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1.
Cureus ; 16(4): e59191, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38807811

ABSTRACT

Allergic rhinitis (AR) and nasal polyps (NP) are common inflammatory disorders of the upper airways that often coexist and significantly impact patients' quality of life. This comprehensive review explores the intricate relationship between AR and NP, elucidating the underlying mechanisms, clinical manifestations, and management strategies. Immunological mechanisms, genetic predispositions, and environmental factors contribute to the development and progression of both conditions. Pharmacological therapies, including intranasal corticosteroids and biologic agents, are cornerstone treatments for managing AR with NP. At the same time, surgical interventions such as functional endoscopic sinus surgery (FESS) may be necessary in refractory cases. Emerging therapies, including immunomodulatory agents and precision medicine approaches, hold promise in improving treatment outcomes. A multidisciplinary approach, personalized treatment plans, and patient education are essential for optimizing clinical practice. Future research should focus on identifying novel therapeutic targets, conducting large-scale clinical trials, exploring precision medicine approaches, and investigating the role of the microbiome. Addressing these research priorities and implementing evidence-based treatment strategies can improve outcomes for patients with AR and NP.

2.
Sci Rep ; 14(1): 8311, 2024 04 09.
Article in English | MEDLINE | ID: mdl-38594449

ABSTRACT

Several bacteria of environmental and clinical origins, including some human-associated strains secrete a cross-kingdom signaling molecule indole-3-acetic acid (IAA). IAA is a tryptophan (trp) derivative mainly known for regulating plant growth and development as a hormone. However, the nutritional sources that boost IAA secretion in bacteria and the impact of secreted IAA on non-plant eukaryotic hosts remained less explored. Here, we demonstrate significant trp-dependent IAA production in Pseudomonas juntendi NEEL19 when provided with ethanol as a carbon source in liquid cultures. IAA was further characterized to modulate the odor discrimination, motility and survivability in Drosophila melanogaster. A detailed analysis of IAA-fed fly brain proteome using high-resolution mass spectrometry showed significant (fold change, ± 2; p ≤ 0.05) alteration in the proteins governing neuromuscular features, audio-visual perception and energy metabolism as compared to IAA-unfed controls. Sex-wise variations in differentially regulated proteins were witnessed despite having similar visible changes in chemo perception and psychomotor responses in IAA-fed flies. This study not only revealed ethanol-specific enhancement in trp-dependent IAA production in P. juntendi, but also showed marked behavioral alterations in flies for which variations in an array of proteins governing odor discrimination, psychomotor responses, and energy metabolism are held responsible. Our study provided novel insights into disruptive attributes of bacterial IAA that can potentially influence the eukaryotic gut-brain axis having broad environmental and clinical implications.


Subject(s)
Drosophila melanogaster , Plant Growth Regulators , Animals , Humans , Drosophila melanogaster/metabolism , Plant Growth Regulators/metabolism , Indoleacetic Acids/pharmacology , Indoleacetic Acids/metabolism , Bacteria/metabolism , Ethanol/pharmacology
3.
Inflamm Res ; 2024 Apr 26.
Article in English | MEDLINE | ID: mdl-38668877

ABSTRACT

Lipoxins (LXs) are a class of endogenous bioactive lipid mediators that are involved in the regulation of inflammation. They exert immunomodulatory effects by regulating the behaviour of various immune cells, including neutrophils, macrophages, and T and B cells, by promoting the clearance of apoptotic neutrophils. This helps to dampen inflammation and promote tissue repair. LXs regulate the expression of many inflammatory genes by modulating the levels of transcription factors, such as nuclear factor κB (NF-κB), activator protein-1 (AP-1), nerve growth factor-regulated factor 1A binding protein 1 (NGF), and peroxisome proliferator activated receptor γ (PPAR-γ), which are elevated in various diseases, such as respiratory tract diseases, renal diseases, cancer, neurodegenerative diseases, and viral infections. Lipoxin-mediated signaling is involved in chronic inflammation, cancer, diabetes-associated kidney disease, lung injury, liver injury, endometriosis, respiratory tract diseases, neurodegenerative diseases, chronic cerebral hypoperfusion, and retinal degeneration. In this study, we systematically investigated the intricate network of lipoxin signaling by analyzing the relevant literature. The resulting map comprised 467 molecules categorized as activation/inhibition, enzyme catalysis, gene and protein expression, molecular associations, and translocation events. This map serves as a valuable resource for understanding the complexity of lipoxin signaling and its impact on various cellular functions.

