Doxorubicin (DOX), an effective chemotherapeutic drug used in the treatment of various cancers, is limited in its clinical applications due to cardiotoxicity. Recent studies suggest that transplanted adult stem cells inhibit DOX-induced cardiotoxicity. However, the effects of transplanted embryonic stem (ES) and induced pluripotent stem (iPS) cells are completely unknown in DOX-induced left ventricular dysfunction following myocardial infarction (MI). In brief, C57BL/6 mice were divided into five groups: Sham, DOX-MI, DOX-MI+cell culture (CC) media, DOX-MI+ES cells, and DOX-MI+iPS cells. Mice were injected with cumulative dose of 12 mg/kg of DOX and 2 weeks later, MI was induced by coronary artery ligation. Following ligation, 5×104 ES or iPS cells were delivered into the peri-infarct region. At day 14 post-MI, echocardiography was performed, mice were sacrificed, and hearts were harvested for further analyses. Our data reveal apoptosis was significantly inhibited in ES and iPS cell transplanted hearts compared with respective controls (DOX-MI+ES: 0.48±0.06% and DOX-MI+iPS: 0.33±0.05% vs. DOX-MI: 1.04±0.07% and DOX-MI+CC: 0.96±0.21%; p<0.05). Furthermore, a significant increase in levels of Notch-1 (p<0.05), Hes1 (p<0.05), and pAkt (p<0.05) were observed whereas a decrease in the levels of PTEN (p<0.05), a negative regulator of Akt, was evident following stem cell transplantation. Moreover, hearts transplanted with stem cells demonstrated decreased vascular and interstitial fibrosis (p<0.05) as well as MMP-9 expression (p<0.01) compared with controls. Additionally, heart function was significantly improved (p<0.05) in both cell-transplanted groups. In conclusion, our data show that transplantation of ES and iPS cells blunt DOX-induced adverse cardiac remodeling, which is associated with improved cardiac function, and these effects are mediated by the Notch pathway.

Recent studies suggest that disturbed blood flow-induced shear stress can induce atherosclerosis (ATH) in humans and animals without a high fat diet. Therefore, we hypothesize that partial ligation of the left carotid artery can generate disturbed blood flow and shear stress and would lead to ATH in a predisposed genetic model of Apo E(-/-) mice. The partial left carotid artery model was generated by ligating three out of four branches of the left carotid artery compared with controls which experienced similar surgery conditions but no ligation. Animals were sacrificed 2 weeks post-ligation and examined for plaque formation, infiltration of leukocytes, pro-inflammatory immune response, and blood flow velocity. Our findings suggest a significant (p < 0.05) increase in plaque formation and lipid deposition in the partial ligated animals compared with controls, confirmed with hematoxylin and eosin and oil red O staining. Furthermore, there was a significant (p < 0.05) increase in the number of M1 macrophages and release of pro-inflammatory cytokines, IL-6 and TNFα, as compared with the control. Moreover, partial ligated carotid arteries demonstrated disturbed blood flow as their systolic velocity was significantly reduced. In conclusion, our data suggest that partial ligation of the left carotid artery induces disturbed flow and shear stress in the predisposed genetic model of Apo E(-/-) mice and leads to significantly developed ATH. Similarities to clinical patients who develop ATH independent of a high fat diet show that this could be a potential animal model to examine various parameters in ATH.

Doxorubicin (Dox) is a potent chemotherapeutic drug known for its dose-dependent and serious adverse effects, such as cardiotoxicity and myotoxicity. Dox-induced cardiotoxicity (DIC) and muscle toxicity (DIMT) have been studied; however, the mechanisms of Dox-induced apoptosis in soleus muscle are not well defined. Our data shows that with Dox treatment, there is a significant increase in oxidative stress, apoptosis, proapoptotic protein BAX, pPTEN levels, and wnt3a and β-catenin activity (p < 0.05). Moreover, Dox treatment also resulted in decreased antioxidant levels, antiapoptotic BCL2, pAKT, p-mTOR, and endogenous levels of sFRP2 in the soleus muscle tissue (p < 0.05). Secreted frizzled-related protein 2 (sFRP2) treatment attenuated the adverse effects of DIMT and apoptosis in the soleus muscle, evidenced by a decrease in oxidative stress, apoptosis, BAX, pPTEN, and wnt3a and β-catenin activity, as well as an increase in antioxidants, BCL2, pAKT, p-MTOR, and sFRP2 levels (p < 0.05). This data suggests that Dox-induced oxidative stress and apoptosis is mediated through both the Akt-mTOR and wnt/β-catenin pathways. Moreover, the data also shows that sFRP2 modulates these two pathways by increasing signaling of Akt-mTOR and decreased signaling of the wnt/β-catenin pathway. Therefore, our data suggests that sFRP2 has valuable therapeutic potential in reversing Dox-induced oxidative stress and apoptosis in soleus muscle mediated through the Akt-mTOR pathway.

