Brain Functional Correlates of Recall of Life Events in Medication-Naïve Adolescents with Borderline Personality Disorder.

INTRODUCTION: Recall of autobiographical events has been found to be impaired in borderline personality disorder (BPD), but few studies have examined if this impairment has brain functional correlates. This study evaluated brain functional alterations during autobiographical recall using medication-naive adolescent patients to avoid potential confounding effects of treatment. METHODS: Thirty-two adolescent female patients with BPD who were never-medicated and without psychiatric comorbidity and 33 matched healthy females underwent fMRI while they viewed individualized cue words that evoked autobiographical memories. Control conditions included viewing non-memory-evoking cues and a low-level baseline (cross-fixation). RESULTS: During autobiographical recall, in comparison to the low-level baseline, the BPD patients showed increased brain activity in regions including the posterior hippocampus, the lingual and calcarine cortex, and the precuneus compared to the healthy controls. The BPD patients also showed a failure to deactivate the right dorsolateral prefrontal cortex during autobiographical recall. No patient-control differences were found when memory-evoking words were compared to non-memory-evoking words. DISCUSSION/CONCLUSIONS: This study finds evidence of hippocampal/lingual/calcarine/precuneus hyperactivation to stimuli that evoke autobiographical memories in patients with BPD. As the changes were seen in never-treated patients without other comorbidities, they could be considered intrinsic to the disorder. Our study also adds to existing evidence for failure of deactivation in BPD, this time outside the default mode network.

Turn-on Fluorescent Biosensors for Imaging Hypoxia-like Conditions in Living Cells.

We present the synthesis, photophysical properties, and biological application of nontoxic 3-azo-conjugated BODIPY dyes as masked fluorescent biosensors of hypoxia-like conditions. The synthetic methodology is based on an operationally simple N═N bond-forming protocol, followed by a Suzuki coupling, that allows for a direct access to simple and underexplored 3-azo-substituted BODIPY. These dyes can turn on their emission properties under both chemical and biological reductive conditions, including bacterial and human azoreductases, which trigger the azo bond cleavage, leading to fluorescent 3-amino-BODIPY. We have also developed a practical enzymatic protocol, using an immobilized bacterial azoreductase that allows for the evaluation of these azo-based probes and can be used as a model for the less accessible and expensive human reductase NQO1. Quantum mechanical calculations uncover the restructuration of the topography of the S1 potential energy surface following the reduction of the azo moiety and rationalize the fluorescent quenching event through the mapping of an unprecedented pathway. Fluorescent microscopy experiments show that these azos can be used to visualize hypoxia-like conditions within living cells.

Identifying mindfulness and acceptance as mediators between negative affect, functional disability and emotional distress in patients with fibromyalgia.

OBJECTIVES: Fibromyalgia (FM) is a prevalent disabling condition characterised by chronic widespread pain. It is considered a complex illness in which the prognosis is conditioned by affective and cognitive mediators still largely unknown in FM. To investigate the correlation between psychological variables (acceptance, negative affect, and mindfulness) and functional disability or physical impact, anxiety/depression symptoms and emotional distress, and also to evaluate the mediating role of acceptance and mindfulness between negative affect, physical impact, anxiety/depression and emotional distress in individuals with FM. METHODS: Two hundred and fifty-one patients with FM who met the 2010 ACR criteria were included and filled out validated self-reported screening measures. The study explored Pearson's correlation coefficients and multiple mediation using a Preacher and Hayes's computational software tool, including the indirect effect associated with the two mediators (mindfulness and acceptance). RESULTS: Functional disability or physical impact, anxiety/depression symptoms and emotional distress correlated positively with negative affect (r= 0.580) and negatively with acceptance and mindfulness (r= -0.579 and r= -0.471; all p-values <0.001), respectively. The mediation analyses showed that acceptance and mindfulness mediated the relationship between negative affect and dependent variables such as physical impact, anxiety/depression symptoms and distress. CONCLUSIONS: The findings highlight that mindfulness and acceptance have a significant indirect effect on physical impact, anxiety/depression and emotional distress when controlling for negative affect as an independent variable in the FM patients. Future investigation should replicate and extend these outcomes in other study populations to determine the mediating role of mindfulness and acceptance in FM.

