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The efficient and prolonged neurotransmission is reliant on the coordinated action of numerous synaptic proteins in the presynaptic compartment that remodels synaptic vesicles for neurotransmitter packaging and facilitates their exocytosis. Once a cycle of neurotransmission is completed, membranes and associated proteins are endocytosed into the cytoplasm for recycling or degradation. Both exocytosis and endocytosis are closely regulated in a timely and spatially constrained manner. Recent research demonstrated the impact of dysfunctional synaptic vesicle retrieval in causing retrograde degeneration of midbrain neurons and has highlighted the importance of such endocytic proteins, including auxilin, synaptojanin1 (SJ1), and endophilin A (EndoA) in neurodegenerative diseases. Additionally, the role of other associated proteins, including leucine-rich repeat kinase 2 (LRRK2), adaptor proteins, and retromer proteins, is being investigated for their roles in regulating synaptic vesicle recycling. Research suggests that the degradation of defective vesicles via presynaptic autophagy, followed by their recycling, not only revitalizes them in the active zone but also contributes to strengthening synaptic plasticity. The presynaptic autophagy rejuvenating terminals and maintaining neuroplasticity is unique in autophagosome formation. It involves several synaptic proteins to support autophagosome construction in tiny compartments and their retrograde trafficking toward the cell bodies. Despite having a comprehensive understanding of ATG proteins in autophagy, we still lack a framework to explain how autophagy is triggered and potentiated in compact presynaptic compartments. Here, we reviewed synaptic proteins' involvement in forming presynaptic autophagosomes and in retrograde trafficking of terminal cargos. The review also discusses the status of endocytic proteins and endocytosis-regulating proteins in neurodegenerative diseases and strategies to combat neurodegeneration.
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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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Annual variations in animal's physiological functions are an essential strategy to deal with seasonal challenges which also vary according to the time of year. Information regarding annual adaptations in the immune-competence to cope with seasonal stressors in reptiles is scarce. The present research plan was designed to analyze the presence of circannual immune rhythms in defense responses of the leucocytes in an ophidian, Natrix piscator. Peripheral blood leucocytes were obtained, counted, and superoxide anion production, neutrophil phagocytosis, and nitrite release were tested to assess the innate immune functions. Peripheral blood lymphocytes were separated by centrifugation (utilizing density gradient) and the cell proliferation was measured. The Cosinor rhythmometry disclosed the presence of significant annual rhythms in the number of leucocytes, superoxide anion production, nitric oxide production, and proliferation of stimulated lymphocytes. The authors found that respiratory burst activity and proliferative responses of lymphocytes were crucial immune responses that showed the annual rhythm. It was summarized that the immune function of the N. piscator is a labile attribute that makes the animal competent to cope with the seasonal stressor by adjustment in the potency of response.
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Leucocitos , Fagocitosis , Estaciones del Año , Superóxidos , Animales , Leucocitos/inmunología , Leucocitos/metabolismo , Superóxidos/metabolismo , Óxido Nítrico/metabolismo , Proliferación Celular , Estallido Respiratorio , Linfocitos/inmunología , Linfocitos/metabolismo , Inmunidad InnataRESUMEN
Autism spectrum disorder (ASD) is a neurodevelopmental disorder based on synaptic abnormalities. The estimated prevalence rate of male individuals diagnosed with ASD prevails over females is in a proportion of 4:1. Consequently, males remain the main focus in ASD studies in clinical and experimental settings. Meanwhile, some studies point to an underestimation of this disorder in females. In this work, we studied the sex differences of the synaptic and behavioral phenotypes of ASD mouse models. Juvenile male and female Shank3Δ4-22 and Cntnap2-/- mutant mice and their WT littermates were used in the experiments. The animals were subjected to a Three-Chamber Sociability Test, then euthanized, and the whole cortex was used for the evaluation of the synaptic phenotype. Protein levels of glutamatergic (NR1) and GABAergic (GAD1 and VGAT) neuronal markers were measured. Protein level of synaptophysin (Syp) was also measured. Dendritic spine density in somatosensory neurons was analyzed by Golgi staining methods. Spine Density and GAD1, NR1, VGAT, and Syp levels were significantly reduced in Shank3Δ4-22 and Cntnap2-/- mice compared to the control group irrespective of sex, indicating impaired synaptic development in the mutant mice. These results were consistent with the lack of differences in the three-chamber sociability test between male and female mice. In conclusion, female ASD mice of both mutations undergo similar synaptic aberrations as their male counterparts and need to be studied along with the male animals. Finally, this work urges the psychiatry scientific community to use both sexes in their investigations.