4.
Pediatr Rheumatol Online J ; 22(1): 39, 2024 Mar 20.
Article in English | MEDLINE | ID: mdl-38509613

ABSTRACT

BACKGROUND: Physical active lifestyles are essential throughout growth and maturation and may offer potential preventive and therapeutic benefit in patients with juvenile idiopathic arthritis (JIA). Insufficient physical activity (PA), in contrast, can lead to aggravation of disease-related symptoms. This study aimed to i) examine PA levels in children and adolescents with JIA compared to general population controls and ii) investigate correlates of pronounced physical inactivity in order to identify risk groups for sedentary behaviour. METHODS: Data from children and adolescents with JIA and population controls aged 3 to 17 years documented in the National Pediatric Rheumatologic Database (NPRD) and the German Health Interview and Examination Survey for Children and Adolescents (KiGGS) were used. Self-reported PA was collected from parents/guardians of children up to 11 years of age or adolescents 12 years of age and older. To compare PA-related data, age- and sex-specific pairwise analyses were conducted considering NPRD/KiGGS participants' data from 2017. Correlates of physical inactivity among patients were identified using a linear regression model. RESULTS: Data of 6,297 matched-pairs (mean age 11.2 ± 4.2 years, female 67%, patients' disease duration 4.5 ± 3.7 years, persistent oligoarthritis 43%) were available for evaluation. Almost 36% of patients aged 3-17 years (vs. 20% of controls) achieved the WHO recommended amount of PA, while PA steadily decreased with age (18% of patients aged ≥ 12 years) and varied between JIA categories. Female adolescents and patients with enthesitis-related arthritis were least likely to achieve the minimum recommended level of PA. Physical inactivity was associated with female sex, higher age at disease onset, longer disease duration, more functional disability (C-HAQ) and higher disease activity (cJADAS-10). CONCLUSIONS: Depending on JIA category, children and adolescents with JIA were similarly or even more likely to achieve the WHO recommended minimum level of PA compared to general population controls. However, since a large proportion of young JIA patients appear to be insufficiently physically active, engagement in targeted efforts to promote PA is urgently needed.


Subject(s)
Arthritis, Juvenile , Male , Child , Humans , Female , Adolescent , Prospective Studies , Arthritis, Juvenile/complications , Exercise , Life Style , Sedentary Behavior
5.
RMD Open ; 10(1)2024 Feb 15.
Article in English | MEDLINE | ID: mdl-38360038

ABSTRACT

OBJECTIVE: Interim analysis of the RELIANCE registry, an on-going, non-interventional, open-label, multicentre, prospective study evaluating the long-term safety, dosing regimens and effectiveness of canakinumab in patients with cryopyrin-associated periodic syndromes (CAPS), familial Mediterranean fever (FMF), tumour-necrosis factor receptor-associated periodic syndrome (TRAPS) or mevalonate-kinase deficiency (MKD)/hyperimmunoglobulin-D syndrome (HIDS). METHODS: From September 2017 for patients with CAPS, and June 2018 for patients with FMF, TRAPS or MKD/HIDS, the registry enrolled paediatric (aged ≥2 years) and adult patients (aged ≥18 years) receiving canakinumab as part of their routine medical care. Safety, canakinumab dose, disease activity and quality of life outcome measures were evaluated at baseline and every 6 months until end of study visit. RESULTS: At the analysis cut-off date (December 2020), 168 patients (91 CAPS, 54 FMF, 16 TRAPS and 7 MKD/HIDS) were enrolled. 85 (50.9%) patients were female and 72 (43.1%) were children (<18 years). The median patient age was 20.0 years (range 2.0-79.0 years). In the CAPS cohort, serious infections and serious adverse drug-reactions were more common in patients receiving higher than the recommended starting dose (SD) of canakinumab. A trend to receive >SD of canakinumab was observed in the pooled population. The majority of patients were reported as having either absent or mild/moderate disease activity (physician's global assessment) from baseline to Month 30, with a stable proportion of patients (~70%) in remission under canakinumab treatment. Patient-reported disease activity (Visual Analogue Scale (VAS), Autoinflammatory Disease Activity Index), fatigue (VAS); markers of inflammation (C-reactive protein, serum amyloid A and erythrocyte sedimentation rate) remained well-controlled throughout. CONCLUSION: Data from this analysis confirm the long-term safety and effectiveness of canakinumab for the treatment of CAPS, FMF, TRAPS and MKD/HIDS.


