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Aromatase inhibitors play a critical therapeutic role in treating ER+ breast cancer, especially in postmenopausal women. However, their efficacy is often limited by resistance and severe side effects. Identifying new compounds that can disrupt aromatase enzyme function is essential. In this study, structural anomalies in the aromatase enzyme were corrected through energy minimization, and the structure was validated via Ramachandran plot. We screened 170,269 natural compounds from the ASINEX Biodesign library using high-throughput screening algorithms to target the aromatase enzyme. Molecular docking identified three compounds: BDD30170158, BDE33872639, and BDE30177677, all showing stable binding interactions with the aromatase enzyme. Molecular dynamics simulations over 100 ns confirmed the conformational stability of these compounds. Although all three compounds exhibited the desired pharmacokinetic and drug metabolism properties, only one compound (BDE33872639) was identified as a non-blocker, demonstrating a reduced risk of adverse cardiac effects. This compound exhibits significant potential as a novel aromatase inhibitor, warranting further experimental research to develop it as a therapeutic option for ER+ breast cancer.
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Proinflammatory T-lymphocytes recruited into the brain and spinal cord mediate multiple sclerosis (MS) and currently there is no cure for MS. IFN-γ-producing Th1 cells induce ascending paralysis in the spinal cord while IL-17-producing Th17 cells mediate cerebellar ataxia. STAT1 and STAT3 are required for Th1 and Th17 development, respectively, and the simultaneous targeting of STAT1 and STAT3 pathways is therefore a potential therapeutic strategy for suppressing disease in the spinal cord and brain. However, the pharmacological targeting of STAT1 and STAT3 presents significant challenges because of their intracellular localization. We have developed a STAT-specific single-domain nanobody (SBT-100) derived from camelids that targets conserved residues in Src homolog 2 (SH2) domains of STAT1 and STAT3. This study investigated whether SBT-100 could suppress experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. We show that SBT-100 ameliorates encephalomyelitis through suppressing the expansion of Th17 and Th1 cells in the brain and spinal cord. Adoptive transfer experiments revealed that lymphocytes from SBT-100-treated EAE mice have reduced capacity to induce EAE, indicating that the immunosuppressive effects derived from the direct suppression of encephalitogenic T-cells. The small size of SBT-100 makes this STAT-specific nanobody a promising immunotherapy for CNS autoimmune diseases, including multiple sclerosis.
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Encefalomielitis Autoinmune Experimental , Anticuerpos de Dominio Único , Células Th17 , Animales , Femenino , Ratones , Camélidos del Nuevo Mundo , Encefalomielitis Autoinmune Experimental/inmunología , Encefalomielitis Autoinmune Experimental/terapia , Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Ratones Endogámicos C57BL , Enfermedades Neuroinflamatorias/inmunología , Enfermedades Neuroinflamatorias/tratamiento farmacológico , Anticuerpos de Dominio Único/farmacología , Anticuerpos de Dominio Único/inmunología , Anticuerpos de Dominio Único/uso terapéutico , Médula Espinal/patología , Médula Espinal/efectos de los fármacos , Médula Espinal/inmunología , Factor de Transcripción STAT1/metabolismo , Factor de Transcripción STAT3/metabolismo , Células TH1/inmunología , Células TH1/efectos de los fármacos , Células Th17/inmunología , Células Th17/efectos de los fármacosRESUMEN
Background: Severe post-acne scarring has been implicated as a cause of considerable psychological distress, mainly among adolescents. Subcision and microneedling are cutting-edge treatment options available nowadays. Aim: In this study, we aimed to compare the efficacy of microneedling with platelet-rich plasma (PRP) against subcision with PRP in treating atrophic post-acne scars in a split-face study design. Materials and Methods: Fifty patients with atrophic post-acne facial scars were included in this prospective interventional study. Group A included the left side of the face managed by microneedling with PRP and group B included the right side of the face that was subjected to subcision with PRP. Results were assessed based on Goodman and Baron qualitative and quantitative grading. Results: In our study, at the end of the treatment, on the left side, 5 (10%) had 1 grade of improvement showing good response, 35 (70%) had 2 grades of improvement showing very good response, and 10 (20%) had 3 grades of improvement showing excellent response. On the right side, 1 (2%) patient had no improvement in acne grade showing poor response, 9 (18%) had 1 grade of improvement showing good response, 25 (50%) had 2 grades of improvement showing very good response, whereas 15 (30%) had 3 grades of improvement showing excellent response. Conclusion: Till date, apart from ours no other study has compared the two modalities head-to-head with adjuvant PRP in both groups. Although both modalities showed statistically significant results individually, there was no significant difference in qualitative improvement of acne scars between the two groups.
