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Background: Mental illness is among the most common health conditions in the U.S., yet clients needing mental health services such as psychotherapy may not be able to receive these services because of mental health providers such as psychiatric/mental health nurse practitioners (PMHNPs). PMHNP students could be used as future clinicians to address this gap. However, little is known about PMHNP students' attitudes, knowledge, and modality preferences for providing psychotherapy., Aims: The purpose of this study was to qualitatively assess how PMHNP students' attitudes, knowledge, and modality preferences may change after educational exposure to this content in theories and modalities of psychotherapy course in a post-master's PMHNP program., Methods: A qualitative description design was used to collect data from formal writing assignments of 33 PMHNP students at the beginning and end of a one-semester course on theories and psychotherapy modalities. Responses were analyzed to form themes and categories while maintaining qualitative rigor., Results: Attitudes, knowledge, and preferred psychotherapeutic modalities changed from the beginning of the course when compared to the end. An increase in comfort, knowledge, and the preferred number of modalities increased both qualitatively and quantitatively throughout the course., Conclusions: Providing psychotherapy is an essential skill that is an important component of PMHNP education. More research is needed to learn the most efficient ways to increase attitudes, knowledge, and preferred modality. PMHNP faculty should encourage students to develop and refine beginning competency in psychotherapy during PMHNP educational programs.

As a result of significant advances in antiretroviral therapy (ART), the number of people living with human immunodeficiency virus (PLWH) who are alive well into their senior years has increased significantly in recent years. While increased life expectancy is a highly desired outcome for PLWH, it brings with it a number of challenges that are only now starting to be understood and fully appreciated. These challenges include higher rates of co-morbidities, polypharmacy, drug side effects, and cognitive deficits, as well as numerous psychosocial issues such as stigma, loneliness, and depression. Older PLWH also face challenges related to housing, health insurance, and long-term care. This review will discuss many of the challenges faced by older PLWH and present clinical and public health responses with suggested interventions that may improve outcomes for this population., (© 2024 Wiley Periodicals LLC.)

The prevalence of stress- and anxiety-related disorders is increasing along with widespread demand for anxiolytics. Due to drug supply shortages and access restrictions, nonprescription remedies have gained popularity. In addition, the marketing of herbals and botanicals as low-cost and all-natural products with fewer access restrictions has increased their use. The current article explores the evidence to provide an overview of the current understanding of Ashwagandha ( Withania somnifera ), an anxiolytic and apoptogenic herb with therapeutic and health-promoting potentials to help the body reduce stress and maintain a homeostatic state. Due to poor quality controls and diversity of Ashwagandha products, clinical trials on Ashwagandha's effectiveness in anxiety-related conditions reveal conflicting results, although many show favorable findings. Furthermore, health care professionals, such as nurses, advanced practice nurses, physicians, physician assistants, and pharmacists, need to be aware of variability in Ashwagandha products, quality controls, reported evidence regarding use, safety profile, and clinical implications in stress reduction. [ Journal of Psychosocial Nursing and Mental Health Services, 62 (4), 33-40.].

Abstract: Human trafficking (HT) affects an estimated 40.3 million people globally with 24.9 million people affected in forced labor and 4.8 million in forced sexual exploitation. An estimated 18,000 people are trafficked yearly into the United States. Reports suggest that between 63% and 87% of trafficked persons were seen by health care professionals and were unrecognized while in captivity. The authors designed and implemented an innovative pedagogical intervention for nurse practitioner (NP) students using a 10-min simulation-based education encounter with a standardized patient depicting a potential sex or labor HT clinical presentation. Results demonstrated that simulation-based education is a feasible way to provide HT education to NP students. It is imperative that future NPs receive education/training about HT to recognize potential victims and promote access to appropriate resources., Competing Interests: Competing interests: The authors report no conflicts of interest., (Copyright © 2023 American Association of Nurse Practitioners.)

Gambling disorders are a serious public health problem. This manuscript will provide a comprehensive overview on this topic. Gambling disorder involves repeated patterns of gambling behaviors, that result in significant distress or impairment in a person's interpersonal relationships, employment, educational/career opportunities, and finances over a period of 12 months. Gambling is defined as an activity that involves risking something of value with the hopes of acquiring something of greater value. Comparable to substance use disorders, individuals with a gambling disorder may be unsuccessful in exercising control over their problematic behavior, engage in the behavior despite negative consequences, and have preoccupations/cravings to gamble. Gambling disorder has higher comorbidity rates of mental disorders including depression, anxiety, substance use, and personality disorders. Gamblers rarely seek treatment. Treatments must be tailored to the individual which may include psychological interventions, cognitive behavioral therapy, gamblers anonymous, and psychopharmacological agents such as selective serotonin reuptake inhibitors, mood stabilizers, and opioid antagonists to treat clinical symptoms.

The current article is a comprehensive overview of electroconvulsive therapy (ECT) for treatment-resistant depression (TRD), especially with suicidality and psychosis. Common misconceptions and stigma associated with ECT are discussed. Major depressive disorder, one of the most prevalent lifetime mental disorders, is often associated with significant impairments that impacts one's ability to function. Antidepressants may be efficacious in treating depression; however, approximately one third of individuals do not respond to psychotropic medications. Therefore, other treatment options, such as ECT, must be considered for those who do not respond to medications, have psychosis, or are suicidal. [ Journal of Psychosocial Nursing and Mental Health Services, 61 (6), 11-17.].