Subject(s)
Antibodies, Monoclonal, Humanized , Cryopyrin-Associated Periodic Syndromes , Familial Mediterranean Fever , Mevalonate Kinase Deficiency , Adult , Humans , Child , Female , Adolescent , Male , Prospective Studies , Quality of Life , Familial Mediterranean Fever/drug therapy , Cryopyrin-Associated Periodic Syndromes/diagnosis , Cryopyrin-Associated Periodic Syndromes/drug therapy , Mevalonate Kinase Deficiency/drug therapy , Mevalonate Kinase Deficiency/etiology , Registries
6.
Nat Commun ; 15(1): 1794, 2024 Feb 27.
Article in English | MEDLINE | ID: mdl-38413594

ABSTRACT

Ex vivo cellular system that accurately replicates sickle cell disease and ß-thalassemia characteristics is a highly sought-after goal in the field of erythroid biology. In this study, we present the generation of erythroid progenitor lines with sickle cell disease and ß-thalassemia mutation using CRISPR/Cas9. The disease cellular models exhibit similar differentiation profiles, globin expression and proteome dynamics as patient-derived hematopoietic stem/progenitor cells. Additionally, these cellular models recapitulate pathological conditions associated with both the diseases. Hydroxyurea and pomalidomide treatment enhanced fetal hemoglobin levels. Notably, we introduce a therapeutic strategy for the above diseases by recapitulating the HPFH3 genotype, which reactivates fetal hemoglobin levels and rescues the disease phenotypes, thus making these lines a valuable platform for studying and developing new therapeutic strategies. Altogether, we demonstrate our disease cellular systems are physiologically relevant and could prove to be indispensable tools for disease modeling, drug screenings and cell and gene therapy-based applications.


Subject(s)
Anemia, Sickle Cell , beta-Thalassemia , Humans , beta-Thalassemia/genetics , beta-Thalassemia/therapy , Fetal Hemoglobin/genetics , Fetal Hemoglobin/metabolism , Anemia, Sickle Cell/drug therapy , Anemia, Sickle Cell/genetics , Hematopoietic Stem Cells/metabolism , Genotype , CRISPR-Cas Systems
7.
Acta Trop ; 252: 107142, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38331083

ABSTRACT

Helminth parasites modulate the host immune system to ensure a long-lasting asymptomatic form of infection generally, mediated by the secretion of immunomodulatory molecules and one such molecule is a homologue of human host cytokine, Macrophage migratory Inhibitory Factor (hMIF). In this study, we sought to understand the role of homologue of hMIF from the lymphatic filarial parasite, Wuchereria bancrofti (Wba-MIF2), in the immunomodulation of the Streptozotocin (STZ)-induced Type1 Diabetes Mellitus (T1DM) animal model. Full-length recombinant Wba-MIF2 was expressed and found to have both oxidoreductase and tautomerase activities. Wba-MIF2 recombinant protein was treated to STZ induced T1DM animals, and after 5 weeks pro-inflammatory (IL-1, IL-2, IL-6, TNF-α, IFN-γ) and anti-inflammatory (IL-4, IL-10) cytokines and gene expressions were determined in sera samples and spleen respectively. Pro-inflammatory and anti-inflammatory cytokine levels were significantly (p<0.05) up-regulated and down-regulated respectively, in the STZ-T1DM animals, as compared to treated groups. Histopathology showed macrophage infiltration and greater damage of islets of beta cells in the pancreatic tissue of STZ-T1DM animals, than Wba-MIF2 treated STZ-T1DM animals. The present study clearly showed the potential of Wba-MIF2 as an immunomodulatory molecule, which could modulate the host immune system in the STZ-T1DM mice model from a pro-inflammatory to anti-inflammatory milieu.


