ABSTRACT
The appropriate growth of the neurons, accurate organization of their synapses, and successful neurotransmission are indispensable for sensorimotor activities. These processes are highly dynamic and tightly regulated. Extensive genetic, molecular, physiological, and behavioral studies have identified many molecular candidates and investigated their roles in various neuromuscular processes. In this article, we show that Beadex (Bx), the Drosophila LIM only (LMO) protein, is required for motor activities and neuromuscular growth of Drosophila. The larvae bearing Bx7, a null allele of Bx, and the RNAi-mediated neuronal-specific knockdown of Bx show drastically reduced crawling behavior, a diminished synaptic span of the neuromuscular junctions (NMJs) and an increased spontaneous neuronal firing with altered motor patterns in the central pattern generators (CPGs). Microarray studies identified multiple targets of Beadex that are involved in different cellular and molecular pathways, including those associated with the cytoskeleton and mitochondria that could be responsible for the observed neuromuscular defects. With genetic interaction studies, we further show that Highwire (Hiw), a negative regulator of synaptic growth at the NMJs, negatively regulates Bx, as the latter's deficiency was able to rescue the phenotype of the Hiw null mutant, HiwDN. Thus, our data indicate that Beadex functions downstream of Hiw to regulate the larval synaptic growth and physiology.NEW & NOTEWORTHY A novel role for Beadex (Bx) regulates the larval neuromuscular junction (NMJ) structure and function in a tissue-specific manner. Bx is expressed in a subset of Toll-6-expressing neurons and is involved in regulating synaptic span and physiology, possibly through its negative interaction with Highwire (Hiw). The findings of this study provide insights into the molecular mechanisms underlying NMJ development and function and warrant further investigation to understand the role of Bx in these processes fully.
Subject(s)
Drosophila Proteins , Larva , Neuromuscular Junction , Animals , Neuromuscular Junction/physiology , Neuromuscular Junction/metabolism , Neuromuscular Junction/growth & development , Drosophila Proteins/metabolism , Drosophila Proteins/genetics , Larva/growth & development , LIM Domain Proteins/metabolism , LIM Domain Proteins/genetics , Drosophila melanogaster/growth & development , Central Pattern Generators/physiology , Central Pattern Generators/metabolism , DrosophilaABSTRACT
Acinetobacter baumannii is observed as a common species of Gram-negative bacteria that exist in soil and water. Despite being accepted as a typical component of human skin flora, it has become an important opportunistic pathogen, especially in healthcare settings. The pathogenicity of A. baumannii is attributed to its virulence factors, which include adhesins, pili, lipopolysaccharides, outer membrane proteins, iron uptake systems, autotransporter, secretion systems, phospholipases etc. These elements provide the bacterium the ability to cling to and penetrate host cells, get past the host immune system, and destroy tissue. Its infection is a major contributor to human pathophysiological conditions including pneumonia, bloodstream infections, urinary tract infections, and surgical site infections. It is challenging to treat infections brought on by this pathogen since this bacterium has evolved to withstand numerous drugs and further emergence of drug-resistant A. baumannii results in higher rates of morbidity and mortality. The long-term survival of this bacterium on surfaces of medical supplies and hospital furniture facilitates its frequent spread in humans from one habitat to another. There is a need for urgent investigations to find effective drug targets for A. baumannii as well as designing novel drugs to reduce the survival and spread of infection. In the current review, we represent the specific features, pathogenesis, and molecular intricacies of crucial drug targets of A. baumannii. This would also assist in proposing strategies and alternative therapies for the prevention and treatment of A. baumannii infections and their spread.
