Neuroendocrine Factors Research Articles

Investigating Neuroendocrine Regulation in Physiological Processes: Advancements in Techniques, Challenges and Future Direction for Human Health

Neuroendocrine regulation plays a pivotal role in orchestrating various physiological processes in organisms. The neuroendocrine system is a complex, multifaceted process that acts as a resource distributor in the body, monitoring and regulating a variety of physiological functions like metabolism, reproduction, stress response, and immunity by using complicated signaling pathways and sophisticated feedback mechanisms that use hormones, neurotransmitters, and neural circuits. This study aims to investigate the intricate mechanisms by which neuroendocrine signals modulate physiological functions. Adjuvant neuroendocrine strategies such as the use of neurotransmitters, hormones, pharmacotherapy, surgical intervention, and emerging technologies play an invaluable role in alleviating symptoms and improving outlooks for people suffering from these conditions. Through a comprehensive review of current literature, we explore the role of neuroendocrine pathways in regulating processes such as metabolism, reproduction, stress response, and immune function. We highlight the involvement of key neuroendocrine factors such as hormones, neuropeptides, and neurotransmitters in modulating these physiological processes. Additionally, authors discuss emerging research avenues and potential clinical implications of understanding neuroendocrine regulation in health and disease.

Macrophytes mitigate Microcystis aeruginosa-induced fish appetite suppression via intestinal metabolite regulation

Cyanobacterial blooms and aquatic macrophytes can affect the health, physiology, and behavior of freshwater fish. Changes in food intake can be a key indicator of stress in teleost fish, while changes in metabolite abundance in the gut can indicate a shift in metabolic priorities, including response to environmental stressors. Here, we exposed stone moroko (Pseudorasbora parva) to the cyanobacterium Microcystis aeruginosa and/or the macrophyte Ottelia acuminata and analyzed changes in fish health, appetite regulation, and intestinal metabolome after 96-h exposures. We found that O. acuminata treatment didn’t change the tested indicators, while exposure to M. aeruginosa increased concentrations of appetite-inhibiting factors, such as CART and GLP-1, and decreased concentrations of stimulatory factors like orexin. Exploration of the metabolome following exposure revealed that the appetite-inhibiting influence of M. aeruginosa was positively correlated with key metabolites of lipid, amino acid, and cholesterol metabolism, especially those associated with bile acid synthesis and secretion. Further, the presence of O. acuminata decreased the adverse effects of M. aeruginosa among neuro-endocrine regulatory factors, which could be explained by altered regulation of intestinal amino acid metabolites. The deeper mechanism by which O. acuminata moderates the harmful effects of M. aeruginosa remains to be identified.

A Complex Condition; Polycystic Ovary Syndrome (PCOS): A Review of its Recent Advanced Treatment

Abstract: Polycystic ovary syndrome (PCOS) is a common endocrine and metabolic disorder affecting women worldwide. It refers to a condition that often has ‘poly’ liquid containing sacks around ovaries. It affects reproductive-aged females, giving rise to menstrual and related reproductive issues. PCOS is marked by hormonal imbalance, often resulting in hyperandrogenism. Women with PCOS might experience abnormal insulin activity and complications such as acne, mood swings, hirsutism, obesity, and infertility. The disease is linked with severe clinical ailments such as type 2 diabetes (T2DM), cardiovascular diseases (CVDs), and cancer. A faulty lifestyle, neuroendocrine factors, genetic causes, and androgen exposures often cause PCOS. The approach of society towards physiological problems such as PCOS in women is that it must be under the veil that is the ultimate barrier to the early diagnosis of PCOS. Thus, this review summarizes the causes, symptoms, pathophysiology, diagnosis, and possible treatment (medical, herbal, and lifestyle improvement, acupuncture, and bariatric surgery) related to PCOS.

The Ability of Indigenous Plants in Alleviating Rheumatoid Arthritis: A Comprehensive Review.

