Chronic kidney disease (CKD) is a major contributor to the development of heart failure with preserved ejection fraction (HFpEF), whereas the underlying mechanism of cardiorenal HFpEF is still elusive. The aim of this study was to investigate the role of cardiac fibrosis in a rat model of cardiorenal HFpEF and explore whether treatment with Telmisartan, an inhibitor of renin-angiotensin-aldosterone system (RAAS), can ameliorate cardiac fibrosis and preserve diastolic function in cardiorenal HFpEF. Male rats were subjected to 5/6 subtotal nephrectomy (SNX) or sham operation (Sham), and rats were allowed four weeks to recover and form a stable condition of CKD. Telmisartan or vehicle was then administered p.o. (8 mg/kg/d) for 12 weeks. Blood pressure, brain natriuretic peptide (BNP), echocardiography, and cardiac magnetic resonance imaging were acquired to evaluate cardiac structural and functional alterations. Histopathological staining, real-time polymerase chain reaction (PCR) and western blot were performed to evaluate cardiac remodeling. SNX rats showed an HFpEF phenotype with increased BNP, decreased early to late diastolic transmitral flow velocity (E/A) ratio, increased left ventricular (LV) hypertrophy and preserved ejection fraction (EF). Pathology revealed increased cardiac fibrosis in cardiorenal HFpEF rats compared with the Sham group, while chronic treatment with Telmisartan significantly decreased cardiac fibrosis, accompanied by reduced markers of fibrosis (collagen I and collagen III) and profibrotic cytokines (α-smooth muscle actin, transforming growth factor-β1, and connective tissue growth factor). In addition, myocardial inflammation was decreased after Telmisartan treatment, which was in a linear correlation with cardiac fibrosis. Telmisartan also reversed LV hypertrophy and E/A ratio, indicating that Telmisartan can improve LV remodeling and diastolic function in cardiorenal HFpEF. In conclusion, cardiac fibrosis is central to the pathology of cardiorenal HFpEF, and RAAS modulation with Telmisartan is capable of alleviating cardiac fibrosis and preserving diastolic dysfunction in this rat model.
Mesenchymal stem cell-derived exosomes (MSC-exos) are considered an important restorative treatment for ischemic stroke. However, the migration ability and survival of exogenous MSC-exos remain unclear. Here, we investigated whether MSC-exos migrate into the ischemic brain and play a protective role against ischemic stroke.MSC-exos labeled with DiR were injected intravenously into mice with ischemic stroke. Near-infrared fluorescence (NIRF) images were obtained on days 0, 1, 3, 5, 7, 10, and 14, and magnetic resonance (MR) images were obtained on days 1, 7 and 14. On day 14, the functional outcomes, angiogenesis, neurogenesis, and white matter remodeling were assessed, and Western blot assays were performed.Fluorescence signals from the MSC-exos appeared in the injured brain from day 1 and peaked on day 3. The immunofluorescence staining of the brain samples revealed that the MSC-exos were localized in neurons. The behavioral scores and T2-weighted imaging indicated that the MSC-exos improved neurological functional recovery after stroke. In addition, the in vivo MR-diffusion tensor imaging (DTI) indicated that the exogenous MSC-exos increased the fractional anisotropy (FA) value, fiber length, and fiber number ratio. Furthermore, in the mice with ischemic stroke treated with MSC-exos, angiogenesis and neurogenesis were significantly improved, and the expression of IL-1β was reduced.MSC-exos can migrate into the brains of mice with ischemic stroke and exert therapeutic effects against ischemic stroke; therefore, MSC-exos may have broad clinical applications in the future.
Renal fibrosis is a hallmark of chronic kidney disease, while efficient therapy against renal fibrosis is still lacking. In this study, we investigated the role of a novel small-molecule compound VCP979 on renal fibrosis and inflammation in a rat model of unilateral ureteral obstruction (UUO). One week after the UUO surgery, rats were administered VCP979 by gavage for one week, and after treatment, magnetic resonance imaging of T1rho mapping and histopathological analysis were performed to evaluate renal fibrosis in vivo and ex vivo. This study showed that treatment with VCP979 effectively reduced renal fibrosis, extracellular matrix accumulation, and alleviated epithelial–mesenchymal transition in UUO rats, as well as improved renal function. In vivo T1rho mapping displayed increased T1rho values in the UUO rats, which was decreased after VCP979 treatment, and a positive correlation was detected between the T1rho values and the percentage of fibrotic area. Moreover, the administration of VCP979 also ameliorated the inflammatory cytokines expression and the infiltration of macrophages in renal tissues. Mechanistically, VCP979 treatment inhibited the activation of p38 mitogen–activated protein kinase, nuclear factor-kappa B, and transforming growth factor-β1/Smads signaling pathways. These results indicated that VCP979 could be an effective therapeutic agent for alleviating renal fibrosis and inflammation in the rat model of UUO via its antifibrotic and anti-inflammatory effects.
