Effects of glucocorticoids on the growth and chemosensitivity of carcinoma cells are heterogeneous and require high concentration of functional glucocorticoid receptors

AIM: To determine how glucocorticoids (GCs) may affect the growth and chemosensitivity of common carcinoma cells.METHODS: The effect of dexamethasone (DEX) on growth and chemosensitivity was assessed in 14 carcinoma cell lines. The function of GC receptors (GR) was assessed by MMTV reporter assay. Overexpression of GR was done by in vitro transfection and expression of a GR-expressing vector. Immunohistochemical stain of tissues and cells were done by PA1-511A, an anti-GR monoclonal antibody.RESULTS: DEX inhibited cell growth of four (MCF-7, MCF-7/MXR1, MCF-7/TPT300, and HeLa), increased cisplatin cytotoxicity of one (SiHa), and decreased cisplatin cytotoxicity of two (H460 and Hep3B) cell lines. The GR content of the seven cell lines affected by DEX was significantly higher than those of the seven cell lines unaffected by DEX(5.2±2.5×104 sites/cell vs 1.3±1.4×104 sites/cell, P= 0.005).Only two DEX-unresponsive cell lines (NPC-TW01 and NPCTW04) contained high GR amounts in the range (1.9-8.1×104sites/cell) of the seven DEX-responsive cell lines. The GR function of NPC-TW01 and NPC-TW04, however, was found to be impaired. The importance of high cellular amount of GR in mediating DEX susceptibility of the cells was further exemplified by GR dose-dependent drug resistance to cisplatin of AGS, a cell line with low GR content and was unaffected by DEX before transfection of GR-expressing vector. Immunohistochemical studies of human cancer tissues showed that 5 of the 45 (11.1%) breast cancer and 43 of the 85 (50.6%) non-small cell lung cancer had high GR contents at the ranges of the GC-responsive carcinoma cell lines.CONCLUSION: The growth and chemosensitivity of human carcinomas with high GR contents may be affected by GC. However, in light of the heterogeneous and even contradictive effects of GC on these cells, routine examination of GR contents of human carcinoma tissues may not be clinically useful until other markers that help predict the ultimate effect of GC on individual patients are identified.

Effects of glucocorticoid and glucocorticoid receptors on stress-induced neurogenesis suppression

Studies have shown that cerebral ischemia activates neurogenesis and that stress inhibits neurogenesis.However,the role of stress hormone levels on neurogenesis following cerebral ischemia remains poorly understood.The present study explored the possible regulatory mechanisms of adult neurogenesis under pathological conditions by examining changes and regulation of glucocorticoid receptors in adult rats subjected to transient unilateral middle cerebral artery suture occlusion.Corticosterone levels gradually increased following middle cerebral artery occlusion,and the number of glucocorticoid receptor-positive cells decreased.The number of5-bromodeoxyuridine-and nestin-positive cells significantly increased at 1 and 2 weeks after ischemia.A large number of doublecortin-positive cells migrated from the hippocampus to the cortex.At 3 weeks post-surgery,the number of 5-bromodeoxyuridine-and nestin-positive cells significantly reduced in the subventricular zone.Increased corticosterone levels decreased vascular endothelial cell proliferation and neurogenesis,and the number of glucocorticoid receptor-positive cells decreased.In the sham surgery group,vascular endothelial cell proliferation related to post-ischemic cerebral rehabilitation was not detected.Corticosterone levels increased,but the number and distribution of glucocorticoid receptor-positive cells were not changed.However,normal neuregenesis and migration of neural stem cells existed in the adult rat brain in the sham surgery group.Results suggested that glucocorticoid receptors influenced neurogenesis and were negatively regulated by glucocorticoid levels following focal cerebral ischemia and reperfusion.

