Evaluation of Rap1GAP and Epac1 Gene Expression in Endometriosis

Objective: Endometriosis is a female reproductive system disease in which endometrial tissue are found in other women organs. Various factors are effective in the development of endometriosis and due to the interaction of genetics and environmental factors, this disease is a multifactorial disease. MAPK/ERK and PI3K/Akt/mTOR pathways are activated by growth factors and steroid hormones and known as two important pathways involved in the processes of growth, proliferation and survival of endometriosis cells. Raps, monomeric GTPase of Ras family, are able to activate these pathways independently of Ras. The goal of our study was to evaluated the expression level of Rap1GAP and Epac1 gene, as two important RapGAPs (GTPase-activating proteins) and RapGEFs (guanine nucleotide exchange factors) respectively, in endometriosis tissues and normal endometrium tissues.Materials and Methods: In this study, 15 samples of women without signs of endometriosis were taken as control samples, 15 ectopic and 15 eutopic samples were taken from women with endometriosis using laparoscopic surgery. The expression of Epac1 and Rap1GAP genes was investigated by Real-time PCR technique and results were analysis by One-Way ANOVA test.Results: Epac1 upregulated significantly in ectopic tissues compared to eutopic and control tissues (Their P-value were <0.0001). Rap1GAP expression was lower in ectopic tissues compared to control samples (P-value was 0.003) and eutopic tissues (P-value was 0.001).Conclusion: Based on these results, it may be concluded that changes in the expression of the Rap1GAP and Epca1 genes may play role in the pathways involved in the pathogenesis, displacement, and migration of endometriosis cells.

Research Progress on the Effect of Epilepsy and Antiseizure Medications on PCOS Through HPO Axis

Epilepsy is a common chronic neurological disease that manifests as recurrent seizures. The incidence and prevalence of epilepsy in women are slightly lower than those in men. Polycystic ovary syndrome (PCOS), a reproductive endocrine system disease, is a complication that women with epilepsy are susceptible to, and its total prevalence is 8%–13% in the female population and sometimes as high as 26% in female epilepsy patients. The rate of PCOS increased markedly in female patients who chose valproate (VPA), to 1.95 times higher than that of other drugs. In addition, patients receiving other anti-seizure medications (ASMs), such as lamotrigine (LTG), oxcarbazepine (OXC), and carbamazepine (CBZ), also have reproductive endocrine abnormalities. Some scholars believe that the increase in incidence is related not only to epilepsy itself but also to ASMs. Epileptiform discharges can affect the activity of the pulse generator and then interfere with the reproductive endocrine system by breaking the balance of the hypothalamic–pituitary–ovarian (HPO) axis. ASMs may also cause PCOS-like disorders of the reproductive endocrine system through the HPO axis. Moreover, other factors such as hormone metabolism and related signalling pathways also play a role in it.

Timing is everything: Clinical courses of Hunter syndrome associated with age at initiation of therapy in a sibling pair

Hunter syndrome, or mucopolysaccharidosis (MPS) II, is a rare lysosomal disorder characterized by progressive, multi-system disease. As most symptoms cannot be reversed once established, early detection and treatment prior to the onset of clinical symptoms are critical. However, it is difficult to identify affected individuals early in disease, and therefore the long-term outcomes of initiating treatment during this optimal time period are incompletely described. We report long-term clinical outcomes of treatment when initiated prior to obvious clinical signs by comparing the courses of two siblings with neuronopathic Hunter syndrome (c.1504T>G[p.W502G]), one who was diagnosed due to clinical disease (Sibling-O, age 3.7 years) and the other who was diagnosed before disease was evident (Sibling-Y, age 12 months), due to his older sibling’s findings. The brothers began enzyme replacement therapy within a month of diagnosis. Around the age of 5 years, Sibling-O had a cognitive measurement score in the impaired range of <55 (average range 85-115), whereas Sibling-Y at this age received a score of 91. Sibling-O has never achieved toilet training and needs direct assistance with toileting, dressing, and washing, while Sibling-Y is fully toilet-trained and requires less assistance with daily activities. Both siblings have demonstrated sensory-seeking behaviors, hyperactivity, impulsivity, and sleep difficulties; however, Sibling-O demonstrates physical behaviors that his brother does not, namely biting, pushing, and frequent elopement. Since the time of diagnosis, Sibling-O has experienced significant joint contractures and a steady deterioration in mobility leading to the need for an adaptive stroller at age 11, while Sibling-Y at age 10.5 could hike more than 6 miles without assistance. After nearly a decade of therapy, there were more severe and life-limiting disease manifestations for Sibling-O; data from caregiver interview indicated substantial differences in Quality of Life for the child and the family, dependent on timing of ERT. The findings from this sibling pair provide evidence of superior somatic and neurocognitive outcomes associated with presymptomatic treatment of Hunter syndrome, aligned with current considerations for newborn screening.

