The most common form of senile dementia is Alzheimer's disease (AD), which is characterized by the extracellular deposition of amyloid β-peptide (Aβ) plaques and the intracellular formation of ...neurofibrillary tangles (NFTs) in the cerebral cortex. Tau abnormalities are commonly observed in many neurodegenerative diseases including AD, Parkinson's disease, and Pick's disease. Interestingly, tau-mediated formation of NFTs in AD brains shows better correlation with cognitive impairment than Aβ plaque accumulation; pathological tau alone is sufficient to elicit frontotemporal dementia, but it does not cause AD. A growing amount of evidence suggests that soluble Aβ oligomers in concert with hyperphosphorylated tau (pTau) serve as the major pathogenic drivers of neurodegeneration in AD. Increased Aβ oligomers trigger neuronal dysfunction and network alternations in learning and memory circuitry prior to clinical onset of AD, leading to cognitive decline. Furthermore, accumulated damage to mitochondria in the course of aging, which is the best-known nongenetic risk factor for AD, may collaborate with soluble Aβ and pTau to induce synapse loss and cognitive impairment in AD. In this review, I summarize and discuss the current knowledge of the molecular and cellular biology of AD and also the mechanisms that underlie Aβ-mediated neurodegeneration.
Hox genes have been implicated in the evolution of many animal body patterns, but the molecular events underlying trait modification have not been elucidated. Pigmentation of the posterior male ...abdomen is a recently acquired trait in the
Drosophila melanogaster lineage. Here, we show that the Abdominal-B (ABD-B) Hox protein directly activates expression of the
yellow pigmentation gene in posterior segments. ABD-B regulation of pigmentation evolved through the gain of ABD-B binding sites in a specific
cis-regulatory element of the
yellow gene of a common ancestor of sexually dimorphic species. Within the
melanogaster species group, male-specific pigmentation has subsequently been lost by at least three different mechanisms, including the mutational inactivation of a key ABD-B binding site in one lineage. These results demonstrate how Hox regulation of traits and target genes is gained and lost at the species level and have general implications for the evolution of body form at higher taxonomic levels.
Nitric oxide (NO) serves as an evolutionarily conserved signaling molecule that plays an important role in a wide variety of cellular processes. Extensive studies in Drosophila melanogaster have ...revealed that NO signaling is required for development, physiology, and stress responses in many different types of cells. In neuronal cells, multiple NO signaling pathways appear to operate in different combinations to regulate learning and memory formation, synaptic transmission, selective synaptic connections, axon degeneration, and axon regrowth. During organ development, elevated NO signaling suppresses cell cycle progression, whereas downregulated NO leads to an increase in larval body size via modulation of hormone signaling. The most striking feature of the Drosophila NO synthase is that various stressors, such as neuropeptides, aberrant proteins, hypoxia, bacterial infection, and mechanical injury, can activate Drosophila NO synthase, initially regulating cellular physiology to enable cells to survive. However, under severe stress or pathophysiological conditions, high levels of NO promote regulated cell death and the development of neurodegenerative diseases. In this review, I highlight and discuss the current understanding of molecular mechanisms by which NO signaling regulates distinct cellular functions and behaviors.
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•Nitric oxide (NO) serves as a multifunctional signaling molecule within and between cells in Drosophila.•The Drosophila NO synthase produces NO in response to various types of stressors including aberrant proteins and hypoxia.•The combinatorial control by multiple NO signaling pathways seems to regulate diverse cellular processes in Drosophila.•NO signaling in Drosophila plays a protective or destructive role in various stress conditions.
Nitric oxide (NO) serves as an evolutionarily conserved signaling molecule that plays an important role in a wide variety of cellular processes. Extensive studies in Drosophila melanogaster have ...revealed that NO signaling is required for development, physiology, and stress responses in many different types of cells. In neuronal cells, multiple NO signaling pathways appear to operate in different combinations to regulate learning and memory formation, synaptic transmission, selective synaptic connections, axon degeneration, and axon regrowth. During organ development, elevated NO signaling suppresses cell cycle progression, whereas downregulated NO leads to an increase in larval body size via modulation of hormone signaling. The most striking feature of the Drosophila NO synthase is that various stressors, such as neuropeptides, aberrant proteins, hypoxia, bacterial infection, and mechanical injury, can activate Drosophila NO synthase, initially regulating cellular physiology to enable cells to survive. However, under severe stress or pathophysiological conditions, high levels of NO promote regulated cell death and the development of neurodegenerative diseases. In this review, I highlight and discuss the current understanding of molecular mechanisms by which NO signaling regulates distinct cellular functions and behaviors.
Understanding the mechanisms underlying the morphological divergence of species is one of the central goals of evolutionary biology. Here, we analyze the genetic and molecular bases of the divergence ...of body pigmentation patterns between
Drosophila yakuba and its sister species
Drosophila santomea. We found that loss of pigmentation in
D. santomea involved the selective loss of expression of the
tan and
yellow pigmentation genes. We demonstrate that
tan gene expression was eliminated through the mutational inactivation of one specific
tan cis-regulatory element (CRE) whereas the Tan protein sequence remained unchanged. Surprisingly, we identify three independent loss-of-function alleles of the
tan CRE in the young
D. santomea lineage. We submit that there is sufficient empirical evidence to support the general prediction that functional evolutionary changes at pleiotropic loci will most often involve mutations in their discrete, modular
cis-regulatory elements.