Kava is a neuroactive medicinal herb that can induce pharmacological effects when ingested. As an herbal remedy, kava exhibits sedative, anesthetic, euphoriant, and entheogenic effects. Kava is used as a relaxant, pain reliever, and remedy for anxiety and insomnia. In the United States, kava is marketed as a safe dietary supplement. Kava's popularity is on the rise due to heightened awareness and interest in natural plant-based health alternatives. Although meta-analyses and systematic reviews of kava use in treating anxiety are favorable, results remain inconsistent. Due to poor quality control, diversity of kava products, and lack of standardization, health care professionals, such as nurses, advanced practice nurses, physicians, physician assistants, and pharmacists, need to be familiar with the pharmacology, possible polydrug interactions, and management of kava use as a remedy for anxiety-related conditions. The purpose of the current article is to provide an overview of kava and its use as a remedy for psychological issues, such as anxiety and nervousness. [ Journal of Psychosocial Nursing and Mental Health Services, 60 (12), 17-24.].

Abstract: Substance use disorders (SUDs) do not discriminate. Anyone can be affected regardless of age, sex, ethnicity, socioeconomic status, or profession. Nurses with SUDs present serious risks to both their patients and the nursing profession. Frontline nurses' responsibility to provide patients with safe, high-quality care may be too great a challenge for those with SUDs, resulting in adverse consequences. Early recognition and treatment of nurses with SUDs promotes patient safety and retention in the profession. For this reason, all nurses and other health care professionals should be able to recognize behaviors associated with SUDs and should be familiar with the available treatment modalities., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Transgender clients report experiencing discrimination and differential treatment by health care providers in clinical settings. This pilot study assessed prelicensure nursing students' attitudes, beliefs, and willingness to provide care for transgender individuals., Method: Participants enrolled in an adult health nursing course were asked to complete a demographic questionnaire, the Transgender Attitudes and Beliefs Survey, and a Willingness to Provide Clinical Care questionnaire., Results: Almost all of the participants reported positive attitudes toward transgender clients. Almost all of the participants reported a willingness to provide nursing skills; one participant was unwilling to perform genital or anal-related care., Conclusion: The majority of the prelicensure nursing students in this pilot study indicated they were willing to provide nursing care for transgender clients. More research is needed to assess prelicensure nursing students' learning needs regarding the provision of nursing care for transgender individuals. [ J Nurs Educ . 2022;61(6):322-325.] .

Objective: Some interventions have been developed and tested to reduce high risk sexual behaviors among Hispanic/Latino gay, bisexual, and men who have sex with men (MSM). The purpose of this paper is to critically appraise published interventions designed to reduce high risk sexual behaviors among Hispanic/Latino gay, bisexual, and MSM., Design/sample/measurement: A critical appraisal of published interventions designed to reduce high risk sexual behaviors among Hispanic/Latino gay, bisexual, and MSM was conducted. Using guidelines established by the Johns Hopkins Nursing Evidence-Based Practice Rating Scale published research articles were categorized and evaluated using these guidelines., Results: The critical appraisal identified nine intervention studies that met all inclusion criteria. The critical appraisal of these interventions highlighted strengths and weaknesses of these interventions which should be considered when developing future interventions to decrease high risk sexual practices among Hispanic/Latino gay, bisexual, and MSM., Conclusion: While several interventions have been created to specifically address HIV infection among Hispanic/Latino gay, bisexual, and MSM, these interventions were varied. Suggestions for future intervention development to decrease high risk sexual behaviors among Hispanic/Latino gay, bisexual, and MSM based on the findings of the critical appraisal of the literature are included., (© 2021 Wiley Periodicals LLC.)

Abstract: This case report presents a 40-year-old man presenting with mixed mental health symptoms including depression, anxiety, euphoria, sleep cycle disturbances, and alcohol use over several years. Multiple providers see the patient in varying specialties, initially focusing on depression, anxiety, and, later, substance use. Alcohol misuse can shadow underlying mental disorders. Therefore, early recognition and collaborative management are imperative to unveil the possibility of comorbid mental health disorders., Competing Interests: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the article., (Copyright © 2022 International Nurses Society on Addictions.)

In the United States, encounters related to mental and substance use disorders are common in emergency departments (EDs). Altered mental status (AMS) is a frequent presentation seen in EDs across the country. Individuals may present to the ED with altered thought processes, which may be attributed to intoxication from substances and/or psychoses, conditions that require immediate care and management. Health care providers must always ascertain the etiology of AMS, which may be challenging owing to the various causes of this impairment. The current article provides an overview of the most common disorders associated with AMS, which include underlying medical conditions, substance use, and mental disorders. [ Journal of Psychosocial Nursing and Mental Health Services, 59 (9), 16-25.].

