Over the last decade, fluctuations of retinoids (RETs), also known as vitamin A and derivatives, have proved to be useful biomarkers to assess the environmental chemical pressure on a wide variety of non-target vertebrates. This use of RET-based biomarkers is of particular interest in the non-target sentinel species Gammarus fossarum in which RETs were shown to influence crucial physiological functions. To study and probe this metabolism in this crustacean model, a UHPLC-MS/MS method was developed to 1) identify and 2) monitor several endogenous RETs in unexposed females throughout their reproductive cycle. Then, females were exposed in controlled conditions to exogenous all-trans retinoic acid (atRA) and citral (CIT), a RA synthesis inhibitor, to simulate an excess or deficiency in RA. Perturbation of vitamin A metabolism by pesticides was further studied in response to methoprene (MET), a juvenile hormone analog as well as glyphosate (GLY). The developed method allowed, for the first time in this model, the identification of RA metabolites (all-trans 4-oxo and 13-cis 4-oxo RA), RA isomers (all-trans and 13-cis RA) as well as retinaldehyde (RALD) isomers (all-trans, 11-cis, and 13-cis RALD) and showed two distinct phases in the reproductive cycle. Retinoic acid successfully increased the tissular concentration of both RA isomers and CIT proved to be efficient at perturbating the conversion from RALD to RA. Methoprene perturbed the ratios between RA isomers whereas GLY had no observed effects on the RET system of G. fossarum females. We were able to discriminate different dynamics of RET perturbations by morphogens (atRA or CIT) or MET which highlights the plausible mediation of RETs in MET-induced disorders. Ultimately, our study shows that RETs are influenced by exposure to MET and strengthen their potential to assess aquatic ecosystem chemical status.
2023-01-27·Biology of reproduction
Differential responsiveness of spermatogonia to retinoic acid dictates precocious differentiation but not meiotic entry during steady-state spermatogenesis.
作者: Taylor A Johnson ; Bryan A Niedenberger ; Oleksandr Kirsanov ; Ellen V Harrington ; Taylor Malachowski ; Christopher B Geyer
The foundation of mammalian spermatogenesis is provided by undifferentiated spermatogonia, comprised of spermatogonial stem cells (SSCs) and transit-amplifying progenitors that differentiate in response to retinoic acid (RA) and are committed to enter meiosis. Our laboratory recently reported that the foundational populations of SSCs, undifferentiated progenitors, and differentiating spermatogonia are formed in the neonatal testis in part based on their differential responsiveness to RA. Here, we expand on those findings to define the extent to which RA responsiveness during steady-state spermatogenesis in the adult testis regulates spermatogonial fate. Our results reveal both progenitor and differentiating spermatogonia throughout the testis are capable of responding to exogenous RA, but their resulting fates were quite distinct - undifferentiated progenitors precociously differentiated and proceeded into meiosis on a normal timeline, while differentiating spermatogonia were unable to hasten their entry into meiosis. This reveals spermatogonia responding to RA must still complete the 8.6 day differentiation program prior to their entry into meiosis. Addition of exogenous RA enriched testes with preleptotene and pachytene spermatocytes one and two seminiferous cycles later, respectively, supporting recent clinical studies reporting increased sperm production and enhanced fertility in subfertile men on long-term RA analog treatment. Collectively, our results reveal a well-buffered system exists within mammalian testes to regulate spermatogonial RA exposure, that exposed undifferentiated progenitors can precociously differentiate, but must complete a normal-length differentiation program prior to entering meiosis, and that daily RA treatments increased numbers of advanced germ cells by directing undifferentiated progenitors to continuously differentiate.
Deciphering the role of retinoic acid in hepatic patterning and induction in the mouse.