Rheumatoid Arthritis is a long-lasted, inflammatory, systemic autoimmune disease that predominantly manifests in people between the ages of 30 and 50 Rheumatoid arthritis is characterized by more than a half-hour of morning stiffness in the affected joints, fever, soreness, swelling, weight loss, tiredness, warm joints, and subcutaneous rheumatoid nodules. Hormonal, genetic, epigenetic, reproductive, and neuroendocrine risk factors, as well as comorbid host variables, are the categories of host-related risk factors associated with the evolution of RA. Additional risk variables that have been linked to RA include food, environmental variables, socioeconomic status, smoking, microbiome, infection agents, and other airborne exposures. The objective of RA therapies is to minimise joint deformity and destruction, minimise discomfort and inflammation in the joints, and maximise joint function.Growing data suggests that the course of Rheumatoid Arthritis is affected by the minimisation of disease activity caused by disease-modifying medications, and that patients may benefit from early antirheumatic medication delivery that modifies illness. While numerous herbs have been explored for their anti-inflammatory properties, it is important to note that not all herbs have been thoroughly researched. This review focuses on seventeen native plant species that have shown either promising or established anti-arthritic effects based on preclinical and clinical studies where available. The review highlights the biochemical and immunological attributes of these herbs, summarizing their therapeutic potential for RA management while also acknowledging the limitations and gaps in current research. This examination provides insights into the potential of these herbal treatments for RA and calls for further research to explore their efficacy and safety in greater depth.

MA19.03 SMARCA4 Controls State Plasticity in SCLC Through Regulation of Neuroendocrine Transcription Factors and REST Splicing

MA19.03 SMARCA4 Controls State Plasticity in SCLC Through Regulation of Neuroendocrine Transcription Factors and REST Splicing

Effects of prenatal cocaine exposure on estrous cycle, and behavior and expression of estrogen receptor alpha and oxytocin during estrus and diestrus in mice offspring.

Increasing evidence indicates that prenatal cocaine exposure may result in many developmental and long-lasting neurological and behavioral effects. The behaviors of female animals are strongly associated with the estrous cycle. Estrogen receptors and oxytocin are important neuroendocrine factors that regulate social behavior and are of special relevance to females. However, whether prenatal cocaine exposure induces estrous cycle changes in offspring and whether neurobehavioral changes in estrus and diestrus offspring differ remains unclear. On gestational day 12, mice were administered cocaine once daily for seven consecutive days, then the estrous cycle was examined in adult female offspring, as well as locomotion, anxiety level, and social behaviors, and the expression of estrogen receptor alpha-immunoreactive and oxytocin-immunoreactive neurons were compared between estrus and diestrus offspring. Prenatal cocaine exposure resulted in the shortening of proestrus and estrus in the offspring. During estrus and diestrus, prenatally cocaine-exposed offspring showed increased anxiety levels and changed partial social behaviors; their motility showed no significant differences in estrus, but declined in diestrus. Prenatal cocaine exposure reduced estrogen receptor alpha-immunoreactive expression in the medial preoptic area, ventromedial hypothalamic nucleus, and arcuate nucleus and oxytocin-immunoreactive expression in the paraventricular nucleus in estrus and diestrus offspring. These results suggest that prenatal cocaine exposure induces changes in the offspring's estrous cycle and expression of estrogen receptor alpha and oxytocin in a brain region-specific manner and that prenatal cocaine exposure and the estrous cycle interactively change motility and partial social behavior. Estrogen receptor alpha and oxytocin signaling are likely to play important concerted roles in mediating the effects of prenatal cocaine exposure on the offspring.