Evolution of male genitalia in the Drosophila repleta species group (Diptera: Drosophilidae).

The Drosophila repleta group comprises more than one hundred species that inhabit several environments in the Neotropics and use different hosts as rearing and feeding resources. Rather homogeneous in their external morphology, they are generally distinguished by the male genitalia, seemingly their fastest evolving morphological trait, constituting an excellent model to study patterns of genital evolution in the context of a continental adaptive radiation. Although much is known about the evolution of animal genitalia at population level, surveys on macroevolutionary scale of this phenomenon are scarce. This study used a suite of phylogenetic comparative methods to elucidate the macroevolutionary patterns of genital evolution through deep time and large continental scales. Our results indicate that male genital size and some aspects of shape have been evolving by speciational evolution, probably due to the microevolutionary processes involved in species mate recognition. In contrast, several features of the aedeagus shape seemed to have evolved in a gradual fashion, with heterogeneous evolutionary phenotypic rates among clades. In general, the tempo of the evolution of aedeagus morphology was constant from the origin of the group until the Pliocene, when it accelerated in some clades that diversified mainly in this period. The incidence of novel ecological conditions in the tempo of aedeagus evolution and the relationship between species mate recognition and speciation in the Drosophila repleta group are discussed.

Association between psychological constructs and physical and emotional distress in individuals with fibromyalgia.

OBJECTIVES: Psychological factors and physical and emotional distress are frequently identified in fibromyalgia (FM). Previous reports have explored the relationship between some of these variables and functional disability and emotional distress in the disease; however, additional links with other potential psychological factors are unknown. This study aimed to assess the association between psychological variables and functional disability and emotional distress in individuals with FM. METHODS: This prospective, cross-sectional cohort study included 251 FM patients aged over 18 years. Demographic and clinical characteristics and outcome measures were recorded for each participant. Multiple linear regression analysis was performed to identify associations between the psychological factors. RESULTS: The findings suggest significant associations between psychological variables and physical impact and emotional distress (anxiety and depression) (all p-values < 0.0001). Positive and negative affect, mindfulness, and perceived injustice were strongly associated with the physical and emotional impact (all p-values < 0.05) in the sample. CONCLUSIONS: The study provides useful insights into the domains of physical and emotional distress. The findings should be incorporated into personalised treatments aimed at reducing functional disability and improving quality of life in patients with fibromyalgia.

Three-year prevalence of self-harm behaviors among the reasons for emergency visits of children and adolescents.

Self-harm in the paediatric population is an emerging problem that has been associated with disability and an increased risk of suicide. The objective of the study is to analyse the prevalence of self-harming behaviour as a reason for paediatric emergency consultations.

Design and Characterization of Chitosan Nanoformulations for the Delivery of Antifungal Agents.

Among different Candida species triggering vaginal candidiasis, Candida albicans is the most predominant yeast. It is commonly treated using azole drugs such as Tioconazole (TIO) and Econazole (ECO). However, their low water solubility may affect their therapeutic efficiency. Therefore, the aim of this research was to produce a novel chitosan nanocapsule based delivery system comprising of TIO or ECO and to study their suitability in vaginal application. These systems were characterized by their physicochemical properties, encapsulation efficiency, in vitro release, storage stability, cytotoxicity, and in vitro biological activity. Both nanocapsules loaded with TIO (average hydrodynamic size of 146.8 ± 0.8 nm, zeta potential of +24.7 ± 1.1 mV) or ECO (average hydrodynamic size of 127.1 ± 1.5 nm, zeta potential of +33.0 ± 1.0 mV) showed excellent association efficiency (99% for TIO and 87% for ECO). The analysis of size, polydispersity index, and zeta potential of the systems at 4, 25, and 37 °C (over a period of two months) showed the stability of the systems. Finally, the developed nanosystems presented fungicidal activity against C. albicans at non-toxic concentrations (studied on model human skin cells). The results obtained from this study are the first step in the development of a pharmaceutical dosage form suitable for the treatment of vaginal candidiasis.