Cell therapy is emerging as a new strategy to circumvent the adverse effects of heart disease. Many experimental and clinical studies investigating the transplantation of cells into the injured myocardium have yielded promising results. Moreover, data from these reports show that transplanted stem cells can engraft within the myocardium, differentiate into major cardiac cell types, and improve cardiac function. However, results from clinical trials show conflicting results. These trials demonstrate significant improvements in cardiac function for up to 6 months. However, these improved functions were diminished when examined at 18 months. In this review, we will discuss the current literature available on cell transplantation, covering studies ranging from animal models to clinical trials.

The management of functional adrenocortical carcinoma (ACC) is challenging as it involves treating the underlying endocrinological abnormalities such as hypercortisolism. Competitive glucocorticoid receptor antagonist such as mifepristone (Korlym®) can be used to treat dysglycemia secondary to hypercortisolism. A 59-year-old male was admitted for dizziness and lightheadedness. Past medical history was significant for hypertension, and obesity. During evaluation, patient was found to have a random blood glucose of 663 mg/dL and a hemoglobin A1c of 14.4% with a previous of 5.8%. After admission, patient required 62.9 units of IV insulin over 9 hours to stabilize blood glucose. Due to the high insulin requirement and clinical presentation, a concern for hypercortisolism was considered and workup revealed an 8am cortisol level of 28.3 mcg/dL, and dexamethasone suppression test with cortisol of 50.4 mcg/dL, dexamethasone level 209 ng/dL and ACTH of &lt;5 pg/mL. Patient was discharged on glargine 40 units SC BID and aspart 10 units SC TID AC. Seventeen days after discharge, patient was admitted with hyperglycemia (233 mg/dL), hypokalemia (2.5 mg/dL), abdominal pain, nausea, and vomiting. CT of abdomen revealed a 9.3 x 10.8 x 9 cm retroperitoneal mass arising from the left adrenal. Patient was started on mifepristone (Korlym®) 600mg PO daily while inpatient as his acute hyperglycemia was insufficiently controlled for consideration to open adrenalectomy. Within 24 hours of starting therapy, patient’s insulin requirement was de-escalated, and euglycemia was maintained for 20 days until surgery. Postoperative pathology demonstrated a 12.1cm resected tumor consistent with adrenocortical carcinoma. No clinical signs of adrenal insufficiency occurred postoperatively despite not stopping mifepristone (Korlym®) prior to surgery. Discussion: Adrenocortical carcinomas (ACC) are rare malignancies with an annual incidence of 0.7–2 cases per million population. They carry a poor prognosis with 5-year survival between 16–47%. The clinical presentation varies on the functional activity of these tumors and approximately 60% of them are cortisol secreting. The management of functioning-ACCs is challenging. Our patient presented with hyperglycemia secondary to hypercortisolism that was recurrent and difficult to control. He was started on mifepristone (Korlym®), a FDA approved potent competitive glucocorticoid receptor antagonist for the treatment of dysglycemia secondary to all forms of Cushing disease. In our patient, mifepristone provided a significant and rapid glycemic control, requiring to decrease the dose of insulin. Conclusion: This case demonstrates a safe and acute use of mifepristone (Korlym®) without initial titration in an inpatient monitored setting making this medication a viable option for management and optimization of hyperglycemia secondary to hypercortisolism. This research was supported (in whole or in part) by HCA Healthcare and/or an HCA Healthcare affiliated entity. The views expressed in this publication represent those of the authors and do not necessarily express the official views of the HCA Healthcare or any of its affiliated entities.