Subject(s)
Acinetobacter Infections , Acinetobacter baumannii , Anti-Bacterial Agents , Drug Resistance, Multiple, Bacterial , Virulence Factors , Acinetobacter baumannii/pathogenicity , Acinetobacter baumannii/drug effects , Humans , Acinetobacter Infections/drug therapy , Acinetobacter Infections/microbiology , Virulence Factors/metabolism , Anti-Bacterial Agents/therapeutic use , Anti-Bacterial Agents/pharmacology , AnimalsABSTRACT
Na+/H+ antiporters facilitate the exchange of Na+ for H+ across the cytoplasmic membrane in prokaryotic and eukaryotic cells. These transporters are crucial to maintain the homeostasis of sodium ions, consequently pH, and volume of the cells. Therefore, sodium/proton antiporters are considered promising therapeutic targets in humans. The Na+/H+ antiporter in Escherichia coli (Ec-NhaA), a prototype of cation-proton antiporter (CPA) family, transports two protons and one sodium (or Li+) in opposite direction. Previous mutagenesis experiments on Ec-NhaA have proposed Asp164, Asp163, and Asp133 amino acids with the significant implication in functional and structural integrity and create site for ion-binding. However, the mechanism and the sites for the binding of the two protons remain unknown and controversial which could be critical for pH regulation. In this study, we have explored the role of Glu78 in the regulation of pH by Ec-NhaA. Although we have created various mutants, E78C has shown a considerable effect on the stoichiometry of NhaA and presented comparable phenotypes. The ITC experiment has shown the binding of ~ 5 protons in response to the transport of one lithium ion. The phenotype analysis on selective medium showed a significant expression compared to WT Ec-NhaA. This represents the importance of Glu78 in transporting the H+ across the membrane where a single mutation with Cys amino acid alters the number of H+ significantly maintaining the activity of the protein.
Subject(s)
Escherichia coli Proteins , Escherichia coli , Glutamic Acid , Mutagenesis, Site-Directed , Sodium-Hydrogen Exchangers , Escherichia coli Proteins/genetics , Escherichia coli Proteins/chemistry , Escherichia coli Proteins/metabolism , Glutamic Acid/metabolism , Glutamic Acid/chemistry , Sodium-Hydrogen Exchangers/genetics , Sodium-Hydrogen Exchangers/chemistry , Sodium-Hydrogen Exchangers/metabolism , Escherichia coli/genetics , Escherichia coli/metabolism , Hydrogen-Ion Concentration , Ion Exchange , Models, MolecularABSTRACT
We study the influence of confinement on the dynamics of translocation of a linear polymer chain in a good solvent through a cone-shaped pore. Using the Langevin dynamics simulations, we calculate both the first attempt time and translocation time as a function of the position of the back wall and apex angle α. As the in vivo confining environment is inherently dynamic, we extended the present study to explore the consequences of a periodically driven back wall and apex angles on the translocation dynamics. Our findings reveal that the translocation time initially decreases as the driving frequency increases, but increases after a certain frequency. The frequency at which the translocation time is found to be minimum is referred to as the resonance activation. Analyzing the distribution of translocation times around this frequency renders interesting information about the translocation process. We further explore the translocation dynamics by calculating the residence time of individual monomers, shedding light on the microscopic aspects of the process.
ABSTRACT
By 24th Sep. 2021, there are more than 229 million COVID-19 cases worldwide, the researchers are tirelessly working to discover and develop an efficient drug molecule against this devastative viral infection. This study aims to evaluate the inhibitory efficiency of the organic acids and phenolic compounds present in Brassica oleracea (Tronchuda Cabbage) against spike glycoprotein in SARS-CoV-2. Thirty-seven phytocompounds are screened on the basis of their molecular weight (<500 g/mol) and 14 ligands are docked using Autodock Vina and Autodock4 (version 4.2.6). The stability of the top five docked complexes was analyzed using classical molecular dynamics (MD) simulation. ADMET analysis is performed for the top five compounds and their targets are identified using SwissTargetPrediction. Phytoactives from B. oleracea namely Astragalin, 3-p-coumaroylquinic acid, 4-p-coumaroylquinic acid and sinapoyl-D-glucoside showed high binding affinities and free energy of binding during molecular docking and MD simulation studies (â¼ 8.5-9.0 kcal/mol) for the spike glycoprotein trimer of SARS-CoV2. The ADMET analysis revealed that these phytocompounds have good solubility in the aqueous phase and that they don't penetrate the blood brain barrier. Moreover, there is no P-gp substrate inhibition, CYP1A2 inhibition, CYP2C19 inhibition, CYP2C9 inhibition, CYP2D6 inhibition and CYP3A4 inhibition observed for these compounds. Additionally, zero PAINS alerts were reported. These findings from molecular docking and MD simulation studies suggest that astragalin and coumaroylquinic acids from Tronchuda cabbage possess potential inhibitory capacity against spike glycoprotein trimer of SARS-CoV-2 and could be further taken up as lead targets for drug discovery.