Objectives: Five nationally representative U.S. federal data sources consistently showed the link between poverty and poor health outcomes. To determine the modality effective in teaching students about poverty and health, this study compared the attitudes toward poverty of students participating in the Community Action Poverty Simulation (CAPS) and the poverty table-top simulation (Dwell™)., Methods: In this quasi-experimental study, undergraduate and graduate nursing students and physical therapy students participated in either CAPS or a table-top simulation (TTS) depending on their semester of enrollment in the relevant course. The Undergraduate Perception of Poverty Tracking Survey (UPPTS) was administered before and after each simulation., Results: The analysis included 118 matched pairs. Using MANOVA tests, the authors found no group difference in the overall change of attitude after the simulations (p = .232). However, by the subscale analyses, TTS significantly increased students' willingness to help (p = .008, η 2  = 0.058) and their empathy toward those living in poverty (p = .039, η 2  = 0.039)., Conclusion: TTS participants had more elements of improvement, but both modalities were found to change participants' attitudes., (© 2021 Wiley Periodicals, Inc.)

Mental health disorders are common in the United States and may cause significant disturbances in all aspects of a person's life. Individuals with mental health disorders often present to emergency departments for health care. Recognizing and managing common psychiatric emergencies may be challenging for non-mental health providers. The Diagnostic Statistical Manual-5 diagnostic criteria will be discussed and reviewed for panic attack and panic disorder. Both pharmacologic and nonpharmacologic treatment strategies will also be addressed. Adverse drug reactions associated with antipsychotics and selective serotonin reuptake inhibitors are another common psychiatric emergency that will be examined, offering potential management strategies. The objective of this clinical manuscript is to educate emergency health care providers about specific psychiatric emergencies, including panic attack, panic disorder, and adverse drug reactions associated with mental health treatment medications., (Copyright © 2021 Emergency Nurses Association. Published by Elsevier Inc. All rights reserved.)

Abstract: Ayahuasca is a pan-Amazonian botanical hallucinogenic decoction made from a mixture of the bark of the Banisteriopsis caapi plant, containing a monoamine oxidase inhibitor, and Psychotria viridis (Rubiaceae) or Diplopterys cabrerana shrubs containing a serotonergic 2A receptor agonist, N,N-dimethyltryptamine, a powerful psychoactive substance. Ayahuasca is a traditional psychoactive sacrament that has been used for shamanic ceremonies for centuries. Ayahuasca is acclaimed for spiritual and psychotherapeutic benefits and is gaining popularity in the United States. Potential risks involved with usage of this hallucinogenic drug include psychotic episodes related to N,N-dimethyltryptamine and serotonin syndrome, which can be potentially life threatening. The consequences of ayahuasca use remain uncertain because of poor quality control, unpredictability, and polydrug interactions. Nurses, advanced practice nurses, and other healthcare providers working in outpatient settings, hospitals, and treatment centers need to be familiar with the pharmacology, possible drug interactions, and management for ayahuasca ingestion for optimal decision making. Nurses are well positioned to facilitate understanding and to advise and educate the public about the potential risks associated with ayahuasca ingestion., Competing Interests: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the article., (Copyright © 2021 International Nurses Society on Addictions.)

Introduction: Human immunodeficiency virus (HIV) is a significant health issue among Hispanic men who have sex with men (MSM). Despite existing research, no studies have compared psychosocial factors by self-reported HIV antibody status., Method: Participants ( n = 150) completed measures of social support, loneliness, depressive symptoms, substance use, and sexual behaviors., Results: Participants with a self-reported HIV-antibody positive status reported lower levels of social support and higher levels of illicit substance use. Hispanic MSM with an unknown HIV antibody status reported more sexual partners., Conclusion: More research is needed to address psychosocial factors (social support, loneliness, depressive symptoms), substance use, and sexual behaviors among Hispanic MSM.

Kratom is an herbal drug originating from the Mitragyna speciosa, a plant indigenous to Southeast Asia. Kratom has been widely used for its stimulant and opioid-like effects derived from its main psychoactive alkaloid properties mitragynine and 7-hydroxymitragynine. In the United States, kratom is gaining popularity as an herbal and natural dietary supplement, as well as a natural and legal alternative to narcotics. Kratom use is typically accompanied by increasing tolerance and dependence making it highly problematic. Kratom's potentially toxic and lethal properties have become an emerging public health threat. Due to deficiencies of governmental controls and its rising prevalence among individuals who ingest kratom, health care providers need to be familiar with the pharmacology, adverse effects, and problems associated with kratom ingestion when caring for individuals. [Journal of Psychosocial Nursing and Mental Health Services, 57(12), 15-20.]., (Copyright 2019, SLACK Incorporated.)

There are many challenges facing healthcare professionals. One such challenge is the continuous introduction of new synthetic drugs. Synthetic drugs pose many difficulties to providers, including identification of the drug ingested, management of symptoms, ensuring safety of the patient and his or her environment, and continual monitoring after the initial symptoms, because synthetic cathinones have many long-term effects on an individual. One such synthetic drug, flakka, is a potent second-generation synthetic cathinone. Because flakka inhibits the reuptake of norepinephrine and dopamine, which are involved in one's perception of pleasure, it causes inflated feelings and also causes signs and symptoms of psychosis. Flakka also induces various exaggerated symptoms, such as feelings of incredible strength, disorientation, aggression, and altered thought processes, and also can cause hyperthermia, coma, and death. Healthcare professionals need to understand the nature of flakka ingestion, the various symptoms a user may exhibit, and the long-term symptoms a person may have once the acute recovery phase has ended. Once the initial phase of ingestion is over and the patient is medically stabilized, the patient may experience signs and symptoms of psychosis or other psychiatric disorders. It is paramount that healthcare professionals are able to recognize the signs and symptoms of flakka ingestion, know the steps to take to ensure safety of the patient and those around him or her, and also know how to facilitate the patient's recovery.