Subject(s)
Diabetes Mellitus, Experimental , Diabetes Mellitus, Type 1 , Filarioidea , Macrophage Migration-Inhibitory Factors , Parasites , Humans , Animals , Mice , Wuchereria bancrofti , Macrophage Migration-Inhibitory Factors/genetics , Macrophage Migration-Inhibitory Factors/metabolism , Parasites/metabolism , Streptozocin , Immunologic Factors , Diabetes Mellitus, Experimental/genetics , Anti-Inflammatory Agents , Intramolecular Oxidoreductases
9.
Z Rheumatol ; 83(1): 28-33, 2024 Feb.
Article in German | MEDLINE | ID: mdl-37945990

ABSTRACT

With the diagnosis and treatment optimization board, the Society for Pediatric and Adolescent Rheumatology (GKJR) has developed a new format for expert-based discussion of rare and complex diseases. So far, 32 cases, predominantly from the areas of hyperinflammation, systemic lupus erythematosus, myositis and nonbacterial osteomyelitis, could be discussed in 8 conferences. The digital format enabled a high number of participants and the involvement of national and international experts. Rare diseases increasingly present modern medicine with challenges, which the GKJR meets with the new format.


Subject(s)
Lupus Erythematosus, Systemic , Rheumatology , Humans , Adolescent , Child , Lupus Erythematosus, Systemic/diagnosis , Lupus Erythematosus, Systemic/therapy
10.
J Maxillofac Oral Surg ; 22(4): 813-819, 2023 Dec.
Article in English | MEDLINE | ID: mdl-38105862

ABSTRACT

Purpose: To determine the positional variations of the greater palatine foramen in different facial skeletal relationships and discuss its surgical implications on the Trimble's modification of Lefort I osteotomy. Materials and Methods: This retrospective study examined 50 computed tomography scans of patients a total of 100 sides. The sample was divided into four groups: Class 1, Class 2, Class 3 malocclusion and Unilateral cleft lip and palate). The outcome variables included the distance between anterior, middle and posterior points of the GPF to the distal of second molar and variables to assess relative position of the GPF to the posterior maxilla. Outcome measures were to demonstrate intra- and intergroup variability. Results: Fifty patients (100 sides) were divided into four groups. This included 23 males and 27 females with a mean age of 24.1 years. Significant intergroup variability was observed between all the parameters that demonstrate the relative position of the GPF to (i) the maxillary second molar and (ii) the posterior maxilla. The analysis revealed that the GPF was positioned significantly anterior in Class 2 patients when compared with Class 3 patients. Conclusion: The GPF exhibits significant positional variability in different facial skeletal relationships which should be borne in mind while designing and performing the Trimble's modification of the Lefort 1 osteotomy.