ABSTRACT
Much of the research on Na+/H+ exchange has been done in prokaryotic models, mainly on the NhaA Na+/H+-exchanger from Escherichia coli (EcNhaA). Two conserved aspartate residues, Asp-163 and Asp-164, are essential for transport and are candidates for possible binding sites for the two H+ that are exchanged for one Na+ to make the overall transport process electrogenic. More recently, a proposed mechanism of transport for EcNhaA has suggested direct binding of one of the transported H+ to the conserved Lys-300 residue, a salt bridge partner of Asp-163. This contention is supported by a study reporting that substitution of the equivalent residue, Lys-305, of a related Na+/H+ antiporter, NapA from Thermus thermophilus, renders the transporter electroneutral. In this work, we sought to establish whether the Lys-300 residue and its partner Asp-163 are essential for the electrogenicity of EcNhaA. To that end, we replaced Lys-300 with Gln, either alone or together with the simultaneous substitution of Asp-163 with Asn, and characterized these transporter variants in electrophysiological experiments combined with H+ transport measurements and stability analysis. We found that K300Q EcNhaA can still support electrogenic Na+/H+ antiport in EcNhaA, but has reduced thermal stability. A parallel electrophysiological investigation of the K305Q variant of TtNapA revealed that it is also electrogenic. Furthermore, replacement of both salt bridge partners in the ion-binding site of EcNhaA produced an electrogenic variant (D163N/K300Q). Our findings indicate that alternative mechanisms sustain EcNhaA activity in the absence of canonical ion-binding residues and that the conserved lysines confer structural stability.
Subject(s)
Escherichia coli Proteins/metabolism , Escherichia coli/metabolism , Sodium-Hydrogen Exchangers/metabolism , Amino Acid Substitution , Escherichia coli/genetics , Escherichia coli Proteins/genetics , Glutamine , Ion Transport/physiology , Lysine , Mutation, Missense , Protein Stability , Sodium-Hydrogen Exchangers/geneticsABSTRACT
The mechanisms underlying synaptic differentiation, which involves neuronal membrane and cytoskeletal remodeling, are not completely understood. We performed a targeted RNAi-mediated screen of Drosophila BAR-domain proteins and identified islet cell autoantigen 69â kDa (ICA69) as one of the key regulators of morphological differentiation of the larval neuromuscular junction (NMJ). We show that Drosophila ICA69 colocalizes with α-Spectrin at the NMJ. The conserved N-BAR domain of ICA69 deforms liposomes in vitro Full-length ICA69 and the ICAC but not the N-BAR domain of ICA69 induce filopodia in cultured cells. Consistent with its cytoskeleton regulatory role, ICA69 mutants show reduced α-Spectrin immunoreactivity at the larval NMJ. Manipulating levels of ICA69 or its interactor PICK1 alters the synaptic level of ionotropic glutamate receptors (iGluRs). Moreover, reducing PICK1 or Rab2 levels phenocopies ICA69 mutation. Interestingly, Rab2 regulates not only synaptic iGluR but also ICA69 levels. Thus, our data suggest that: (1) ICA69 regulates NMJ organization through a pathway that involves PICK1 and Rab2, and (2) Rab2 functions genetically upstream of ICA69 and regulates NMJ organization and targeting/retention of iGluRs by regulating ICA69 levels.