Relapsed disease: off-the-shelf immunotherapies vs customized engineered products

Innovations in immuno-oncology for lymphomas have outpaced therapeutic developments in any other cancer histology. In the 1990s, rituximab, a CD20 monoclonal antibody, drastically changed treatment paradigms for B-cell non-Hodgkin lymphomas (B-NHLs). In parallel, the concept that T cells could be genetically reprogrammed and regulated to address tumor cell evasion was developed. Twenty years later, this concept has materialized—3 customized engineered CD19 chimeric antigen receptor T-cell (CART) constructs have been embraced as third-line therapies and beyond for aggressive B-NHL. Responses with CARTs are durable in 30% to 40% of patients, with consistent results in older patients, primary refractory disease, high-grade B-cell lymphoma, and patients with concurrent secondary central nervous system disease, all features historically associated with poorer outcomes. Challenges associated with the administration of CARTs include cumbersome and time-consuming manufacturing processes, toxicities, and cost, not to mention a substantial risk of relapse. Fortunately, as our understanding of how to manipulate the immune system to achieve full antitumor potential has grown, so has the rapid development of off-the-shelf immunotherapies, with CD20/CD3 bispecific antibodies standing out above all others. These agents have shown promising activity in aggressive B-NHL and have the potential to circumvent some of the challenges encountered with customized engineered products. However, toxicities remain substantial, dosing schedules intensive, and experience limited with these agents. Novel customized and off-the-shelf therapeutics as well as rational combinations of these agents are underway. Ultimately, growing experience with both customized engineered and off-the-shelf immunotherapies will provide guidance on optimal methods of delivery and sequencing.

Detoxification II Prescription Suppresses the Th-17/IL-17 Inflammatory Axis to Improve the Liver Function of ACLF-Rats via Inactivating the P38MAPK Pathway

Hepatitis is a metabolic system disease which is a serious challenge to the medical and healthcare system of the world. This study attempted to investigate the therapeutic effect and illustrate the regulation pharmacological mechanism of Detoxification II Prescription on ACLF. In this study, the rats were injected with D-galactosamine to establish ACLF-rat models, and the levels of cholinesterase (CHE), alanine aminotransferase (ALT), aspartate aminotransferase (AST), albumin (ALB), and total bilirubin (TBiL) were measured with the related kits to reflect the liver functions of the rats. The levels of IL-17, IL-6, and IFN-γ in the serums of the rats were detected by qRT-PCR, and the percentages of Th-17 cells in CD4+ cells of the rats were measured by flow cytometry assay. In the results, the increased ALT, AST, TBiL, IL-6, IL-17, IFN-γ, and percentage of Th-17 cells in CD4+ and decreased ALB and CHE were found in the serums of the ACLF-rats, while Detoxification II Prescription could partly reverse those indexes of the ACLF-rats. Moreover, it was also found that Detoxification II Prescription could inhibit the expression of P38MAPK, and P38MAPK downregulation obviously improved the liver function indexes of the ACLF-rats including the levels of ALT, AST, TBiL, IL-6, IL-17, IFN-γ, and percentage of Th-17 cells in CD4+ cells. In conclusion, this study suggested that Detoxification II Prescription could suppress the Th-17/IL-17 inflammatory axis to improve the liver function of ACLF-rats via inhibiting the activity of the P38MAPK pathway.

OxPhos Dysfunction Causes Hypermetabolism and Reduces Lifespan in Cells and in Patients with Mitochondrial Diseases

Patients with primary mitochondrial diseases present with fatigue and multi-system disease, are often lean, and die prematurely, but the mechanistic basis for this clinical picture remains unclear. Integrating data from 17 cohorts of patients with mitochondrial diseases (n=690), we find that clinical mitochondrial disorders increase resting energy expenditure, a state termed hypermetabolism. In a longitudinal cellular model of primary patient-derived fibroblasts from multiple donors, we show that genetic and pharmacological disruptions of oxidative phosphorylation (OxPhos) similarly trigger increased energy consumption in a cell-autonomous manner, despite near-normal OxPhos coupling efficiency. Hypermetabolism was associated with mtDNA instability, activation of the integrated stress response, increased extracellular secretion of age-related cytokines and metabokines including GDF15, as well as an accelerated rate of telomere erosion and epigenetic aging, and a reduced Hayflick limit. Finally, we generate a longitudinal RNASeq and DNA methylation resource dataset, which reveals conserved, energetically demanding, genome-wide recalibrations to OxPhos dysfunction. Hypermetabolism, or the increased energetic cost of living in mitochondrial diseases, has important biological and clinical implications.

Emerging evolution trends of application of natural products in Alzheimer’s disease

The main objective of this review was to explore the research foci and emerging trends of application of natural products in AD from 1990 to 2019 and evaluated publications qualitatively and quantitatively. CiteSpace V. 4.0 was used to identify top authors, journals, institutions, countries, keywords, co-cited articles, and trends and obtain the visual knowledge maps. Results revealed that the USA, People’s Republic of China and India were the major research countries in this field, while the Western Europe and North America were the areas with frequent international cooperation. Moreover, there was a close collaboration between universities and research institutes. The J Alzheimers Dis was the most productive journal. Alzheimers disease, natural product, brain, central nervous system, disease, and oxidative stress are some of the high centrality and high frequency keywords in the co-occurrence analysis; Indicating Alzheimers disease and its pathogenesis and natural product remain the hotspots in the field. This paper provides an insight into the application of natural products in AD, and provides useful information for AD researchers to find potential collaborators and cooperative institutions.