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Xanthelasma palpebrarum (XP) is a benign cosmetic condition. Although the role of CO2 laser is well described, there are only a few studies on Erbium: YAG in XP. Similarly, trichloroacetic acid (TCA) is commonly used in XP. However, there are only a few studies comparing these modalities in the treatment of XP. Aim: To evaluate the effectiveness and safety of Erbium: YAG laser and 50% TCA in the treatment of XP with the role of dermoscope in the evaluation of lesions. Materials and Methods: A total of 20 subjects were randomly allocated into two groups: group A (TCA) and group B (laser). All patients were subcategorized into three grades viz. I (mild), II (moderate), and III (severe) using a self-devised scoring system. Results: About 25% and 70% of patients achieved complete clearance in groups A and B, respectively (P = 0.017). The rate of recurrence was 40% and 15% in groups A and B. Dyspigmentation and erythema were the most common side effects. Pretreatment dermoscopic evaluation of the lesion showed a network of brown streaks on a background of a yellowish structureless area and was used to assess the area and margins of the lesion where the adipose tissue was found during the procedure and serial assessment of the lesion.
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Plantaricin LD1 was purified from a potential probiotic strain, Lactobacillus plantarum LD1 previously isolated from indigenous food, Dosa. In this study, we have performed a detailed mechanism of action of plantaricin LD1 against Escherichia coli ATCC 25922 considering Micrococcus luteus MTCC 106 as control. The plantaricin LD1 showed a minimum inhibitory concentration (MIC) of 34.57 µg/mL and a minimum bactericidal concentration (MBC) of 138.3 µg/mL against M. luteus MTCC 106, whereas MIC 69.15 µg/mL and MBC 276.6 µg/mL were found against E. coli ATCC 25922. The efflux of potassium ions, dissipation of membrane potential (∆ψ), and transmembrane pH gradient (∆pH) of plantaricin LD1-treated cells suggested the membrane-acting nature of plantaricin LD1. Plantaricin LD1 also caused degradation of the genomic DNA of the target strains tested. The cell killing was confirmed by staining with propidium iodide and visualized under light and electron microscopes. The bacteriocin-treated cells were found to be ruptured, swollen, and elongated. Thus, the findings indicate plantaricin LD1 kills E. coli ATCC 25922 by interacting with the cell membrane resulting in the efflux of intracellular contents and also causing degradation of nucleic acids leading to cell death.
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Transcription factor MAFB regulates various homeostatic functions of macrophages. This study explores the role of MAFB in brown adipose tissue (BAT) thermogenesis using macrophage-specific Mafb-deficient (Mafbf/f::LysM-Cre) mice. We find that Mafb deficiency in macrophages reduces thermogenesis, energy expenditure, and sympathetic neuron (SN) density in BAT under cold conditions. This phenotype features a proinflammatory environment that is characterized by macrophage/granulocyte accumulation, increases in interleukin-6 (IL-6) production, and IL-6 trans-signaling, which lead to decreases in nerve growth factor (NGF) expression and reduction in SN density in BAT. We confirm MAFB regulation of IL-6 expression using luciferase readout driven by IL-6 promoter in RAW-264.7 macrophage cell lines. Immunohistochemistry shows clustered organization of NGF-producing cells in BAT, which are primarily TRPV1+ vascular smooth muscle cells, as additionally shown using single-cell RNA sequencing and RT-qPCR of the stromal vascular fraction. Treating Mafbf/f::LysM-Cre mice with anti-IL-6 receptor antibody rescues SN density, body temperature, and energy expenditure.