Chloroquine, an amino quinolone derivative commonly used as an anti-malarial drug, is known to impart an unpleasant taste. Little research has been done to study chloroquine taste in insects, ...therefore, we examined both the deterrant properties and mechanisms underlying chloroquine perception in fruit flies. We identified the antifeedant effect of chloroquine by screening 21 gustatory receptor (Grs) mutants through behavioral feeding assays and electrophysiology experiments. We discovered that two molecular sensors, GR22e and GR33a, act as chloroquine receptors, and found that chloroquine-mediated activation of GRNs occurs through S-type sensilla. At the same time, we successfully recapitulated the chloroquine receptor by expressing GR22e in ectopic gustatory receptor neurons. We also found that GR22e forms a part of the strychnine receptor. We suggest that the Drosophila strychnine receptor might have a very complex structure since five different GRs are required for strychnine-induced action potentials.
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•Chloroquine is a potent anti-feedant at the range of 0.1–10 mM.•GR22e and GR33a are required for chloroquine avoidance behavior.•GR22e is also required for strychnine sensation.•GR22e is essential for recapitulating a chloroquine receptor as well as a strychnine receptor.
This study aims to investigate the potential analgesic properties of the crude extract of
leaves using in vivo experiments and in silico analysis. The extract, in a dose-dependent manner, exhibited a ...moderate analgesic property (~54% pain inhibition in acetic acid-induced writhing test), which is significant (**
< 0.001) as compared to the control group. The complex inflammatory mechanism involves diverse pathways and they are inter-connected. Therefore, multiple inflammatory modulator proteins were selected as the target for in silico analysis. Computational analysis suggests that all the selected targets had different degrees of interaction with the phytochemicals from the extract. Rutin (RU), protocatechuic acid (PA), vanillic acid (VA), and ferulic acid (FA) could regulate multiple targets with a robust efficiency. None of the compounds showed selectivity to Cyclooxygenase-2 (COX-2). However, regulation of COX and lipoxygenase (LOX) cascade by PA can reduce non-steroidal analgesic drugs (NSAIDs)-related side effects, including asthma. RU showed robust regulation of cytokine-mediated pathways like RAS/MAPK and PI3K/NF-kB by inhibition of EGFR and IKBα (IKK), which may prevent multi-organ failure due to cytokine storm in several microbial infections, for example, SARS-CoV-2. Further investigation, using in vivo and in vitro experiments, can be conducted to develop multi-target anti-inflammatory drugs using the isolated compounds from the extract.
The blood–brain barrier (BBB) exhibits a highly selective permeability to support the homeostasis of the central nervous system (CNS). The tight junctions in the BBB microvascular endothelial cells ...seal the paracellular space to prevent diffusion. Thus, disruption of tight junctions results in harmful effects in CNS diseases and injuries. It has recently been demonstrated that glucocorticoids have beneficial effects on maintaining tight junctions in both in vitro cell and in vivo animal models. In the present study, we found that dexamethasone suppresses the expression of JMJD3, a histone H3K27 demethylase, via the recruitment of glucocorticoid receptor α (GRα) and nuclear receptor co-repressor (N-CoR) to the negative glucocorticoid response element (nGRE) in the upstream region of JMJD3 gene in brain microvascular endothelial cells subjected to TNFα treatment. The decreased JMJD3 gene expression resulted in the suppression of MMP-2, MMP-3, and MMP-9 gene activation. Dexamethasone also activated the expression of the claudin 5 and occludin genes. Collectively, dexamethasone attenuated the disruption of the tight junctions in the brain microvascular endothelial cells subjected to TNFα treatment. Therefore, glucocorticoids may help to preserve the integrity of the tight junctions in the BBB via transcriptional and post-translational regulation following CNS diseases and injuries.
Transmembrane semaphorins (Semas) serve evolutionarily conserved guidance roles, and some function as both ligands and receptors. However, the molecular mechanisms underlying the transduction of ...these signals to the cytoskeleton remain largely unknown. We have identified two direct regulators of Rho family small GTPases, pebble (a Rho guanine nucleotide exchange factor GEF) and RhoGAPp190 (a GTPase activating protein GAP), that show robust interactions with the cytoplasmic domain of the Drosophila Sema-1a protein. Neuronal pebble and RhoGAPp190 are required to control motor axon defasciculation at specific pathway choice points and also for target recognition during Drosophila neuromuscular development. Sema-1a-mediated motor axon defasciculation is promoted by pebble and inhibited by RhoGAPp190. Genetic analyses show that opposing pebble and RhoGAPp190 functions mediate Sema-1a reverse signaling through the regulation of Rho1 activity. Therefore, pebble and RhoGAPp190 transduce transmembrane semaphorin-mediated guidance cue information that regulates the establishment of neuronal connectivity during Drosophila development.
► Sema-1a reverse signaling is required for motor axon guidance ► Neuronal pebble and RhoGAPp190 control motor axon defasciculation ► Sema-1a reverse signaling is regulated by opposing pebble and RhoGAPp190 functions ► Pebble and RhoGAPp190 directly couple Sema-1a to neuronal cytoskeletal dynamics
Signal transduction events downstream of guidance cue receptors facilitate neural circuit elaboration. Jeong et al. find in Drosophila that opposing functions of two RhoGTPase activity regulators, pebble and RhoGAPp190, mediate transmembrane Sema-1a reverse signaling to establish motor neuron connectivity.
Decoding the molecular mechanisms underlying axon guidance is key to precise understanding of how complex neural circuits form during neural development. Although substantial progress has been made ...over the last three decades in identifying numerous axon guidance molecules and their functional roles, little is known about how these guidance molecules collaborate to steer growth cones to their correct targets. Recent studies in Drosophila point to the importance of the combinatorial action of guidance molecules, and further show that selective fasciculation and defasciculation at specific choice points serve as a fundamental strategy for motor axon guidance. Here, I discuss how attractive and repulsive guidance cues cooperate to ensure the recognition of specific choice points that are inextricably linked to selective fasciculation and defasciculation, and correct pathfinding decision-making.
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