Cortico-striatal gamma oscillations are modulated by dopamine D3 receptors in dyskinetic rats

Long-term levodopa administration can lead to the development of levodopa-induced dyskinesia.Gamma oscillations are a widely recognized hallmark of abnormal neural electrical activity in levodopa-induced dyskinesia.Currently,studies have reported increased oscillation power in cases of levodopa-induced dyskinesia.However,little is known about how the other electrophysiological parameters of gamma oscillations are altered in levodopa-induced dyskinesia.Furthermore,the role of the dopamine D3 receptor,which is implicated in levodopa-induced dyskinesia,in movement disorder-related changes in neural oscillations is unclear.We found that the cortico-striatal functional connectivity of beta oscillations was enhanced in a model of Parkinson’s disease.Furthermore,levodopa application enhanced cortical gamma oscillations in cortico-striatal projections and cortical gamma aperiodic components,as well as bidirectional primary motor cortex(M1)↔dorsolateral striatum gamma flow.Administration of PD128907(a selective dopamine D3 receptor agonist)induced dyskinesia and excessive gamma oscillations with a bidirectional M1↔dorsolateral striatum flow.However,administration of PG01037(a selective dopamine D3 receptor antagonist)attenuated dyskinesia,suppressed gamma oscillations and cortical gamma aperiodic components,and decreased gamma causality in the M1→dorsolateral striatum direction.These findings suggest that the dopamine D3 receptor plays a role in dyskinesia-related oscillatory activity,and that it has potential as a therapeutic target for levodopa-induced dyskinesia.

Effects of Ovariectomy and 17<i>β</i>-Estradiol Replacement on Dopamine D2 Receptors in Female Rats: Consequences on Sucrose, Alcohol, Water Intakes and Body Weight

Background: Mechanisms underlying overeating-induced obesity in post-menopausal woman include functional lack of 17β-estradiol dysregulating dopamine D2 receptors, thereby inducing food addiction, glucose craving or alcohol dependence through reward circuitry. This study aimed at further understanding 17β-estradiol and dopamine D2 receptors interferences in the etiology of woman obesity. Method: Seventy-two Wistar female rats weighing 200 - 205 g, individually-housed, were divided into non-ovariectomized control (C = 6 groups) and ovariectomized rats (OVX = 6 groups) which were concurrently subjected to the following treatments: Non-drug-treated (DMSO vehicle), 17β-estradiol (E2, 5 μg/kg, s.c.), sulpiride (SUL, 20 mg/kg, i.p.), bromocriptine (BR, 0.1 mg/kg, i.p.), E2 + SUL or E2 + BR, designating the 6 constitutive groups of either control or ovariectomy. Within each experimental group, consumption of different solutions (10% alcohol, 10% sucrose and water) as well as food intake and body weight were daily measured, for 10 consecutive days. Results: This study indicated that D2S was a specific inducer of alcohol and food intakes, but reduced sugar consumption. In addition, 17β- estradiol regulated the body weight set point, modulating D2S functions towards increased food intake at lower weights and decreased food intake at higher weights. D2S met the slow genomic actions induced by 17β-estradiol. Conversely, D2L inhibited alcohol and food intakes, but induced specifically sugar consumption, thereby regulating blood glucose levels and promoting energy expenditure in reducing body weight. Indeed, 17β-estradiol exerted a tonic inhibition on D2L which was released by OVX, exacerbating sugar intake and increasing body weight. D2L mediated the rapid metabolic effects of 17β-estradiol. Conclusion: Our results supported physiological data reporting that activation of the mostly expressed presynaptically D2S-class autoreceptors decreased dopamine release stimulating food intake, whereas activation of the predominantly postsynaptic isoform D2L receptors increased dopamine activity inhibiting food intake. Our studies indicated that 17β-estradiol acted on the two types of D2 receptors showing opposite functions to equilibrate energy intake vs. expenditure for weight set point regulation. Our data also supported biochemical findings reporting that 17β-estradiol induced D2 genes transcriptional regulation, thereby involving both types of D2 receptors in the etiology of obesity. The combined dysregulated effects of D2L and D2S receptors, as 17β-estradiol was lacking, would be causal factors underlying the etiology of obesity.

