Neural mechanisms of dopamine function in learning and memory in Caenorhabditis elegans.

Research into learning and memory over the past decades has revealed key neurotransmitters that regulate these processes, many of which are evolutionarily conserved across diverse species. The monoamine neurotransmitter dopamine is one example of this, with countless studies demonstrating its importance in regulating behavioural plasticity. However, dopaminergic neural networks in the mammalian brain consist of hundreds or thousands of neurons, and thus cannot be studied at the level of single neurons acting within defined neural circuits. The nematode Caenorhabditis elegans (C. elegans) has an experimentally tractable nervous system with a completely characterized synaptic connectome. This makes it an advantageous system to undertake mechanistic studies into how dopamine encodes lasting yet flexible behavioural plasticity in the nervous system. In this review, we synthesize the research to date exploring the importance of dopaminergic signalling in learning, memory formation, and forgetting, focusing on research in C. elegans. We also explore the potential for dopamine-specific fluorescent biosensors in C. elegans to visualize dopaminergic neural circuits during learning and memory formation in real-time. We propose that the use of these sensors in C. elegans, in combination with optogenetic and other light-based approaches, will further illuminate the detailed spatiotemporal requirements for encoding behavioural plasticity in an accessible experimental system. Understanding the key molecules and circuit mechanisms that regulate learning and forgetting in more compact invertebrate nervous systems may reveal new druggable targets for enhancing memory storage and delaying memory loss in bigger brains.

Behavioral Tests for Associative Learning in Caenorhabditis elegans.

Learning is critical for survival as it provides the capacity to adapt to a changing environment. At the molecular and cellular level, learning leads to alterations within neural circuits that include synaptic rewiring, synaptic plasticity, and protein level/gene expression changes. There has been substantial progress in recent years on dissecting how learning and memory is regulated at the molecular and cellular level, including the use of compact invertebrate nervous systems as experimental models. This progress has been facilitated by the establishment of robust behavioral assays that generate a quantifiable readout of the extent to which animals learn and remember. This chapter will focus on protocols of behavioral tests for associative learning using the nematode Caenorhabditis elegans, with its unparalleled genetic tractability, compact nervous system of ~300 neurons, high level of conservation with mammalian systems, and amenability to a suite of behavioral tools and analyses. Specifically, we will provide a detailed description of the methods for two behavioral assays that model associative learning, one measuring appetitive olfactory learning and the other assaying aversive gustatory learning.

Melatonin ameliorates high glucose-induced autophagy in Schwann cells.

Diabetic neuropathy (DN) is a condition in which nerve fibers are continually exposed to high glucose-induced free radicals. Recent discoveries demonstrated that melatonin is an indole hormone that contributes to neuroprotection through the modulation of autophagy. Herein, this study aims to examine the neuroprotective effects of melatonin on Schwann cells under high glucose conditions. 3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide (MTT) assay was used to measure cell viability. The activation of autophagosomes was determined using acridine orange staining (AO). Western blot assay was used to measure the expression of proteins involved in autophagy and endoplasmic reticulum (ER) stress. Our results demonstrated that melatonin at 1 µM has the highest protective effects on high glucose-induced cell death. Melatonin concentrations of 5 and 10 µM were found to be the most effective in reducing autophagy induced by high glucose. Under high glucose conditions, the protein expressions of LC3, ATF4, ATF6, CHOP, PERK and eIF2-α were up-regulated in Schwann cells. However, melatonin attenuated these changes by downregulating LC3 and the ER stress markers ATF4, ATF6, CHOP, PERK and eIF2-α protein expressions in Schwann cells. In conclusion, melatonin alleviates high glucose-induced autophagy in Schwann cells through PERK-eIF2α-ATF4-CHOP signaling pathways.

COVID-19 Anti-Vaccine Sentiments in Malaysia: Narratives of Comments from Facebook Post.