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Trastorno del Espectro Autista , Trastorno Autístico , Ratones , Femenino , Masculino , Animales , Trastorno del Espectro Autista/genética , Mutación , Conducta Animal/fisiología , Corteza Cerebral , Modelos Animales de Enfermedad , Proteínas de Microfilamentos/genética , Proteínas del Tejido Nervioso/genéticaRESUMEN
SIGNIFICANCE STATEMENT: This study sheds light on the central role of adenine nucleotide translocase 2 (ANT2) in the pathogenesis of obesity-induced CKD. Our data demonstrate that ANT2 depletion in renal proximal tubule cells (RPTCs) leads to a shift in their primary metabolic program from fatty acid oxidation to aerobic glycolysis, resulting in mitochondrial protection, cellular survival, and preservation of renal function. These findings provide new insights into the underlying mechanisms of obesity-induced CKD and have the potential to be translated toward the development of targeted therapeutic strategies for this debilitating condition. BACKGROUND: The impairment in ATP production and transport in RPTCs has been linked to the pathogenesis of obesity-induced CKD. This condition is characterized by kidney dysfunction, inflammation, lipotoxicity, and fibrosis. In this study, we investigated the role of ANT2, which serves as the primary regulator of cellular ATP content in RPTCs, in the development of obesity-induced CKD. METHODS: We generated RPTC-specific ANT2 knockout ( RPTC-ANT2-/- ) mice, which were then subjected to a 24-week high-fat diet-feeding regimen. We conducted comprehensive assessment of renal morphology, function, and metabolic alterations of these mice. In addition, we used large-scale transcriptomics, proteomics, and metabolomics analyses to gain insights into the role of ANT2 in regulating mitochondrial function, RPTC physiology, and overall renal health. RESULTS: Our findings revealed that obese RPTC-ANT2-/- mice displayed preserved renal morphology and function, along with a notable absence of kidney lipotoxicity and fibrosis. The depletion of Ant2 in RPTCs led to a fundamental rewiring of their primary metabolic program. Specifically, these cells shifted from oxidizing fatty acids as their primary energy source to favoring aerobic glycolysis, a phenomenon mediated by the testis-selective Ant4. CONCLUSIONS: We propose a significant role for RPTC-Ant2 in the development of obesity-induced CKD. The nullification of RPTC-Ant2 triggers a cascade of cellular mechanisms, including mitochondrial protection, enhanced RPTC survival, and ultimately the preservation of kidney function. These findings shed new light on the complex metabolic pathways contributing to CKD development and suggest potential therapeutic targets for this condition.
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Riñón , Insuficiencia Renal Crónica , Masculino , Animales , Ratones , Proteínas de Transporte de Membrana Mitocondrial , Fibrosis , Adenosina Trifosfato , Insuficiencia Renal Crónica/etiologíaRESUMEN
Plamepsin II has been identified as a therapeutic target in the Plasmodium falciparum's life cycle and may lead to a drastic reduction in deaths caused by malaria worldwide. Africa flora is rich in medicinal qualities and possesses both simple and complex bioactive phytochemicals. This study utilized computational approaches like molecular docking, molecular dynamics simulation, quantum chemical calculations and ADMET to evaluate the plasmepsin II inhibitory properties of phytochemicals isolated from African antimalarial plants. Molecular docking was carried out to estimate the binding affinity of 229 phytochemicals whereby ekeberin A, dichamanetin, 10-hydroxyusambaresine, chamuvaritin and diuvaretin were selected. Further, RMSD and RMSF plots from the 100 ns simulation results showed that the screened phytochemicals were stable in the enzyme's binding pocket. The quantum chemical calculation revealed that all the phytochemicals are strong electrophiles, while ekeberin A was identified as the most stable and dichamanetin as the most reactive. Also, ADMET studies established the drug candidacy of the phytochemicals. Thus, these phytochemicals could act as good antimalarial agents after extensive in vitro and in vivo studies.Communicated by Ramaswamy H. Sarma.