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Tejido Adiposo Pardo , Frío , Interleucina-6 , Macrófagos , Factor de Transcripción MafB , Neuronas , Termogénesis , Animales , Factor de Transcripción MafB/metabolismo , Factor de Transcripción MafB/genética , Tejido Adiposo Pardo/metabolismo , Ratones , Macrófagos/metabolismo , Neuronas/metabolismo , Interleucina-6/metabolismo , Células RAW 264.7 , Factor de Crecimiento Nervioso/metabolismo , Metabolismo Energético , Masculino , Ratones Endogámicos C57BLRESUMEN
Cannabidiol (CBD), derived from Cannabis sativa, has gained remarkable attention for its potential therapeutic applications. This thorough analysis explores the increasing significance of CBD in treating neurological conditions including epilepsy, multiple sclerosis, Parkinson's disease, and Alzheimer's disease, which present major healthcare concerns on a worldwide scale. Despite the lack of available therapies, CBD has been shown to possess a variety of pharmacological effects in preclinical and clinical studies, making it an intriguing competitor. This review brings together the most recent findings on the endocannabinoid and neurotransmitter systems, as well as anti-inflammatory pathways, that underlie CBD's modes of action. Synthesized efficacy and safety assessments for a range of neurological illnesses are included, covering human trials, in vitro studies, and animal models. The investigation includes how CBD could protect neurons, control neuroinflammation, fend off oxidative stress, and manage neuronal excitability. This study emphasizes existing clinical studies and future possibilities in CBD research, addressing research issues such as regulatory complications and contradicting results, and advocates for further investigation of therapeutic efficacy and ideal dose methodologies. By emphasizing CBD's potential to improve patient well-being, this investigation presents a revised viewpoint on its suitability as a therapeutic intervention for neurological illnesses.
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Enfermedad de Alzheimer , Cannabidiol , Epilepsia , Animales , Humanos , Cannabidiol/farmacología , Cannabidiol/uso terapéutico , Epilepsia/tratamiento farmacológicoRESUMEN
In the world's flower trade, gladiolus (Gladiolus spp.) is ranked first among bulbous flowers and eighth among cut flowers, with more than 30,000 different cultivars being grown. Mass multiplication and commercialization are restricted by the traditional propagation methods. However, the large-scale proliferation and improvement of the gladiolus have been accomplished with the aid of plant tissue culture and other biotechnological techniques. The current review includes a thorough examination of the growth and development parameters required for successful in vitro gladiolus development as well as cormel formation. Moreover, focus is being given to various techniques and methods such as in vitro cytogenetic stability and modification of chromosome number, in vitro mutagenesis and selection of pest resistance, in vitro identification and selection to develop virus-free germplasm, cryopreservation, synthetic seed technology, identifying virus diseases by RT-PCR, somaclonal variation, and protoplast and somatic hybridization. Molecular markers and their applications for genetic diversity analysis, relationships between different genotypes, and clonal stability analysis in Gladiolus species have been conducted by several research groups worldwide and are also being discussed. The article also covers efforts to enhance the functionality of plant phenotypes through genetic transformation. Future prospects for further improvement of ornamental gladiolus are also explored. Overall, the current review provides insight into the applications of basic and advanced biotechnological tools for gladiolus improvement.