Background: There is disparity in the nursing work-force of minority leaders. The aim of this article is to describe and evaluate an innovative program designed to provide mentorship and increase leadership skills of minority nursing students., Method: An innovative mentorship program was developed including coordination of financial aid meetings, incorporating technology, enacting an online preimmersion course, choosing and training mentors, hosting a lunch-and-lead leadership series, and using intensive review sessions and tutoring. Program evaluation data were analyzed using mixed methods., Results: All 40 participants passed the NCLEX-RN and had obtained employment after the program. Of the 20 respondents, 25% already had obtained a leadership role in nursing. Qualitative data about the program revealed categories of leadership, networking, mentorship, more time, and gratitude., Conclusion: This program was successful in promoting retention, graduation, and development of future minority nurse leaders. [J Nurs Educ. 2018;57(9):526-534.]., (Copyright 2018, SLACK Incorporated.)

Aims and Objectives: Explore different methods by which intimate partner violence screening practices are implemented in clinic and emergency settings and better understand barriers and facilitators., Background: Healthcare visits provide an opportunity for providers to identify and provide assistance to victims of intimate partner violence. However, wide variation exists in the implementation of screening and response protocols. In addition, providers experience barriers and facilitators to intimate partner violence screening and response. A comprehensive understanding of these factors is necessary to improve the role that providers play in detection and intervention of intimate partner violence., Design: Qualitative descriptive research design., Methods: Sixteen healthcare facilities were recruited from a large metropolitan area in the USA. Data were collected through semi-structured, in-depth interviews with individuals knowledgeable about intimate partner violence screening and response within their facility. Data were analysed using directive content analysis., Results: Major themes and patterns concerning intimate partner violence screening and response were identified within the following areas: procedural characteristics, barriers, facilitators and additional needs. Patient-provider communication and operational/facility characteristics emerged as critical aspects that impact the successful implementation of intimate partner violence screening and response programmes. Differences were found between clinic and emergency settings stemming from variations in health delivery models., Conclusions: Results provide important information on how healthcare facilities implement intimate partner violence screening and response, suggestions for practice improvement and directions for future interventions. Additional guidance is needed to ensure intimate partner violence identification, and response procedures are effective and tailored to needs of patients, providers and the facility., Relevance to Clinical Practice: Nurses are in a strategic position to play a pivotal role in identification of and response to intimate partner violence. It is essential that nurses are cognizant of this, and understand the actions they can take to assist patients who have been victims of intimate partner violence. Recommendations on how to do this are provided., (© 2016 John Wiley & Sons Ltd.)

This article will review an innovative on-line preimmersion course for a hybrid doctor of nursing practice (DNP) program and a traditional face-to-face doctor of philosophy nursing program. The doctoral candidates include both postbaccalaureate and postmaster's students. The authors of the preimmersion course developed and initiated the course in order to address various issues that have surfaced in discussions between students and faculty. Examples of common themes identified include writing skills, statistics, life-work-school balance, and navigating instructional technology. Doctoral studies may pose challenges to students studying nursing, in regard to academic rigor and experiencing on-line education for the first time, especially for students who have been out of school for an extended amount of time or are not accustomed to a nontraditional classroom; thus, having a preimmersion course established may facilitate a smooth transition to rigorous academic studies in a hybrid program. The course, which was developed and delivered through Blackboard, a learning management system, includes the following 9 preimmersion modules: academic strategies (learning styles, creating an effective PowerPoint presentation), library support (introduction to the university library, literature review tutorial, and citation styles), mindfulness, wellness, statistics essentials, writing express, DNP capstone, netiquette, and DNP/doctor of philosophy mentorship. Each module consists of various tools that may promote student success in specific courses and the programs in general. The purpose of designing the preimmersion course is to decrease attrition rates and increase success of the students. While the majority of students have succeeded in their coursework and been graduated from the program, the authors of this article found that many students struggled with the work, life, and school balance. Future work will include the evaluation of results from graduate students enrolled in the program., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Purpose: This study examines policies and procedures for identifying and responding to intimate partner violence (IPV) among different types of health care settings., Methods: This epidemiologic, cross-sectional, observational study design collected data from June 2014 to January 2015 through a telephone questionnaire from a stratified random sample of 288 health care facilities in Miami-Dade County, Florida. An overall response rate of 76.2% was achieved from 72 primary care clinics, 93 obstetrics/gynecology clinics, 106 pediatric clinics, and 17 emergency departments (EDs)., Results: There is a general awareness of the importance of IPV screening with 78.1% of facilities (95% CI, 73.9%-82.3%) reporting some type of IPV screening procedures. Wide variation exists, however, in how practices are implemented, with only 35.3% of facilities (95% CI, 29.5%-41.1%) implementing multicomponent, comprehensive IPV screening and response programs. Differences were also observed by setting with EDs reporting the most comprehensive programs., Conclusions: This study yields important empirical information regarding the extent to which IPV screening and response procedures are currently being implemented in both clinic and acute health care settings along with areas where improvements are needed., (Copyright © 2016 Jacobs Institute of Women's Health. Published by Elsevier Inc. All rights reserved.)