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Glioblastoma multiforme (GBM) is a prevalent and aggressive primary brain tumor, presenting substantial treatment challenges and high relapse rates. GBM is characterized by alterations in molecular signaling and enzyme expression within malignant cells. This tumor exhibits elevated nitric oxide (NO.) levels. NO. is a crucial signaling molecule involved in the regulation of neuronal functions, synaptic transmission, and cell proliferation. It is primarily synthesized from L-arginine by nitric oxide synthase (NOS) enzymes. The increased levels of NO. in GBM stem from dysregulated activity and expression of clinically relevant NOS isoforms, particularly inducible NOS (iNOS) and neuronal NOS (nNOS). Based on this knowledge, we hypothesize that targeted pharmacological intervention with N6-(1-iminoethyl)-L-lysine (L-NIL), an iNOS inhibitor, and 7-Nitroindazole (7-NI), an nNOS inhibitor, may suggest a promising therapeutic strategy for the treatment of GBM. To test our hypothesis, we utilized the U87-MG cell line as an in vitro model of GBM. Our results showed that treatment with L-NIL and 7-NI led to a reduction in NO. levels, NOS activity, and clonogenic proliferation in U87-MG cells. These findings suggest that NO. and NOS enzymes might be prospective therapeutic targets for GBM.
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Glioblastoma , Humanos , Glioblastoma/tratamiento farmacológico , Inhibidores Enzimáticos/farmacología , Recurrencia Local de Neoplasia , Óxido Nítrico Sintasa/metabolismo , Óxido Nítrico Sintasa de Tipo I/metabolismo , Óxido Nítrico Sintasa de Tipo II/genética , Óxido Nítrico Sintasa de Tipo II/metabolismo , Óxido Nítrico/metabolismo , Proliferación CelularRESUMEN
Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by behavioral deficits such as abnormalities in communication, social interaction, anxiety, and repetitive behavior. We have recently shown that the Shank3 mutation in mice representing a model of ASD causes excessive nitric oxide (NO) levels and aberrant protein S-nitrosylation. Further, 10-day daily injections of 7-NI, a neuronal nitric oxide synthase inhibitor, into Shank3Δ4-22 and Cntnap2(-/-) mutant mice (models of ASD) at a dose of 80 mg/kg reversed the manifestations of ASD phenotype. In this study, we proposed an extended release of 7-NI using a novel drug system. Importantly, unlike the intraperitoneal injections, our new preparation of poly (sebacic acid-co-ricinoleic acid) (PSARA) gel containing 7-NI was injected subcutaneously into the mutant mice only once. The animals underwent behavioral testing starting from day 3 post-injection. It should be noted that the developed PSARA gel formulation allowed a slow release of 7-NI maintaining the plasma level of the drug at â¼45 µg/ml/day. Further, we observed improved memory and social interaction and reduced anxiety-like behavior in Shank3 mutant mice. This was accompanied by a reduction in 3-nitrotyrosine levels (an indicator of nitrative/nitrosative stress) in plasma. Overall, we suggest that our single-dose formulation of PSARA gel is very efficient in rendering a therapeutic effect of 7-NI for at least 10 days. This approach may provide in the future a rational design of an effective ASD treatment using 7-NI and its clinical translation.
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Trastorno del Espectro Autista , Trastorno Autístico , Ratones , Animales , Trastorno Autístico/genética , Trastorno del Espectro Autista/tratamiento farmacológico , Trastorno del Espectro Autista/genética , Trastorno del Espectro Autista/metabolismo , Indazoles , Conducta Animal , Modelos Animales de Enfermedad , Proteínas de Microfilamentos , Proteínas del Tejido NerviosoRESUMEN
Annual rhythms in immune function are the reflection of a crucial physiological strategy to deal with environmental stressors. The fish are pivotal animal models to study the annual rhythm and to understand the evolution of the vertebrate biological system. The current research was planned to assess the annual changes in the innate immune functions of immune cells in a teleost, Channa punctatus. Head kidney and splenic macrophage phagocytosis, superoxide generation, and nitrite release were evaluated to assess innate immunity. Cell-mediated immunity was measured through head kidney and splenic lymphocyte proliferation in presence of mitogens. The superoxide anion generation by the cells of head kidney and spleen was maximum in October. A bimodal pattern in nitrite production was observed with the first peak in November and the second in March. Cosinor analysis revealed a statistically significant annual rhythm in nitrite production. Similarly, phagocytosis and lymphocyte proliferation also showed statistically significant annual rhythms. It was concluded that animals maintain an optimum immune response in seasonally changing environments. Elevated immunity during certain times of the year might assist animals deal with seasonal environmental stressors. Further research may be focused upon measuring survival rate and reproductive success after season induced elevated immunity.