11.
PLoS Pathog ; 19(11): e1011770, 2023 Nov.
Article in English | MEDLINE | ID: mdl-37988347

ABSTRACT

Signalling pathways in malaria parasite remain poorly defined and major reason for this is the lack of understanding of the function of majority of parasite protein kinases and phosphatases in parasite signalling and its biology. In the present study, we have elucidated the function of Protein Kinase 2 (PfPK2), which is known to be indispensable for the survival of human malaria parasite Plasmodium falciparum. We demonstrate that it is involved in the invasion of host erythrocytes, which is critical for establishing infection. In addition, PfPK2 may also be involved in the maturation of the parasite post-invasion. PfPK2 regulates the release of microneme proteins like Apical Membrane Antigen 1 (AMA1), which facilitates the formation of Tight Junction between the merozoite and host erythrocyte- a key step in the process of invasion. Comparative phosphoproteomics studies revealed that PfPK2 may be involved in regulation of several key proteins involved in invasion and signalling. Furthermore, PfPK2 regulates the generation of cGMP and the release of calcium in the parasite, which are key second messengers for the process of invasion. These and other studies have shed light on a novel signalling pathway in which PfPK2 acts as an upstream regulator of important cGMP-calcium signalling, which plays an important role in parasite invasion.


Subject(s)
Parasites , Protein Kinases , Animals , Humans , Protein Kinases/metabolism , Protozoan Proteins/genetics , Protozoan Proteins/metabolism , Parasites/metabolism , Calcium/metabolism , Plasmodium falciparum/metabolism , Erythrocytes/parasitology
12.
Cureus ; 15(9): e45565, 2023 Sep.
Article in English | MEDLINE | ID: mdl-37868480

ABSTRACT

Pituitary macroadenoma and angiofibroma are two distinct and diverse types of tumors that can develop in different anatomical locations and clinical characteristics and are not typically related to each other in terms of their hormonal or developmental aspects. This case describes an adult male with pituitary macroadenoma with nasal angiofibroma. A 35-year-old male was diagnosed with pituitary macroadenoma and incidentally found to have juvenile nasopharyngeal angiofibroma (NPA). The patient underwent a diagnostic workup, including imaging studies and hormonal assays, which confirmed the concomitant presence of both tumors. The patient underwent successful endoscopic surgical excision of the NPA and transnasal transsphenoidal endoscopic pituitary macroadenoma excision as a two-stage operation. The patient was followed up postoperatively and had no evidence of tumor recurrence or hormonal imbalances. The importance of complete and comprehensive diagnostic workup and multidisciplinary management in achieving successful and optimum treatment outcomes for coexisting NPA and pituitary macroadenoma in an adult patient is highlighted in the present report.

13.
Front Plant Sci ; 14: 1233248, 2023.
Article in English | MEDLINE | ID: mdl-37692421

ABSTRACT

Abiotic stresses such as drought, salinity, and heat stress significantly affect rice crop growth and production. Under uncertain climatic conditions, the concurrent multiple abiotic stresses at different stages of rice production became a major challenge for agriculture. Hence, improving rice's multiple abiotic stress tolerance is essential to overcome unprecedented challenges under adverse environmental conditions. A significant challenge for rice breeding programs in improving abiotic stress tolerance involves multiple traits and their complexity. Multiple traits must be targeted to improve multiple stress tolerance in rice and uncover the mechanisms. With this hypothesis, in the present study gene stacking approach is used to integrate multiple traits involved in stress tolerance. The multigene transgenics co-expressing Pennisetum glaucum 47 (Pg47), Pea 68 (p68), Pennisetum glaucum Heat Shock Factor 4(PgHSF4), and Pseudomonas Aldo Keto Reductase 1 (PsAKR1) genes in the rice genotype (AC39020) were developed using the in-planta transformation method. The promising transgenic lines maintained higher yields under semi-irrigated aerobic cultivation (moisture stress). These 15 promising transgenic rice seedlings showed improved shoot and root growth traits under salinity, accelerating aging, temperature, and oxidative stress. They showed better physiological characteristics, such as chlorophyll content, membrane stability, and lower accumulation of reactive oxygen species, under multiple abiotic stresses than wild-type. Enhanced expression of transgenes and other stress-responsive downstream genes such as HSP70, SOD, APX, SOS, PP2C, and P5CS in transgenic lines suggest the possible molecular mechanism for imparting the abiotic stress tolerance. This study proved that multiple genes stacking as a novel strategy induce several mechanisms and responsible traits to overcome multiple abiotic stresses. This multigene combination can potentially improve tolerance to multiple abiotic stress conditions and pave the way for developing climate-resilient crops.