Clinical Components of Borderline Personality Disorder and Personality Functioning.

BACKGROUND: Impairment in personality functioning (PF) represents a salient criterion of the DSM-5 alternative diagnostic model for personality disorders (AMPD). The main goal of this study is to analyze the relationship of the borderline personality disorder (BPD) clinical components derived from the DSM-5 categorical diagnostic model (affective dysregulation, behavioral dysregulation, and disturbed relatedness) with personality organization (PO), i.e., PF, assessed by the Structured Interview of Personality Organization (STIPO). METHODS: STIPO and the Structured Clinical Interviews for DSM-IV (SCID-I and -II) were administered to 206 BPD patients. The relationship between PO and BPD components were studied using Spearman correlations and independent linear regression analyses. RESULTS: Significant positive correlations were observed between STIPO scores and several DSM-5 BPD criteria and comorbid psychiatric disorders. STIPO dimensions mainly correlated with disturbed relatedness and, to a lesser extent, affective dysregulation components. Each BPD clinical component was associated with specific STIPO dimensions. CONCLUSIONS: Both diagnostic models, DSM-5 BPD criteria and PO, are not only related but complementary concepts. The results of this study particularly recommend STIPO for the assessment of relational functioning, which is a major domain of the Personality Functioning Scale Levels of the DSM-5 AMPD.

Dimensional Personality Assessment among a Chronic Fatigue Syndrome (CFS) sample with Personality Inventory for DSM-5 (PID-5).

INTRODUCTION: Personality Disorders (PD) are highly prevalent among Chronic Fatigue Syndrome (CFS) patients, but studies based on the DSM-5 are still scarce. Validated instruments have not yet been specifically used in CFS patients. Therefore, our aim was to analyze the differences in personality facets and domains profiles among CFS patients with and without a PD using the Personality Inventory for DSM-5 (PID-5). Additionally, we analyzed the ability of this instrument to predict PD in a sample of CFS patients. This instrument is validated for PDs, but not for CFS. METHODS: All of the 84 CFS patients were evaluated through a clinical interview and underwent psychopathological evaluation with the SCID I and SCID II. Dimensional personality facets and domains were evaluated with the PID-5, according to DSM-5. RESULTS: In our sample, 54 (64%) of the patients fulfilled the criteria of a PD. The most significant facets in CFS with PD in comparison to those patients without a PD were Separation Insecurity, Perseveration, Withdrawal, Depressivity, Rigid Perfectionism, Unusual Beliefs and Experiences. Negative Affectivity and Detachment were the two significant domains in CFS-PD patients. In the regression analyses, only Detachment and Rigid Perfectionism constituted a prognostic factor leading to high probability of an endorsed PD. Conclussion. According to these results, the PID-5 domains and facets could be adequate and useful to differentiate between PD and non-PD patients in clinical samples and suggest a more frequent dimensional personality profile in CFS patients.

Comorbidity in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis: A Nationwide Population-Based Cohort Study.

