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Objectives: The purpose of this study was to evaluate the antiarrhythmic potential of mesenchymal stem cells (MSC) under a different environment. Background: Little is known about how environmental status affects antiarrhythmic potential of MSCs. Methods: To investigate the effect of paracrine factors secreted from MSCs under different circumstances on arrhythmogenicity in rats with myocardial infarction, we injected paracrine media (PM) secreted under hypoxic, normoxic conditions (hypoxic PM and normoxic PM), and MSC into the border zone of infarcted myocardium in rats. Results: We found that the injection of hypoxic PM, but not normoxic PM, markedly restored conduction velocities, suppressed focal activity, and prevented sudden arrhythmic deaths in rats. Underlying this electrophysiological alteration was a decrease in fibrosis, restoration of connexin 43, alleviation of Ca(2+) overload, and recovery of Ca(2+)-regulatory ion channels and proteins, all of which is supported by proteomic data showing that several paracrine factors including basic fibroblast growth factor, insulinlike growth factor 1, hepatocyte growth factor, and EF-hand domain-containing 2 are potential mediators. When compared with PM, MSC injection did not reduce or prevent arrhythmogenicity, suggesting that the antiarrhythmic or proarrhythmic potential of MSC is mainly dependent on paracrine factors. Conclusions: A hypoxic or normoxic environment surrounding MSC affects the type and properties of the growth factors or cytokines, and these secreted molecules determine the characteristics of the electro-anatomical substrate of the surrounding myocardium. [ABSTRACT FROM AUTHOR]

Our research explores the detrimental effects of microplastic (MP) exposure on adipose tissue aging and function, emphasizing the potential health risks associated with environmental pollutants. Utilizing both in vivo and in vitro models, we discovered that MPs accumulate in adipose tissues, leading to cellular senescence, inflammation, and hindered adipogenic differentiation. Notably, our findings demonstrate that MPs prompt an aging response in both epididymal and inguinal white adipose tissue, increase senescence-associated β-galactosidase activity, and upregulate key senescence and inflammatory markers. Furthermore, we show that MPs disrupt normal adipogenic differentiation by reducing lipid droplet formation and downregulating critical adipogenic markers. These insights highlight the urgent need for further investigation into the long-term consequences of MP pollution on biological aging and underscore the importance of developing public health strategies to mitigate these effects., (© 2024. The Author(s).)

Endothelial-to-mesenchymal transition (EndMT) is a complex biological process of cellular transdifferentiation by which endothelial cells (ECs) lose their characteristics and acquire mesenchymal properties, leading to cardiovascular remodeling and complications in the adult cardiovascular diseases environment. Melatonin is involved in numerous physiological and pathological processes, including aging, and has anti-inflammatory and antioxidant activities. This molecule is an effective therapeutic candidate for preventing oxidative stress, regulating endothelial function, and maintaining the EndMT balance to provide cardiovascular protection. Although recent studies have documented improved cardiac function by melatonin, the mechanism of action of melatonin on EndMT remains unclear. The present study investigated the effects of melatonin on induced EndMT by transforming growth factor-β2/interleukin-1β in both in vivo and in vitro models. The results revealed that melatonin reduced the migratory ability and reactive oxygen species levels of the cells and ameliorated mitochondrial dysfunction in vitro. Our findings indicate that melatonin prevents endothelial dysfunction and inhibits EndMT by activating related pathways, including nuclear factor kappa B and Smad. We also demonstrated that this molecule plays a crucial role in restoring cardiac function by regulating the EndMT process in the ischemic myocardial condition, both in vessel organoids and myocardial infarction (MI) animal models. In conclusion, melatonin is a promising agent that attenuates EC dysfunction and ameliorates cardiac damage compromising the EndMT process after MI., (© 2024 The Authors. Journal of Pineal Research published by John Wiley & Sons Ltd.)