Blockage of glucocorticoid receptors during memory acquisition,retrieval and reconsolidation prevents the expression of morphine-induced conditioned place preferences in mice

Association between the reward caused by consuming drugs and the context in which they are consumed is essential in the formation of morphine-induced conditioned place preference(CPP).Glucocorticoid receptor(GRs)activation in different regions of the brain affects reward-based reinforcement and memory processing.A wide array of studies have demonstrated that blockage of GRs in some brain areas can have an effect on reward-related memory;however,to date there have been no systematic studies about the involvement of glucocorticoids(GCs)in morphine-related reward memory.Here,we used the GR antagonist RU38486 to investigate how GRs blockage affects the sensitization and CPP behavior during different phases of reward memory included acquisition,retrieval and reconsolidation.Interestingly,our results showed RU38486 has the ability to impair the acquisition,retrieval and reconsolidation of reward-based memory in CPP and sensitization behavior.But RU38486 by itself cannot induce CPP or conditioned place aversion(CPA)behavior.Our data provide a much more complete picture of the potential effects that glucocorticoids have on the reward memory of different phases and inhibit the sensitization behavior.

Blockage of glucocorticoid receptors during memory acquisition, retrieval and reconsolidation prevents the expression of morphine-induced conditioned place preferences in mice

Association between the reward caused by consuming drugs and the context in which they are consumed is essential in the formation of morphine-induced conditioned place preference (CPP). Glucocorticoid receptor (GRs) activation in different regions of the brain affects reward-based reinforcement and memory processing. A wide array of studies have demonstrated that blockage of GRs in some brain areas can have an effect on reward-related memory; however, to date there have been no systematic studies about the involvement of glucocorticoids (GCs) in morphine-related reward memory. Here, we used the GR antagonist RU38486 to investigate how GRs blockage affects the sensitization and CPP behavior during different phases of reward memory included acquisition, retrieval and reconsolidation. Interestingly, our results showed RU38486 has the ability to impair the acquisition, retrieval and reconsolidation of reward-based memory in CPP and sensitization behavior. But RU38486 by itself cannot induce CPP or conditioned place aversion (CPA) behavior. Our data provide a much more complete picture of the potential effects that glucocorticoids have on the reward memory of different phases and inhibit the sensitization behavior.

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.

Comparison of inebilizumab or rituximab in addition to glucocorticoid therapy for neuromyelitis optica spectrum disorders

AIM:To investigate the short-term efficacy and safety of inebilizumab for neuromyelitis optica spectrum disorders(NMOSD).METHODS:A total of 33 patients with NMOSD treated with inebilizumab(Group INB,n=15)or rituximab(Group RTX,n=18)in addition to high-dose glucocorticoids were included.Both groups underwent hormone shock therapy during the acute phase.Subsequently,Group INB received inebilizumab injections during the remission phase,while Group RTX received rituximab injections.A comparison of aquaporins 4(AQP4)titer values,peripheral blood B lymphocyte counts,and visual function recovery was conducted before and 8wk after treatment.Additionally,adverse reactions and patient tolerability were analyzed after using inebilizumab treatment regimes.RESULTS:Following inebilizumab treatment,there was a significantly improvement in the visual acuity of NMOSD patients(P<0.05),accompanied by a notable decrease in AQP4 titer values and B lymphocyte ratio(P<0.05).Moreover,inebilizumab treatment showed a partial effect in preventing optic nerve atrophy(P<0.05).However,there were no significant differences in other therapeutic effects compared to rituximab,which has previously demonstrated substantial therapeutic efficacy(P>0.05).Furthermore,inebilizumab exhibited higher safety levels than that of rituximab injections.CONCLUSION:The combination of inebilizumab and high-dose glucocorticoids proves to be effective.In comparison to rituximab injections,inebilizumab displays better tolerance and safety.Moreover,it demonstrates a partial effect in preventing optic nerve atrophy.Thus,it stands as an effective method to reduce the disability rates and improve the daily living ability of patients with NMOSD.