The anti-vaccination movement was an ongoing issue in Malaysia, a Muslim-majority country, even before the COVID-19 pandemic. It is unclear whether the introduction of new COVID-19 vaccines would similarly provoke anti-vaccine sentiments. This study analyzed COVID-19 anti-vaccine sentiments in the Malaysian community. Anti-vaccine comments from Facebook page posts were extracted. The qualitative software QSR-NVivo 10 was used to manage, code and analyze the data. The fast-track COVID-19 vaccine evoked the fear of unknown long-term effects, safety, effectiveness and the duration of protection. The halal status of the COVID-19 vaccines is important. Although it is permissible to use vaccines that are not certified halal under the state of darurah (emergency), there was doubt that the current state has reached the stage of darurah that warrants the use of vaccines. COVID-19 vaccine microchip conspiracy theories were raised. COVID-19 is viewed as only severe for vulnerable populations, and hence vaccination is not needed for the healthy. There were opinions that coronavirus treatments would be more beneficial than vaccination. The anti-COVID-19 vaccine sentiments uncovered in this study provide important insights for the formulation of public health messages to instill confidence in new COVID-19 vaccines. Despite the pandemic being nearly over and many people worldwide having received COVID-19 vaccines, the findings provide important insight into potential issues regarding the introduction of new vaccines in the event of future pandemics.

CCAT 1- A Pivotal Oncogenic Long Non-Coding RNA in Colorectal Cancer.

Colorectal cancer (CRC) is ranked as the third most common cancer and second deadliest cancer in both men and women in the world. Currently, the cure rate and 5-year survival rate of CRC patients remain relatively low. Therefore, discovering a novel molecular biomarker that can be used to improve CRC screening, diagnosis, prognosis, and treatment would be beneficial. Long non-coding RNA colon cancer-associated transcript 1 (CCAT 1) has been found overexpressed in CRC and is associated with CRC tumorigenesis and treatment outcome. CCAT 1 has a high degree of specificity and sensitivity, it is readily detected in CRC tissues and is significantly overexpressed in both premalignant and malignant CRC tissues. Besides, CCAT 1 is associated with clinical manifestation and advanced features of CRC, such as lymph node metastasis, high tumor node metastasis stage, differentiation, invasion, and distant metastasis. In addition, they can upregulate oncogenic c-MYC and negatively modulate microRNAs via different mechanisms of action. Furthermore, dysregulated CCAT 1 also enhances the chemoresistance in CRC cells while downregulation of them reverses the malignant phenotypes of cancer cells. In brief, CCAT 1 serves as a potential screening, diagnostic and prognostic biomarker in CRC, it also serves as a potential therapeutic marker to treat CRC patients.

Neuropeptide signalling shapes feeding and reproductive behaviours in male Caenorhabditis elegans.

Sexual dimorphism occurs where different sexes of the same species display differences in characteristics not limited to reproduction. For the nematode Caenorhabditis elegans, in which the complete neuroanatomy has been solved for both hermaphrodites and males, sexually dimorphic features have been observed both in terms of the number of neurons and in synaptic connectivity. In addition, male behaviours, such as food-leaving to prioritise searching for mates, have been attributed to neuropeptides released from sex-shared or sex-specific neurons. In this study, we show that the lury-1 neuropeptide gene shows a sexually dimorphic expression pattern; being expressed in pharyngeal neurons in both sexes but displaying additional expression in tail neurons only in the male. We also show that lury-1 mutant animals show sex differences in feeding behaviours, with pharyngeal pumping elevated in hermaphrodites but reduced in males. LURY-1 also modulates male mating efficiency, influencing motor events during contact with a hermaphrodite. Our findings indicate sex-specific roles of this peptide in feeding and reproduction in C. elegans, providing further insight into neuromodulatory control of sexually dimorphic behaviours.

Cannabidiol induces autophagy and improves neuronal health associated with SIRT1 mediated longevity.

Autophagy is a catabolic process to eliminate defective cellular molecules via lysosome-mediated degradation. Dysfunctional autophagy is associated with accelerated aging, whereas stimulation of autophagy could have potent anti-aging effects. We report that cannabidiol (CBD), a natural compound from Cannabis sativa, extends lifespan and rescues age-associated physiological declines in C. elegans. CBD promoted autophagic flux in nerve-ring neurons visualized by a tandem-tagged LGG-1 reporter during aging in C. elegans. Similarly, CBD activated autophagic flux in hippocampal and SH-SY5Y neurons. Furthermore, CBD-mediated lifespan extension was dependent on autophagy genes (bec-1, vps-34, and sqst-1) confirmed by RNAi knockdown experiments. C. elegans neurons have previously been shown to accumulate aberrant morphologies, such as beading and blebbing, with increasing age. Interestingly, CBD treatment slowed the development of these features in anterior and posterior touch receptor neurons (TRN) during aging. RNAi knockdown experiments indicated that CBD-mediated age-associated morphological changes in TRNs require bec-1 and sqst-1, not vps-34. Further investigation demonstrated that CBD-induced lifespan extension and increased neuronal health require sir-2.1/SIRT1. These findings collectively indicate the anti-aging benefits of CBD treatment, in both in vitro and in vivo models, and its potential to improve neuronal health and longevity.