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Autism spectrum disorders (ASDs) include a wide range of neurodevelopmental disorders. Several reports showed that mutations in different high-risk ASD genes lead to ASD. However, the underlying molecular mechanisms have not been deciphered. Recently, they reported a dramatic increase in nitric oxide (NO) levels in ASD mouse models. Here, they conducted a multidisciplinary study to investigate the role of NO in ASD. High levels of nitrosative stress biomarkers are found in both the Shank3 and Cntnap2 ASD mouse models. Pharmacological intervention with a neuronal NO synthase (nNOS) inhibitor in both models led to a reversal of the molecular, synaptic, and behavioral ASD-associated phenotypes. Importantly, treating iPSC-derived cortical neurons from patients with SHANK3 mutation with the nNOS inhibitor showed similar therapeutic effects. Clinically, they found a significant increase in nitrosative stress biomarkers in the plasma of low-functioning ASD patients. Bioinformatics of the SNO-proteome revealed that the complement system is enriched in ASD. This novel work reveals, for the first time, that NO plays a significant role in ASD. Their important findings will open novel directions to examine NO in diverse mutations on the spectrum as well as in other neurodevelopmental disorders. Finally, it suggests a novel strategy for effectively treating ASD.
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Trastorno del Espectro Autista , Ratones , Animales , Trastorno del Espectro Autista/genética , Óxido Nítrico , Neuronas , Biomarcadores , Proteínas de Microfilamentos , Proteínas del Tejido NerviosoRESUMEN
One of the most well-known anti-targets defining medication cardiotoxicity is the voltage-dependent hERG K + channel, which is well-known for its crucial involvement in cardiac action potential repolarization. Torsades de Pointes, QT prolongation, and sudden death are all caused by hERG (the human Ether-à-go-go-Related Gene) inhibition. There is great interest in creating predictive computational (in silico) tools to identify and weed out potential hERG blockers early in the drug discovery process because testing for hERG liability and the traditional experimental screening are complicated, expensive and time-consuming. This study used 2D descriptors of a large curated dataset of 6766 compounds and machine learning approaches to build robust descriptor-based QSAR and predictive classification models for KCNH2 liability. Decision Tree, Random Forest, Logistic Regression, Ada Boosting, kNN, SVM, Naïve Bayes, neural network and stochastic gradient classification classifier algorithms were used to build classification models. If a compound's IC50 value was between 10 µM and less, it was classified as a blocker (hERG-positive), and if it was more, it was classified as a non-blocker (hERG-negative). Matthew's correlation coefficient formula and F1score were applied to compare and track the developed models' performance. Molecular docking and dynamics studies were performed to understand the cardiotoxicity relating to the hERG-gene. The hERG residues interacting after 100 ns are LEU:697, THR:708, PHE:656, HIS:674, HIS:703, TRP:705 and ASN:709 and the hERG-ligand-16 complex trajectory showed stable behaviour with lesser fluctuations in the entire simulation of 200 ns.Communicated by Ramaswamy H. Sarma.
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Canales de Potasio Éter-A-Go-Go , Simulación de Dinámica Molecular , Humanos , Simulación del Acoplamiento Molecular , Canales de Potasio Éter-A-Go-Go/química , Canales de Potasio Éter-A-Go-Go/metabolismo , Relación Estructura-Actividad Cuantitativa , Teorema de Bayes , Cardiotoxicidad , Bloqueadores de los Canales de Potasio/farmacología , Bloqueadores de los Canales de Potasio/química , Aprendizaje Automático , Interacciones FarmacológicasRESUMEN
Methanethiol (M) and water (W) clusters like dimers (M1W1, M2, and W2), trimers (M1W2, M2W1, M3, and W3), and tetramers (M1W3, M2W2, M3W1, M4, and W4) were studied to assess the strength of sulfur-centered hydrogen bonding using different levels of theories, viz, HF, MP2, MP3, MP4, B3LYP, B3LYP-D3, CCSD, CCSD(T)-F12, and CCSD(T) along with aug-cc-pVNZ (where N = D, T, and Q) basis sets. Interaction energies were found to be in the range of -3.3 to -5.3 kcal/mol for the dimers, -8.0 to -16.7 kcal/mol for the trimers, and -13.5 to -29.5 kcal/mol for the tetramers at the B3LYP-D3/CBS limit level of theory. Normal modes of vibrations computed at the B3LYP/cc-pVDZ level of theory were seen to be in good agreement with the experimental values. Local energy decomposition calculations using the DLPNO-CCSD(T) level of theory indicated the domination of electrostatic interactions' contribution to the interaction energy in all cluster systems. Furthermore, atoms in molecules and natural bond orbital calculations both carried out at the B3LYP-D3/aug-cc-pVQZ level of theory aided in visualizing the hydrogen bonds besides proving a rationale for the strength of the hydrogen bonds and thereby the stability of these cluster systems.