Vasopressin drives aberrant myeloid differentiation of hematopoietic stem cells, contributing to depression in mice

Psychological stress is often linked to depression and can also impact the immune system, illustrating the interconnectedness of mental health and immune function. Hematopoietic stem cells (HSCs) can directly sense neuroendocrine signals in bone marrow and play a fundamental role in the maintenance of immune homeostasis. However, it is unclear how psychological stress impacts HSCs in depression. Here, we report that neuroendocrine factor arginine vasopressin (AVP) promotes myeloid-biased HSC differentiation by activating neutrophils. AVP administration increases neutrophil and Ly6Chi monocyte production by triggering HSCs that rely on intrinsic S100A9 in mice. When stimulated with AVP, neutrophils return to the bone marrow and release interleukin 36G (IL-36G), which interacts with interleukin 1 receptor-like 2 (IL-1RL2) on HSCs to produce neutrophils with high Elane expression that infiltrate the brain and induce neuroinflammation. Together, these findings define HSCs as a relay between psychological stress and myelopoiesis and identify the IL-36G-IL-1RL2 axis as a potential target for depression therapy.

Intranasal Application of Diluted Saline Alleviates Ischemic Brain Injury in Association with Suppression of Vasopressin Neurons

Plain Language SummaryNeuroendocrine disorders during cerebral stroke are a major etiology of ischemic brain injury that occurs following the occlusion of the cerebral artery. A hypothalamic neuropeptide, antidiuretic hormone or vasopressin (VP), is a key neuroendocrine factor in ischemic brain injury. To identify the way to reduce the overly produced VP following the stroke, this study used a rat model of cerebral stroke and tested the effects of intranasal application/drops of low concentration saline-0.09% NaCl (IAL) on VP neuronal activity that determines VP secretion. The results revealed for the first time that IAL inhibition of stroke-evoked VP neuronal activation and its associated brain damage is related to IAL inhibition of ischemia-evoked astrocytic process retraction around VP neurons and increase in excitatory inputs on VP neurons from the mitral cells in the activated olfactory bulb in the ischemic side. Similar but weaker effects also occurred at oxytocin neurons that co-exist with VP neurons but exert neural protective effects. These findings highlight that IAL (or commercially available purified water?) inhibition of VP neuronal activity may provide a simply available protective strategy in the early stage of cerebral stroke after further clinical trials.

Mother-Offspring Bonding after Calving in Water Buffalo and Other Ruminants: Sensory Pathways and Neuroendocrine Aspects.

The cow-calf bonding is a process that must be developed within the first six hours after calving. Both the buffalo dam and the newborn calf receive a series of sensory cues during calving, including olfactory, tactile, auditory, and visual stimuli. These inputs are processed in the brain to develop an exclusive bond where the dam provides selective care to the filial newborn. The limbic system, sensory cortices, and maternal-related hormones such as oxytocin mediate this process. Due to the complex integration of the maternal response towards the newborn, this paper aims to review the development of the cow-calf bonding process in water buffalo (Bubalus bubalis) via the olfactory, tactile, auditory, and visual stimuli. It will also discuss the neuroendocrine factors motivating buffalo cows to care for the calf using examples in other ruminant species where dam-newborn bonding has been extensively studied.

SMARCA4 controls state plasticity in small cell lung cancer through regulation of neuroendocrine transcription factors and REST splicing

IntroductionSmall Cell Lung Cancer (SCLC) can be classified into transcriptional subtypes with distinct degrees of neuroendocrine (NE) differentiation. Recent evidence supports plasticity among subtypes with a bias toward adoption of low-NE states during disease progression or upon acquired chemotherapy resistance. Here, we identify a role for SMARCA4, the catalytic subunit of the SWI/SNF complex, as a regulator of subtype shift in SCLC.MethodsATACseq and RNAseq experiments were performed in SCLC cells after pharmacological inhibition of SMARCA4. DNA binding of SMARCA4 was characterized by ChIPseq in high-NE SCLC patient derived xenografts (PDXs). Enrichment analyses were applied to transcriptomic data. Combination of FHD-286 and afatinib was tested in vitro and in a set of chemo-resistant SCLC PDXs in vivo.ResultsSMARCA4 expression positively correlates with that of NE genes in both SCLC cell lines and patient tumors. Pharmacological inhibition of SMARCA4 with FHD-286 induces the loss of NE features and downregulates neuroendocrine and neuronal signaling pathways while activating non-NE factors. SMARCA4 binds to gene loci encoding NE-lineage transcription factors ASCL1 and NEUROD1 and alters chromatin accessibility, enhancing NE programs. Enrichment analysis applied to high-confidence SMARCA4 targets confirmed neuron related pathways as the top GO Biological processes regulated by SMARCA4 in SCLC. In parallel, SMARCA4 also controls REST, a known suppressor of the NE phenotype, by regulating SRRM4-dependent REST transcript splicing. Furthermore, SMARCA4 inhibition drives ERBB pathway activation in SCLC, rendering SCLC tumors sensitive to afatinib.ConclusionsThis study nominates SMARCA4 as a key regulator of the NE state plasticity and defines a novel therapeutic strategy for SCLC.

