FNDC5 induces M2 macrophage polarization and promotes hepatocellular carcinoma cell growth by affecting the PPARγ/NF-κB/NLRP3 pathway.

PURPOSE: The purpose of this study was to investigate the effect of FNDC5 expression levels in hepatocellular carcinoma on the phenotypic changes of macrophages in tumor tissues. METHODS: In this study, we established an in vitro co-culture system of hepatocellular carcinoma cells and macrophages. Then we performed overexpression or knockdown of FNDC5 gene in hepatocellular carcinoma cells to observe the effect of changes in FNDC5 expression level on the phenotypic changes of THP-1 macrophages. And the conclusions obtained in the in vitro assay were further validated by a subcutaneous tumorigenic nude mice model. RESULTS: Our findings suggest that elevated FNDC5 expression in hepatocellular carcinoma cells lead to an increased M2 phenotype and decreased M1 phenotype in macrophages. This effect may be achieved by elevating PPARγ levels in macrophages while decreasing NF-κB and NLRP3 levels. These changes could be reversed by using PPARγ inhibitors. CONCLUSION: We preliminarily demonstrated that FNDC5 in hepatocellular carcinoma cells promotes the polarization of M2 macrophages by affecting the PPARγ/NF-κB/NLRP3 pathway.

Bone marrow mesenchymal stem cells inhibit cardiac hypertrophy by enhancing FoxO1 transcription.

Bone marrow-derived mesenchymal stem cells (BMSCs) have therapeutic potential for certain heart diseases. Previous studies have shown that stem cells inhibit cardiac hypertrophy; however, it is necessary to explore the mechanisms underlying this effect. This study aimed to investigate the possible mechanism underlying the inhibitory effect of BMSCs on cardiomyocyte hypertrophy. We induced cardiomyocyte hypertrophy in cultured rat cells through isoproterenol (ISO) treatment with or without BMSC coculture. A microarray was performed to analyze messenger RNA expression in response to ISO treatment and BMSC coculture. Pathway enrichment analysis showed that the expression of differential genes was closely related to the 5'-adenosine monophosphate-activated protein kinase (AMPK) signaling pathway and that the expression of forkhead box O 1 (FoxO1) was significantly increased in the presence of BMSCs. Furthermore, we determined the expression levels of p-AMPK/AMPK and p-FoxO1/FoxO1 by western blot analysis. The expression of p-AMPK/AMPK was upregulated, whereas that of p-FoxO1/FoxO1 was downregulated upon coculturing with BMSCs. The AMPK-specific antagonist Compound C inhibited the downregulation of p-FoxO1/FoxO1 induced by the BMSC coculture. Furthermore, treatment with the specific FoxO1 antagonist AS1842856 reduced the inhibitory effects of BMSCs on cardiomyocyte hypertrophy in vivo and in vitro. Our present study demonstrates the inhibition of cardiomyocyte hypertrophy by BMSCs, which occurs partly through the AMPK-FoxO1 signaling pathway.

Cardiac thrombotic stability determined by contrast-enhanced echocardiography: investigative protocol and preliminary results.

OBJECTIVE: This study's intent was to test a new system for scoring cardiac thrombotic stability, based on contrast-enhanced ultrasound (CEUS). METHODS: We used human whole blood for an in vitro thrombotic model involving 1-h (T1h) and 7-day (T7d) subsets. The T1h group was monitored for 1 h continuously to observe for the formation of a new thrombus on the original thrombus base. Changes in thrombotic CEUS images, histologic features, and shear wave elastography were recorded over time. We also studied 28 patients diagnosed with cardiac thrombi, each examined by transthoracic echocardiography and CEUS.Thrombi were scored for substrate (Ts) and hardness (Th) based on the visualized degree of contrast penetration into the thrombi. Statistical analyses of Ts and Th reflected thrombolytic time and risk of embolism to other organs. RESULTS: Histologically, the loosely constructed ends of in vitro thrombi solidified over time. In addition, the average Young's modulus of thrombi over time indicated a progressive increase in hardness. Contrast-enhancing agents were able to penetrate fresh, loose thrombi only, not chronic, stable thrombi. As Ts and Th increased, prolonged thrombolytic time and greater risk of embolism to other organs were apparent. CONCLUSIONS: Our data suggest that this new CEUS scoring system correlates well with cardiac thrombotic hardness and the quality of its underlying substrate, serving to quantify thrombotic stability.