In the pediatric critical care setting, change of shift report/handoff does not traditionally occur at the bedside. During report, the nurses share important information that promotes patient safety and continuity of care. The goal of educating the nursing staff about family-centered care and shift report at the bedside is to promote better communication, a more comprehensive handoff, enhanced patient safety, engagement of the patient/family, and increased patient/family and staff satisfaction.

The endothelin A receptor (ET(A)R) autocrine pathway is overexpressed in many malignancies, including ovarian carcinoma. In this tumor, engagement of ET(A)R triggers tumor growth, survival, neoangiogenesis, and invasion. To evaluate whether ET(A)R represents a new target in cancer treatment, we examine in vitro and in vivo the effect of the selective ET(A)R antagonist ABT-627 (atrasentan), a small p.o. bioavailable molecule, in mono- and combination therapy with taxane. ABT-627 effectively inhibits cell proliferation, vascular endothelial growth factor (VEGF) secretion of ovarian carcinoma cell lines, and primary cultures. ET(A)R blockade also results in the sensitization to paclitaxel-induced apoptosis. In ovarian carcinoma xenografts, in which the ET-1/ET(A)R autocrine pathway is overexpressed, tumor growth was significantly inhibited in ABT-627-treated mice compared with control. The therapeutic efficacy of ABT-627 was associated with a significant reduction in microvessel density, expression of VEGF, and matrix metalloproteinase-2, and increased the percentage of apoptotic tumor cells. Combined treatment of ABT-627 with paclitaxel produced additive antitumor, apoptotic, and antiangiogenic effects. These findings demonstrate that the small molecule ABT-627 is a candidate for clinical testing as an antitumor agent in ovarian cancer patients, especially in combination with taxane therapy. Interruption of ET(A)R signaling therefore, represents, a promising therapeutic strategy in ovarian carcinoma.

In human papillomavirus (HPV)-positive cervical cancer cells, the endothelin A receptor (ET(A)R) mediates an endothelin-1-induced mitogenic effect, thus representing a relevant target for antitumor therapy. Here, we describe the complete inhibition of human cervix carcinoma growth by blocking the ET(A)R. In nude mice, the ET(A)R-selective antagonist atrasentan inhibits the growth and the neoangiogenesis of cervical carcinoma cell xenografts. Two cycles of treatment completely revert tumor growth. Atrasentan displays additive effects when administered in combination with the cytotoxic drug paclitaxel. These results demonstrate that by inhibiting cell proliferation and angiogenesis, this small molecule may help to control cervical cancer by either monotherapy or combination therapy.

Endothelin-1 (ET-1) is a potent mitogenic and angiogenic factor for ovarian carcinoma cell lines, which acts selectively through the ET(A) receptor (ET(A)R). A previous study demonstrated that ET-1 is present at high concentrations in ovarian cancer ascites, indicating a direct role in the progression and metastasis of ovarian carcinoma. In this study, we investigated whether ET-1 could induce production and activation of tumour-associated proteinases in ovarian carcinoma cells. As demonstrated by ELISA, we found that the secretion of matrix metalloproteinase (MMP)-2 and MMP-9, urokinase-type plasminogen activator and plasminogen activator inhibitor type-1 and -2 was upregulated by ET-1 in a dose-dependent manner in the HEY cell line. In addition, the MMPs in ET-1-treated cells are consistently active, as shown by MMP gelatinase activity assay. Finally, we demonstrated that BQ-123, an antagonist of ET(A)R, inhibited the ET-1-induced tumour protease secretion and activity, suggesting that ET-1/ET(A)R may play an important role in the progression and metastasis of ovarian carcinoma, activating multiple proteinase cascades.

Human papillomaviruses (HPVs) are associated with cervical cancer and interact with growth factors that may enhance malignant transformation of cervical carcinoma cells. Endothelin-1 (ET-1) is released from HPV-transfected keratinocytes and induces increased growth response in these cell lines in comparison with normal cells. HPV-positive cancer cells secrete ET-1 and express mRNA for ET-1 and its receptors, whereas HPV-negative carcinoma cell lines express only the ET(B) receptor (ET(B)R) mRNA and do not secrete ET-1. In HPV-positive cancer cells, ET(A)R mediates the ET-1-induced mitogenic effect and sustains the basal growth rate of unstimulated cervical tumour cells. Therefore, ET-1 may be involved in the neoplastic growth of HPV-associated cervical carcinoma, where the increased ET-1 autocrine loop can be targeted for antitumour therapy. In the present work, the action of specific antagonists of ET(A)R (BQ-123 and ABT-627), was analysed in CaSki and C33A cells that are derived from human cervical carcinoma. CaSki cells are HPV-16-positive, produce ET-1 and possess ET(A)R and ET(B)R, whereas the C33A line is HPV-negative, does not secrete ET-1 and has no ET(A)R. In HPV-positive cancer cells ABT-627 strongly inhibited the proliferation induced by ET-1 and substantially reduced the basal growth rate of unstimulated cervical tumour cells, whereas the ET(B)R antagonist had no effect. These results demonstrate that ET-1 participates in the progression of neoplastic growth in HPV-associated carcinoma, in which ET(A)R expression is increased and could be targeted for antitumour therapy. In conclusion, an ET-1 autocrine loop is involved in tumour cell proliferation via ET(A)R, and ABT-627 is effective in controlling proliferation of cervical carcinoma cells.