Exploiting flow cytometry for the unbiased quantification of protein inclusions in Caenorhabditis elegans.

The aggregation of proteins into inclusions or plaques is a prominent hallmark of a diverse range of pathologies including neurodegenerative diseases. The quantification of such inclusions in Caenorhabditis elegans models of aggregation is usually achieved by fluorescence microscopy or other techniques involving biochemical fractionation of worm lysates. Here, we describe a simple and rapid flow cytometry-based approach that allows fluorescently tagged inclusions to be enumerated in whole worm lysate in a quantitative and unbiased fashion. We demonstrate that this technique is applicable to multiple C. elegans models of aggregation and importantly, can be used to monitor the dynamics of inclusion formation in response to heat shock and during ageing. This includes the characterisation of physicochemical properties of inclusions, such as their apparent size, which may reveal how aggregate formation is distinct in different tissues or at different stages of pathology or ageing. This new method can be used as a powerful technique for the medium- to high-throughput quantification of inclusions in future studies of genetic or chemical modulators of aggregation in C. elegans.

Edible Bird's Nest: Recent Updates and Industry Insights Based On Laboratory Findings.

Edible bird's nest (EBN) is a traditional Chinese delicacy made of the saliva of swiftlets found in Southeast Asia. With increasing demands for EBN, quality control of EBN products is important for safe consumption. The processing steps are particularly important for efficient extraction of bioactive compounds. Geographical location, collection place, and harvesting season contribute to differences in nutritional contents in EBN. Concerns regarding presence of adulterant, chemical, and microbial contaminants in EBN as well as authentication and chemical composition measuring methods are discussed in this review. Recent discoveries of beneficial health functions of EBN in antimicrobial and antiviral actions, immunomodulation, cancer prevention and treatment, tissue regeneration, cardiometabolic maintenance, antioxidant action and neuroprotection are also reviewed. Our review provides an update on the recent research on EBN.

Investigating the molecular mechanisms of learning and memory using Caenorhabditis elegans.

Learning is an essential biological process for survival since it facilitates behavioural plasticity in response to environmental changes. This process is mediated by a wide variety of genes, mostly expressed in the nervous system. Many studies have extensively explored the molecular and cellular mechanisms underlying learning and memory. This review will focus on the advances gained through the study of the nematode Caenorhabditis elegans. C. elegans provides an excellent system to study learning because of its genetic tractability, in addition to its invariant, compact nervous system (~300 neurons) that is well-characterised at the structural level. Importantly, despite its compact nature, the nematode nervous system possesses a high level of conservation with mammalian systems. These features allow the study of genes within specific sensory-, inter- and motor neurons, facilitating the interrogation of signalling pathways that mediate learning via defined neural circuits. This review will detail how learning and memory can be studied in C. elegans through behavioural paradigms that target distinct sensory modalities. We will also summarise recent studies describing mechanisms through which key molecular and cellular pathways are proposed to affect associative and non-associative forms of learning.

Cannabidiol regulates CB1-pSTAT3 signaling for neurite outgrowth, prolongs lifespan, and improves health span in Caenorhabditis elegans of Aß pathology models.

Cannabidiol (CBD), a phytocannabinoid from the Cannabis sativa plant, exhibits a broad spectrum of potential therapeutic properties for neurodegenerative diseases. An accumulation of amyloid-ß (Aß) protein is one of the most important neuropathology in neurodegenerative diseases like Alzheimer's disease (AD). Data on the effect of CBD on the amelioration of Aß-induced neurite degeneration and its consequences of life and health spans is sparse. This study aimed to investigate the effects of CBD on neurite outgrowth in cells and lifespan and health span in Caenorhabditis elegans (C. elegans). In human SH-SY5Y neuronal cells, CBD prevented neurite lesion induced by Aß1-42 and increased the expression of fatty acid amide hydrolase (FAAH) and cannabinoid receptor 1 (CB1R). Furthermore, CBD both protected the reduction of dendritic spine density and rescued the activity of synaptic Ca2+ /calmodulin-dependent protein kinase II (CaMKII) from Aß1-42 toxicity in primary hippocampal neurons. In C. elegans, we used the transgenic CL2355 strain of C. elegans, which expresses the human Aß peptide throughout the nervous system and found that CBD treatment extended lifespan and improved health span. The neuroprotective effect of CBD was further explored by observing the dopaminergic neurons using transgenic dat-1: GFP strains using the confocal microscope. This study shows that CBD prevents the neurite degeneration induced by Aß, by a mechanism involving CB1R activation, and extends lifespan and improves health span in Aß-overexpressing worms. Our findings support the potential therapeutic approach of CBD for the treatment of AD patients.