14.
Amino Acids ; 55(8): 993-1001, 2023 Aug.
Article in English | MEDLINE | ID: mdl-37311859

ABSTRACT

Gastric cancers are highly heterogeneous, deep-seated tumours associated with late diagnosis and poor prognosis. Post-translational modifications (PTMs) of proteins are known to be well-associated with oncogenesis and metastasis in most cancers. Several enzymes which drive PTMs have also been used as theranostics in cancers of the breast, ovary, prostate and bladder. However, there is limited data on PTMs in gastric cancers. Considering that experimental protocols for simultaneous analysis of multiple PTMs are being explored, a data-driven approach involving reanalysis of mass spectrometry-derived data is useful in cataloguing altered PTMs. We subjected publicly available mass spectrometry data on gastric cancer to an iterative searching strategy for fetching PTMs including phosphorylation, acetylation, citrullination, methylation and crotonylation. These PTMs were catalogued and further analyzed for their functional enrichment through motif analysis. This value-added approach delivered identification of 21,710 unique modification sites on 16,364 modified peptides. Interestingly, we observed 278 peptides corresponding to 184 proteins to be differentially abundant. Using bioinformatics approaches, we observed that majority of these altered PTMs/proteins belonged to cytoskeletal and extracellular matrix proteins, which are known to be perturbed in gastric cancer. The dataset derived by this mutiPTM investigation can provide leads to further investigate the potential role of altered PTMs in gastric cancer management.


Subject(s)
Stomach Neoplasms , Humans , Stomach Neoplasms/drug therapy , Proteomics/methods , Protein Processing, Post-Translational , Phosphorylation , Proteins , Peptides , Acetylation
15.
Biochim Biophys Acta Gen Subj ; 1867(7): 130382, 2023 07.
Article in English | MEDLINE | ID: mdl-37207907

ABSTRACT

Fusarium wilt of banana is a destructive widespread disease caused by Fusarium oxysporum f. sp. cubense (Foc) that ravaged banana plantations globally, incurring huge economic losses. Current knowledge demonstrates the involvement of several transcription factors, effector proteins, and small RNAs in the Foc-banana interaction. However, the precise mode of communication at the interface remains elusive. Cutting-edge research has emphasized the significance of extracellular vesicles (EVs) in trafficking the virulent factors modulating the host physiology and defence system. EVs are ubiquitous inter- and intra-cellular communicators across kingdoms. This study focuses on the isolation and characterization of Foc EVs from methods that make use of sodium acetate, polyethylene glycol, ethyl acetate, and high-speed centrifugation. Isolated EVs were microscopically visualized using Nile red staining. Further, the EVs were characterized using transmission electron microscopy, which revealed the presence of spherical, double-membrane, vesicular structures ranging in size from 50 to 200 nm (diameter). The size was also determined using the principle based on Dynamic Light Scattering. The Foc EVs contained proteins that were separated using SDS-PAGE and ranged between 10 and 315 kDa. Mass spectrometry analysis revealed the presence of EV-specific marker proteins, toxic peptides, and effectors. The Foc EVs were found to be cytotoxic, whose toxicity increased with EVs isolated from the co-culture preparation. Taken together, a better understanding of Foc EVs and their cargo will aid in deciphering the molecular crosstalk between banana and Foc.


Subject(s)
Fusarium , Musa , Plant Diseases , Transcription Factors
16.
J Cell Commun Signal ; 17(3): 1113-1120, 2023 Sep.
Article in English | MEDLINE | ID: mdl-37142846