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The increase of antibiotic-resistant bacterial pathogens has created challenges in treatment and warranted the design of antibiotics against comparatively less exploited targets. The peptidoglycan (PG) biosynthesis delineates unique pathways for the design and development of a novel class of drugs. Mur ligases are an essential component of bacterial cell wall synthesis that play a pivotal role in PG biosynthesis to maintain internal osmotic pressure and cell shape. Inhibition of these enzymes can interrupt bacterial replication and hence, form attractive targets for drug discovery. In the present work, we focused on the PG biosynthesis pathway enzyme, UDP-N-acetylpyruvylglucosamine reductase, from Salmonella enterica serovar Typhi (stMurB). Biophysical characterization of purified StMurB was performed to gauge the molecular interactions and estimate thermodynamic stability for determination of attributes for possible therapeutic intervention. The thermal melting profile of MurB was monitored by circular dichroism and validated through differential scanning calorimetry experiment. Frequently used chemical denaturants, GdmCl and urea, were employed to study the chemical-induced denaturation of stMurB. In the search for natural compound-based inhibitors, against this important drug target, an in silico virtual screening based investigation was conducted with modeled stMurB structure. The three top hits (quercetin, berberine, and scopoletin) returned were validated for complex stability through molecular dynamics simulation. Further, fluorescence binding studies were undertaken for the selected natural compounds with stMurB alone and with NADPH bound form. The compounds scopoletin and berberine, displayed lesser binding to stMurB whereas quercetin exhibited stronger binding affinity than NADPH. This study suggests that quercetin can be evolved as an inhibitor of stMurB enzyme.
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Berberina , Salmonella typhi , NADP , Quercetina , Escopoletina , Antibacterianos/farmacologíaRESUMEN
SARS-CoV-2, the causing agent of coronavirus disease (COVID-19), first broke out in Wuhan and rapidly spread worldwide, resulting in a global health emergency. The lack of specific drugs against the coronavirus has made its spread challenging to control. The main protease (Mpro) is a key enzyme of SARS-CoV-2 used as a key target in drug discovery against the coronavirus. Medicines derived from plant phytoconstituents have been widely exploited to treat various diseases. The present study has evaluated the potential of Illicium verum (star anise) phytoconstituents against Mpro by implementing a computational approach. We performed molecular docking and molecular dynamics simulation study with a set of 60 compounds to identify their potential to inhibit the main protease (Mpro) of SARS-CoV-2. DFT study and post dynamics free energy calculations were also performed to strengthen the findings. The identified four compounds by docking study exhibited the highest potential compared to other selected phytoconstituents. Further, density functional theory (DFT) calculation, molecular dynamics simulation and post dynamics MM-GBSA energy calculation predicted Verimol-G as a potential compound, which formed stable interactions through the catalytic dyad residues. The HOMO orbital energy (-0.250038) from DFT and the post dynamics binding free energy calculation (-73.33 Kcal/mol) correlate, suggesting Verimol-G is the best inhibitor compared to the other phytoconstituents. This compound also complies with the ADME properties of drug likeliness. Thus, based on a computational study, we suggest that Verimol G may be developed as a potential inhibitor against the main protease to combat COVID-19.Communicated by Ramaswamy H. Sarma.