Endothelin-1 (ET-1) is present at high concentrations in ovarian cancer ascites and is overexpressed in primary and metastatic ovarian carcinomas. In these tumours the presence of ET-1 is associated with enhanced neovascularization and with vascular endothelial growth factor (VEGF) expression. In these tumour cells, ET-1 acts as an autocrine growth factor selectively through the receptor ET(A), which is predominantly expressed in tumour cells. Furthermore, ET-1 produced by ovarian tumour cells stimulates VEGF production and VEGF-mediated angiogenic effects through ET(A) binding. These results demonstrate that activation of the ET(A) in ovarian carcinoma cells promotes cell proliferation, neovascularization and invasion, which are the principal hallmarks of malignant transformation. The present study was designed to investigate the effects of the ET(A)-selective antagonist ABT-627 on the ET-1-induced mitogenic effect in both primary cultures (PMOV1 and PMOV2) and cell lines (OVCA 433 and HEY) of ovarian carcinoma. All tumour cells express the components of the ET-1 system and secrete ET-1. ET(A) blockade by ABT-627 inhibits ET-1-induced mitogenic effects. The ET(B) antagonist BQ-788 is ineffective although all cell lines express both ET(A) and ET(B) mRNAs. In conclusion, our results demonstrate that ABT-627 is capable of inhibiting the proliferative activity of ET-1, suggesting that this potent ET(A) antagonist may provide a novel approach to the multidisciplinary treatment of ovarian carcinoma.

The aim of this study was to evaluate the role of endothelin-1 (ET-1) in the sensitivity of ovarian carcinoma to paclitaxel, one of the most common drugs used for the management of this tumour histotype. ET-1 is a powerful mitogenic peptide produced by ovarian carcinomas and it acts as an autocrine growth factor, selectively through ET(A) receptor (ET(A)R), which is predominantly expressed in this tumour. OVCA 433 and HEY, two ovarian carcinoma cell lines, which produce elevated amounts of ET-1 and express abundantly high-affinity ET(A)Rs, were used. As demonstrated by sub-G(1) peak in DNA content histograms and terminal transferase deoxytidyl uridine end labelling assay, we found that paclitaxel induces cytotoxic effect through the activation of apoptosis in both cell lines. When the treatment with paclitaxel was performed in association with ET-1, paclitaxel-induced apoptosis was inhibited. In order to evaluate which ET-1 receptor mediated the effect of ET-1 on protection from paclitaxel-induced apoptosis, we performed experiments using two selective antagonists for ET(A)R (BQ-123) and for ET(B)R (BQ-788). We showed that ET(A)R blockade inhibits the ET-1-induced survival activity against paclitaxel-mediated apoptosis. However, no effect was observed on blocking ET(B)R with BQ-788. Our results establish a novel role for ET-1 in determining survival of ovarian carcinoma cells and suggest that pharmacological ET(A)R blockade using a specific ET(A)R antagonist may provide a novel approach to the treatment of ovarian carcinoma in combination therapy.

Endothelin-1 (ET-1) is a powerful mitogenic peptide produced by different tumors. In ovarian carcinoma cells, ET-1 acts as an autocrine growth factor, selectively through ET(A) receptor (ET(A)R), which is predominantly expressed in tumor cells. The aim of this study was to examine whether ET-1 plays a role in the sensitivity of three ovarian carcinoma cell lines (OVCA 433, HEY, and SK-OV-3) to apoptosis induced by two different stimuli. Our results demonstrated that the addition of ET-1 markedly inhibited serum withdrawal and paclitaxel-induced apoptosis in a concentration-dependent manner, as demonstrated by Annexin-V assay, sub-G(1) peak in DNA content histograms, internucleosomal DNA fragmentation, and terminal deoxynucleotidyl transferase-mediated dUTP biotin nick-end labeling method. Pretreatment of the cells with an ET(A)R antagonist, BQ 123, reversed the ET-1-induced protective effect. Paclitaxel-induced apoptosis resulted in the phosphorylation of Bcl-2 that was suppressed by the addition of ET-1. Further analysis of the signaling pathway demonstrated that ET-1 stimulated Akt activation. The phosphatidylinositol 3-kinase (PI3-K) inhibitor wortmannin blocked ET-1-induced Akt phosphorylation. Inhibition of ET-1-stimulated mitogen-activated protein kinase activity did not affect ET-1 protection from paclitaxel-mediated apoptosis. Moreover, BQ 123 blocked the Akt-mediated pathway activated by ET-1, sensitizing ovarian carcinoma cells to paclitaxel treatment. These results establish a novel role for ET-1 in determining protection of ovarian carcinoma cells against paclitaxel-induced apoptosis through Bcl-2-dependent and PI3-K-mediated Akt pathways and suggest that ET-1 and ET(A)R could represent important targets for anticancer therapy.