Rare double orifice mitral valve malformation associated with bicuspid aortic valve in Turner syndrome: diagnosed by a series of novel three-dimensional echocardiography and literature review.

BACKGROUND: Patients with both double orifice mitral valve (DOMV) and bicuspid aortic valve (BAV) malformation are rare. Although DOMV or BAV can be detected in some genetic syndromes, it has not been reported to simultaneously appear in Turner syndrome (TS). TrueVue, TouchVue, and TrueVue Glass are the latest technologies in advanced three-dimensional echocardiography (3DE), which is an important information supplement to two-dimensional echocardiography (2DE) for the diagnosis of congenital cardiac malformations. Herein we report the novel use of the above-mentioned technologies in the diagnosis and evaluation of a rare, combined valve malformation. Meanwhile, we also reviewed the literature for cases involving both DOMV and BAV and their association with various genetic syndromes. CASE PRESENTATION: We present the case of a 5-year-old girl diagnosed with TS because of a developmental delay. DOMV and BAV were found through echocardiographic examination. Three-dimensional transthoracic echocardiography as well as a series of novel advanced techniques were applied to clearly display the spatial structure of all tiers of the mitral valve apparatus, aortic valve, and arch to facilitate an accurate diagnosis. CONCLUSIONS: This is the first case in which both DOMV and BAV were associated with TS. Innovative TrueVue and TrueVue Glass offer unprecedented photographic stereoscopic images, while TouchVue technology greatly improved the ultrasonic diagnostic workflow and the diagnostic performance of rare valve malformations by adding virtual light sources to display realistic light-shadow effects.

A stepwise-targeting strategy for the treatment of cerebral ischemic stroke.

BACKGROUND: Effective amelioration of neuronal damages in the case of cerebral ischemic stroke (CIS) is essential for the protection of brain tissues and their functional recovery. However, most drugs can not penetrate the blood-brain barrier (BBB), resulting in the poor therapeutic outcomes. RESULTS: In this study, the derivatization and dual targeted delivery technologies were used to actively transport antioxidant melatonin (MLT) into the mitochondria of oxidative stress-damaged cells in brain tissues. A mitochondrial targeting molecule triphenylphosphine (TPP) was conjugated to melatonin (TPP-MLT) to increase the distribution of melatonin in intracellular mitochondria with the push of mitochondrial transmembrane potential. Then, TPP-MLT was encapsulated in dual targeted micelles mediated by TGN peptide (TGNYKALHPHNG) with high affinity for BBB and SHp peptide (CLEVSRKNG) for the glutamate receptor of oxidative stress-damaged neural cells.TGN/SHp/TPP-MLT micelles could effectively scavenge the overproduced ROS to protect neuronal cells from oxidative stress injury during CIS occurrence, as reflected by the improved infarct volume and neurological deficit in CIS model animals. CONCLUSIONS: These promising results showed this stepwise-targeting drug-loaded micelles potentially represent a significant advancement in the precise treatment of CIS.

Clinical diagnostic value of contrast-enhanced ultrasonography in the diagnosis of cardiac masses: A pilot study.