BACKGROUND: Previous studies have shown evidence of comorbid conditions in chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME). OBJECTIVE: To estimate the prevalence of comorbidities and assess their associations using a nationwide population-based database of a Spanish CFS/ME cohort. METHOD: A nationally representative, retrospective, cross-sectional cohort study (2008-2015) assessed 1757 Spanish subjects who met both the 1994 Centers for Disease Control and Prevention/Fukuda definition and 2003 Canadian Criteria for CFS/ME. Sociodemographic and clinical data, comorbidities, and patient-reported outcome measures at baseline were recorded. A cluster analysis based on baseline clinical variables was performed to classify patients with CFS/ME into 5 categories according to comorbidities. A multivariate logistic regression analysis was conducted adjusting for potential confounding effects such as age and sex; response and categorical predictor variables were also assessed. RESULTS: A total of 1757 CFS/ME patients completed surveys were collected. We identified 5 CFS/ME clusters: group 1-fibromyalgia, myofascial pain, multiple chemical hypersensitivity, sicca syndrome, epicondylitis, and thyroiditis; group 2-alterations of ligaments and subcutaneous tissue, hypovitaminosis D, psychopathology, ligamentous hyperlaxity, and endometriosis. These 2 subgroups comprised mainly older women, with low educational level, unemployment, high levels of fatigue, and poor quality of life; group 3-with hardly any comorbidities, comprising mainly younger women, university students or those already employed, with lower levels of fatigue, and better quality of life; group 4-poorly defined comorbidities; and group 5-hypercholesterolemia. CONCLUSION: Over 80% of a large population-based cohort of Spanish patients with CFS/ME presented comorbidities. Among the 5 subgroups created, the most interesting were groups 1-3. Future research should consider multidisciplinary approaches for the management and treatment of CFS/ME with comorbid conditions.

Differences in the association between childhood trauma history and borderline personality disorder or attention deficit/hyperactivity disorder diagnoses in adulthood.

Common environmental etiological factors between borderline personality disorder (BPD) and attention deficit/hyperactivity disorder (ADHD) have not been fully studied. The main aim of this study was to investigate the relationship between childhood trauma histories, assessed by the Childhood Trauma Questionnaire-Short Form (CTQ-SF), with adult BPD, ADHD or BPD-ADHD diagnoses. Comorbid BPD-ADHD patients exhibited significantly higher clinical severity and higher scores in the Total Neglect Scale, compared to BPD and ADHD patients, and only a marginal difference was observed for Sexual Abuse when BPD and ADHD patients were compared. Physical Trauma Scales were associated with ADHD diagnosis, whereas Emotional Abuse and Sexual Abuse Scales were associated with BPD or BPD-ADHD diagnoses. The study findings support the association between experiencing traumatic events in childhood and a higher clinical severity of BPD in adulthood. Furthermore, physical trauma history in childhood could be associated with the persistence of ADHD in adulthood and emotional or sexual abuse with later development of BPD or comorbid BPD-ADHD. Whereas experiencing childhood traumas is associated with later development of more general psychopathology, our study supports that a specific type of traumatic event could increase the risk for the consolidation of a concrete psychiatric disorder in the trajectory from childhood to adulthood of vulnerable subjects.

The role of hypothalamus-pituitary-adrenal genes and childhood trauma in borderline personality disorder.

Current knowledge suggests that borderline personality disorder (BPD) results from the interaction between genetic and environmental factors. Research has mainly focused on monoaminergic genetic variants and their modulation by traumatic events, especially those occurring during childhood. However, to the best of our knowledge, there are no studies on the genetics of hypothalamus-pituitary-adrenal (HPA) axis, despite its vulnerability to early stress and its involvement in BPD pathogenesis. The aim of this study was to investigate the contribution of genetic variants in the HPA axis and to explore the modulating effect of childhood trauma in a large sample of BPD patients and controls. DNA was obtained from a sample of 481 subjects with BPD and 442 controls. Case-control differences in allelic frequencies of 47 polymorphisms in 10 HPA axis genes were analysed. Modulation of genetic associations by the presence of childhood trauma was also investigated by dividing the sample into three groups: BPD with trauma, BPD without trauma and controls. Two FKBP5 polymorphisms (rs4713902-C and rs9470079-A) showed significant associations with BPD. There were also associations between BPD and haplotype combinations of the genes FKBP5 and CRHR1. Two FKBP5 alleles (rs3798347-T and rs10947563-A) were more frequent in BPD subjects with history of physical abuse and emotional neglect and two CRHR2 variants (rs4722999-C and rs12701020-C) in BPD subjects with sexual and physical abuse. Our findings suggest a contribution of HPA axis genetic variants to BPD pathogenesis and reinforce the hypothesis of the modulating effect of childhood trauma in the development of this disorder.