Olfactory receptors in neural regeneration in the central nervous system

Olfactory receptors are crucial for detecting odors and play a vital role in our sense of smell,influencing behaviors from food choices to emotional memories.These receptors also contribute to our perception of flavor and have potential applications in medical diagnostics and environmental monitoring.The ability of the olfactory system to regenerate its sensory neurons provides a unique model to study neural regeneration,a phenomenon largely absent in the central nervous system.Insights gained from how olfactory neurons continuously replace themselves and reestablish functional connections can provide strategies to promote similar regenerative processes in the central nervous system,where damage often results in permanent deficits.Understanding the molecular and cellular mechanisms underpinning olfactory neuron regeneration could pave the way for developing therapeutic approaches to treat spinal co rd injuries and neurodegenerative diseases like Alzheimer's disease.Olfa ctory receptors are found in almost any cell of eve ry orga n/tissue of the mammalian body.This ectopic expression provides insights into the chemical structures that can activate olfactory receptors.In addition to odors,olfactory receptors in ectopic expression may respond to endogenous compounds and molecules produced by mucosal colonizing microbiota.The analysis of the function of olfactory receptors in ectopic expression provides valuable information on the signaling pathway engaged upon receptor activation and the receptor's role in proliferation and cell differentiation mechanisms.This review explo res the ectopic expression of olfa ctory receptors and the role they may play in neural regeneration within the central nervous system,with particular attention to compounds that can activate these receptors to initiate regenerative processes.Evidence suggests that olfactory receptors could serve as potential therapeutic targets for enhancing neural repair and recovery following central nervous system injuries.

Effects of 17<i>β</i>-Estradiol on Dopamine D2 Receptors in Thiamine-Deficient Female Rats: Consequences on Sucrose, Alcohol, Water Intakes and Body Weight

Our previous studies showed that 17β-estradiol (E2) modulated dopamine D2 receptor in regulating body weight set-point. The aim of this study was to understand whether thiamine deficiency influenced the E2 modulation on dopamine D2 receptors, using bromocriptine mesylate (BR) and sulpiride (SUL) as selective central dopamine-D2 receptors agonist and antagonist respectively. We studied the E2-dopamine D2 receptors interferences in a 10-day thiamine-deficient female rats for which consumptions of water, sugar, alcohol and food were daily-recorded and their consequences on body weights assessed. Our results showed that the volume of water daily ingested doubled in thiamine-deficient female rats (OXT), while sugar and alcohol consumptions collapsed with decreased weight and food consumption. On the one hand, thiamine potentiated D2/BR activity (bromocriptine-activated D2 receptors) to induce sugar intake and inhibited the same D2/BR receptors to induce water intake. On the other hand, thiamine promoted D2/SUL receptors (sulpiride-inhibited D2 receptors) for enhanced alcohol intake, increased food consumption and weight gain. Taking together, thiamine modulated the actions of 17β-estradiol on both D2/BR and D2/SUL receptors activities.

Effects of Ovariectomy and 17β-Estradiol Replacement on the Activity of Dopamine D2 Receptors in the Selection of Macronutrients Carbohydrates, Lipids and Proteins in Females Rats

17β-estradiol modulates the activity of D2 receptors in the regulation of food intake and body weight. The functional lack of 17β-estradiol in postmenopausal women could create a dietary imbalance and cause body weight gain. This study aimed to better understand the interferences that could exist between 17β-estradiol, D2 receptors and the selection of carbohydrate, fat and protein consumption, as well as their consequences on body weight gain by using an animal model of the menopause. Ovariectomy exacerbates the consumption of foods rich in lipids. Thus confirming an inhibitory action of 17β-estradiol (E2) on the consumption of these types of foods. This consumption stimulates body weight gain, which is promoted by the high caloric content of these foods and not by the amount consumed. Our results showed a direct involvement of D2 receptors in food choice. This choice would be made according to the two (2) isoforms of the D2 receptors. The D2/BR isoform directs towards a high carbohydrate consumption, without causing a gain in body weight. While D2/SUL, promotes high fat food consumption, causing an increase in body weight. In women, 17β-estradiol modulates the activity ratio between these two D2 receptor isoforms to ensure energy and homeostatic balance, stabilizing food intake and body weight.