OBJECTIVES: To assess the qualitative and quantitative characteristics of suspected cardiac masses by contrast-enhanced ultrasonography (CEUS) and to evaluate its usefulness. METHODS: Twenty-eight adult patients with suspected cardiac masses were selected for this study. All of them were examined by conventional transthoracic echocardiography (TTE) and CEUS. The location, attachment point, basement, morphology, size, boundary, internal echo, shape change, range of motion, length, area, effect on hemodynamics, and peak enhancement of the masses (A1), and adjacent normal myocardium (A2) were measured. Then, the A1 to A2 ratio was calculated and the above parameters were analyzed. RESULTS: The benign lesions showed regular morphology and clear-boundary uniform enhancement of the contrast agent. Malignant lesions showed an irregular shape, unclear boundary with surrounding tissue, and uneven enhancement of the contrast agent. The normal myocardial perfusion intensity was the same; there was no enhancement inside a simple thrombus, and the A1 of the benign lesion was lower than that of the normal myocardium (mean value [dB] ± SD, 0.63 ± 0.42); the A2 of the malignant lesion was higher than that of the normal myocardium (mean value [dB] ± SD, 1.49 ± 0.09). The difference in the ratio of A1 to A2 between groups was statistically significant (P < .05). CONCLUSIONS: Contrast-enhanced ultrasonography can assess the basic biological characteristics and properties of cardiac masses and has a high diagnostic accuracy for differentiation of a thrombus from a tumor or a benign tumor from a malignant tumor.

Isolated metastasis of hepatocellular carcinoma in the right ventricle.

BACKGROUND: Hepatocellular carcinoma (HCC) with right ventricle metastasis without inferior vena cava and right atrium involvement is very rare and the prognosis of HCC with RV metastasis is generally poor. The mass in the cardiac chamber may lead to lethal instability of hemodynamics, however, the initial symptom is probably non-specific, which means that diagnosis timely becomes even harder. CASE PRESENTATION: We present a 63-year-old male with isolated metastasis of HCC in the right ventricle which caused inflow obstruction. Moreover, we reviewed a series of studies of isolated metastasis of hepatocellular carcinoma between 1980 and 2018, and summarized the relative outcomes. CONCLUSIONS: Isolated metastasis of hepatocellular carcinoma in the right ventricle is extraordinarily rare. It may damage cardiac structure and broke hemodynamic balance. Multimodality imaging plays an important in accurate pre-operation assessment. Nowadays, palliative treatments could relieve fatal symptoms to some degree, however, standard treatment has not been well established.

Irisin stimulates cell proliferation and invasion by targeting the PI3K/AKT pathway in human hepatocellular carcinoma.

Irisin is a newly identified myokine that may be cancer-associated, and its impact on liver cancer is unclear. To understand the roles of irisin in liver cancer, we investigated its effect in HepG2 and SMCC7721 hepatocellular carcinoma cells, and the underlying mechanisms. We determined irisin levels in liver tissues and serum samples obtained from patients by using real-time polymerase chain reaction and enzyme-linked immunosorbent assay. Irisin levels in cancerous livers were significantly upregulated compared with those in control livers, but serum irisin levels remained unchanged. Additionally, we evaluated the effects of different concentrations of human recombinant modified and active (glycosylated) irisin (IM) or human recombinant nonmodified irisin (INM) on cell migration, proliferation, viability, and invasiveness. CCK8, transwell, and scratching assays demonstrated that irisin significantly increased cell proliferation, invasion, and migration through activation of the PI3K/AKT pathway. Irisin-induced cell proliferation, migration, and invasion were blocked by a PI3K inhibitor (LY294002). Irisin also decreased the cytotoxicity of doxorubicin in HepG2 cells. These data indicate that increased irisin levels may have protective roles in liver cancer cells through partial activation of the PI3K/AKT pathway, which may facilitate liver cancer progression and decrease the sensitivity to chemotherapy.

Investigation for the quality factors on the tablets containing medicated pellets.