作者: Taylor M Guertin ; Amrita Palaria ; Jesse Mager ; Lisa L Sandell ; Paul A Trainor ; Kimberly D Tremblay
Retinoic acid (RA), a metabolite of vitamin A, is a small molecule and morphogen that is required for embryonic development. While normal RA signals are required for hepatic development in a variety of vertebrates, a role for RA during mammalian hepatic specification has yet to be defined. To examine the requirement for RA in murine liver induction we performed whole embryo culture with the small molecule RA inhibitor, BMS493, to attenuate RA signaling immediately prior to hepatic induction and through liver bud formation. BMS493-treated embryos demonstrated a significant loss of hepatic specification that was confined to the prospective dorsal anterior liver bud. Examination of RA-attenuated embryos demonstrates that while the liver bud displays normal expression of foregut endoderm markers and the hepato-pancreatobiliary domain marker, PROX1, the dorsal/anterior liver bud excludes the critical hepatic marker, HNF4α, indicating that RA signals are required for dorsal/anterior hepatic induction. These results were confirmed and extended by careful examination of Rdh10trex/trex embryos, which carry a genetic perturbation in RA synthesis. At E9.5 Rdh10trex/trex embryos display a similar yet more significant loss of the anterior/dorsal liver bud. Notably the anterior/dorsal liver bud loss correlates with the known dorsal-ventral gradient of the RA synthesis enzyme, Aldh1a2. In addition to altered hepatic specification, the mesoderm surrounding the liver bud is disorganized in RA abrogated embryos. Analysis of E10.5 Rdh10trex/trex embryos reveals small livers that appear to lack the dorsal/caudal lobes. Finally, addition of exogenous RA prior to hepatic induction results in a liver bud that has failed to thicken and is largely unspecified. Taken together our ex vivo and in vivo evidence demonstrate that the generation of normal RA gradients is required for hepatic patterning, specification, and growth.
HANGZHOU, China, Aug. 7, 2023 /PRNewswire/ -- During the
Chinese Medical Association
11th National Academic Conference on Respiratory Endoscopy and
Interventional Pulmonology on August 5, Broncus (2216.HK) announced postoperative 6-month data of a registered clinical trial on RF II, the world's first transbronchial pulmonary radiofrequency ablation system for lung cancer. The data were reported by Professor Li Shiyue from the leading site, the First Affiliated Hospital of Guangzhou Medical University.
RF II, developed by Broncus, is the world's only transbronchial radiofrequency ablation system dedicated to lung cancer treatment. With the patented intelligent real-time monitoring function, RF II can prevent excessively fast rise of local temperature when in use, and ensure stable output of radiofrequency energy, thus ablating lung cancer safely and effectively.
The registered clinical study of RF II is a prospective, multicenter, and single-group target-value clinical trial. In the study, patients need to undergo bronchoscopies first. Then, with the use of the system, the doctor can quickly and accurately reach the cancer through the bronchoscope and ablated the cancer. The primary endpoint of the study is the 6-month complete ablation rate of the main lesion.
Clinical data show significant efficacy of RF II for the treatment of lung cancer
Professor Li Shiyue from the First Affiliated Hospital of Guangzhou Medical University, the coordinating principal investigator of the RF II study, reported postoperative 6-month data of the study. Data show that 126 patients used the system for the treatment of lung cancer, with a technical success rate of 99.35% and a 6-month complete ablation rate of the main lesion being 92.06%. Meanwhile, there is a relatively low incidence of common complications such as pneumothorax and bleeding in thermal ablation for lung cancer in this study. The results have well proven the safety and efficacy of RF II.
RF II is bringing new hopes for global lung cancer patients
The postoperative 6-month data of the study suggest that RF II shows a huge breakthrough compared with traditional radiofrequency techniques. For patients enrolled in the study, the treatment effect of this product is excellent. The noticeable complete ablation rate verifies that RF II can completely ablate lung lesions in a safe and effective way.
As the world's first transbronchial pulmonary radiofrequency ablation system for lung cancer, the clinical value of RF II has been well recognized and triggered heated discussion by nationwide respiratory intervention experts, based on its 6-month data of the clinical study. Looking ahead, Broncus will continue to announce follow-up data of the patients at 12 months postoperatively.
Zhan Guowei, CEO of Broncus, said: "As a pioneer in the field of Interventional Pulmonology, Broncus has developed multiple innovative therapeutic solutions, ushering in a new era of the industry. The outstanding postoperative 6-month data of the RF II clinical trial well demonstrates its clinical value. As the therapeutics market increases, RF II is ready for market access in several major countries. Broncus is a representative Chinese exporter of innovative medical devices. Looking into the future, we will continue to develop innovation and bring new therapeutic options for global doctors and patients."
Chinese Medical Association National Academic Conference on Respiratory Endoscopy and
The Conference was organized by the Chinese Medical Association and its Chinese Thoracic Society. The 11th Conference was held in Guangzhou, Guangdong province from August 4 to 6, 2023. The event was aimed at promoting academic progress and exchanges of experiences. Talks were held based on issues associated with respiratory endoscopy and interventional pulmonology by sections, including mechanism, diagnosis, precision treatment, and complication management, with specialties like medicine and surgery, intervention, imaging and pathology to be involved. The latest academic progress, ideas, therapies，and clinical experiences were shared in the event, along with all-round discussions and exchanges.
SOURCE Broncus Holding Corporation