An Ayurvedic methodology for managing PCOD - A Case Report

Polycystic ovarian disease (PCOD) is a heterogenous endocrine disorder characterized by ovarian cysts, anovulation, and hormonal fluctuations, impacting women’s health in various ways. PCOD has transformed into a lifestyle disorder due to sedentary habits, excessive consumption of fast food, and an unhealthy lifestyle. Predisposing risk factors such as genetics, neuroendocrine factors, lifestyle and environmental influences, as well as obesity, play significant roles in the development of PCOD. In Ayurveda, PCOD cannot be correlated to any one particular disease; it can be related to certain diseases like Vandhya, Nasthartava, Aratava Kshaya, Pushpaghni Jataharini, etc. and must be controlled according to the Dosha Dushya vitiation. In this present case study, a 21 year old female patient came with symptoms of scanty menses, acne over face and weight gain in the OPD of Kayachikitsa. The USG report reveals PCOD changes in both ovaries as both ovaries are bulky in size right ovary, vol = 18cc and left ovary, vol = 13.2cc with multiple peripherally arranged follicles with central echogenic stroma. The result was determined based on the relief of clinical symptoms and the findings from the ultrasound report. Therefore, in this case study, drugs such as Dashmool Kwath, Narikanti, Cystogrit diamond etc. was given which have Lekhaniya properties results into reducing the size of ovary and effectively alleviate Kapha Dosha and Ama, facilitating the treatment of Sroto-Dusti and removing obstructions caused by Apana Vayu, ultimately enhancing menstrual flow.

Adult and infantile seborrheic dermatitis: update on current state of evidence and potential research frontiers.

Seborrheic dermatitis (SD) is a highly prevalent dermatological condition globally. The condition demonstrates bimodal presentation with what is commonly thought to be two subtypes: adult/adolescent seborrheic dermatitis (ASD) and infantile seborrheic dermatitis (ISD). Despite the common prevalence of ASD and ISD, there remains uncertainty around the underlying pathogenetic mechanisms, risk factors, and appropriate classification of the disease(s). This narrative review summarizes the current understanding of the epidemiology, presentation, and pathogenetic factors like epidermal barrier dysfunction, lipid abnormalities, and cutaneous microbiome for ASD and ISD. Elements such as immune responsiveness, neuroendocrine factors, and genetics in these disease states are also investigated. Throughout our review, we highlight shared features and discrepancies between ASD and ISD that are present in the literature and discuss potential avenues for future research that explore these disease states. We aim to contribute to the medical discourse on ASD and ISD and increase awareness of the need for additional research around these conditions, ultimately informing better targeting of therapeutics moving forward.

Severe PTSD is marked by reduced oxytocin and elevated vasopressin

Neuroendocrine analyses of posttraumatic stress disorder (PTSD) have generally focused on hypothalamic-pituitary-adrenal (HPA) axis alterations. In the present analyses, we examine two additional neuroendocrine factors that have been previously implicated in biological stress responses: oxytocin (OT) and arginine vasopressin (AVP). Here we examined basal neuropeptide status in military veterans clinically diagnosed with PTSD (n = 29) and in two non-traumatized comparison groups with previous stress exposure (n = 11 SWAT trainees and n = 21 ultramarathon runners). PTSD patients showed low levels of plasma OT and high levels of AVP. The ratio of AVP/OT robustly related to PTSD status, and emerged as a statistically plausible mediator of relationships between the number of personal traumatic experiences and subsequent PTSD symptom burden. Over the course of behavioral therapy for PTSD, measures of OT showed a significant but modest normalization. Plasma cortisol levels were not statistically different among the three groups. This study suggests that AVP/OT ratios may represent a neuroendocrine predictor of severe PTSD, as well as a potential treatment response biomarker.