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Introduction: IL-27 is a heterodimeric cytokine composed of Ebi3 and IL-27p28 and can exert proinflammatory or immune suppressive effects depending on the physiological context. Ebi3 does not contain membrane-anchoring motifs, suggesting that it is a secreted protein while IL-27p28 is poorly secreted. How IL-27p28 and Ebi3 dimerize in-vivo to form biologically active IL-27 is unknown. Major impediment to clinical use of IL-27 derives from difficulty of determining exact amount of bioavailable heterodimeric IL-27 needed for therapy. Methods: To understand how IL-27 mediates immune suppression, we characterized an innate IL-27-producing B-1a regulatory B cell population (i27-Breg) and mechanisms i27-Bregs utilize to suppress neuroinflammation in mouse model of uveitis. We also investigated biosynthesis of IL-27 and i27-Breg immunobiology by FACS, immunohistochemical and confocal microscopy. Results: Contrary to prevailing view that IL-27 is a soluble cytokine, we show that i27-Bregs express membrane-bound IL-27. Immunohistochemical and confocal analyses co-localized expression of IL-27p28 at the plasma membrane in association with CD81 tetraspanin, a BCR-coreceptor protein and revealed that IL-27p28 is a transmembrane protein in B cells. Most surprising, we found that i27-Bregs secrete IL-27-containing exosomes (i27-exosomes) and adoptive transfer of i27-exosomes suppressed uveitis by antagonizing Th1/Th17 cells, up-regulating inhibitory-receptors associated with T-cell exhaustion while inducing Treg expansion. Discussion: Use of i27-exosomes thus obviates the IL-27 dosing problem, making it possible to determine bioavailable heterodimeric IL-27 needed for therapy. Moreover, as exosomes readily cross the blood-retina-barrier and no adverse effects were observed in mice treated with i27-exosome, results of this study suggest that i27-exosomes might be a promising therapeutic approach for CNS autoimmune diseases.
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Enfermedades Autoinmunes , Exosomas , Interleucina-27 , Uveítis , Ratones , Animales , Exosomas/metabolismo , Células TH1RESUMEN
In order to prevent the growth of pathogens in food, bacteriocins produced by various probiotic lactic acid bacteria have been recognized as potential substitutes of chemical preservatives. In this study, enterocin LD3 was purified from the cell-free supernatant of a food isolate, Enterococcus hirae LD3 using multistep chromatography. In the fruit juice, lethal concentration (LC50) of enterocin LD3 was found to be 260 µg/mL against Salmonella enterica subsp. enterica serovar Typhimurium ATCC 13311. The cells treated with enterocin LD3 were red colour indicating dead cells after propidium iodide staining, while untreated cells were found blue after staining with 4', 6-diamidino-2-phenylindole. The mechanism of cell killing was analyzed using infrared spectrum of cells treated with enterocin LD3 which was found altered in the range of 1,094.30 and 1,451.82 cm-1 corresponding to nucleic acids and phospholipids, respectively. The morphology of target cells were severely ruptured and lysed as observed under electron microscopy. Thus, the present study suggested that enterocin LD3 showed bactericidal activity against Salm. enterica subsp. enterica serovar Typhimurium ATCC 13311 and may be applied as a bio-preservative for the safety of fruit juices.
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Magnaporthe oryzae, the rice blast fungus, is one of the most dangerous rice pathogens, causing considerable crop losses around the world. In order to explore the rice blast-resistant sources, initially performed a large-scale screening of 277 rice accessions. In parallel with field evaluations, fifty-two rice accessions were genotyped for 25 major blast resistance genes utilizing functional/gene-based markers based on their reactivity against rice blast disease. According to the phenotypic examination, 29 (58%) and 22 (42%) entries were found to be highly resistant, 18 (36%) and 29 (57%) showed moderate resistance, and 05 (6%) and 01 (1%), respectively, were highly susceptible to leaf and neck blast. The genetic frequency of 25 major blast resistance genes ranged from 32 to 60%, with two genotypes having a maximum of 16 R-genes each. The 52 rice accessions were divided into two groups based on cluster and population structure analysis. The highly resistant and moderately resistant accessions are divided into different groups using the principal coordinate analysis. According to the analysis of molecular variance, the maximum diversity was found within the population, while the minimum diversity was found between the populations. Two markers (RM5647 and K39512), which correspond to the blast-resistant genes Pi36 and Pik, respectively, showed a significant association to the neck blast disease, whereas three markers (Pi2-i, Pita3, and k2167), which correspond to the blast-resistant genes Pi2, Pita/Pita2, and Pikm, respectively, showed a significant association to the leaf blast disease. The associated R-genes might be utilized in rice breeding programmes through marker-assisted breeding, and the identified resistant rice accessions could be used as prospective donors for the production of new resistant varieties in India and around the world.