Subject(s)
Autoantigens/metabolism , Drosophila Proteins/metabolism , Drosophila melanogaster/metabolism , Neuromuscular Junction/metabolism , rab2 GTP-Binding Protein/metabolism , Animals , Cells, Cultured , Gene Knockdown Techniques , Larva/metabolism , Liposomes , Mutation/genetics , Protein Subunits/metabolism , Protein Transport , Pseudopodia/metabolism , RNA Interference , Receptors, Ionotropic Glutamate/metabolism , Synapses/metabolismABSTRACT
Na+/H+ antiporters are located in the cytoplasmic and intracellular membranes and play crucial roles in regulating intracellular pH, Na+, and volume. The NhaA antiporter of Escherichia coli is the best studied member of the Na+/H+ exchanger family and a model system for all related Na+/H+ exchangers, including eukaryotic representatives. Several amino acid residues are important for the transport activity of NhaA, including Lys-300, a residue that has recently been proposed to carry one of the two H+ ions that NhaA exchanges for one Na+ ion during one transport cycle. Here, we sought to characterize the effects of mutating Lys-300 of NhaA to amino acid residues containing side chains of different polarity and length (i.e. Ala, Arg, Cys, His, Glu, and Leu) on transporter stability and function. Salt resistance assays, acridine-orange fluorescence dequenching, solid supported membrane-based electrophysiology, and differential scanning fluorometry were used to characterize Na+ and H+ transport, charge translocation, and thermal stability of the different variants. These studies revealed that NhaA could still perform electrogenic Na+/H+ exchange even in the absence of a protonatable residue at the Lys-300 position. However, all mutants displayed lower thermal stability and reduced ion transport activity compared with the wild-type enzyme, indicating the critical importance of Lys-300 for optimal NhaA structural stability and function. On the basis of these experimental data, we propose a tentative mechanism integrating the functional and structural role of Lys-300.
Subject(s)
Escherichia coli Proteins/metabolism , Escherichia coli/metabolism , Lysine/chemistry , Sodium-Hydrogen Exchangers/metabolism , Biological Transport , Biological Transport, Active , Crystallography, X-Ray , Fluorometry , Hydrogen-Ion Concentration , Mutagenesis, Site-Directed , Mutation , Phenotype , Protein Structure, Secondary , Protein Transport , Spectrometry, FluorescenceABSTRACT
BACKGROUND: Coats plus syndrome is an autosomal recessive, pleiotropic, multisystem disorder characterized by retinal telangiectasia and exudates, intracranial calcification with leukoencephalopathy and brain cysts, osteopenia with predisposition to fractures, bone marrow suppression, gastrointestinal bleeding and portal hypertension. It is caused by compound heterozygous mutations in the CTC1 gene. CASE PRESENTATION: We encountered a case of an eight-year old boy from an Indian family with manifestations of Coats plus syndrome along with an unusual occurrence of dextrocardia and situs inversus. Targeted resequencing of the CTC1 gene as well as whole exome sequencing (WES) were conducted in this family to identify the causal variations. The identified candidate variations were screened in ethnicity matched healthy controls. The effect of CTC1 variation on telomere length was assessed using Southern blot. A novel homozygous missense mutation c.1451A > C (p.H484P) in exon 9 of the CTC1 gene and a rare 3'UTR known dbSNP variation (c.*556 T > C) in HES7 were identified as the plausible candidates associated with this complex phenotype of Coats plus and dextrocardia. This CTC1 variation was absent in the controls and we also observed a reduced telomere length in the affected individual's DNA, suggesting its likely pathogenic nature. The reported p.H484P mutation is located in the N-terminal 700 amino acid regionthat is important for the binding of CTC1 to ssDNA through its two OB domains. WES data also showed a rare homozygous missense variation in the TEK gene in the affected individual. Both HES7 and TEK are targets of the Notch signaling pathway. CONCLUSIONS: This is the first report of a genetically confirmed case of Coats plus syndrome from India. By means of WES, the genetic variations in this family with unique and rare complex phenotype could be traced effectively. We speculate the important role of Notch signaling in this complex phenotypic presentation of Coats plus syndrome and dextrocardia. The present finding will be useful for genetic diagnosis and carrier detection in the family and for other patients with similar disease manifestations.