Endothelin-1 (ET-1) is present at high concentrations in ovarian cancer ascites and is overexpressed in primary and metastatic ovarian carcinoma. In these cells, ET-1 acts as an autocrine mitogenic and angiogenic factor selectively through the ET(A) receptor (ET(A)R). We investigated at mRNA and protein levels whether ET-1 could affect the expression and activation of metastasis-related proteinases and whether this process was associated with ovarian tumor cell invasion. ELISA, gelatin zymography, Western blot, and reverse transcription-PCR analyses demonstrated that in two ovarian carcinoma cell lines (HEY and OVCA 433), the expression of matrix metalloproteinase (MMP) -2, -9, -3, -7, and -13 was up-regulated and activated by ET-1. Moreover we observed that ET-1 was able to enhance the secretion and activation of membrane-type metalloproteinase-1, a critical mediator of invasiveness. The secretion of tissue inhibitor of metalloproteinase-1 and -2 was decreased by ET-1, which increased the net MMP/tissue inhibitor of metalloproteinase balance and the gelatinolytic capacity. In addition, ET-1 induced overexpression of urokinase-type plasminogen activator, its receptor, and plasminogen activator inhibitor type-1 and -2. Finally, we demonstrated that, in HEY and OVCA 433 cells, ET-1 dose-dependently increased migration and MMP-dependent invasion through Matrigel. BQ123, an antagonist of the ET(A)R, inhibited the ET-1-induced tumor protease activity and subsequent increase in cell migration and invasion. These findings demonstrate that ET-1 promotes ovarian carcinoma cell invasion, acting through the ET(A)R by up-regulating secretion and activation of multiple tumor proteinases. Therefore, ET-1 may represent a key component of more aggressive ligand-induced invasiveness of ovarian carcinoma.

Endothelin-1 (ET-1) has been shown to be mitogenic for endothelial and several tumor cells through an autocrine mechanism. In this study we evaluated whether the tumorigenic KS IMM cell line deriving from Kaposi's sarcoma (KS), a highly angiogenic tumor, is susceptible to ET-1 mitogenic activity. By reverse transcriptase-polymerase chain reaction, we detected ET-1 mRNA expression and both ET(A) receptor (ET(A)R) and ET(B)R mRNA transcripts in the KS IMM cells. High concentrations of ET-1 are released from the KS IMM cells and competition-binding studies demonstrated that these cells also express functional ET(A)R and ET(B)R with high affinity for ET-1 and ET-1/ET-3, respectively. Expression of ET-1 and cognate receptors could be detected by immunohistochemical method in vitro, in KS IMM xenograft, and in tissue sections of a human KS lesion. Furthermore ET-1 induces a marked and dose-dependent increase in [3H]thymidine incorporation comparable to that elicited by vascular endothelial growth factor. Addition of both selective ET(B)R antagonist (BQ 788) and ET(A)R antagonist (BQ 123), completely blocked ET-1-induced mitogenic response and reduced the basal growth rate of unstimulated cells, suggesting that both receptors mediated the proliferative signal. Such findings demonstrate that ET-1 participates on KS pathogenesis acting as an autocrine growth factor and that ET-1 receptor antagonists may thus be novel candidates for therapeutic intervention.

The endothelial cell-derived endothelin-1 (ET-1) is a potent mitogen for endothelial cells, vascular smooth muscle cells, and tumor cells. In this study, we analyzed the role of ET-1 on human umbilical vein endothelial cell (HUVEC) phenotype related to different stages of angiogenesis. ET-1 promoted HUVEC proliferation, migration, and invasion in a dose-dependent manner. The ET(B) receptor (ET(B)R) antagonist, BQ 788, blocked the angiogenic effects induced by ET-1, whereas the ET(A)R antagonist was less effective. ET-1 stimulated matrix metalloproteinase-2 mRNA expression and metalloproteinase-2 production, as determined by reverse transcriptase-polymerase chain reaction and gelatin zymography. Furthermore ET-1 was able to enhance HUVEC differentiation into cord vascular-like structures on Matrigel. When tested in combination with vascular endothelial growth factor (VEGF), ET-1 enhanced VEGF-induced angiogenic-related effects on endothelial cells in vitro. Finally, using the Matrigel plug neovascularization assay in vivo, ET-1 in combination with VEGF stimulated an angiogenic response comparable to that elicited by basic fibroblast growth factor. These findings demonstrated that ET-1 induces angiogenic responses in cultured endothelial cells through ET(B)R and that stimulates neovascularization in vivo in concert with VEGF. ET-1 and its receptors acting as angiogenic regulators might represent new targets for anti-angiogenic therapy.

Endothelin-1 (ET-1) is overexpressed in ovarian carcinomas and acts, via ET(A) receptors (ET(A)R), as an autocrine growth factor. In this study we investigate the role of ET-1 in the neovascularization of ovarian carcinoma. Archival specimens of primary (n = 40) and metastatic (n = 8) ovarian tumors were examined by immunohistochemistry for angiogenic factor and receptor expression and for microvessel density using antibodies against CD31, ET-1, vascular endothelial growth factor (VEGF), and their receptors. ET-1 expression correlated with neovascularization and with VEGF expression. The localization of functional ET(A)R and ET(A)R mRNA expression, as detected by autoradiography and in situ hybridization, was evident in tumors and in intratumoral vessels, whereas ET(B)R were expressed mainly in endothelial cells. High levels of ET-1 were detected in the majority of ascitic fluids of patients with ovarian carcinoma and significantly correlated with VEGF ascitic concentration. Furthermore ET-1, through ET(A)R, stimulated VEGF production in an ovarian carcinoma cell line, OVCA 433, by an extent comparable to hypoxia. Finally, conditioned media from OVCA 433 as well as ascitic fluids caused an increase in endothelial cell migration and the ET-1 receptor blockade significantly inhibited this angiogenic response. These findings indicate that ET-1 could modulate tumor angiogenesis, acting directly and in part through VEGF.

