Asymmetries of Left and Right Adrenal Glands in Neural Innervation and Glucocorticoids Production.

The adrenal gland is paired peripheral end organs of the neuroendocrine system and is responsible for producing crucial stress hormones from its two functional compartments, the adrenal cortex, and the adrenal medulla under stimuli. Left-right asymmetry in vertebrates exists from the central nervous system to peripheral paired endocrine glands. The sided difference in the cerebral cortex is extensively investigated, while the knowledge of asymmetry of paired endocrine glands is still poor. The present study aims to investigate the asymmetries of bilateral adrenal glands, which play important roles in stress adaptation and energy homeostasis via steroid hormones produced from the distinct functional zones. Left and right adrenal glands from male C57BL/6J mice were initially histologically analyzed, and high-throughput RNA sequencing was then used to detect the gene transcriptional difference between left and right adrenal glands. Subsequently, the enrichment of functional pathways and ceRNA regulatory work was validated. The results demonstrated that the left adrenal gland had higher tissue mass and levels of energy expenditure, whereas the right adrenal gland appeared to be more potent in glucocorticoid secretion. Further analysis of adrenal stem/progenitor cell markers predicted that Shh signaling might play an important role in the left-right asymmetry of adrenal glands. Of the hub miRNAs, miRNA-466i-5p was identified in the left-right differential innervation of the adrenal glands. Therefore, the present study provides evidence that there are asymmetries between the left and right adrenal glands in glucocorticoid production and neural innervation, in which Shh signaling and miRNA-466i-5p play an important role.

Selenium substituted axitinib reduces axitinib side effects and maintains its anti-renal tumor activity.

Axitinib is a potent vascular endothelial growth factor receptor (VEGFR) inhibitor, which has a strong inhibitory effect on the three isoforms of VEGFR 1-3. Having strong therapeutic efficacy, its broad use is limited by its side effects such as hypertension, proteinuria, cardiovascular damage, and liver and kidney dysfunction. Selenium compounds are broadly reported to have a good protective effect on cardiovascular disease, inflammation, infection, and immune function. In this study, a selenium substitute of axitinib was synthesized, and its anti-renal cell carcinoma activity and side effects were investigated. The results of the study indicated that Se-axitinib had potent antitumor activity on renal cell carcinoma (RCC), alleviated vascular hyperpermeability, and also alleviated axitinib-related side effects including hypertension, liver dysfunction and kidney dysfunction significantly. Therefore, we suggest that Se-axitinib could be a solution to the severe side effects of VEGFR inhibitors and provide evidence to improve the outcome of RCC treatment.

Losartan Alleviates the Side Effects and Maintains the Anticancer Activity of Axitinib.

Axitinib is one of the most potent inhibitors of the vascular endothelial growth factor (VEGF) receptor and shows strong antitumor activity toward various malignant tumors. However, its severe side effects affect the quality of life and prognosis of patients. Losartan, which functions as a typical angiotensin receptor blocker, controls the average arterial pressure of patients with essential hypertension and protects against hypertension-related secondary diseases, including proteinuria and cardiovascular injury. To explore the effects of losartan on side effects caused by axitinib and its antitumor activity, several animal experiments were conducted. This study first analyzed and explored the effect of losartan on the amelioration of side effects in Wistar rats caused by axitinib. The results showed that the systolic blood pressure of Wistar rats was significantly increased by about 30 mmHg in 7 days of axitinib treatment, while the combination of losartan significantly reduced the blood pressure rise caused by axitinib. The Miles experimental model and mouse xenograft tumor model were further used to evaluate the effect of losartan on the antitumor effect of axitinib. The result clearly demonstrated that losartan has no significant influence on axitinib-related low vascular permeability and antitumor activity. In summary, our results showed that the combination of axitinib and losartan significantly reduced the side effects and maintained the antitumor effects of axitinib. This study provides information for overcoming VEGF receptor inhibitor-related side effects.

Anastatin Derivatives Alleviate Myocardial Ischemia-Reperfusion Injury via Antioxidative Properties.

(±)-Anastatins A and B are flavonoids isolated from Anastatica hierochuntica. In a previous study, twenty-four di- and tri-substituted novel derivatives of anastatins were designed and their preliminary antioxidant activities were evaluated. In the present study, the protective effect of myocardial ischemia-reperfusion (I/R) and the systematic antioxidant capacity of 24 derivatives were further studied. Compound 13 was the most potent among all the compounds studied, which increased the survival of H9c2 cells to 80.82%. The antioxidant capability of compound 13 was evaluated in ferric reducing antioxidant power, 2,2'-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) radical scavenging, and 2,2-diphenyl-1-picrylhydrazyl assays. It was observed that compound 13 significantly reduced infarcted areas and improved histopathological and electrocardiogram changes in rats with myocardial I/R injury. Moreover, compound 13 decreased the leakage rates of serum lactate dehydrogenase, creatine kinase, and malonyldialdehyde from rat myocardial tissues and increased the level of glutathione and superoxide dismutase activities following myocardial I/R injury in rats. Taken together, we concluded that compound 13 had potent cardioprotective effects against myocardial I/R injury both in vitro and in vivo owing to its extensive antioxidant activities.