Subject(s)
Ataxia/genetics , Basic Helix-Loop-Helix Transcription Factors/genetics , Brain Neoplasms/genetics , Calcinosis/genetics , Central Nervous System Cysts/genetics , Dextrocardia/complications , Exome/genetics , Leukoencephalopathies/genetics , Muscle Spasticity/genetics , Mutation, Missense , Retinal Diseases/genetics , Seizures/genetics , Sequence Analysis, DNA , Telomere-Binding Proteins/genetics , Animals , Ataxia/complications , Ataxia/pathology , Base Sequence , Brain Neoplasms/complications , Brain Neoplasms/pathology , Calcinosis/complications , Calcinosis/pathology , Central Nervous System Cysts/complications , Central Nervous System Cysts/pathology , Child , Genomics , Homozygote , Humans , India , Leukoencephalopathies/complications , Leukoencephalopathies/pathology , Male , Muscle Spasticity/complications , Muscle Spasticity/pathology , Pedigree , Phenotype , Receptors, Notch/metabolism , Retinal Diseases/complications , Retinal Diseases/pathology , Seizures/complications , Seizures/pathology , Signal Transduction , Telomere/geneticsABSTRACT
We investigate the influence of varying confinement on the dynamics of polymer translocation through a cone-shaped channel. For this, a linear polymer chain is modeled using self-avoiding walks on a square lattice. The cis side of a cone-shaped channel has a finite volume, while the trans side has a semi-infinite space. The confining environment is varied either by changing the position of the back wall while keeping the apex angle fixed or altering the apex angle while keeping the position of the back wall fixed. In both cases, the effective space Ï, which represents the number of monomers in a chain relative to the total number of accessible sites within the cone, is reduced due to the imposed confinement. Consequently, the translocation dynamics are affected. We analyze the entropy of the confined system as a function of Ï, which exhibits nonmonotonic behavior. We also calculate the free energy associated with the confinement as a function of a virtual coordinate for different positions of the back wall (base of the cone) along the conical axis for various apex angles. Employing the Fokker-Planck equation, we calculate the translocation time as a function of Ï for different solvent conditions across the channel. Our findings indicate that the translocation time decreases as Ï increases, but it eventually reaches a saturation point at a certain value of Ï. Moreover, we highlight the possibility of controlling the translocation dynamics by manipulating the solvent quality across the channel. Furthermore, our investigation delves into the intricacies of polymer translocation through a cone-shaped channel, considering both repulsive and neutral interactions with the channel wall. This exploration unveils nuanced dynamics and sheds light on the factors that significantly impact translocation within confined channels.
ABSTRACT
OBJECTIVE: DNA repair genes and their variants have been found to alter the risk of oral cancer. METHOD: The level of expression of XRCC3, NBS1, and OGG1 genes among 20 cases of oral cancer, 6 pre-oral cancer, and 50 healthy control subjects was measured with RT-PCR. All the subjects were also genotyped for XRCC3 rs861539 C>T, NBS1 rs1805794 C>G, and OGG1 rs1052133 C>G polymorphisms by the PCR-RFLP method; their genotypes were correlated with their level of expression. Further, a localized fold structure analysis of the mRNA sequence surrounding the studied SNPs was performed with RNAfold. RESULTS: Results showed increased expression of XRCC3, NBS1, and OGG1 transcripts among oral cancer (4.49 fold, 3.45 fold, and 3.27 fold) as well as pre-oral cancer (3.04 fold, 5.32 fold, and 1.74 fold) as compared to control subjects. The transcript level of OGG1 was found to be significantly increased (6.68 fold, p-value 0.009) with the GG genotype compared to the CC genotype. The C>T polymorphism of XRCC3 and the C>G polymorphism of OGG1 result in an apparent change in its mRNA secondary structure. Folding energy with the C allele for XRCC3 C>T polymorphism was lower than that of the T allele (MFE C vs T: -50.20 kcal/mol vs -48.70 kcal/mol). In the case of OGG1 C>G polymorphism MFE for the C allele was higher (-23.30 kcal/mole) than with the G allele (-24.80 kcal/mol). CONCLUSION: Our results showed elevated levels of XRCC3, NBS1, and OGG1 both in oral cancer and pre-oral cancer conditions, which indicates their role as prospective biomarkers of oral cancer and pre-cancerous lesions. SNPs in these genes alter their level of expression, possibly by altering the secondary structure of their transcript. However, due to the small sample size our study can only provide a suggestive conclusion and warned future study with large sample size to verify our findings.