Hepatocellular carcinoma (HCC) has very poor prognosis due to its immunosuppressive properties. An effective measure to regulate tumor immunity is brachytherapy, which uses 125I seeds planted into tumor. T cell immune receptors with immunoglobulin and ITIM domains (TIGIT) is highly expressed in HCC. The TIGIT-targeted probe is expected to be an effective tool for indicating immunomodulation of 125I seed brachytherapy in HCC. In this study, We constructed a novel peptide targeting TIGIT to evaluate the immune regulation of 125I seed brachytherapy for HCC by near-infrared fluorescence (NIRF).Expression of TIGIT by immunofluorescence (IF) and flow cytometry (FCM) in different part and different differentiated human liver cancer tissues was verified. An optical fluorescence probe (Po-12) containing a NIRF dye and TIGIT peptide was synthesized for evaluating the modulatory effect of 125I seed brachytherapy. Lymphocytes uptake by Po-12 were detected by FCM and confocal microscopy. The distribution and accumulation of Po-12 in vivo were explored by NIRF imaging in subcutaneous and orthotopic tumors. IHC and IF staining were used to verify the expression of TIGIT in the tumors.TIGIT was highly expressed in HCC and increased with tumor differentiation. The dye-labeled peptide (Po-12) retained a stable binding affinity for the TIGIT protein in vitro. Accumulation of fluorescence intensity (FI) increased with time extended in subcutaneous H22 tumors, and the optimal point is 1 h. TIGIT was highly expressed on lymphocytes infiltrated in tumors and could be suppressed by 125I seed brachytherapy. Accumulation of Po-12-Cy5 was increased in tumor-bearing groups while declined in 125I radiation group.
The objective of this study was to observe the expression of transforming growth factor-β1 (TGF-β1) in myocardial tissue and the concentration of serum B-type natriuretic peptide (BNP) in myocardial remodeling of Sprague-Dawley rats induced by isoproterenol (ISO) and the effects of carvedilol intervention.Thirty rats were divided randomly into three groups: (1) Control group: rats were injected with 5 mL/(kg·d) of saline for 10 days, followed by 10 mL/(kg·d) of saline by gavage for 4 weeks. (2) Model group: rats were injected with 5 mg/(kg·d) ISO for 10 days, followed by 10 mL/(kg·d) of saline by gavage for 4 weeks. (3) Treatment group: rats were injected with 5 mg/(kg·d) ISO for 10 days, followed by 10 mg/(kg·d) carvedilol by gavage for 4 weeks. Following treatments, the Cardiac Weight Index (CWI) was measured. The pathological changes to myocardial tissue were observed by HE staining and Masson's trichrome staining. The mRNA expression of TGF-β1 was determined by RT-PCR. The protein expression of TGF-β1 was detected by immunohistochemistry and Western blot. The concentration of serum BNP was measured by ELISA.According to our results, no significant pathological changes were observed in myocardial tissue of the control group. The denaturation, hypertrophy, edema and necrosis of myocardial cells as well as increased collagen fibers in myocardial tissue of the model group, were more pronounced compared to the treatment group. The CWI, level of TGF-β1 in myocardial tissue, and the concentration of serum BNP of the model group, were significantly higher than that of the treatment group, and those of the treatment group were significantly higher than in the control group. There were significant differences among the three groups. There were also significant differences between any two groups.The expression of TGF-β1 in myocardial tissue was upregulated and the concentration of serum BNP was increased in myocardial remodeling of SD rats induced by ISO. Carvedilol intervention can downregulate the expression of TGF-β1 and decrease the concentration of BNP, inhibiting myocardial remodeling, and improve cardiac function.
Type 2 diabetes mellitus (T2DM) is associated with severe axonal/white matter (WM) injury and poor functional outcomes following ischemic stroke. T2DM induces activation of p38 mitogen-activated protein kinases (MAPKs), which may be linked to the axonal/WM damage. In the present study, adult male C57BL/6J mice with streptozotocin (STZ)-induced T2DM mice were subjected to photothrombotic ischemic stroke and treatment with p38 MAPK inhibitors. The novel p38 MAPK inhibitor, VCP979, significantly promoted axonal/WM remodeling, neural progenitor cell migration, and improved functional recovery in T2DM mice. In vivo diffusion tensor imaging (DTI) revealed that the fractional anisotropy (FA) value, fiber number ratio, and fiber length were increased in the VCP979-treated group. Thus, VCP979 improves axonal/WM remodeling and functional outcomes in a diabetic mouse stroke model. DTI may aid in visualizing axonal/WM remodeling and evaluating the therapeutic efficacy of VCP979.
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