Metabotropic glutamate receptors and nitric oxide in dopaminergic neurotoxicity

Dopaminergic neurotoxicity is characterized by damage and death of dopaminergic neurons.Parkinson's disease(PD)is a neurodegenerative disorder that primarily involves the loss of dopaminergic neurons in the substantia nigra.Therefore,the study of the mechanisms,as well as the search for new targets for the prevention and treatment of neurodegenerative diseases,is an important focus of modern neuroscience.PD is primarily caused by dysfunction of dopaminergic neurons;however,other neurotransmitter systems are also involved.Research reports have indicated that the glutamatergic system is involved in different pathological conditions,including dopaminergic neurotoxicity.Over the last two decades,the important functional interplay between dopaminergic and glutamatergic systems has stimulated interest in the possible role of metabotropic glutamate receptors(mGluRs)in the development of extrapyramidal disorders.However,the specific mechanisms driving these processes are presently unclear.The participation of the universal neuronal messenger nitric oxide(NO)in the mechanisms of dopaminergic neurotoxicity has attracted increased attention.The current paper aims to review the involvement of mGluRs and the contribution of NO to dopaminergic neurotoxicity.More precisely,we focused on studies conducted on the rotenone-induced PD model.This review is also an outline of our own results obtained using the method of electron paramagnetic resonance,which allows quantitation of NO radicals in brain structures.

Effect of PDⅠAdministration on Dopamine Receptors mRNAs Expression in the Lesioned Striatum of PD Rat Model

To study the effect of PD Ⅰ administration on dopamine receptors （DR, , DRz ） mRNAs expression in the lesioned striatum of the PD rat model and confirm if PDⅠ has the effect of dopamine receptor agonist. The PD rats with unilateral 6-hydroxydopamine lesioned were administrated with PD Ⅰ , L-dopa methyl/benserazide, L-dopa methyl/benserazide/ PD Ⅰ , normal saline respectively for 4 weeks and their behavioral changes were observed. Then the rats were sacrificed and RT-PCR technique was used to detect changes of dopamine receptors （DR1, DR2） mRNAs expression in the ipsilateral striatum 1 day after the last treatment. The results showed that treatment with PD Ⅰ plus L-dopa resulted in a stable contralateral rotation behavior; treatment with L-dopa resulted in a progressively increased contralateral rotation behavior. Rotation behavior induced by anhydromorphine decreased with PD Ⅰ or PD Ⅰ plus L-dopa treatment. Treatment With L-dopa or PD Ⅰ plus L-dopa, up-regulation of DR, mRNA and down-regulation of DR2 mRNA were observed in the ipsilateral striatum which were more obvious than that treated with PD Ⅰ or vehicle （P〈0. 05）. It was concluded that long-term treatment with PD Ⅰ could alleviate the behavior of PD rats. PD Ⅰ had no apparent effect on the dopamine receptors （DRI , DRz ） mRNAs expression in the ipsilateral striatum and the PD Ⅰ has no agonist effect on dopamine receptors.

M_(4) muscarinic receptors regulates dopamine/DARPP-32 signaling and glutamate transmis⁃sion to balance dopaminergic D1 function in mouse dorsal striatum

OBJECTIVE Abnormal striatal dopaminergic and glutamatergic neurotransmis⁃sion is central to the pathophysiology of schizo⁃phrenia.In this study,we investigated the roles of M4 receptor interplay with D1 signaling in stria⁃tal neurotransmission that affect glutamatergic transmission to control the etiology of neuropsy⁃chiatric disorders.METHODS To study dorsal striatum(DS)region-specific neuronal and behav⁃ioral responses modulated by M4 receptors,we used clustered regularly interspaced short palin⁃dromic repeats-associated protein 9 technology to generate mice lacking M4 in the dorsal stria⁃tum(DS-M4-KD).The M4 positive allosteric modu⁃lator,VU0467154,were used to study the phar⁃macologically profiles with M4 receptor stimula⁃tion in WT mice.Oxotremorine M(Oxo-M),a no subtype-selective muscarinic agonist,was used to show that mAchRs activation,in order to dissect the particular function of M4,in DS-M4-KD mice.Open filed test and forced swim test were used to assess the change of psychiatric-like behav⁃iors.Western blotting and immunohistochemistry were used to detect protein levels of phosphory⁃lation site of dopamine-and cAMP-regulated phosphoprotein of 32 ku(DARPP-32).Whole-cell patch-clamp recording was used to assess M4-mediated cholinergic inhibition of glutamater⁃gic synaptic input transmission.RESULTS West⁃ern blotting and immunohistochemistry assay showed VU0467154(5 mg·kg-1,ip)promoted phosphorylation of DARPP-32 at Thr75,and atten⁃uated D1-dependent phosphorylation of DARPP-32 at Thr34 within the mouse DS.Consistently,the Oxo-M(4μg,icv)also increased DARPP-32 phosphorylation at site Thr75 to reversed phos⁃phorylation at site Thr34 in WT mice,but not in DS-M4-KD mice.In parallel with altered DARPP-32 responses,VU0467154 or Oxo-M evoked a psychological stress response and reversed D1-induced hyperlocomotion in mice in open field test and force swim tests.However,Oxo-M sup⁃pression of D1-depengdeng behavioral respons⁃es was impaired in DS-M4-KD mice.Whole-cell patch recording showed that VU0467154 or Oxo-M mediated endogenous cholinergic inhibition of miniature excitatory postsynaptic currents through M4 receptors,which in turn suppressed D1-depen⁃dent glutamatergic synaptic transmission in the DS.CONCLUSION This study provides evidence for the role of M4 receptors in regulation of dopa⁃mine/DARPP-32 signaling and glutamate respons⁃es in the DS,and therefore modulation of psychi⁃atric behaviors associated with D1 signaling.This results indicate the mechanisms of treatments targeting M4 in psychiatric disorders.