Subject(s)
Biomarkers, Tumor , Cell Cycle Proteins , DNA Glycosylases , DNA Repair , DNA-Binding Proteins , Mouth Neoplasms , Nuclear Proteins , Polymorphism, Single Nucleotide , Humans , Mouth Neoplasms/genetics , Mouth Neoplasms/pathology , DNA Glycosylases/genetics , Biomarkers, Tumor/genetics , Male , DNA Repair/genetics , Case-Control Studies , Middle Aged , DNA-Binding Proteins/genetics , Female , Nuclear Proteins/genetics , Cell Cycle Proteins/genetics , Genotype , Carcinoma, Squamous Cell/genetics , Carcinoma, Squamous Cell/pathology , Adult , RNA, Messenger/genetics , Genetic Predisposition to DiseaseABSTRACT
Cancer has a devastating impact globally regardless of gender, age, and community, which continues its severity to the population due to the lack of efficient strategy for the cancer diagnosis and treatment. According to the World Health Organisation report, one out of six people dies due to this deadly cancer and we need effective strategies to regulate it. In this context, trace element has a very hidden and unexplored role and require more attention from investigators. The variation in concentration of trace elements was observed during comparative studies on a cancer patient and a healthy person making them an effective target for cancer regulation. The percentage of trace elements present in the human body depends on environmental exposure, food habits, and habitats and could be instrumental in the early diagnosis of cancer. In this review, we have conducted inclusive analytics on trace elements associated with the various types of cancers and explored the several methods involved in their analysis. Further, intricacies in the correlation of trace elements with prominent cancers like prostate cancer, breast cancer, and leukaemia are represented in this review. This comprehensive information on trace elements proposes their role during cancer and as biomarkers in cancer diagnosis.
Subject(s)
Breast Neoplasms , Prostatic Neoplasms , Trace Elements , Male , Humans , Trace Elements/analysis , Environmental Exposure/analysis , BiomarkersABSTRACT
Gallbladder cancer (GBC) is an uncommon condition in which malignant (cancer) cells are detected in gallbladder tissue. Cancer is often triggered when normal cells turn malignant and begin to spread. Cancer can also be caused by genetic anomalies that result in uncontrolled cell proliferation and tumor development. MicroRNAs (also known as miRNAs or miRs) are a group of small, endogenous, non-coding RNAs of 19-23 nucleotides in length, which play a key role in post-transcriptional gene regulation. These miRNAs serve as negative gene regulators by supervising target genes and regulating biological processes, including cell proliferation, migration, invasion, and apoptosis. Cancer development and progression relate to aberrant miRNA expression. This review demonstrated the implication of various genetic factors and microRNAs in developing and regulating GBC. This suggests the potential of genes and RNAs as the diagnostic, prognostic, and therapeutic targets in gallbladder cancer.
Subject(s)
Gallbladder Neoplasms , Gene Expression Regulation, Neoplastic , MicroRNAs , Gallbladder Neoplasms/genetics , Gallbladder Neoplasms/pathology , Humans , MicroRNAs/genetics , Cell Proliferation/genetics , Animals , Apoptosis/genetics , Molecular Targeted Therapy , Biomarkers, Tumor/geneticsABSTRACT
Infectious disorders known as Neglected Tropical Diseases (NTDs) initially affect the world's underprivileged citizens. They have been disregarded for many years, first as a result of a general indifference to such a developing world and, more recently, as an outcome of the intense attention on AIDS, TB, and malaria. Tropical diseases mostly affect the region where health and hygiene are sacrificed, and most of the population lacks access to sufficient food and living resources. WHO has drafted and released the directions for regulation, pre-vention, and successful eradication of NTDs as per the revised roadmap of 2021-2030. This shifts from vertical disease programs to integrated cross-cutting methods. In the current work, we have provided comprehensive information on various aspects of neglected tropical dis-eases, including the clinical management of NTDs. This encompasses the causative agent of the diseases, their symptoms, pathogenesis, diagnosis, treatment, prognosis, and epidemio-logical perspective of major NTDs. This review will shed light on several perspectives of NTDs having influential roles in proposing strategies to control and treat them around the world.