Sleep Analysis in Adult C. elegans Reveals State-Dependent Alteration of Neural and Behavioral Responses.

Sleep, a state of quiescence associated with growth and restorative processes, is conserved across species. Invertebrates including the nematode Caenorhabditis elegans exhibit sleep-like states during development, satiety, and stress. Here, we describe behavior and neural activity during sleep and awake states in adult C. elegans hermaphrodites using new microfluidic methods. We observed effects of fluid flow, oxygen, feeding, odors, and genetic perturbations on long-term sleep behavior over 12 h. We developed a closed-loop sleep detection system to automatically deliver chemical stimuli to assess sleep-dependent changes to evoked neural responses in individual animals. Sleep increased the arousal threshold to aversive stimulation, yet the associated sensory neuron and first-layer interneuron responses were unchanged. This localizes adult sleep-dependent neuromodulation within interneurons presynaptic to the premotor interneurons, rather than afferent sensory circuits. However, sleep prolonged responses in appetitive chemosensory neurons, suggesting that sleep modulates responsiveness specifically across sensory systems rather than broadly damping global circuit activity.SIGNIFICANCE STATEMENT Much is known about molecular mechanisms that facilitate sleep control. However, it is unclear how these pathways modulate neural circuit-level sensory processing or how misregulation of neural activity contributes to sleep disorders. The nematode Caenorhabditis elegans provides the ability to study neural circuitry with single-neuron resolution, and recent studies examined sleep states between developmental stages and when stressed. Here, we examine an additional form of spontaneous sleep in adult C. elegans at the behavioral and neural activity levels. Using a closed-loop system, we show that delayed behavioral responses to aversive chemical stimulation during sleep arise from sleep-dependent sensorimotor modulation localized presynaptic to the premotor circuit, rather than early sensory circuits.

Amyotrophic Lateral Sclerosis: Proteins, Proteostasis, Prions, and Promises.

Amyotrophic lateral sclerosis (ALS) is characterized by the progressive degeneration of the motor neurons that innervate muscle, resulting in gradual paralysis and culminating in the inability to breathe or swallow. This neuronal degeneration occurs in a spatiotemporal manner from a point of onset in the central nervous system (CNS), suggesting that there is a molecule that spreads from cell-to-cell. There is strong evidence that the onset and progression of ALS pathology is a consequence of protein misfolding and aggregation. In line with this, a hallmark pathology of ALS is protein deposition and inclusion formation within motor neurons and surrounding glia of the proteins TAR DNA-binding protein 43, superoxide dismutase-1, or fused in sarcoma. Collectively, the observed protein aggregation, in conjunction with the spatiotemporal spread of symptoms, strongly suggests a prion-like propagation of protein aggregation occurs in ALS. In this review, we discuss the role of protein aggregation in ALS concerning protein homeostasis (proteostasis) mechanisms and prion-like propagation. Furthermore, we examine the experimental models used to investigate these processes, including in vitro assays, cultured cells, invertebrate models, and murine models. Finally, we evaluate the therapeutics that may best prevent the onset or spread of pathology in ALS and discuss what lies on the horizon for treating this currently incurable disease.

Melatonin promotes Schwann cell dedifferentiation and proliferation through the Ras/Raf/ERK and MAPK pathways, and glial cell-derived neurotrophic factor expression.

Upon peripheral nerve injury (PNI), continuous proliferation of Schwann cells is critical for axon regeneration and tubular reconstruction for nerve regeneration. Melatonin is a hormone that is able to induce proliferation in various cell types. In the present study, the effects of melatonin on promoting Schwann cell proliferation and the molecular mechanism involved were investigated. The present results showed that melatonin enhanced the melatonin receptors (MT1 and MT2) expression in Schwann cells. Melatonin induced Schwann cell dedifferentiation into progenitor-like Schwann cells, as observed by immunofluorescence staining, which showed Sox2 marker expression. In addition, melatonin enhanced Schwann cell proliferation, mediated by the upregulation of glial cell-derived neurotropic factor (GNDF) and protein kinase C (PKC). Furthermore, the Ras/Raf/ERK and MAPK signaling pathways were also involved in Schwann cell dedifferentiation and proliferation. In conclusion, melatonin induced Schwann cell dedifferentiation and proliferation via the Ras/Raf/ERK, MAPK and GDNF/PKC pathways. The present results suggested that melatonin could be used to enhance the recovery of PNI.