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Magnaporthe , Oryza , Oryza/genética , Resistencia a la Enfermedad/genética , Enfermedades de las Plantas/microbiología , Fitomejoramiento , Marcadores Genéticos , GenotipoRESUMEN
Context: Hypospadias is a common urological anomaly which could be surgically corrected with good cosmetic results. Aims: We aimed to detect changes in urinary flow parameters both before and after tubularised incised plate urethroplasty (TIPU) using uroflowmetry. Settings and Design: Data collected were clinically implemented hypothesising the probability of urethrocutaneous fistula following stricture with Qmax variation. Materials and Methods: This study is a prospective analysis done from December 2017 to October 2019. A total of 104 cases of anterior hypospadias were included in the study. A single surgical unit did TIPU. Pre-operative and post-operative uroflowmetry was done, and Qmax was recorded at 3 months, 6 months and 1 year after surgery. Mean Qmax was calculated for all intervals. A significant decrease in Qmax of a child (<2 standard deviation) was ascertained. Urethral calibration was done in those cases with a significant decrease of Qmax and analysed statistically. Results: The mean age was 6.97 ± 2.41 years. Out of 104 children, 73 (70.2%) and 31 (29.8%) had distal and mid-shaft hypospadias, respectively. The pre-operative mean Qmax of the population was 6.20 ± 0.42 ml/s. Arithmetic mean Qmax at 3 months, 6 months and 1 year was 8.53 ± 0.42, 11.18 ± 0.47 and 13.71 ± 0.44 ml/s, respectively. On comparing the pre-operative with post-operative mean Qmax, a significant increase was found postoperatively (P < 0.0001). Twenty-four patients had significantly decreased Qmax value after 6 months. In these patients, follow-up urethral dilation was done with significant improvement. Conclusion: The changes in maximum flow rate (Qmax) are suitable for use in routine follow-up. A significant decrease in Qmax over time indicates the onset of urethral stricture. These cases are to be intervened before venturing to redo urethroplasty.
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Hipospadias , Procedimientos de Cirugía Plástica , Niño , Masculino , Humanos , Lactante , Preescolar , Hipospadias/cirugía , Estudios de Seguimiento , Procedimientos Quirúrgicos Urológicos Masculinos/métodos , Uretra/cirugía , Resultado del TratamientoRESUMEN
Coronavirus disease-19 (COVID-19) is caused by severe acute respiratory syndrome coronavirus -2 (SARS-CoV-2) and is responsible for a higher degree of morbidity and mortality worldwide. There is a smaller number of approved therapeutics available to target the SARS-CoV-2 virus, and the virus is evolving at a fast pace. So, there is a continuous need for new therapeutics to combat COVID-19. The main protease (Mpro ) enzyme of SARS-CoV-2 is essential for replication and transcription of the viral genome, thus could be a potent target for the treatment of COVID-19. In the present study, we performed an in-silico screening analysis of 400 diverse bioactive inhibitors with proven antibacterial and antiviral properties against Mpro drug target. Ten compounds showed a higher binding affinity for Mpro than the reference compound (N3), with desired physicochemical properties. Furthermore, in-depth docking and superimposition revealed that three compounds (MMV1782211, MMV1782220, and MMV1578574) are actively interacting with the catalytic domain of Mpro . In addition, the molecular dynamics simulation study showed a solid and stable interaction of MMV178221-Mpro complex compared to the other two molecules (MMV1782220, and MMV1578574). In line with this observation, MM/PBSA free energy calculation also demonstrated the highest binding free energy of -115.8â kJ/mol for MMV178221-Mpro compound. In conclusion, the present in silico analysis revealed MMV1782211 as a possible and potent molecule to target the Mpro and must be explored inâ vitro and inâ vivo to combat the COVID-19.
