereoselective discrimination of myo-inositol (myo-Ins) and D-chiro-inositol (D-chiro-Ins) by means of bovine serum albumin (BSA) adsorption onto a multi-walled carbon nanotube (MWCNT) graphite screen-printed electrode (MWCNT-GSPE), previously functionalized by the electropolymerization of methylene blue (MB). After a morphological characterization, the enantioselective biosensor platform was electrochemically characterized after each modification step by differential pulse voltammetry (DPV) and electrochemical impedance spectroscopy (EIS). The results show that the binding affinity between myo-Ins and BSA was higher than that between D-chiro-Ins and BSA, confirming the different interactions exhibited by the novel BSA/MB/MWCNT/GSPE platform towards the two diastereoisomers. The biosensor showed a linear response towards both stereoisomers in the range of 2-100 μM, with LODs of 0.5 and 1 μM for myo-Ins and D-chiro-Ins, respectively. Moreover, a stereoselectivity coefficient α of 1.6 was found, with association constants of 0.90 and 0.79, for the two stereoisomers, respectively. Lastly, the proposed biosensor allowed for the determination of the stereoisomeric composition of myo-/D-chiro-Ins mixtures in commercial pharmaceutical preparations, and thus, it is expected to be successfully applied in the chiral analysis of pharmaceuticals and illicit drugs of forensic interest.
Topics: Inositol; Methylene Blue; Stereoisomerism
PubMed: 38005597
DOI: 10.3390/s23229211 -
International Journal of Molecular... May 2024For the past 70 years, the dopamine hypothesis has been the key working model in schizophrenia. This has contributed to the development of numerous inhibitors of... (Review)
Review
For the past 70 years, the dopamine hypothesis has been the key working model in schizophrenia. This has contributed to the development of numerous inhibitors of dopaminergic signaling and antipsychotic drugs, which led to rapid symptom resolution but only marginal outcome improvement. Over the past decades, there has been limited research on the quantifiable pathological changes in schizophrenia, including premature cellular/neuronal senescence, brain volume loss, the attenuation of gamma oscillations in electroencephalograms, and the oxidation of lipids in the plasma and mitochondrial membranes. We surmise that the aberrant activation of the aryl hydrocarbon receptor by toxins derived from gut microbes or the environment drives premature cellular and neuronal senescence, a hallmark of schizophrenia. Early brain aging promotes secondary changes, including the impairment and loss of mitochondria, gray matter depletion, decreased gamma oscillations, and a compensatory metabolic shift to lactate and lactylation. The aim of this narrative review is twofold: (1) to summarize what is known about premature cellular/neuronal senescence in schizophrenia or schizophrenia-like disorders, and (2) to discuss novel strategies for improving long-term outcomes in severe mental illness with natural senotherapeutics, membrane lipid replacement, mitochondrial transplantation, microbial phenazines, novel antioxidant phenothiazines, inhibitors of glycogen synthase kinase-3 beta, and aryl hydrocarbon receptor antagonists.
Topics: Humans; Antipsychotic Agents; Schizophrenia; Psychotic Disorders; Animals; Brain; Cellular Senescence
PubMed: 38892092
DOI: 10.3390/ijms25115904