A Path to Persistence after EGFR Inhibition.

Residual cancer cells persist even after targeted therapies, serving as a reservoir for the subsequent acquisition of genetic alterations that lead to acquired drug resistance and tumor relapse. These initial drug-tolerant persisters (DTP) are phenotypically heterogenous with transient phenotypes attributed to epigenetic, metabolic, and cell-cycle changes. DTPs are responsible for the inevitable relapse seen in EGFR-mutant non-small cell lung cancer (NSCLC) despite high initial response to tyrosine kinase inhibitor (TKI) treatment. While past in vitro studies identified diverse drivers of drug-tolerant persistence to EGFR TKIs in NSCLC, the resultant phenotypic plasticity is not well understood and in vivo models of persistence are lacking. In this issue of Cancer Research, Hu and colleagues used patient-derived xenograft models of EGFR-mutant lung cancer treated with the third-generation TKI osimertinib to investigate mechanisms of persistence at the time of maximal response. Using bulk and single-cell RNA sequencing, the authors identified a DTP transcriptional cluster mediated by the key neuroendocrine lineage transcription factor ASCL1, which triggers an epithelial-to-mesenchymal transition transcriptional program. ASCL1 overexpression increased osimertinib tolerance in vitro as well, apparently independent of its role in neuroendocrine differentiation. Interestingly, the ability of ASCL1 to induce persistence was context dependent as this occurred only in epigenetically permissive cells. Overall, these findings contribute to our understanding of DTP heterogeneity seen after osimertinib treatment and provide insights into potential therapeutic targets. See related article by Hu et al., p. 1303.

Mechanisms of neurocentral-eyestalk-intestinal immunotoxicity in whiteleg shrimp Litopenaeus vannamei under ammonia nitrogen exposure

Ammonia-N, as the most toxic nitrogenous waste, has high toxicity to marine animals. However, the interplay between ammonia-induced neuroendocrine toxicity and intestinal immune homeostasis has been largely overlooked. Here, a significant concordance of metabolome and transcriptome–based “cholinergic synapse” supports that plasma metabolites acetylcholine (ACh) plays an important role during NH4Cl exposure. After blocking the ACh signal transduction, the release of dopamine (DA) and 5-hydroxytryptamine (5-HT) in the cerebral ganglia increased, while the release of NPF in the thoracic ganglia and NE in the abdominal ganglia, and crustacean hyperglycemic hormone (CHH) and neuropeptide F (NPF) in the eyestalk decreased, finally the intestinal immunity was enhanced. After bilateral eyestalk ablation, the neuroendocrine system of shrimp was disturbed, more neuroendocrine factors, such as corticotropin releasing hormone (CRH), adrenocorticotropic-hormone (ACTH), ACh, DA, 5-HT, and norepinephrine (NE) were released into the plasma, and further decreased intestinal immunity. Subsequently, these neuroendocrine factors reach the intestine through endocrine or neural pathways and bind to their receptors to affect downstream signaling pathway factors to regulate intestinal immune homeostasis. Combined with different doses of ammonia-N exposure experiment, these findings suggest that NH4Cl may exert intestinal toxicity on shrimp by disrupting the cerebral ganglion-eyestalk axis and the cerebral ganglion-thoracic ganglion-abdominal ganglion axis, thereby damaging intestinal barrier function and inducing inflammatory response.