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COVID-19 , Humanos , Antivirales/farmacología , Reposicionamiento de Medicamentos , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Inhibidores de Proteasas/química , SARS-CoV-2RESUMEN
Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is one of the rapid spreading coronaviruses that belongs to the Coronaviridae family. The rapidly evolving nature of SARS-CoV-2 results in a variety of variants with a capability of evasion to existing therapeutics and vaccines. So, there is an imperative need to discover potent drugs that can able to disrupt the function of multiple drug targets to tackle the SARS-CoV-2 menace. Here in this study, we took the different targets of SARS-CoV-2 prepared in the Schrodinger maestro. The library of the DrugBank database is screened against the selected crucial targets. Our molecular docking, Molecular Mechanics/Generalized Born Surface Area (MMGBSA), and molecular dynamics simulation studies led to identifying dinaciclib and theodrenaline as potential drugs against multiple drug targets: main protease, NSP15-endoribonuclease and papain-like-protease, of SARS-CoV-2. Dinaciclib with papain-like protease and NSP15-endoribonuclease show the docking score of -7.015 and -8.737, respectively, while the theodrenaline with NSP15-endoribonuclease and main protease produced the docking score of -8.507 and -7.289, respectively. Furthermore, the binding free energy calculations with MM/GBSA and molecular dynamics simulation studies of the complexes confirm the reliability of the drugs. The selected drugs are capable of binding to multiple targets simultaneously, thus withstanding their activity of target disruption in different variants of SARS-CoV-2. Although, the repurposed drugs are showing potent activity, but may need further in-vitro and in-vivo validations.Communicated by Ramaswamy H. Sarma.
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COVID-19 , Humanos , Simulación del Acoplamiento Molecular , Papaína , Reproducibilidad de los Resultados , SARS-CoV-2 , Péptido Hidrolasas , Endorribonucleasas , Simulación de Dinámica Molecular , Inhibidores de ProteasasRESUMEN
Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is a member of the Coronaviridae family, causing major destructions to human life directly and indirectly to the economic crisis around the world. Although there is significant reporting on the whole genome sequences and updated data for the different receptors are widely analyzed and screened to find a proper medication. Only a few bioassay experiments were completed against SARS-CoV-2 spike protein. We collected the compounds dataset from the PubChem Bioassay database having 1786 compounds and split it into the ratio of 80-20% for model training and testing purposes, respectively. Initially, we have created 11 models and validated them using a fivefold validation strategy. The hybrid consensus model shows a predictive accuracy of 95.5% for training and 94% for the test dataset. The model was applied to screen a virtual chemical library of Natural products of 2598 compounds. Our consensus model has successfully identified 75 compounds with an accuracy range of 70-100% as active compounds against SARS-CoV-2 RBD protein. The output of ML data (75 compounds) was taken for the molecular docking and dynamics simulation studies. In the complete analysis, the Epirubicin and Daunorubicin have shown the docking score of -9.937 and -9.812, respectively, and performed well in the molecular dynamics simulation studies. Also, Pirarubicin, an analogue of anthracycline, has widely been used due to its lower cardiotoxicity. It shows the docking score of -9.658, which also performed well during the complete analysis. Hence, after the following comprehensive pipeline-based study, these drugs can be further tested in vivo for further human utilization.Communicated by Ramaswamy H. Sarma.