Sustained and controlled pellets are considered as one of the ideal dosage forms. Due to the large coverage area of pellets, loaded drugs can be absorbed completely in the body and bioavailability is improved correspondingly. Coated pellets-containing tablet is a special oral formulation consisting of various pellets with different release rate. Desired rate of drug release rate can be achieved by adjusting the proportion of pellets. However, this formulation faces strict requirements in the process of preparation. Several factors will influence release behavior of tablets, including pellet cores, coating, and tabletting. Therefore, these factors will be investigated sufficiently in this review to provide valuable information for manufacturing process.

Elevated expression of periostin in diabetic cardiomyopathy and the effect of valsartan.

BACKGROUND: Periostin, an extracellular matrix protein, plays a significant role in adverse cardiac remodeling. However, no report has documented the function of periostin in left ventricular remodeling of streptozototin (STZ)-induced diabetic rats. The aim of the present study was to observe the expression of periostin in Wistar rat's myocardium of diabetic cardiomyopathy (DCM) and the effect of valsartan on it. METHODS: Immunohistochemistry, real-time polymerase chain reaction, and Western blot analysis were used to determine the degree of expression and location of periostin, transforming growth factor (TGF)-ß1, TGF-ß1 type II receptor (TGF-ß1 R II), and Type I and III collagens in the myocardium of STZ-induced diabetic rats. RESULTS: Periostin, TGF-ß1, TGF-ß1 R II, and Type I and III collagens were significantly increased in the myocardium of diabetic rats compared with control group on both messenger ribonucleic acid and protein levels. In addition, diabetic rats treated with valsartan could have reduced expression of periostin and improved cardiac remodeling of DCM. CONCLUSIONS: Periostin may play a crucial role in cardiac remodeling and myocardial interstitial fibrosis process of DCM and it could be one of the important mechanisms for valsartan to improve the ventricular remodeling of DCM.

Male patients with primary Sjögren's syndrome have unique clinical manifestations and circulating lymphocyte profiles.

OBJECTIVES: We aimed to explore the relationship between clinical characteristics and circulating lymphocyte profiles in Chinese male patients with primary Sjögren's syndrome (pSS). METHOD: Data from 397 patients with pSS were analyzed retrospectively. 37 were male, which is a prevalence of 9.3%. The clinical, laboratory, and immunophenotypic profiles of peripheral blood lymphocyte subsets were compared between male and female pSS patients. RESULTS: Male patients with primary Sjögren's syndrome have unique clinical manifestations and circulating lymphocyte profiles. Male patients complained more about xerophthalmia and presented with more extra-glandular manifestations as compared with female patients. The CD4+/CD8+ ratio (P = 0.030), the prevalence of CD4-CD8- T cells in lymphocytes (P = 0.020), the absolute number of CD4-CD8- T cells (P = 0.035), the prevalence of CD4+ T cells in lymphocytes (P < 0.001), and the absolute number of CD4+ T cells (P = 0.023) were significantly lower in male patients compared to female patients. On the other hand, the prevalence of CD8+CD28+ T cells (P = 0.030) and CD4+CD25high T cells (P = 0.040) in lymphocytes was significantly higher in male patients than in female patients. Moreover, compared to females with pSS, an elevated serum IgG level, low C3 and C4 levels, anti-SSB positivity, and ANA titers of ≥ 1:160 positivity were more frequent in male with pSS. CONCLUSIONS: Male patients with pSS have distinctive peripheral blood lymphocyte subpopulations, present with more severe clinical symptoms and immunological features, and have an unfavorable prognosis. Key Points • Male patients with pSS have more severe clinical symptoms and specific characteristics of peripheral blood lymphocyte subsets. • Male pSS patients exhibit a higher intensity of the disease (as evaluated by ESSDAI). • Male patients with pSS require individualized treatment regimens and closer follow-up.

Doxorubicin caused apoptosis of mesenchymal stem cells via p38, JNK and p53 pathway.