The role of neuropeptides in learning: Insights from C. elegans.

Learning is critical for survival as it provides the capacity to adapt to a changing environment. At the molecular and cellular level, learning leads to alterations within neural circuits that include synaptic rewiring and synaptic plasticity. These changes are mediated by signalling molecules known as neuromodulators. One such class of neuromodulators are neuropeptides, a diverse group of short peptides that primarily act through G protein-coupled receptors. There has been substantial progress in recent years on dissecting the role of neuropeptides in learning circuits using compact yet powerful invertebrate model systems. We will focus on insights gained using the nematode Caenorhabditis elegans, with its unparalleled genetic tractability, compact nervous system of ∼300 neurons, high level of conservation with mammalian systems and amenability to a suite of behavioural analyses. Specifically, we will summarise recent discoveries in C. elegans on the role of neuropeptides in non-associative and associative learning.

NPY/NPF-Related Neuropeptide FLP-34 Signals from Serotonergic Neurons to Modulate Aversive Olfactory Learning in Caenorhabditis elegans.

Aversive learning is fundamental for animals to increase chances of survival. In addition to classical neurotransmitters, neuropeptides have emerged to modulate such complex behaviors. Among them, neuropeptide Y (NPY) is well known to promote aversive memory acquisition in mammals. Here we identify an NPY/neuropeptide F (NPF)-related neuropeptide system in Caenorhabditis elegans and show that this FLP-34/NPR-11 system is required for learning negative associations, a process that is reminiscent of NPY signaling in mammals. The Caenorhabditis elegans NPY/NPF ortholog FLP-34 displays conserved structural hallmarks of bilaterian-wide NPY/NPF neuropeptides. We show that it is required for aversive olfactory learning after pairing diacetyl with the absence of food, but not for appetitive olfactory learning in response to butanone. To mediate diacetyl learning and thus integrate the aversive food context with the diacetyl odor, FLP-34 is released from serotonergic neurons and signals through its evolutionarily conserved NPY/NPF GPCR, NPR-11, in downstream AIA interneurons. NPR-11 activation in the AIA integration center results in avoidance of a previously attractive stimulus. This study opens perspectives for a deeper understanding of stress conditions in which aversive learning results in excessive avoidance.SIGNIFICANCE STATEMENT Aversive learning evolved early in evolution to promote avoidance of dangerous and stressful situations. In addition to classical neurotransmitters, neuropeptides are emerging as modulators of complex behaviors, including learning and memory. Here, we identified the evolutionary ortholog of neuropeptide Y/neuropeptide F in the nematode Caenorhabditis elegans, and we discovered that it is required for olfactory aversive learning. In addition, we elucidated the neural circuit underlying this avoidance behavior, and we discovered a novel coordinated action of Caenorhabditis elegans neuropeptide Y/neuropeptide F and serotonin that could aid in our understanding of the molecular mechanisms underlying stress disorders in which excessive avoidance results in maladaptive behaviors.

Melatonin inhibits high glucose-induced ox-LDL/LDL expression and apoptosis in human umbilical endothelial cells.

BACKGROUND: Cardiovascular disease (CVD) is one of the major cause of mortality in diabetic patients. Evidence suggests that hyperglycemia in diabetic patients contributes to increased risk of CVD. This study is to investigate the therapeutic effects of melatonin on glucose-treated human umbilical vein endothelial cells (HUVEC) and provide insights on the underlying mechanisms. MATERIALS AND METHODS: Cell viability was determined using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Reactive oxygen species (ROS) and membrane potential was detected using 2',7'-dichlorofluorescein diacetate and 5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolcarbocyanine iodide (JC-1) dye staining, respectively. While, cell apoptosis was determined by Annexin-V staining and protein expression was measured using Western blot. RESULTS: Our results suggested that melatonin inhibited glucose-induced ROS elevation, mitochondria dysfunction and apoptosis on HUVEC. Melatonin inhibited glucose-induced HUVEC apoptosis via PI3K/Akt signaling pathway. Activation of Akt further activated BcL-2 pathway through upregulation of Mcl-1 expression and downregulation Bax expression in order to inhibit glucose-induced HUVEC apoptosis. Besides that, melatonin promoted downregulation of oxLDL/LOX-1 in order to inhibit glucose-induced HUVEC apoptosis. CONCLUSIONS: In conclusion, our results suggested that melatonin exerted vasculoprotective effects against glucose-induced apoptosis in HUVEC through PI3K/Akt, Bcl-2 and oxLDL/LOX-1 signaling pathways.