Borderline Personality Disorder and Personality Inventory for DSM-5 (PID-5): Dimensional personality assessment with DSM-5.

INTRODUCTION: Borderline personality disorder (BPD) diagnosis has been considered highly controversial. The Diagnostic and Statistical Manual of Mental Disorders 5th edition (DSM-5) proposes an alternative hybrid diagnostic model for personality disorders (PD), and the Personality Inventory for DSM-5 (PID-5) has adequate psychometric properties and has been widely used for the assessment of the dimensional component. METHODS: Our aim was to analyze the utility of the personality traits presented in Section III of the DSM-5 for BPD diagnosis in an outpatient clinical sample, using the Spanish version of the PID-5. Two clinical samples were studied: BPD sample (n=84) and non-BPD sample (n=45). Between-sample differences in PID-5 scores were analyzed. RESULTS: The BPD sample obtained significantly higher scores in most PID-5 trait facets and domains. Specifically and after regression logistic analyses, in BPD patients, the domains of Negative Affectivity and Disinhibition, and the trait facets of emotional lability, [lack of] restricted affectivity, and impulsivity were more significantly associated with BPD. CONCLUSIONS: Although our findings are only partially consistent with the algorithm proposed by DSM-5, we consider that the combination of the PID-5 trait domains and facets could be useful for BPD dimensional diagnosis, and could further our understanding of BPD diagnosis complexity.

Impulsive clinical profile of Borderline Personality Disorder with comorbid Substance Use Disorder.

INTRODUCTION: Borderline Personality Disorder (BPD) is one of the Personality Disorder most frequently associated with Substance Use Disorder (SUD). According to different models, the Behavioral dysregulation-BPD subgroup has a higher prevalence of SUD and certain impulsivity behaviors than the other two subgroups. METHODS: Out of 156 BPD patients, 47 were in the Behavioral dysregulation-BPD subgroup, 55 in Affective dysregulation, and 54 in Disturbed relatedness. All patients completed the SCID-II for DSM-IV Axis II Disorders, SCID-I for DSM-IV Axis I Disorders, Barratt Impulsiveness Scale (BIS-11) and Revised Diagnostic Interview for Borderlines (DIB-R). RESULTS: In the comparison of the BPD subgroups, Behavioral dysregulation showed significantly more prevalence of SUD (alcohol and cocaine), and tendency for anxiolytics, higher impulsivity (DIB-R, but none in BIS-11), and higher number of suicide attempts and psychiatric admissions, although these was not significant in comparison with the other subgroups. CONCLUSIONS: This should be especially useful in the discrimination of BPD patients for different therapeutic approaches and prognoses.

Study of prevalence of Personality Disorders in inmate men sample with Substance Use Disorders using of PDQ-4+ Self-Report.

INTRODUCTION: The study focused on examining the prevalence of Personality Disorders (PD) in 51 male inmates diagnosed with Substance Use Disorders (SUDs) lifetime within a specialized unit at a prison. METHODS: The instruments administered included the Structured Clinical Interview for DSM-IV Axis I and the Personality Diagnostic Questionnaire-4+. RESULTS: The type of crime most frequently committed by the incarcerated was the robbery (76.5%), including robbery with violence. 45.1% of the patients screened positive for Antisocial PD, followed by 35.3% for Paranoid and 23.5% for Obsessive Compulsive PD. The results reflect a male inmate sample exhibiting a clinical profile characterized by SUDs and PD, with almost half of the total sample presenting Antisocial PD. CONCLUSIONS: The presence of Antisocial and Paranoid PD with SUD suggests a more complex personality profile, with a tendency to carry out more aggressive crimes, including robbery with violence. A more comprehensive PD assessment should be carried out in prison settings in order to identify dangerous individuals who are at risk of recidivism.