Study of the Effects of Glucocorticoid on Growth and Adult Final Height in Children with Primary Nephrotic Syndrome

Objective: To analyze the epidemiological characteristics of growth, as well as factors associated with growth retardation in children with primary nephrotic syndrome (PNS), and to investigate the effect of glucocorticoid (GC) use duration on growth retardation in these children. Methods: Clinical and laboratory data of 353 PNS children treated at our hospital from July 2014 to June 2015 were collected through the medical record management system. Height, weight, and GC usage were recorded. Follow-up assessments were conducted in August 2022 for the original group, recording height, weight, and GC usage. Height and weight were evaluated using standard deviation scores (SDS). Categorical data were analyzed using chi-square test while continuous measurement data were analyzed using t-test or rank-sum test. Linear regression was used to assess the association between two single independent variables, and logistic regression analysis was used to screen for risk factors related to growth retardation in children with PNS. Results: Among the 353 PNS children enrolled in this study, male-to-female ratio of 2.64:1 (256 males vs 97 females). A total of 119 children exhibited growth retardation, incidence rate of 33.71%. The duration of GC usage among those with growth retardation was significantly longer compared to those without it (762.81 ± 934.50 days vs 263.77 ± 420.49 days;p Conclusion: PNS children treated with GC have a high incidence of growth retardation, and a high proportion of short stature in adulthood, especially in children with growth retardation in childhood, most of them have short stature after grown up. Time of GC usage is a risk factor for growth retardation in children with PNS.

Progress in the Use of Glucocorticoids and Biological Agents in Non-Infectious Uveitis

One of the main immune-mediated diseases that lead to avoidable blindness is non-infectious uveitis. Glucocorticoids are the first-line therapy choice for noninfectious uveitis;however, biologics are also showing promise in the management of this condition. The description of glucocorticoid and biologic usage in non-infectious uveitis is the main topic of this paper.

Melanocortin 3,5 receptors immunohistochemical expression in colonic mucosa of inflammatory bowel disease patients:A matter of disease activity?

BACKGROUND Melanocortin 3 and 5 receptors(i.e.,MC3R and MC5R)belong to the melanocortin family.However,data regarding their role in inflammatory bowel diseases(IBD)are currently unavailable.AIM This study aims to ascertain their expression profiles in the colonic mucosa of Crohn’s disease(CD)and ulcerative colitis(UC),aligning them with IBD disease endoscopic and histologic activity.METHODS Colonic mucosal biopsies from CD/UC patients were sampled,and immunohisto-chemical analyses were conducted to evaluate the expression of MC3R and MC5R.Colonic sampling was performed on both traits with endoscopic scores(Mayo endoscopic score and CD endoscopic index of severity)consistent with inflamed mucosa and not consistent with disease activity(i.e.,normal appearing mucosa).RESULTS In both CD and UC inflamed mucosa,MC3R(CD:+7.7 fold vs normal mucosa,P<0.01;UC:+12 fold vs normal mucosa,P<0.01)and MC5R(CD:+5.5 fold vs normal mucosa,P<0.01;UC:+8.1 fold vs normal mucosa,P<0.01)were significantly more expressed compared to normal mucosa.CONCLUSION MC3R and MC5R are expressed in the colon of IBD patients.Furthermore,expression may differ according to disease endoscopic activity,with a higher degree of expression in the traits affected by disease activity in both CD and UC,suggesting a potential use of these receptors in IBD pharmacology.

Role of bitter contributors and bitter taste receptors:a comprehensive review of their sources,functions and future development

Bitterness,one of the 5“basic tastes”,is usually undesired by humans.However,abundant literature reported that bitter fruits and vegetables have beneficial health effects due to their bitter contributors.This review provided an updated overview of the main bitter contributors of typical bitter fruits and vegetables and their health benefits.The main bitter contributors,including phenolics,terpenoids,alkaloids,amino acids,nucleosides and purines,were summarized.The bioactivities and wide range of beneficial effects of them on anti-cancers,anti-inflammations,anti-microbes,neuroprotection,inhibiting chronic and acute injury in organs,as well as regulating behavior performance and metabolism were reported.Furthermore,not only did the bitter taste receptors(taste receptor type 2 family,T2Rs)show taste effects,but extra-oral T2Rs could also be activated by binding with bitter components,regulating physiological activities via modulating hormone secretion,immunity,metabolism,and cell proliferation.This review provided a new perspective on exploring and explaining the nutrition of bitter foods,revealing the relationship between the functions of bitter contributors from food and T2Rs.Future trends may focus on revealing the possibility of T2Rs being targets for the treatment of diseases,exploring the mechanism of T2Rs mediating the bioactivities,and making bitter foods more acceptable without getting rid of bitter contributors.