BACKGROUND/AIMS: Doxorubicin is a widely used chemotherapeutic agent, but its clinical use is restricted because of a high risk of cardiotoxicity. Bone marrow-derived mesenchymal stem cells (BMSCs) may repair ischaemically damaged myocardium through transdifferentiation and paracrine action. The aim of this study is to investigate if doxorubicin causes the apoptosis of BMSCs and in turn impairs its healing ability. METHODS: BMSCs were exposed to doxorubicin, and cell apoptosis was determined by western blot and stainings. RESULTS: Doxorubicin reduced the survival ratio and caused the apoptosis of BMSCs, with the increase of intracellular ROS level and depolarization of mitochondrial membrane potential. The ROS scavenger NAC abrogated these consequences. Moreover, doxorubicin markedly activated phosphorylated ERK, p38 and JNK proteins in BMSCs. The specific inhibitors for p38 (SB203580) and JNK (SP600125) may abolish doxorubicin-induced apoptosis of BMSCs but the specific ERK inhibitor (PD98059) not, indicating p38 and JNK activation contribute to BMSCs apoptosis. Also, the phosphorylated and total p53 proteins were increased in doxorubicin-treated BMSCs. Proapoptotic cleaved caspases-3 was upregulated and antiapoptotic Bcl-2 protein was reduced in doxorubicin-treated BMSCs. At last, ELISA assay showed that doxorubicin treatment reduced the VEGF and IGF-1 released by BMSCs. CONCLUSION: Taken together, doxorubicin caused BMSCs apoptosis associated with p38, JNK and p53 pathways.

Co-delivery of doxorubicin and SIS3 by folate-targeted polymeric micelles for overcoming tumor multidrug resistance.

Multidrug resistance (MDR) is considered as a critical limiting factor for the successful chemotherapy, which is mainly characterized by the overexpression of ATP-binding cassette (ABC) transporter ABCB1 or ABCG2. In this study, folate-targeted polymeric micellar carrier was successfully constructed to co-delivery of doxorubicin (DOX) and SIS3 (FA/DOX/SIS3 micelles), a specific Smad3 inhibitor which sensitizes ABCB1- and ABCG2-overexpressing cancer cells to chemotherapeutic agents. The ratio of DOX to SIS3 in polymeric micelles was determined based on the anti-tumor activity against resistant breast cells. In addition, FA/DOX/SIS3 micelles exhibited a much longer circulation time in blood and were preferentially accumulated in resistant tumor tissue. Pharmacodynamic studies showed that FA/DOX/SIS3 micelles possessed superior anti-tumor activity than other DOX-based treatments. Overall, FA/DOX/SIS3 micelles are a promising formulation for the synergistic treatment of drug-resistant tumor.

A Stepwise Targeting Curcumin Derivative, Ser@TPP@CUR, for Acute Kidney Injury.

Based on the pathological mechanisms of acute kidney injury (AKI), a stepwise targeting curcumin derivative, Ser@TPP@CUR, was developed in this study. Ser@TPP@CUR can be specifically internalized by renal tubular epithelial cells via KIM-1 receptor-mediated endocytosis and then actively distributed in mitochondria under the effect of TPP, a mitochondrial targeting molecule. Both in vitro and in vivo results showed that Ser@TPP@CUR effectively ameliorated injured renal tubular epithelial cells and improved renal functions of AKI mice.

Novel TrueVue series of 3D echocardiography: Revealing the pathological morphology of congenital heart disease.