Human papillomaviruses (HPV) are associated with cervical cancer and interact with growth factors that may enhance malignant transformation of cervical carcinoma cells. Endothelin-1 (ET-1) is released from HPV transfected keratinocytes and induces increased growth response in these cell lines in comparison with normal cells. In the present study several cervical carcinoma cell lines have been analyzed to investigate the expression of ET-1 and its receptors as well as their involvement in tumor growth. All HPV-positive cancer cells secreted ET-1 and expressed mRNA for ET-1 and its receptors, whereas a HPV-negative carcinoma cell line expressed only the ETBR mRNA and didn't secrete ET-1. Binding studies showed that HPV-associated cells expressed an increased number of functional ETAR. ET-1 stimulated a marked dose-dependent increase in [3H]-thymidine incorporation with respect to the normal cells whereas ET-3 and ETBR agonists had no effect. In HPV-positive cancer cells, a specific antagonist of ETAR inhibited the proliferation induced by ET-1 and substantially reduced the basal growth rate of unstimulated cervical tumor cells, whereas the ETBR antagonist had no effect. These results demonstrate that ET-1 participates in the progression of neoplastic growth in HPV-associated carcinoma, in which ETAR are increased and could be targeted for antitumor therapy.

In the present study, we have investigated the expression of endothelin 1 (ET-1) and the ET(A) receptor (ET(A)R) and ET(B) receptor (ET(B)R) in primary (n = 30) and metastatic (n = 8) ovarian carcinomas and their involvement in tumor growth. By reverse transcription-PCR and Northern blot analysis, we detected ET-1 mRNA in 90% of primary and 100% of metastatic ovarian carcinomas. ET-1 mRNA expression was significantly higher in tumors than in normal ovarian tissues (n = 12; P < 0.01). ET(A)R mRNA was also detected in 84% of the carcinomas examined, whereas ET(B)R mRNA was expressed in 50% of the tumors. The in vivo presence of mature ET-1 and ET(A)R was confirmed by immunohistochemistry, demonstrating a higher expression in primary and metastatic cells. Ten primary cultures of ovarian tumors secreted ET-1 and were positive for ET-1 and ET(A)R mRNA, whereas only 40% expressed ET(B)R mRNA. Radioligand binding studies showed that ET-1-producing cells also expressed functional ET(A)R, whereas no specific ET(B)R could be demonstrated. ET-1 stimulated dose-dependent [3H]thymidine incorporation and enhanced the mitogenic effect of epidermal growth factor. The ET(A)R-selective antagonist BQ 123 strongly inhibited ET-1-stimulated growth and substantially reduced the basal growth rate of unstimulated cells, whereas the ET(B)R-selective antagonist BQ 788 had no effect. In conclusion, the present data demonstrate a novel mechanism in the growth control of ovarian carcinoma in vivo mediated by the ET-1 autocrine loop that selectively occurs via the ET(A)R.

Endothelins (ETs), in addition to their systematical activities, exert important functions at the skin level, such as increase of keratinocyte proliferation, neo-angiogenesis and leukocyte chemotaxis, which are among the main characteristics of psoriasis. To assess a possible ET-1 involvement in plaque-type psoriasis, ET-1 determinations were carried out in 15 sera and 8 lesional and non-lesional biopsy skin extracts from psoriatic patients and in 15 sera and 5 biopsy skin extracts from healthy volunteers, sex- and age-matched, using commercially available ELISA kits. A statistical analysis of the results showed that ET-1 levels were increased in sera of psoriatic patients, as compared to normal subjects (p = 0.04). In addition, there was a significant correlation between both serum (r = 0.60, p = 0.02) and lesional skin (r = 0.80, p = 0.03) ET-1 values versus the Psoriasis Area and Severity Index scores. Significant increases of the lesional versus the non-lesional (p = 0.01) and versus the normal (p = 0.04) ET-1 skin extract values were observed, together with a significant correlation between lesional and non-lesional ET-1 skin levels (r = 0.79, p = 0.03). These findings were also confirmed at the mRNA level, using RT-PCR analysis, where increased ET-1 mRNA levels, densitometrically measured, were found in the lesional samples versus non-lesional and normal skin. Since interleukin-8 is involved in psoriasis and shares some biological properties with ET-1, we further evaluated the levels of this cytokine in skin extracts. The behaviour of interleukin-8 paralleled that of ET-1, and a significant correlation between these two molecules was observed in the lesional skin (r = 0.76, p = 0.05). Taken together, these data stress that, as previously described for interleukin-8, ET-1 may be involved in inflammatory processes associated with psoriasis.