Childhood trauma in Chronic Fatigue Syndrome: focus on personality disorders and psychopathology.

INTRODUCTION: Personality Disorders (PDs) and childhood traumatic experiences have been considered risk factors for Chronic Fatigue Syndrome (CFS). However, the relationship between these factors and their associated psychopathological impact has not been explored in this population. This study was designed to evaluate the association between different childhood traumas and the presence and number of PDs and current psychopathology in a sample of CFS patients. MATERIAL AND METHODS: For this purpose, 166 CFS patients were evaluated with the Personality Diagnostic Questionnaire-4+ (PDQ-4+) and the Child Trauma Questionnaire. Other instruments were used to assess the associated psychopathology and the impact of fatigue. RESULTS: Of the total sample, 55 (33.1%) presented childhood trauma, the most frequent of which were emotional neglect (21.7%) and emotional abuse (18.1%). Considering PD presence, 79 (47.6%) patients presented some PD. There were no differences in frequency of physical childhood trauma in patients with and without PD. However, patients with PD had more frequently experienced emotional childhood trauma (OR=2.18, p=0.034). Severity of childhood trauma was related to a higher number of PDs, more severe depressive symptoms (p=0.025) and suicide risk (p=0.001). Patients with PD and any childhood trauma presented more severe depressive and irritable symptoms and a higher suicide risk than those without any PD and non-childhood traumatic event. These patients' psychopathological symptoms were similar to those of patients with childhood trauma and without PD. CONCLUSIONS: These results suggest that emotional childhood trauma but not physical childhood trauma is related to higher frequency of PD presence. More severe childhood emotional and physical traumas are related to a higher number of PDs and to more severe psychopathological symptoms.

Regional analysis of health service utilisation by persons with borderline personality disorders: implications for evidence-informed policy.

BACKGROUND: Borderline Personality Disorder (BPD) has been associated with an intensive use of health resources and a high economic burden. AIMS OF THE STUDY: The aim of this study is to analyze the use of mental healthcare resources by BPD patients, to identify the information gaps on BPD at the regional health databases and to describe specific indicators and patterns of care utilization by persons with BPD in order to guide evidence-informed policy planning in Catalonia (Spain). METHODS: A multi-level cross-design synthesis approach was applied following a mixed quantitative-qualitative analysis to estimate the regional service utilisation of patients with BPD. This framing analysis included estimates based on all available data on the use of services combined with prior expert knowledge gathered through a nominal group of key stakeholders in this field. RESULTS: The estimated year prevalence of BPD was 0.7% but only 9.6% of all BPD patients in Catalonia had any contact with the health care system. Of those, less than half contacted mental health care. BPD represented 1.7% of the total care load in the community mental health centres. A significant information gap was identified in all the official databases and impeded their direct use for planning and resource allocation in BPD. Expert knowledge was required to estimate rates of care utilization at every level of care system (primary care, specialized outpatient care and hospital care). Nevertheless the high pattern of care utilization identified at the databases was accurate according to the experts. DISCUSSION: Detection of BPD was lower than expected in the local, regional and national databases and registries of Catalonia. Local data was judged highly inaccurate by experts in comparison to data available on other mental disorders in the same databases. IMPLICATIONS FOR HEALTH POLICY AND RESEARCH: Specific incentives should be implemented to improve the availability and accuracy of information on BPD at the regional databases. When present, BPD should be coded before other psychiatric disorders in clinical records and health databases. Mental health surveys and psychiatric epidemiological studies should specifically incorporate BPD in their inclusion criteria and further studies on the utilisation pattern of this disorder are needed, both locally and internationally.

Comorbid personality disorders in chronic fatigue syndrome patients: a marker of psychopathological severity.