Multimodal Stimulation in a Microfluidic Device Facilitates Studies of Interneurons in Sensory Integration in C. elegans.

Animals' perception and behavior involve integration of multiple sensory modalities. Caenorhabditis elegans is a useful model for studying multimodal sensory integration, as it has well-characterized neuronal circuits in a relatively simple nervous system. However, most studies based on functional imaging have only been conducted on single modal stimuli, because well-controlled multimodal experiments for C. elegans are technically difficult. For instance, no single systems currently deliver precise stimuli with spatial, temporal, and intensity control, despite prior hypotheses that interneurons do integrate these sensory inputs to control behavior. Here, a microfluidic platform that can easily deliver spatially and temporally controlled combination stimuli to C. elegans is presented. With this platform, both sensory and interneuron activity is measured in response to mechanical and chemical stimulations in a quantitative and high-throughput manner. It is found that the activity of command interneuron PVC can be modulated by prior stimulation both within the same and across different modalities. The roles of monoaminergic and peptidergic signaling are further examined on the process of multimodal integration through PVC activity. The approach exemplified here is envisioned to be broadly applicable in different contexts to elucidate underlying mechanisms and identify genes affecting multisensory integration.

Melatonin Prevents Oxidative Stress-Induced Mitochondrial Dysfunction and Apoptosis in High Glucose-Treated Schwann Cells via Upregulation of Bcl2, NF-κB, mTOR, Wnt Signalling Pathways.

Neuropathy is a complication that affects more than 50% of long-standing diabetic patients. One of the causes of diabetes neuropathy (DN) is the apoptosis of Schwann cells due to prolonged exposure to high glucose and build-up of oxidative stress. Melatonin is a hormone that has a known antioxidant property. In this study, we investigated the protective effect of melatonin on high glucose-induced Schwann cells' apoptosis. Our results revealed that high glucose promoted apoptosis via mitochondrial-related oxidative stress and downregulated Bcl-2 family proteins in Schwann cells. In this signalling pathway, Bcl-2, Bcl-XL and Mcl-1 proteins were down-regulated while p-BAD and Puma proteins were up-regulated by high glucose treatment. Besides, we also proved that high glucose promoted apoptosis in Schwann cells through decreasing the p-NF-κB in the NF-κB signalling pathway. Key regulators of mTOR signalling pathway such as p-mTOR, Rictor and Raptor were also down-regulated after high glucose treatment. Additionally, high glucose treatment also decreased the Wnt signalling pathway downstream proteins (Wnt 5a/b, p-Lrp6 and Axin). Our results showed that melatonin treatment significantly inhibited high glucose-induced ROS generation, restored mitochondrial membrane potential and inhibited high glucose-induced apoptosis in Schwann cells. Furthermore, melatonin reversed the alterations of protein expression caused by high glucose treatment. Our results concluded that melatonin alleviates high glucose-induced apoptosis in Schwann cells through mitigating mitochondrial-related oxidative stress and the alterations of Bcl-2, NF-κB, mTOR and Wnt signalling pathways.

Identification of a Conserved, Orphan G Protein-Coupled Receptor Required for Efficient Pathogen Clearance in Caenorhabditis elegans.

G protein-coupled receptors contribute to host defense across the animal kingdom, transducing many signals involved in both vertebrate and invertebrate immune responses. While it has become well established that the nematode worm Caenorhabditis elegans triggers innate immune responses following infection with numerous bacterial, fungal, and viral pathogens, the mechanisms by which C. elegans recognizes these pathogens have remained somewhat more elusive. C. elegans G protein-coupled receptors have been implicated in recognizing pathogen-associated damage and activating downstream host immune responses. Here we identify and characterize a novel G protein-coupled receptor required to regulate the C. elegans response to infection with Microbacterium nematophilum We show that this receptor, which we designate pathogen clearance-defective receptor 1 (PCDR-1), is required for efficient pathogen clearance following infection. PCDR-1 acts upstream of multiple G proteins, including the C. elegans Gαq ortholog, EGL-30, in rectal epithelial cells to promote pathogen clearance via a novel mechanism.