A systematic review of post-operative infections in pediatric ventriculoperitoneal shunt cases

Background. Hydrocephalus is a prevalent condition in children, affecting both developed and developing countries. Neurosurgical interventions such as ventriculoperitoneal shunts are common, but are associated with a high risk of complications, including infections, which can lead to additional issues and costs. This study aims to review the incidence of infection in pediatric patients before and after ventriculoperitoneal shunt placement, in order to address this issue. Methods. A standard process of analyzing scientific questions using the Population, Intervention, Control, and Outcome (PICO) method was used to develop a protocol for searching research articles in online databases such as PubMed, Cochrane, POPLINE, and ScienceDirect. The articles selected for inclusion in this study met the following criteria: 1) described interventional ventriculoperitoneal shunt placement in pediatrics, 2) focused on cases of ventriculoperitoneal shunt complications with a focus on infection, 3) were published within the last 10 years, and 4) were published in English-language journals with peer review standards. Results. Sixteen articles were identified for review. Seven of these articles mentioned surgical or mechanical interventions as a means of preventing infections, while six articles discussed medical treatment for infection prevention. Three articles described the microorganisms found in cerebrospinal fluid. Conclusion. Future studies should focus on the issues related to ventriculoperitoneal shunt complications and interventions related to immunological, neuroendocrine, and biophysical factors to prevent infections, as well as surgical management and medication administration.

The influence of everyday emotions on mucosal immunity: An intensive longitudinal modeling approach.

Mucosal immunity is a multifaceted system of immunological responses that provides a barrier against pathogenic invasion and can be regulated by psychosocial and neuroendocrine factors. The present study aims to elucidate the association between everyday emotional states, emotion regulation skills, and mucosal immunity by utilizing an ambulatory assessment approach. 30 healthy subjects (61% male; M = 30.18 years old) completed an emotion questionnaire (PANAS) and collected saliva samples via passive drool to determine salivary immunoglobulin-A (S-IgA) excretion rate three times a day over a period of 1 week. In a multi-level model, the influence of emotions on S-IgA, both on a within-subject and between-subject level, was estimated. We found that most of the variation in S-IgA (74%) was accounted for by within-subject changes rather than stable between-subject differences. On a within-subject level, negative emotions had a significant positive effect on S-IgA levels (b = 1.87, p = .015), while positive emotions had no effect. This effect of negative emotions was moderated by the individual emotion regulation skills, with higher regulation skills corresponding to smaller effects (b = -2.67, p = .046). Furthermore, S-IgA levels decreased over the course of a day, indicating circadian rhythmicity (b = -0.13, p = .034). These results highlight the possibilities of intensive longitudinal data to investigate the covariance between psychological and immunological states over time.

Abstract 5830: A first-of-its-kind model that reconstitutes targeted drug-induced cellular transdifferentiation

Abstract Introduction: Lung tumors treated with targeted therapies ultimately relapse due to intra-genic resistance mutations, bypass pathway activation, or cellular lineage changes. Newer precision therapies have higher selectivity and potency against both resistant and activating gene mutations, resulting in a significant increase in incidence of cellular transdifferentiation. The most common form of transdifferentiation is the change from lung adenocarcinomas (LUADs) to small cell lung cancer (t-SCLC) upon drug treatment which remains very poorly understood. Methods: We have combined patient derived xenografts (PDX) and ex vivo lines with multi-omic characterization, high-content image-based morphometry and fluorescence tracking, and single-cell barcode tracing to better understand the process of lung tumor transdifferentiation. Results: We have developed a first-of-its-kind t-SCLC model that reconstitutes ex vivo LUAD to SCLC transdifferentiation. Genomic and transcriptomic analyses of our NSCLC PDX collection identified tumors with mutation in TP53 and RB1, two genes that are altered in virtually all de novo SCLCs. PDX sample CBX336 was identified as having mutations in both TP53 and RB1, in addition to expressing the KRASG12C oncogene. Upon treatment with Sotorasib, CBX336 tumors initially demonstrated slow tumor growth, followed by a dramatic increase in the growth after prolonged drug exposure. Our experimental and computational data suggest a highly coordinated procession toward transdifferentiation with the parallel upregulation of the neuroendocrine transcription factor NEUROD1 across numerous epithelial cellular clones. Conclusions: Our new experimental system allows characterization at the single-cell level. Ongoing work includes the integration of new resources to study lineage reprogramming, and advancing new therapeutic strategies. Citation Format: Priyanka Gopal, Mohamed Abazeed. A first-of-its-kind model that reconstitutes targeted drug-induced cellular transdifferentiation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5830.