Colocalization of dopamine receptors in BDNF-expressing peptidergic neurons in the rat paraventricular nucleus

Brain derived neurotrophic factor(BDNF)in the paraventricular nucleus of the hypothalamus(PVN)can regulate food intake and energy expenditure.However,the regulatory mediator of BDNF positive neurons in the PVN remains unclear.Recently,widespread expression of the dopamine D1 receptor(DRD1)and D2 receptor(DRD2)has been observed in PVN neurons.We hypothesized that dopamine receptors(DRs)are also expressed in BDNF-positive neurons and mediate the function of BDNF in the PVN.Using multiple immunofluorescence assays combined with confocal microscopy,we found that BDNF immunoreactive(IR)neurons were widely distributed throughout the PVN in both the magnocellular and parvocellular regions.The BDNF protein was mainly expressed in the somas of neurons.The distribution of DR-IR neurons exhibited a pattern similar to that of BDNF.Nearly all DRD1 and DRD2 expression occurred within BDNF-IR neurons.

Recent progress in the applications of presynaptic dopaminergic positron emission tomography imaging in parkinsonism

Nowadays,presynaptic dopaminergic positron emission tomography,which assesses deficiencies in dopamine synthesis,storage,and transport,is widely utilized for early diagnosis and differential diagnosis of parkinsonism.This review provides a comprehensive summary of the latest developments in the application of presynaptic dopaminergic positron emission tomography imaging in disorders that manifest parkinsonism.We conducted a thorough literature search using reputable databases such as PubMed and Web of Science.Selection criteria involved identifying peer-reviewed articles published within the last 5 years,with emphasis on their relevance to clinical applications.The findings from these studies highlight that presynaptic dopaminergic positron emission tomography has demonstrated potential not only in diagnosing and differentiating various Parkinsonian conditions but also in assessing disease severity and predicting prognosis.Moreover,when employed in conjunction with other imaging modalities and advanced analytical methods,presynaptic dopaminergic positron emission tomography has been validated as a reliable in vivo biomarker.This validation extends to screening and exploring potential neuropathological mechanisms associated with dopaminergic depletion.In summary,the insights gained from interpreting these studies are crucial for enhancing the effectiveness of preclinical investigations and clinical trials,ultimately advancing toward the goals of neuroregeneration in parkinsonian disorders.

The dopaminergic system and Alzheimer's disease

Alzheimer's disease is a common neurodegenerative disorder in older adults.Despite its prevalence,its pathogenesis remains unclea r.In addition to the most widely accepted causes,which in clude excessive amyloid-beta aggregation,tau hyperphosphorylation,and deficiency of the neurotransmitter acetylcholine,numerous studies have shown that the dopaminergic system is also closely associated with the occurrence and development of this condition.Dopamine is a crucial catecholaminergic neurotransmitter in the human body.Dopamine-associated treatments,such as drugs that target dopamine receptor D and dopamine analogs,can improve cognitive function and alleviate psychiatric symptoms as well as ameliorate other clinical manifestations.Howeve r,therapeutics targeting the dopaminergic system are associated with various adverse reactions,such as addiction and exacerbation of cognitive impairment.This review summarizes the role of the dopaminergic system in the pathology of Alzheimer's disease,focusing on currently available dopamine-based therapies for this disorder and the common side effects associated with dopamine-related drugs.The aim of this review is to provide insights into the potential connections between the dopaminergic system and Alzheimer's disease,thus helping to clarify the mechanisms underlying the condition and exploring more effective therapeutic options.