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.

Expression and functional study of cholecystokinin-A receptors on the interstitial Cajal-like cells of the guinea pig common bile duct

BACKGROUND Many studies have shown that interstitial Cajal-like cell(ICLC)abnormalities are closely related to a variety of dynamic gastrointestinal disorders.ICLCs are pacemaker cells for gastrointestinal movement and are involved in the transmission of nerve impulses.AIM To elucidate the expression profile and significance of cholecystokinin-A(CCK-A)receptors in ICLCs in the common bile duct(CBD),as well as the role of CCK in regulating CBD motility through CCK-A receptors on CBD ICLCs.METHODS The levels of tyrosine kinase receptor(c-kit)and CCK-A receptors in CBD tissues and isolated CBD cells were quantified using the double immunofluorescence labeling technique.The CCK-mediated enhancement of the movement of CBD muscle strips through CBD ICLCs was observed by a muscle strip contraction test.RESULTS Immunofluorescence showed co-expression of c-kit and CCK-A receptors in the CBD muscularis layer.Observations of isolated CBD cells showed that c-kit was expressed on the surface of ICLCs,the cell body and synapse were colored and polygonal,and some cells presented protrusions and formed networks adjacent to the CBD while others formed filaments at the synaptic terminals of local cells.CCK-A receptors were also expressed on CBD ICLCs.At concentrations ranging from 10^(-6) mol/L to 10^(-10) mol/L,CCK promoted CBD smooth muscle contractility in a dose-dependent manner.In contrast,after ICLC removal,the contractility mediated by CCK in CBD smooth muscle decreased.CONCLUSION CCK-A receptors are highly expressed on CBD ICLCs,and CCK may regulate CBD motility through the CCK-A receptors on ICLCs.

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.

Chemokine Receptors CCR1, CCR3, CCR7 and Chemokines CX3CL1 and CCL5 are Significantly Up-Regulated and Very Reliable for Acute Rejection Diagnosis of Kidney Transplants

Background: The allo-immune response following organ transplantation constitutes one of the main determinants concerning both short- and long- term outcomes in renal graft recipients. Chemokines and their receptors play a diversified and important role, either homeostatic or inflammatory and direct different immune-competent cell types to the allograft. While deeply studied in the last two decades, controversy persists as a result of chemokines’ pleiotropic actions. We report our analysis of CCR1, CCR3, CCR7, CCL5 and CX3CL1 expression or synthesis by graft-infiltrating cells in human kidney transplants (KTx). At the same time, we tested their robustness in diagnosing acute rejection. Methods: Fine-needle aspiration biopsies (Fnab) were performed either on days 7 or 14 post-transplantation among stable KTx and on the day of acute rejection (AR) diagnosis. Fnab cytopreparations were studied by the enzymatic avidin-biotin complex staining for CCR1, CCR3, CCR7 and CX3CL1. From another subgroup of cases, Fnab samples were cultured for 48 hours and the supernatants were analysed for CCL5 by ELISA. Results: The group of AR cases showed a significantly up-regulated expression of CCR1, CCR3, CCR7 and CX3CL1 and a significantly higher synthesis of CCL5. The positive predictive values were respectively 92%, 97%, 85%, 76% and 78% and negative predictive values were by the same order, 100%, 73%, 100%, 98% and 83%. Conclusions: Our study permits us to advance that CCR1 and CCR3 play a significant and non-redundant role in acute rejection, and it is the first report of CCR3 association with rejection, probably related to CCL5. The presence inside the graft of significant up-regulation for CCR7 surmises that part of antigen presentation may be performed there without being restricted to secondary lymphoid sites. Our results with CX3CL1 confirm other reports.