ABSTRACT

Macrophage-stimulating protein (MSP), a serum-derived growth factor belonging to the plasminogen-related kringle domain family, is mainly produced by the liver and released into the blood. MSP is the only known ligand for RON ("Recepteur d'Origine Nantais", also known as MST1R), which is a member of the receptor tyrosine kinase (RTK) family. MSP is associated with many pathological conditions, including cancer, inflammation, and fibrosis. Activation of the MSP/RON system regulates main downstream signaling pathways, including phosphatidylinositol 3-kinase/ AKT serine/threonine kinase/ (PI3-K/AKT), mitogen-activated protein kinases (MAPK), c-Jun N-terminal kinase (JNK) & Focal adhesion kinase (FAK). These pathways are mainly involved in cell proliferation, survival, migration, invasion, angiogenesis & chemoresistance. In this work, we created a pathway resource of signaling events mediated by MSP/RON considering its contribution to diseases. We provide an integrated pathway reaction map of MSP/RON that is composed of 113 proteins and 26 reactions based on the curation of data from the published literature. The consolidated pathway map of MSP/RON mediated signaling events contains seven molecular associations, 44 enzyme catalysis, 24 activation/inhibition, six translocation events, 38 gene regulation events, and forty-two protein expression events. The MSP/RON signaling pathway map can be freely accessible through the WikiPathways Database URL: https://classic.wikipathways.org/index.php/Pathway:WP5353 .

17.
J Biomol Struct Dyn ; 41(24): 15196-15206, 2023.
Article in English | MEDLINE | ID: mdl-37029757

ABSTRACT

The calcium/calmodulin dependent protein kinase kinase 2 (CAMKK2) plays a key role in regulation of intracellular calcium levels and signaling pathways. It is involved in activation of downstream signaling pathways that regulate various cellular processes. Dysregulation of CAMKK2 activity has been linked to various diseases including cancer, suggesting that CAMKK2 inhibitors might be beneficial in oncological, metabolic and inflammatory indications. The most pressing issues in small molecule discovery are synthesis feasibility, novel chemical structure and desired biological characteristics. To circumvent this constraint, we employed 'DrugspaceX' for rapid lead identification, followed by repositioning seven FDA-approved drugs for CAMKK2 inhibition. Further, first-level transformation (Set1 analogues) was performed in 'DrugspaceX', followed by virtual screening. The t-SNE visualization revealed that the transformations surrounding Rucaparib, Treprostinil and Canagliflozin are more promising for developing CAMKK2 inhibitors. Second, using the top-ranked Set1 analogues, Set2 analogues were generated, and virtual screening revealed the top-ranked five analogues. Among the top five Set2 analogues, DE273038_5 had the lowest docking score of -11.034 kcal/mol and SA score of 2.59, retaining the essential interactions with Hotspot residues LYS194 and VAL270 across 250 ns simulation period. When compared to the other four compounds, the ligand effectiveness score was 0.409, and the number of rotatable penalties was only three. Further, DE273038_5 after two rounds of transformations was discovered to be novel and had not been previously described in other databases. These data suggest that the new candidate DE273038_5 is likely to have inhibitory activity at the CAMKK2 active site, implying potential therapeutic use.Communicated by Ramaswamy H. Sarma.


Subject(s)
Calcium-Calmodulin-Dependent Protein Kinase Kinase , Calcium , Calcium/metabolism , Calcium-Calmodulin-Dependent Protein Kinase Kinase/chemistry , Calcium-Calmodulin-Dependent Protein Kinase Kinase/metabolism , Catalytic Domain , Signal Transduction
18.
J Cell Commun Signal ; 17(3): 1105-1111, 2023 Sep.
Article in English | MEDLINE | ID: mdl-37014471

ABSTRACT

Trophoblast cell surface antigen 2 (TROP2) is a calcium-transducing transmembrane protein mainly involved in embryo development. The aberrant expression of TROP2 is observed in numerous cancers, including triple-negative breast cancer, gastric, colorectal, pancreatic, squamous cell carcinoma of the oral cavity, and prostate cancers. The main signaling pathways mediated by TROP2 are calcium signaling, PI3K/AKT, JAK/STAT, MAPKs, and ß-catenin signaling. However, collective information about the TROP2-mediated signaling pathway is not available for visualization or analysis. In this study, we constructed a TROP2 signaling map with respect to its role in different cancers. The data curation was done manually by following the NetPath annotation criteria. The described map consists of different molecular events, including 8 activation/inhibition, 16 enzyme catalysis, 19 gene regulations, 12 molecular associations, 39 induced-protein expressions, and 2 protein translocation. The data of the TROP2 pathway map is made freely accessible through the WikiPathways Database ( https://www.wikipathways.org/index.php/Pathway:WP5300 ). Development of TROP2 signaling pathway map.