How dopamine tunes parvalbumin interneurons in the hippocampus:new experimental observations in Alzheimer's disease

Despite decades of dedicated resea rch,Alzheimer's disease (AD) is an age-related and progressive neurodegenerative disorder for which the mechanisms of onset are sti unc ear.AD is cha racterized by featured histological alterations including amyloid-beta (AB) plaque deposition,accumulation of neurofibrillary to ngles of hyperphosphorylated-tau,and neuronal loss,accompanied by progressive cognitive decline and behavioral changes.

Context-dependency in medicine:how neuronal excitability influences the impact of dopamine on cognition

Dopamine,often termed the"feel-good"neurotransmitter,plays a crucial role in myriad physiological and psychological brain processes.While dopamine is primarily associated with pleasure,reward,and motivation,its effects can be quite complex;and this complexity is further compounded when examining how dopamine functions in typical versus disease-affected neural circuits.In pa rticula r,epilepsy,characte rized by heightened brain excitability,is linked to cognitive dysfunction,and dopamine is implicated in elements of both its pathology and treatment.Neuroscience has been successful in describing the synaptic abnormalities believed to contribute to memory issues in epilepsy,aiding in the search for effective therapies for what persists as a major medical issue.

Dopamine D₁- and D₂-Receptors in Immunostimulation under Activation of Mu-Opioid Receptors in Mice with Different Psychoemotional States

The purpose of the present study was to analyze the effect of activation of mu-opioid receptors (mu-OR) on the immune response under blockade of postsynaptic D1-and D2-receptors in mice of the C57BL/6J strain displaying either aggressive or depressive-like behaviors in the social conflict model. It is shown that activation of activation of mu-OR with a highly selective agonist DAGO (100 μg/kg) increased significantly IgM-immune response not only in C57BL/6J mice with an unchanged psychoemotional state but also in mice displaying aggressive or depressive-like behaviors in the social stress model (10 days of agonistic confrontations). Selective blockade of DA receptors of the D1-type with SCH-23390 (1.0 mg/kg with DAGO administration) caused a more pronounced elevation of IgM-immune response than DAGO alone while DAGO effect was completely blocked by prior administration of D2-receptor antagonist haloperidol (1.0 mg/kg). At the same time, both SCH-23390 and haloperidol prevented the immune response increase induced by DAGO injection in mice engaged in aggressive or depressive-like behaviors. Thus, in animals not subjected to social stress DAGO-induced immunostimulation is provided only by D2-receptors, whereas in animals with altered psychoemotional state mu-opioid immunostimulation is mediated by both types of DA receptors—D1 and D2. These data provide evidence for different impacts of the main subtypes of DA receptors in the mediation of immunomodulating effects of mu-opioid system under normal and stressful conditions.

Immunomodulation of Proton-activated G Protein-coupled Receptors in Inflammation

Proton-activated G protein-coupled receptors(GPCRs),initially discovered by Ludwig in 2003,are widely distributed in various tissues.These receptors have been found to modulate the immune system in several inflammatory diseases,including inflammatory bowel disease,atopic dermatitis,and asthma.Proton-activated GPCRs belong to the G protein-coupled receptor family and can detect alternations in extracellular pH.This detection triggers downstream signaling pathways within the cells,ultimately influencing the function of immune cells.In this review,we specifically focused on investigating the immune response of proton-activated GPCRs under inflammatory conditions.

Metabotropic glutamate receptors(mGluRs)in epileptogenesis:an update on abnormal mGluRs signaling and its therapeutic implications

Epilepsy is a neurological disorder characterized by high morbidity,high recurrence,and drug resistance.Enhanced signaling through the excitatory neurotransmitter glutamate is intricately associated with epilepsy.Metabotropic glutamate receptors(mGluRs)are G protein-coupled receptors activated by glutamate and are key regulators of neuronal and synaptic plasticity.Dysregulated mGluR signaling has been associated with various neurological disorders,and numerous studies have shown a close relationship between mGluRs expression/activity and the development of epilepsy.In this review,we first introduce the three groups of mGluRs and their associated signaling pathways.Then,we detail how these receptors influence epilepsy by describing the signaling cascades triggered by their activation and their neuroprotective or detrimental roles in epileptogenesis.In addition,strategies for pharmacological manipulation of these receptors during the treatment of epilepsy in experimental studies is also summarized.We hope that this review will provide a foundation for future studies on the development of mGluR-targeted antiepileptic drugs.