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Leishmania donavani is the causative agent of leishmaniasis, responsible for social and economic disruption, especially in developing countries. Lack of effective drugs with few side effects have necessitated the discovery of newer therapeutic solutions for leishmaniasis. Glycophosphatidylinositol (GPI) synthesis plays a vital role in protozoan cell membranes structural formation and antigenic modification. Hence, any disruption in its biosynthesis can prove fatal to the parasitic protozoans. N-acetylglucosamine-phosphatidylinositol de-N-acetylase (NAGP-deacetylase) is an enzyme from the GPI biosynthetic pathway that catalyzes the deacetylation of N-acetylglucosaminylphosphatidylinositol to glucosaminylphosphatidylinositol, a step essential for the proper functioning of the enzyme. In the quest for novel scaffolds as anti-leishmaniasis agents, we have executed in silico virtual screening, density function theory, molecular dynamics and MM-GBSA based energy calculations with a natural product library and a diverse library set from Chembridge database. Two compounds, 14671 and 4610, were identified at the enzyme's active site and interacted with catalytic residues, Asp43, Asp44, His41, His147, His 150, Arg80 and Arg231. Both molecules exhibited stable conformation in their protein-ligand complexes with binding free energies for compound-14671 and compound-4610 of -54 ± 4 and -50 ± 4 kcal/mol, respectively. These scaffolds can be incorporated in future synthetic determinations, focusing on developing druggable inhibitor support, increasing potency, and introducing species selectivity.Communicated by Ramaswamy H. Sarma.
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Leishmania donovani , Acetilesterasa/metabolismo , Acetilesterasa/farmacología , Fosfatidilinositoles/metabolismo , Fosfatidilinositoles/farmacología , Acetilglucosamina/metabolismo , Acetilglucosamina/farmacología , Simulación de Dinámica Molecular , Simulación del Acoplamiento MolecularRESUMEN
Background: Post burn injury contracture (PBC) neck patients pose a unique challenge for the anesthesiologists. The use of supraglottic device (SGDs) for managing such patients is being increasingly used. We compared i-gel® and LMA BlockBuster™ in PBC adult patients under general anesthesia (GA). Methods: The study included 63 subjects with mild/moderate PBC neck of either sex with American Society of Anesthesiologists Physical Status I and II under GA. Patients with intraoral pathology, mouth opening <2.5 cm, and severe contracture were excluded. Patients were randomly assigned to i-gel® (I) and BlockBuster™ (B) groups. The primary objective of the study was the time for successful insertion. First attempt success rate, oropharyngeal leak pressures (OLP), and complications were also assessed. Results: Mean insertion time was significantly less in Group I as compared to Group B (17.35 ± 1.43 vs. 21.32 ± 1.10 s; P < 0.001), OLP in Group B was significantly higher as compared to Group I (34.03 ± 1.33 vs. 25.23 ± 3.04 cm of H2O; P < 0.001). Group I was found to be statistically easier to insert as compared to Group B (P = 0.011) with reduced requirement of airway maneuvering to insert the device (P = 0.017). Groups were similar in terms of complications. Conclusion: SGDs are attractive option for airway management in mild/moderate degree of PBC neck. i-gel® having shorter insertion time with easier insertion can be favorable at times of emergency while use of LMA BlockBuster™ can be preferred to reduce the risk of aspiration owing to higher OLP.
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BACKGROUND: The genome of SARS-CoV-2, is mutating rapidly and continuously challenging the management and preventive measures adopted and recommended by healthcare agencies. The spike protein is the main antigenic site that binds to the host receptor hACE-2 and is recognised by antibodies. Hence, the mutations in this site were analysed to assess their role in differential infectivity of lineages having these mutations, rendering the characterisation of these lineages as variants of concern (VOC) and variants of interest (VOI). METHODS: In this work, we examined the genome sequence of SARS-CoV-2 VOCs and their phylogenetic relationships with the other PANGOLIN lineages. The mutational landscape of WHO characterized variants was determined and mutational diversity was compared amongst the different severity groups. We then computationally studied the structural impact of the mutations in receptor binding domain of the VOCs. The binding affinity was quantitatively determined by molecular dynamics simulations and free energy calculations. RESULTS: The mutational frequency, as well as phylogenetic distance, was maximum in the case of omicron followed by the delta variant. The maximum binding affinity was for delta variant followed by the Omicron variant. The increased binding affinity of delta strain followed by omicron as compared to other variants and wild type advocates high transmissibility and quick spread of these two variants and high severity of delta variant. CONCLUSION: This study delivers a foundation for discovering the improved binding knacks and structural features of SARS-CoV-2 variants to plan novel therapeutics and vaccine candidates against the virus.