INTRODUCTION: This study was designed to evaluate the presence of personality disorders (PDs) in Chronic Fatigue Syndrome (CFS) patients and to determine their influence on the severity of the associated psychopathology. METHODS: 132 CFS patients were assessed using SCID-I, Personality Diagnostic Questionnaire-4+ (PDQ-4+) with its Clinical Significance Scale, and Fatigue Impact Scale. The Beck Depression Inventory, Buss-Durkee Hostility Inventory and the State-Trait Anxiety Inventory were also administered. RESULTS: 48.5% patients presented PDs, being the most frequent the Obsessive-Compulsive and Avoidant ones. Patients with PDs had more depressive symptoms. Irritability, resentment, suspicion and guilt were the symptoms related with PDQ-4+ total score. CONCLUSIONS: According to these results, PDs may be frequent in CFS patients. This comorbidity is associated with a complex clinical profile, secondary to more severe psychiatric symptoms.

Molecular mechanisms associated with PTHrP-induced proliferation of colon cancer cells.

Parathyroid Hormone-related Protein (PTHrP) is normally produced in many tissues and is recognized for its endocrine, paracrine, autocrine and intracrine modes of action. PTHrP is also implicated in different types of cancer and its expression correlates with the severity of colon carcinoma. Using the human colon cell line Caco-2 we recently obtained evidence that PTHrP, through a paracrine pathway, exerts a protective effect under apoptotic conditions. However, if exogenous PTHrP is able or not to induce the proliferation of these intestinal tumor cells is not known. We found that PTHrP treatment increases the number of live Caco-2 cells. The hormone induces the phosphorylation and nuclear translocation of ERK 1/2, α p38 MAPK, and Akt, without affecting JNK phosphorylation. In addition, PTHrP-dependent ERK phosphorylation is reverted when PI3K activity was inhibited. Following MAPKs nuclear translocation, the transcription factors ATF-1 and CREB were activated in a biphasic manner. In addition PTHrP induces the translocation into the nucleus of ß-catenin, protein that plays key role in maintaining the growth and proliferation of colorectal cancer, and increases the amount of both positive cell cycle regulators c-Myc and Cyclin D. Studies with ERK1/2, α p38 MAPK, and PI3K specific inhibitors showed that PTHrP regulates Caco-2 cell proliferation via these signaling pathways. In conclusion, the results obtained in this work expand our knowledge on the role of exogenous PTHrP in intestinal tumor cells and identify the signaling pathways that are involved in the mitogenic effect of the hormone on Caco-2 cells.

Involvement of ERK1/2, p38 MAPK, and PI3K/Akt signaling pathways in the regulation of cell cycle progression by PTHrP in colon adenocarcinoma cells.

Parathyroid hormone-related peptide (PTHrP) is distributed in most fetal and adult tissues, and its expression correlates with the severity of colon carcinoma. Recently we obtained evidence that in Caco-2 cells, a cell line from human colorectal adenocarcinoma, exogenous PTHrP increases the number of live cells, via ERK1/2, p38 MAPK, and PI3-kinase and induces the expression of cyclin D1, a cell cycle regulatory protein. In this study, we further investigated the role of PTHrP in the regulation of the cell cycle progression in these intestinal cells. Flow cytometry analysis revealed that PTHrP treatment diminishes the number of cells in the G0/G1 phase and increases the number in both S and G2/M phases. The hormone increases the expression of CDK6 and diminishes the amount of negative cell cycle regulators p27Kip1, p15INK4B, and p53. However, PTHrP does not modify the expression of cyclin D3, CDK4, and p16INK4A. In addition, inhibitors of ERK1/2 (PD98059), p38 MAPK (SB203580), and PI3Kinase (LY294002) reversed PTHrP response in Caco-2 cells. Taken together, our results suggest that PTHrP positively modulates cell cycle progression and changes the expression of proteins involved in cell cycle regulation via ERK1/2, p38 MAPK, and PI3K signaling pathways in Caco-2 cells.