Characterization of Domeless receptors and the role of Bd Domeless3 in anti-symbiont-like virus defense in Bactrocera dorsalis

The Janus kinase/signal transducers and activators of transcription(JAK/STAT)signaling pathway play a pivotal role in innate immunity.Among invertebrates,Domeless receptors serve as the key upstream regulators of this pathway.In our study on Bactrocera dorsalis,we identified three cytokine receptors:BdDomeless1,BdDomeless2,and BdDomeless3.Each receptor encompasses five fibronectin-type-III-like(FN III)extracellular domains and a transmembrane domain.Furthermore,these receptors exhibit the increased responsiveness to diverse pathogenic challenges.Notably,only BdDomeless3 is upregulated during symbiont-like viral infections.Moreover,silencing BdDomeless3 enhanced the infectivity of Bactrocera dorsalis cripavirus(BdCV)and B.dorsalis picorna-like virus(BdPLV),underscoring BdDomeless3’s crucial role in antiviral defense of B.dorsalis.Following the suppression of Domeless3 expression,six antimicrobial peptide genes displayed decreased expression,potentially correlating with the rise in viral infectivity.To our knowledge,this is the first study identifying cytokine receptors associated with the JAK/STAT pathway in tephritid flies,shedding light on the immune mechanisms of B.dorsalis.

The Role of Toll-Like Receptors and Nuclear Factor κB p65 Protein in the Pathogenesis of Otitis Media

The role of Toll-like receptor 4 (TLR4) and nuclear factor κB p65 (NF-κB p65) proteins in the pathogenesis of otitis media is explored. In recent years, the incidence of otitis media has been rising globally, becoming a significant threat to human health. More and more studies have found that Toll-like receptor 4 (TLR4), as a member of the Toll-like receptor family, can promote the generation of inflammatory factors and is closely related to the body’s immune response and inflammatory response. Nuclear factor-κB p65 (NF-κB p65) is a nuclear transcription factor that can interact with various cytokines, growth factors, and apoptotic factors, participating in processes such as oxidative stress, apoptosis, and inflammation in the body [1]. This article elaborates on the structure, function, and signaling pathways of TLR4 and NF-κB p65 proteins in the pathogenesis of otitis media, aiming to provide more precise targets and better therapeutic efficacy for the diagnosis and treatment of otitis media. The role of inflammation in disease.

Toll-like receptors 2 polymorphism is associated with psoriasis: A case-control study in the northern Chinese population

Background:Psoriasis is a disease caused by genetics and immune system dysfunction,affecting the skin and joints.Toll-like receptors(TLRs)play an important role in triggering the innate immune response and controlling adaptive immunity.The role of TLR2 in the progression of psoriasis is not well understood.Methods:A case-control study was conducted on a northern Chinese Han population,consisting of psoriasis patients and healthy control subjects.Genotyping was performed using the tetra-primer amplification refractory mutation system-polymerase chain reaction(ARMS-PCR),and allele and genotype frequencies of four SNPs in TLR2 were analyzed in 270 psoriasis patients and 246 healthy controls.Results:Four TLR2 SNPs(rs11938228,rs4696480,rs3804099,rs5743699)were genotyped and found to be in linkage disequilibrium.The genotype distributions of rs11938228 and rs4696480 in two groups were in Hardy-Weinberg equilibrium and statistically significant except for the overdominance model.The haplotypes ATTC and ATCC were found to be protective against psoriasis.Conclusion:Our study found a correlation between TLR2 genetic variations and the likelihood of psoriasis in northern China.

Nuclear receptors and pathogenesis of pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with a median overall survival time of 5 mo and the five years survival less than 5%, a rate essentially unchanged over the course of the years. A well defined progression model of accumulation of genetic alterations ranging from single point mutations to gross chromosomal abnormalities has been introduced to describe the origin of this disease. However, due to the its subtle nature and concurring events PDAC cure remains elusive. Nuclear receptors (NR) are members of a large superfamily of evolutionarily conserved ligand-regulated DNA-binding transcription factors functionally involved in important cellular functions ranging from regulation of metabolism, to growth and development. Given the nature of their ligands, NR are very tempting drug targets and their pharmacological modulation has been widely exploited for the treatment of metabolic and inflammatory diseases. There are now clear evidences that both classical ligand-activated and orphan NR are involved in the pathogenesis of PDAC from its very early stages; nonetheless many aspects of their role are not fully understood. The purpose of this review is to highlight the striking connections that link peroxisome proliferator activated receptors, retinoic acid receptors, retinoid X receptor, androgen receptor, estrogen receptors and the orphan NR Nur, chicken ovalbumin upstream promoter transcription factor II and the liver receptor homologue-1 receptor to PDAC development, connections that could lead to the identification of novel therapies for this disease.