ABSTRACT
Alzheimer's disease (AD) affects millions of people worldwide and is a gradually worsening neurodegenerative condition. The accumulation of abnormal proteins, such as tau and beta-amyloid, in the brain is a hallmark of AD pathology. 14-3-3 proteins have been implicated in AD pathology in several ways. One proposed mechanism is that 14-3-3 proteins interact with tau protein and modulate its phosphorylation, aggregation, and toxicity. Tau is a protein associated with microtubules, playing a role in maintaining the structural integrity of neuronal cytoskeleton. However, in the context of Alzheimer's disease (AD), an abnormal increase in its phosphorylation occurs. This leads to the aggregation of tau into neurofibrillary tangles, which is a distinctive feature of this condition. Studies have shown that 14-3-3 proteins can bind to phosphorylated tau and regulate its function and stability. In addition, 14-3-3 proteins have been shown to interact with beta-amyloid (Aß), the primary component of amyloid plaques in AD. 14-3-3 proteins can regulate the clearance of Aß through the lysosomal degradation pathway by interacting with the lysosomal membrane protein LAMP2A. Dysfunction of lysosomal degradation pathway is thought to contribute to the accumulation of Aß in the brain and the progression of AD. Furthermore, 14-3-3 proteins have been found to be downregulated in the brains of AD patients, suggesting that their dysregulation may contribute to AD pathology. For example, decreased levels of 14-3-3 proteins in cerebrospinal fluid have been suggested as a biomarker for AD. Overall, these findings suggest that 14-3-3 proteins may play an important role in AD pathology and may represent a potential therapeutic target for the disease. However, further research is needed to fully understand the mechanisms underlying the involvement of 14-3-3 proteins in AD and to explore their potential as a therapeutic target.
ABSTRACT
Mosquitoes are important vectors for the transmission of several infectious diseases that lead to huge morbidity and mortality. The exhaustive use of synthetic insecticides has led to widespread resistance and environmental pollution. Using essential oils and nano-emulsions as novel insecticides is a promising alternative approach for controlling vector borne diseases. In the current study, Lantana camara EO and NE were evaluated for their larvicidal and pupicidal activities against Anopheles culicifacies. The inhibitory effect of EO and NE on AChE, NSE (α/ß), and GST was also evaluated and compared. GC-MS analysis of oil displayed 61 major peaks. The stable nano-emulsion with an observed hydrodynamic diameter of 147.62 nm was formed using the o/w method. The nano-emulsion exhibited good larvicidal (LC50 50.35 ppm and LC90 222.84 ppm) and pupicidal (LC50 54.82 ppm and LC90 174.58 ppm) activities. Biochemical evaluations revealed that LCEO and LCNE inhibited AChE, NSE (α/ß), and GST, displaying LCNE to be a potent binder to AChE and NSE enzyme, whereas LCEO showed higher binding potency towards GST. The nano-emulsion provides us with novel opportunities to target different mosquito enzymes with improved insecticidal efficacy. Due to its natural origin, it can be further developed as a safer and more potent larvicide/insecticide capable of combating emerging insecticide resistance.