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Antivirales , Reposicionamiento de Medicamentos , SARS-CoV-2 , Humanos , COVID-19 , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , SARS-CoV-2/efectos de los fármacos , Antivirales/químicaRESUMEN
Background: Acne scarring not only affects the aesthetic appearance of an individual but also has a detrimental effect on mental health and social life. Various treatment modalities are available for acne scars. Aim: In this study, fractional erbium-doped yttrium-aluminum-garnet (Er:YAG) laser resurfacing was compared with 20% trichloroacetic acid (TCA) peeling in terms of efficacy and safety. Materials and Methods: This prospective comparative study included 50 subjects of acne scar who were randomly divided into Groups A and B, 25 patients in each group. Group A was treated with 4 sessions of fractional Er:YAG laser and Group B with 4 session of 20% TCA application as chemical peeling, repeated every 21 days over a period of 3 months. The patients were evaluated for improvement at each visit using Goodman and Baron's qualitative and quantitative acne scar grading. Results: Statistically significant improvement in Goodman and Barron's qualitative acne scar grades was observed in both groups. At the end of therapy, that is, after 12 weeks of therapy, the mean percentage reduction in Goodman and Baron's quantitative acne scar scores was 21.69% ± 16% in Group A and 20.97% ± 8.70% in Group B. In regards of complications, both procedures were well tolerated. Conclusion: We concluded that fractional Er:YAG laser resurfacing and 20% TCA peel application in the treatment of atrophic acne scar are equally efficacious. Both procedures are safe and well tolerated by the patients.
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MAFB is a basic leucine zipper (bZIP) transcription factor specifically expressed in macrophages. We have previously identified MAFB as a candidate marker for tumor-associated macrophages (TAMs) in human and mouse models. Here, we analyzed single-cell sequencing data of patients with lung adenocarcinoma obtained from the GEO database (GSE131907). Analyzed data showed that general macrophage marker CD68 and macrophage scavenger receptor 1 (CD204) were expressed in TAM and lung tissue macrophage clusters, while transcription factor MAFB was expressed specifically in TAM clusters. Clinical records of 120 patients with lung adenocarcinoma stage I (n = 57), II (n = 21), and III (n = 42) were retrieved from Tsukuba Human Tissue Biobank Center (THB) in the University of Tsukuba Hospital, Japan. Tumor tissues from these patients were extracted and stained with anti-human MAFB antibody, and then MAFB-positive cells relative to the tissue area (MAFB+ cells/tissue area) were morphometrically quantified. Our results indicated that higher numbers of MAFB+ cells significantly correlated to increased local lymph node metastasis (nodal involvement), high recurrence rate, poor pathological stage, increased lymphatic permeation, higher vascular invasion, and pleural infiltration. Moreover, increased amounts of MAFB+ cells were related to poor overall survival and disease-free survival, especially in smokers. These data indicate that MAFB may be a suitable prognostic biomarker for smoker lung cancer patients.
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Adenocarcinoma del Pulmón , Neoplasias Pulmonares , Adenocarcinoma del Pulmón/genética , Adenocarcinoma del Pulmón/patología , Animales , Biomarcadores , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/genética , Macrófagos , Factor de Transcripción MafB/genética , Ratones , PronósticoRESUMEN
Spot blotch disease of wheat, caused by the fungus Bipolaris sorokiniana (Sacc.) Shoem., produces several toxins which interact with the plants and thereby increase the blightening of the wheat leaves, and Bipolaroxin is one of them. There is an urgent need to decipher the molecular interaction between wheat and the toxin Bipolaroxin for in-depth understanding of host-pathogen interactions. In the present study, we have developed the three-dimensional structure of G-protein alpha subunit from Triticum aestivum. Molecular docking studies were performed using the active site of the modeled G-protein alpha and cryo-EM structure of beta subunit from T. aestivum and 'Bipolaroxin'. The study of protein-ligand interactions revealed that six H-bonds are mainly formed by Glu29, Ser30, Lys32, and Ala177 of G-alpha with Bipolaroxin. In the beta subunit, the residues of the core beta strand domain participate in the ligand interaction where Lys256, Phe306, and Leu352 formed seven H-bonds with the ligand Bipolaroxin. All-atoms molecular dynamics (MD) simulation studies were conducted for G-alpha and -beta subunit and Bipolaroxin complexes to explore the stability, conformational flexibility, and dynamic behavior of the complex system. In planta studies clearly indicated that application of Bipolaroxin significantly impacted the physio-biochemical pathways in wheat and led to the blightening of leaves in susceptible cultivars as compared to resistant ones. Further, it interacted with the Gα and Gß subunits of G-protein, phenylpropanoid, and MAPK pathways, which is clearly supported by the qPCR results. This study gives deeper insights into understanding the molecular dialogues between Bipolaroxin and the Gα and Gß subunits of the wheat heterotrimeric G-protein during host-pathogen interaction.
