Discovery, semisynthesis, biological activities, and metabolism of ocotillol-type saponins

Background The representative cardiovascular herbs, i.e. Panax, Ligusticum, Carthamus, and Pueraria plants, are traditionally and globally used in the prevention and treatment of various cardiovascular diseases. Modern phytochemical studies have found many medicinal compounds from these plants, and their unique pharmacological activities are being revealed. However, there are few reviews that systematically summarize the current trends of Drug Metabolism/Pharmacokinetic (DMPK) investigations of cardiovascular herbs. Methods Here, the latest understanding, as well as the knowledge gaps of the DMPK issues in drug development and clinical usage of cardiovascular herbal compounds, was highlighted. Results The complicated herb-herb interactions of cardiovascular Traditional Chinese Medicine (TCM) herb pair/formula significantly impact the PK/pharmacodynamic performance of compounds thereof, which may inspire researchers to develop a novel herbal formula for the optimized outcome of different cardiovascular diseases. While the Absorption, Distribution, Metabolism, Excretion and Toxicity (ADME/T) of some compounds has been deciphered, DMPK studies should be extended to more cardiovascular compounds of different medicinal parts, species (including animals), and formulations, and could be streamlined by versatile omics platforms and computational analyses. Conclusion In the context of systems pharmacology, the DMPK knowledge base is expected to translate bench findings to clinical applications, as well as foster cardiovascular drug discovery and development.

Impact of Drug Metabolism/Pharmacokinetics and their Relevance Upon Traditional Medicine-based Cardiovascular Drug Research.

Adrenal androgens, adrenarche, and zona reticularis: A human affair?

Background: The human adrenal cortex undergoes several rapid remodeling steps during its lifetime. In rodents, similar remodeling occurs postnatally in the "X-zone" layer through unknown mechanisms. Furthermore, little is known regarding the impact of thyroid hormone (TH) on adrenal glands in humans. Methods: To investigate the impact of TH on adrenal pathophysiology, we created two genetic murine models mimicking human nonautoimmune hypothyroidism and hyperthyroidism. Moreover, we analyzed serum thyrotropin (TSH) and steroid hormone concentrations in patients diagnosed with congenital hypothyroidism and premature adrenarche (PA). Results: We found that TH receptor beta-mediated hypertrophy of the X-zone significantly elevated the adrenal weights of hyperthyroid women. In the hypothyroid model, the X-zone was poorly developed in both sexes. Moreover, large reciprocal changes in the expression levels of genes that regulate adrenal cortical function were observed with both models. Unexpectedly, up- and downregulation of several genes involved in catecholamine synthesis were detected in the adrenal glands of the hypothyroid and hyperthyroid models, respectively. Furthermore, TSH and adrenal steroid concentrations correlated positively in pediatric patients with congenital hypothyroidism and PA. Conclusions: Our results revealed that congenital hypothyroidism and hyperthyroidism functionally affect adrenal gland development and related steroidogenic activity, as well as the adrenal medulla. 

Congenital Hypothyroidism and Hyperthyroidism Alters Adrenal Gene Expression, Development, and Function

Osteocalcin is a hormone produced in bones by osteoblasts during bone formation. Numerous studies have demonstrated that adrenal gland-derived glucocorticoids inhibit osteocalcin production, which can ultimately cause deleterious bones loss. This loss establishes a unidirectional endocrine relationship between the adrenal glands and bone, however, whether osteocalcin reciprocally regulates glucocorticoid secretion remains unclear. In this issue of the JCI, Yadav and colleagues address how bone-derived osteocalcin influences adrenal organogenesis and function. Using a large variety of animal models, the authors established that embryonic osteocalcin signaling, specifically through the GPR158 receptor, regulates postnatal adrenal steroid concentrations throughout life. This work has translational potential, and we await future investigations that determine whether modulating osteocalcin levels could promote endogenous adrenocortical function in adrenocortical hypoplasia and glucocorticoid deficiency. 

Bones and adrenal organogenesis: how embryonic osteocalcin influences lifelong adrenal function

The sex-specific prevalence of adrenal diseases has been known for a long time. However, the reason for the high prevalence of these diseases in females is not completely understood. Mouse studies have shown that the adult adrenal gland is sexually dimorphic at different levels such as transcriptome, histology, and cell renewal. Here we used RNA-seq to show that in prepubertal mice, male and female adrenal glands were not only sexually dimorphic but also responded differently to the same external stimulus. We previously reported that thyroid hormone receptor β1 (TRβ1) in the adrenal gland is mainly expressed in the inner cortex and the fate of this TRβ1-expressing cell population can be changed by thyroid hormone (triiodothyronine; T3) treatment. In the present study, we found that adrenal glands in prepubertal mice were sexually dimorphic at the level of the transcriptome. Under T3 treatment, prepubertal females had 1162 genes differentially expressed between the saline and T3 groups, whereas in males of the same age, only 512 genes were T3-responsive. Immunostaining demonstrated that several top sexually dimorphic T3-responsive genes, including Cyp2f2 and Dhcr24, were specifically expressed in the adrenal inner cortex, precisely in an area partially overlapping with the X-zone. Under T3 treatment, a unique cortical layer that surrounds the adrenal X-zone expanded significantly, forming a distinct layer peculiar to females. Our findings identified novel marker genes for the inner adrenal cortex, indicating there are different sub-zones in the zona fasciculata. The results also highlight the sex-specific response to thyroid hormone in the mouse adrenal gland.

RNA-Seq Reveals Sub-Zones in Mouse Adrenal Zona Fasciculata and the Sexually Dimorphic Responses to Thyroid Hormone

Gindenosides are the active ingredients of Panax ginseng. 20 (S) -protopanaxadiolocotillol type epimers are the main metabolites of 20 (S) -protopanaxadiol. The previous studies showed that there are stereoselectivity difference in pharmacodynamics and pharmacokinetics between 24R-epimer and 24S-epimer. The purpose of this study was to explore the excretion of the epimers in bile, feces and urine of rat. Liquid chromatography tandem mass spectrometry method has been performed for determination of 24R-epimer and 24S-epimer in bile, feces and urine. 24R-epimer or 24S-epimer was intragastric administered to rats at a single dose of 10 mg x kg(-1). Results showed that after administration the recovery of 24R-epimer and 24S-epimer in feces was 17.69% and 17.09%, respectively, while both of the two epimers were hardly detected in urine. The 48 h cumulative biliary excretion rate of 24R-epimer was 8.01% after administration, while only 1.47% for 24S-epimer. It indicated that there are stereoselectivity in biliary excretion of the epimers with intragastric administration.

Hui Wang

Papers

RNA-Seq Reveals Sub-Zones in Mouse Adrenal Zona Fasciculata and the Sexually Dimorphic Responses to Thyroid Hormone

[Study on excretion of 20 (S) -protopanaxadiolocotillol type epimers in rats].