Peroxisome proliferator-activated receptors as targets to treat metabolic diseases:Focus on the adipose tissue,liver,and pancreas

The world is experiencing reflections of the intersection of two pandemics:Obesity and coronavirus disease 2019.The prevalence of obesity has tripled since 1975 worldwide,representing substantial public health costs due to its comorbidities.The adipose tissue is the initial site of obesity impairments.During excessive energy intake,it undergoes hyperplasia and hypertrophy until overt inflammation and insulin resistance turn adipocytes into dysfunctional cells that send lipotoxic signals to other organs.The pancreas is one of the organs most affected by obesity.Once lipotoxicity becomes chronic,there is an increase in insulin secretion by pancreatic beta cells,a surrogate for type 2 diabetes mellitus(T2DM).These alterations threaten the survival of the pancreatic islets,which tend to become dysfunctional,reaching exhaustion in the long term.As for the liver,lipotoxicity favors lipogenesis and impairs beta-oxidation,resulting in hepatic steatosis.This silent disease affects around 30%of the worldwide population and can evolve into end-stage liver disease.Although therapy for hepatic steatosis remains to be defined,peroxisome proliferator-activated receptors(PPARs)activation copes with T2DM management.Peroxisome PPARs are transcription factors found at the intersection of several metabolic pathways,leading to insulin resistance relief,improved thermogenesis,and expressive hepatic steatosis mitigation by increasing mitochondrial beta-oxidation.This review aimed to update the potential of PPAR agonists as targets to treat metabolic diseases,focusing on adipose tissue plasticity and hepatic and pancreatic remodeling.

Bile acids and their receptors: Potential therapeutic targets in inflammatory bowel disease

Chronic and recurrent inflammatory disorders of the gastrointestinal tract caused by a complex interplay between genetics and intestinal dysbiosis are called inflammatory bowel disease.As a result of the interaction between the liver and the gut microbiota,bile acids are an atypical class of steroids produced in mammals and traditionally known for their function in food absorption.With the development of genomics and metabolomics,more and more data suggest that the pathophysiological mechanisms of inflammatory bowel disease are regulated by bile acids and their receptors.Bile acids operate as signalling molecules by activating a variety of bile acid receptors that impact intestinal flora,epithelial barrier function,and intestinal immunology.Inflammatory bowel disease can be treated in new ways by using these potential molecules.This paper mainly discusses the increasing function of bile acids and their receptors in inflammatory bowel disease and their prospective therapeutic applications.In addition,we explore bile acid metabolism and the interaction of bile acids and the gut microbiota.

The role of purinergic receptors in neural repair and regeneration after spinal cord injury

Spinal cord injury is a serious injury of the central nervous system that results in neurological deficits.The pathophysiological mechanisms underlying spinal cord injury,as well as the mechanisms involved in neural repair and regeneration,are highly complex.Although there have been many studies on these mechanisms,there is no effective intervention for such injury.In spinal cord injury,neural repair and regeneration is an important part of improving neurological function after injury,although the low regenerative ability of nerve cells and the difficulty in axonal and myelin regeneration after spinal cord injury hamper functional recovery.Large amounts of ATP and its metabolites are released after spinal cord injury and participate in various aspects of functional regulation by acting on purinergic receptors which are widely expressed in the spinal cord.These processes mediate intracellular and extracellular signalling pathways to improve neural repair and regeneration after spinal cord injury.This article reviews research on the mechanistic roles of purinergic receptors in spinal cord injury,highlighting the potential role of purinergic receptors as interventional targets for neural repair and regeneration after spinal cord injury.

Dynamic changes of renal cytosol glucocorticoid receptors in rats with passive Heymann nephritis

Renal and hepatic cytosol glucocorticoid receptors (GR) were measured by radio-Ligand binding assay at different stages in rats with passive Heymann nephritis(PHN) induced by the injection of antiserum against renal tubular antigen. The content of renal G

Changes of glucocorticoid receptors in peripheral leukocytes in patients with bronchial asthma

The maximal binding capacity(R0) and dissociation constant(Kd) of glucocorticoid receptors(GR) in peripheral leucocytes and the cortisol(F) level in plasma were estimated in 17 patients with bronchial asthma.The R0 of GR was 12908+2501 sites cell which wa