Aims: This study explored the advantages and limitations of novel series of three-dimensional (3D) echocardiographic techniques and summarized their application methods for congenital heart diseases (CHDs). Method and result: Two-dimensional (2D), traditional 3D echocardiography, and TrueVue plus light and/or Glass novel 3D technologies were performed on 62 patients with CHD, and a clinical survey was designed to judge whether the novel 3D images were more helpful for understanding the cardiac condition and guide treatment than traditional 3D images. TrueVue increased the visual resolution and simulated the true texture of cardiac tissue, significantly improving the display ability of abnormal anatomical structures in CHDs. TrueVue Glass displayed the blood channel and the internal structure of cardiac cavity more intuitively, indicating a new observation aspect not shown by conventional echocardiography. The clinical survey results showed that the new 3D imaging methods effectively increased the diagnostic confidence of echocardiographers, enabled surgeons to better understand the details of lesions, promoted efficient communication, and improved the confidence of both doctors and patients in treatment. Conclusion: The combined application of TrueVue, TrueVue Light, and TrueVue Glass more closely simulated real anatomical features, showed more comprehensive and subtle blood flow in the lumen, not only increased the visual effect but also provided more useful diagnostic information, improved the accuracy of evaluation and treatment of CHD when compared to traditional imaging techniques, indicating that this combined application has significant clinical value.

Correction to "A Stepwise Targeting Curcumin Derivative, Ser@TPP@CUR, for Acute Kidney Injury".

[This corrects the article DOI: 10.1021/acsmedchemlett.1c00585.].

Real-time 3D echocardiographic transilluminated imaging combined with artificially intelligent left atrial appendage measurement for atrial fibrillation interventional procedures.

Aims: This study investigated the feasibility and accuracy of real-time three-dimensional (3D) echocardiographic transilluminated imaging (TrueVue Glass) in left atrial appendage (LAA) anatomical morphology and artificial intelligence (AI)-assisted 3D automated LAA measurement (3D Auto LAA) software in the preoperative evaluation of LAA occlusion (LAAO) in patients with atrial fibrillation (AF). Method and results: Thirty-seven patients with AF were selected. Two-dimensional (2D) and real-time 3D transesophageal echocardiography (RT3D-TEE) were performed preoperatively, using conventional 3D, the new 3D TrueVue Glass mode, and cardiac computed tomography angiography (CCTA) to assess and type the morphology of LAA. Physiological parameters were measured using traditional 2D and 3D manual (3D Manual LAA), 3D Auto LAA, and CCTA. TrueVue Glass for LAA outer contour display was compared with CCTA. Comparisons were based on correlation and consistency in measuring the maximum diameter (LZ max), minimum diameter (LZ min), area (LZ area), and circumference (LZ cir) of LAA landing zone (LZ). Times and variabilities were compared. The concordance rate for external shape of LAA was 97.14% between TrueVue Glass and CCTA. 3D Auto LAA and 3D Manual LAA have a stronger correlation and higher consistency in all parameters. 3D Auto LAA showed higher intra- and interobserver reproducibility and allowed quicker analysis (p < 0.05). LAAO was performed in 35 patients (94.59%), and none of which had serious adverse events. Conclusion: TrueVue Glass is the first non-invasive and radiation-free visualization of the overall external contour of LAA and its adjacent structures. 3D Auto LAA simplifies the measurement, making the preoperative assessment more efficient and convenient while ensuring the accuracy and reproducibility. A combination of the two is feasible for accurate and rapid assessment of LAA anatomy and physiology in AF patients and has practical application in LAAO.

A mitochondria-targeted dual-functional aggregation-induced emission luminogen for intracellular mitochondrial imaging and photodynamic therapy.

A mitochondria-targeted dual-functional aggregation-induced emission luminogen, TPP-TPEDCH, was rationally designed and developed for intracellular mitochondrial imaging and photodynamic therapy. TPP-TPEDCH clearly showed the movements of mitochondria at various time points. Moreover, both in vitro and in vivo results demonstrated its excellent ROS generation ability and strong antitumor activity.

Correction: A mitochondria-targeted dual-functional aggregation-induced emission luminogen for intracellular mitochondrial imaging and photodynamic therapy.

Correction for 'A mitochondria-targeted dual-functional aggregation-induced emission luminogen for intracellular mitochondrial imaging and photodynamic therapy' by Yujie Zhang et al., Biomater. Sci., 2021, 9, 1232-1236, DOI: 10.1039/D0BM02099K.