19.
Sci Rep ; 13(1): 6788, 2023 04 26.
Article in English | MEDLINE | ID: mdl-37100788

ABSTRACT

Gram pod borer, Helicoverpa armigera (Hub.) is the major insect pest of pigeonpea and prediction of number of generations (no. of gen.) and generation time (gen. time) using growing degree days (GDD) approach during three future climate change periods viz., Near (NP), Distant (DP) and Far Distant (FDP) periods at eleven major pigeonpea growing locations of India was attempted. Multi-model ensemble of Maximum (Tmax) and Minimum (Tmin) temperature data of four Representative Concentration Pathways viz., RCP 2.6, 4.5, 6.0 and 8.5 of Coupled Model Inter comparison Project 5 (CMIP5) models was adopted here. The increase in projected Tmax and Tmin are significant during 3 climate change periods (CCPs) viz., the NP, DP and FDP over base line (BL) period under four RCP scenarios at all locations and would be higher (4.7-5.1 °C) in RCP 8.5 and in FDP. More number of annual (10-17) and seasonal (5-8) gens. are expected to occur with greater percent increase in FDP (8 to 38%) over base line followed by DP (7 to 22%) and NP (5to 10%) periods with shortened annual gen. time (4 to 27%) across 4 RCPs. The reduction of crop duration was substantial in short, medium and long duration pigeonpeas at all locations across 4 RCPs and 3 CCPs. The seasonal no.of gen. is expected to increase (5 to 35%) with shortened gen. time (4 to 26%) even with reduced crop duration across DP and FDP climate periods of 6.0 and 8.5 RCPs in LD pigeonpea. More no. of gen. of H. armigera with reduced gen. time are expected to occur at Ludhiana, Coimbatore, Mohanpur, Warangal and Akola locations over BL period in 4 RCPs when normal duration of pigeonpeas is considered. Geographical location (66 to 72%), climate period (11 to 19%), RCPs (5-7%) and their interaction (0.04-1%) is vital and together explained more than 90% of the total variation in future pest scenario. The findings indicate that the incidence of H. armigera would be higher on pigeonpea during ensuing CCPs in India under global warming context.


Subject(s)
Climate Change , Moths , Animals , Global Warming , Temperature , India
20.
ACS Omega ; 8(12): 10954-10967, 2023 Mar 28.
Article in English | MEDLINE | ID: mdl-37008090

ABSTRACT

In the present study, we have improvised a biogenic method to fabricate zinc oxide nanoparticles (ZnO NPs) using chitosan and an aqueous extract of the leaves of Elsholtzia blanda. Characterization of the fabricated products was carried out with the help of ultraviolet-visible, Fourier transform infrared, X-ray diffraction, field emission scanning electron microscopy, high-resolution transmission electron microscopy, selected area electron diffraction, and energy-dispersive X-ray analyses. The size of the improvised ZnO NP measured between 20 and 70 nm and had a spherical and hexagonal shape. The ZnO NPs proved to be highly effective in the antidiabetic test as the sample showed the highest percentage of enzyme inhibition at 74% ± 3.7, while in the antioxidant test, 78% was the maximum percentage of 2,2-diphenyl-1-picrylhydrazyl hydrate scavenging activity. The cytotoxic effect was investigated against the human osteosarcoma (MG-63) cell line, and the IC50 value was 62.61 µg/mL. Photocatalytic efficiency was studied by the degradation of Congo red where 91% of dye degradation was observed. From the various analyses, it can be concluded that the as-synthesized NPs may be suitable for various biomedical applications as well as for environmental remediation.

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