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Interleukin-27 is constitutively secreted by microglia in the retina or brain, and upregulation of IL-27 during neuroinflammation suppresses encephalomyelitis and autoimmune uveitis. However, while IL-35 is structurally and functionally similar to IL-27, the intrinsic roles of IL-35 in CNS tissues are unknown. Thus, we generated IL-35/YFP-knock-in reporter mice (p35-KI) and demonstrated that photoreceptor neurons constitutively secrete IL-35, which might protect the retina from persistent low-grade inflammation that can impair photoreceptor functions. Furthermore, the p35-KI mouse, which is hemizygous at the il12a locus, develops more severe uveitis because of reduced IL-35 expression. Interestingly, onset and exacerbation of uveitis in p35-KI mice caused by extravasation of proinflammatory Th1/Th17 lymphocytes into the retina were preceded by a dramatic decrease of IL-35, attributable to massive death of photoreceptor cells. Thus, while inflammation-induced death of photoreceptors and loss of protective effects of IL-35 exacerbated uveitis, our data also suggest that constitutive production of IL-35 in the retina might have housekeeping functions that promote sterilization immunity in the neuroretina and maintain ocular immune privilege.
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Enfermedades Autoinmunes , Interleucinas , Uveítis , Animales , Modelos Animales de Enfermedad , Regulación de la Expresión Génica , Privilegio Inmunológico , Inflamación/metabolismo , Interleucina-27/metabolismo , Interleucinas/genética , Interleucinas/metabolismo , Ratones , Ratones Endogámicos C57BL , Células Fotorreceptoras/metabolismo , Retina/metabolismo , Células Th17 , Uveítis/metabolismoRESUMEN
Demand of flowers is increasing with time worldwide. Floriculture has become one of the most important commercial trades in agriculture. Although traditional breeding methods like hybridization and mutation breeding have contributed significantly to the development of important flower varieties, flower production and quality of flowers can be significantly improved by employing modern breeding approaches. Novel traits of significance have interest to consumers and producers, such as fragrance, new floral color, change in floral architecture and morphology, vase life, aroma, and resistance to biotic and abiotic stresses, have been introduced by genetic manipulation. The clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein (Cas) system has recently emerged as a powerful genome-editing tool for accurately changing DNA sequences at specific locations. It provides excellent means of genetically improving floricultural crops. CRISPR/Cas system has been utilized in gene editing in horticultural cops. There are few reports on the utilization of the CRISPR/Cas9 system in flowers. The current review summarizes the research work done by employing the CRISPR/Cas9 system in floricultural crops including improvement in flowering traits such as color modification, prolonging the shelf life of flowers, flower initiation, and development, changes in color of ornamental foliage by genome editing. CRISPR/Cas9 gene editing could be useful in developing novel cultivars with higher fragrance and enhanced essential oil and many other useful traits. The present review also highlights the basic mechanism and key components involved in the CRISPR/Cas9 system.