Adrenomedullin in paraventricular nucleus attenuates adipose afferent reflex and sympathoexcitation via receptors mediated nitric oxide-gamma-aminobutyric acid A type receptor pathway in rats with obesity-related hypertension.

BACKGROUND: Hypothalamic paraventricular nucleus (PVN) is an important central site for the control of the adipose afferent reflex (AAR) that increases sympathetic outflow and blood pressure in obesity-related hypertension (OH). METHOD: In this study, we investigated the effects of nitric oxide (NO) and cardiovascular bioactive polypeptide adrenomedullin (ADM) in the PVN on AAR and sympathetic nerve activity (SNA) in OH rats induced by a high-fat diet. RESULTS: The results showed that ADM, total neuronal NO synthase (nNOS) and phosphorylated-nNOS protein expression levels in the PVN of the OH rats were down-regulated compared to the control rats. The enhanced AAR in OH rats was attenuated by PVN acute application of NO donor sodium nitroprusside (SNP), but was strengthened by the nNOS inhibitor nNOS-I, guanylyl cyclase inhibitor (1H-[1,2,4]Oxadiazolo[4,3-a]quinoxalin-1-one, ODQ) and gamma-aminobutyric acid A type receptor (GABAA) antagonist Bicuculline. Moreover, PVN ADM microinjection not only decreased basal SNA but also attenuated the enhanced AAR in OH rats, which were effectively inhibited by ADM receptor antagonist ADM22-52, nNOS-I, ODQ or Bicuculline pretreatment. Bilateral PVN acute microinjection of ADM also caused greater increases in NO and cyclic guanosine monophosphate (cGMP) levels, and nNOS phosphorylation. Adeno-associated virus vectors encoding ADM (AAV-ADM) transfection in the PVN of OH rats not only decreased the elevated AAR, basal SNA and blood pressure (BP), but also increased the expression and activation of nNOS. Furthermore, AAV-ADM transfection improved vascular remodeling in OH rats. CONCLUSION: Taken together, our data highlight the roles of ADM in improving sympathetic overactivation, enhanced AAR and hypertension, and its related mechanisms associated with receptors mediated NO-cGMP-GABAA pathway in OH condition.

Exosome encapsulated ncRNAs in the development of HCC: potential circulatory biomarkers and clinical therapeutic targets.

Hepatocellular carcinoma (HCC) is the sixth most deadly malignant cancer in the world and has the third highest mortality rate among cancer-related deaths worldwide. Its poor prognosis can be attributed to late diagnosis, high risk of recurrence and drug resistance. Therefore, finding a new biomarker to help us in the early diagnosis, and exploring the molecular mechanisms involved in recurrence and drug resistance is a reasonable research direction for clinical treatment of HCC. At present, the exosomes related to HCC have been confirmed to carry ncRNAs, transfer them to target cells, and bind corresponding target molecules. Furthermore, they affect the proliferation and metastasis of hepatocellular carcinoma by promoting angiogenesis, epithelial-mesenchymal transition (EMT), and inhibiting the function of the body's immune system. They play an important role in the recurrence and resistance of HCC. Besides, exosomes are stably expressed in body fluids such as sera, are easy to collect and cause little harm to the human body. They are the best candidates for liquid biopsy. Therefore, exosomal ncRNAs have application prospects as biomarkers and targeted molecules for therapy. This article summarizes the current research involving ncRNAs in HCC-related exosomes.