Subject(s)
Anopheles , Emulsions , Insecticides , Lantana , Larva , Oils, Volatile , Anopheles/drug effects , Oils, Volatile/pharmacology , Oils, Volatile/chemistry , Animals , Lantana/chemistry , Insecticides/pharmacology , Insecticides/chemistry , Larva/drug effects , Kinetics , Acetylcholinesterase/metabolism , Glutathione Transferase/metabolism , Glutathione Transferase/antagonists & inhibitors , Mosquito Vectors/drug effects , Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/chemistry , Mosquito Control/methodsABSTRACT
Axotomized spinal motoneurons (MNs) lose presynaptic inputs following peripheral nerve injury; however, the cellular mechanisms that lead to this form of synapse loss are currently unknown. Here, we delineate a critical role for neuronal kinase dual leucine zipper kinase (DLK)/MAP3K12, which becomes activated in axotomized neurons. Studies with conditional knockout mice indicate that DLK signaling activation in injured MNs triggers the induction of phagocytic microglia and synapse loss. Aspects of the DLK-regulated response include expression of C1q first from the axotomized MN and then later in surrounding microglia, which subsequently phagocytose presynaptic components of upstream synapses. Pharmacological ablation of microglia inhibits the loss of cholinergic C boutons from axotomized MNs. Together, the observations implicate a neuronal mechanism, governed by the DLK, in the induction of inflammation and the removal of synapses.
Subject(s)
Motor Neurons , Synapses , Animals , Mice , Signal Transduction , Complement Activation , Presynaptic Terminals , Mice, KnockoutABSTRACT
Sodium, potassium, and protons are the most important ions for life on earth, and their homeostasis is crucially needed for the survival of cells. The biological cells have developed a system that regulates and maintains the integrity of the cells by facilitating the exchange of these ions. These systems include the specific type of ion transporter membrane proteins such as cation-proton antiporters. Cation proton antiporters induce the active transport of cations like Na+, K+ or Ca+ across the cell membrane in exchange for protons (H+) and make the organism able to survive in alkaline conditions, high or fluctuating pH, stressed temperature or osmolarity. The secondary transporter proteins exploit the properties of various specific structural components to carry out efficient active transport. Ec-NhaA crystal structure was resolved at acidic pH at which the protein is downregulated, which discloses the presence of 12 transmembrane (TM) helices. This structural fold, the "NhaA fold," is speculated to contribute to the cation-binding site and conformational alterations during transport in various antiporters. Irrespective of the variation in the composition of amino acids and lengths of proteins, several other members of the CPA family, such as NmABST, PaNhaP, and MjNhaP1, share the common structural features of the Ec-NhaA. The present review elucidates the existence of CPAs throughout all the kingdoms and the structural intercorrelation with their function. The interplay in the structurefunction of membrane transporter protein may be implemented to explore the plethora of biological events such as conformation, folding, ion binding and translocation etc.
Subject(s)
Antiporters , Escherichia coli Proteins , Antiporters/genetics , Antiporters/metabolism , Protons , Escherichia coli Proteins/metabolism , Escherichia coli/metabolism , Sodium-Hydrogen Exchangers/chemistry , Hydrogen-Ion Concentration , Cations/metabolismABSTRACT
Mycobacterium tuberculosis (MTB) causes one of the ancient diseases, Tuberculosis, affects people around the globe and its severity can be understood by its classification as a second infectious disease after COVID-19 and the 13th leading cause of death according to a WHO report. Despite having advanced diagnostic approaches and therapeutic strategies, unfortunately, TB is still spreading across the population due to the emergence of drug-resistance MTB and Latent TB infection (LTBI). We are seeking for effective approaches to overcome these hindrances and efficient treatment for this perilous disease. Therefore, there is an urgent need to develop drugs based on operative targeting of the bacterial system that could result in both efficient treatment and lesser emergence of MDR-TB. One such promising target could be the secretory systems and especially the Type 7 secretory system (T7SS-ESX) of Mycobacterium tuberculosis, which is crucial for the secretion of effector proteins as well as in establishing host-pathogen interactions of the tubercle bacilli. The five paralogous ESX systems (ESX-1 to EXS-5) have been observed by in silico genome analysis of MTB, among which ESX-1 and ESX-5 are substantial for virulence and mediating host cellular inflammasome. The bacterium growth and virulence can be modulated by targeting the T7SS. In the present review, we demonstrate the current status of therapeutics against MTB and focus on the function and cruciality of T7SS along with other secretory systems as a promising therapeutic target against Tuberculosis.