Abstract 7228: In-vitro efficacy of Dordaviprone/GSK126 combination therapy on castration resistant and neuroendocrine prostate cancer

Abstract Neuroendocrine prostate cancer (NEPC) is an aggressive histologic subtype associated with poor prognosis that commonly arises in later stages as a mechanism of treatment resistance. Activation of oncogenic drivers, in combination with epigenetic changes (such as EZH2 overexpression and DNA methylation) further promotes tumor proliferation and expression of downstream neuroendocrine lineage pathways (in part controlled by transcription factors, including SOX2, ASCL1, and BRN2). Importantly, EZH2 inhibitors (EZH2i) can restore AR expression in CRPC (Ku et al., 2017). Imipridones, including Dordaviprone (ONC201), show promise in treating neuroendocrine tumors by interacting with DRD2 and CLpP (Anderson et al., 2022). These results warrant investigation into the potential for synergism in imipridone/EZH2i combination therapies. In the PCa cell lines LNCap, PC3, 22Rv1, and DU145 the combination of ONC201 and EZH2i GSK126 was assessed. Cell viability data after treatment with ONC201 and GSK126 reveals several dose ranges with potential synergistic activity after 72h. Preliminary western blots after 72 hours of GSK126 treatment indicate modulation of proteins relevant to the mechanism of action of imipridones, specifically DR5 and CLpP, in LNCap, PC3, and 22Rv1. Notably, the decrease in DR5 expression warrants investigation into the effects of EZH2i on TRAIL sensitivity and whether imipridones may rescue DR5 expression to maintain TRAIL sensitivity. Subsequent experiments will investigate dosing and time point-based effects on viability and protein expression, in addition to assessing the synergy of other imipridones and EZH2i’s. Further, while the cell lines PC3, 22Rv1, and DU145 are castration-resistant, the neuroendocrine prostate cell line NCI-H660 will be used as a positive control as it expresses higher neuroendocrine features, including DRD2. Additionally, the modulation in DR5 expression warrants inquiry into the effects of combination therapy on tumor-immune cell interactions. Further, we will manipulate the expression of neuroendocrine transcription factors to assess changes in therapy sensitivity. Citation Format: Connor Purcell, Praveen Srinivasan, Maximilian Pinho-Schwermann, William MacDonald, Elizabeth C. Ding, Vida Tajiknia, Wafik El-Deiry. In-vitro efficacy of Dordaviprone/GSK126 combination therapy on castration resistant and neuroendocrine prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7228.

Treatment of Coronary Heart Disease from the Perspective of Liver Controlling Dispersion

The liver is in charge of distributing and regulating the movement of qi throughout the whole body, coordinating the transportation and transformation of the internal organs in the middle part of the body, promoting the biochemical circulation of qi, blood, and body fluids, and regulating emotions. Liver dysfunction can disrupt the transportation and transformation of qi, blood, and body fluids, causing phlegm turbidity, blood stasis, and other unwanted symptoms. Poor regulation of emotion further aggravates the accumulation of pathological substances, resulting in the obstruction of heart vessels, and ultimately coronary heart disease (CHD). Through regulating lipid metabolism, inflammatory reaction, vasoactive substances, platelet function, neuroendocrine, and other factors, liver controlling dispersing qi plays a comprehensive role in the prognosis of atherosclerosis, the primary cause of CHD. Therefore, it is recommended to treat CHD from the perspective of liver-controlling dispersion.