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COVID-19 , Humanos , Filogenia , COVID-19/genética , SARS-CoV-2/genética , GenómicaRESUMEN
The immune-suppressive role of sex steroids in mammals is well documented, but information on other vertebrates is limited. The present study was planned to analyze the effect of testosterone and progesterone in the modulation of immune functions of leucocytes in a reptile, Natrix piscator. Reptiles are unique organisms and this study is novel in that it provides an insight into immune-reproductive cross-talk in a reptile. Leucocytes were isolated from peripheral blood, cultured with different concentrations of testosterone and progesterone and different immune parameters like phagocytosis, superoxide production, and nitrite release were assessed. Lymphocytes were isolated and cell-mediated immunity was assessed through proliferation responses utilizing tetrazolium salt. Concentration-dependent suppressive effects of both the steroids on immune responses were observed. A differential suppressive effect of testosterone was also observed when a lymphocyte proliferation assay was studied. Using receptor antagonists such as cyproterone acetate and mifepristone restored the immune responses of cultured cells. It was summarized that gonadal steroids mediate a direct suppressive effect on innate and cell-mediated immune responses of blood immune cells. It was concluded that when gonadal steroids are high in reproductive seasons, the immune functions are suppressed to gain optimum reproductive success.
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Annual rhythms are observed in many physiological processes and are an important approach to cope with seasonal stressors. The use of lower vertebrates as an experimental model is crucial to understand the evolution of this biological clock. This study aims to characterize the seasonal variability in the leukocyte immune responses in Channa punctatus. Leukocytes were harvested from peripheral blood and respiratory burst activity, leukocyte phagocytosis, and nitrite production were assessed to study innate immunity. Peripheral blood lymphocytes were segregated by centrifugation (density gradient) and proliferative responses of lymphocytes, in the presence of mitogens, were used to study cell-mediated immunity. Annual rhythms were validated in superoxide anion production, nitrite release and phagocytosis. Cosinor analysis revealed a differential pattern of lymphocyte proliferation which was dependent upon season and mitogen used. It was concluded that seasonal variation in immune activity might be associated with annual adaptation against diseases and the optimum immune status of seasonal breeders like fish helps them fight seasonal changes.
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Mitógenos , Nitritos , Animales , Peces , Agua Dulce , Leucocitos , Estaciones del Año , SuperóxidosRESUMEN
Nitric oxide (NO) is a multifunctional signaling molecule that plays a crucial role in synaptic transmission and neuronal function. Pioneering studies show that nitric oxide (NO) and S-nitrosylation (SNO, the NO-mediated posttranslational modification) can engender nitrosative stress in the brain, contributing to neurodegenerative diseases. Little is known, however, about the aberrant NO signaling in neurodevelopmental disorders including autism spectrum disorder (ASD). We have recently shown that the Shank3 mutation in mice representing a model of ASD causes excessive NO levels and aberrant protein SNO. The glutamatergic system is involved in ASD, specifically in SHANK3 pathology. We used SNOTRAP technology to identify the SNO-proteome in the brain of the Shank3 mutant mice to understand the role of SNO in the glutamatergic system during the development of these mice. We conducted a systems biology analysis of the SNO-proteome to investigate the biological processes and signaling pathways in the brain of juvenile and adult Shank3 mutant and wild-type mice. The Shank3 mutation caused significant SNO-enrichment of a glutamate signaling pathway in the juvenile and adult mutant mice, although different protein subsets were S-nitrosylated in both ages. Cellular compartments analysis showed that "glutamatergic Synapse" is SNO-enriched significantly in the mutant mice of both ages. We also found eight S-nitrosylated proteins involved in glutamate transmission in both ages. 38 SNO-proteins found in the mutant mice are among the high-risk SFARI gene list. Biochemical examination shows a reduction in the levels of NMDA Receptor (NR1) in the cortex and striatum of the mutant mice of both ages. Neuronal NOS knockdown in SHSY-5Y rescued NR1 levels. In conclusion, this study reveals novel SNO of key glutamatergic proteins in Shank3 mutant mice and a cross-talk between nitric oxide and the glutamatergic system.