The rapid aging of the population worldwide presents a significant social and economic challenge, particularly due to osteoporotic fractures, primarily resulting from an imbalance between osteoclast-mediated bone resorption and osteoblast-mediated bone formation. While conventional therapies offer benefits, they also present limitations and a range of adverse effects. This study explores the protective impact of Neorhodomela munita ethanol extract (EN) on osteoporosis by modulating critical pathways in osteoclastogenesis and apoptosis. Raw264.7 cells and Saos-2 cells were used for in vitro osteoclast and osteoblast models, respectively. By utilizing various in vitro methods to detect osteoclast differentiation/activation and osteoblast death, it was demonstrated that the EN's potential to inhibit RANKL induced osteoclast formation and activation by targeting the MAPKs-NFATc1/c-Fos pathway and reducing H 2 O 2 -induced cell death through the downregulation of apoptotic signals. This study highlights the potential benefits of EN for osteoporosis and suggests that EN is a promising natural alternative to traditional treatments.

Rationale: Adenoid cystic carcinoma (AdCC) is a rare malignancy of the breast with a low Ki-67 index and good prognosis. Owing to the rarity of breast AdCC, the misdiagnosis rate is as high as 50%, and there is no consensus or recognized guidelines for the treatment of this disease. Therefore, it is necessary to conduct a detailed clinical and pathological analysis in combination with a literature review to improve our understanding, diagnosis, and treatment of the disease., Methods: A 68-year-old woman sought medical attention due to a recently increasing mass in the breast. The left breast mass was 1.3 cm × 1 cm in size. We analyzed the morphology, immunohistochemistry, and molecular characteristics of the tumor removed by surgery, and reviewed relevant literature., Diagnoses: Solid basal AdCC of the breast., Interventions: We performed biopsy, immunohistochemistry and molecular testing on surgical resection specimens., Outcomes: Combining morphological and immunohistochemical features, it is consistent with solid basal AdCC of the breast, and Fish detected MYB gene break., Lessons: Due to the high misdiagnosis rate of AdCC, accurate histopathological diagnosis is particularly important. At present, breast conserving surgery and local tumor resection are mainly used for the treatment of breast AdCC, and postoperative adjuvant radiotherapy is feasible., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Adipose-derived mesenchymal stem cells (ASCs) have the potential to differentiate into bone, cartilage, fat, and neural cells and promote tissue regeneration and healing. It is known that they can have variable responses to hypoxic conditions. In the present study, we aimed to explore diverse changes in the cells and secretome of ASCs under a hypoxic environment over time and to present the possibility of ASCs as therapeutic agents from a different perspective. The expression differences of proteins between normoxic and hypoxic conditions (6, 12, or 24 h) were specifically investigated in human ASCs using 2-DE combined with MALDI-TOF MS analysis, and secreted proteins in ASC-derived conditioned media (ASC-derived CM) were examined by an adipokine array. In addition, genetic and/or proteomic interactions were assessed using a DAVID and miRNet functional annotation bioinformatics analysis. We found that 64 and 5 proteins were differentially expressed in hypoxic ASCs and in hypoxic ASC-derived CM, respectively. Moreover, 7 proteins among the 64 markedly changed spots in hypoxic ASCs were associated with bone-related diseases. We found that two proteins, cathepsin D (CTSD) and cathepsin L (CTSL), identified through an adipokine array independently exhibited significant efficacy in promoting osteocyte differentiation in bone-marrow-derived mesenchymal stem cells (BM-MSCs). This finding introduces a promising avenue for utilizing hypoxia-preconditioned ASC-derived CM as a potential therapeutic approach for bone-related diseases.

Cardiac tissue damage following ischemia leads to cardiomyocyte apoptosis and myocardial fibrosis. Epigallocatechin-3-gallate (EGCG), an active polyphenol flavonoid or catechin, exerts bioactivity in tissues with various diseases and protects ischemic myocardium; however, its association with the endothelial-to-mesenchymal transition (EndMT) is unknown. Human umbilical vein endothelial cells (HUVECs) pretreated with transforming growth factor β2 (TGF-β2) and interleukin 1β (IL-1β) were treated with EGCG to verify cellular function. In addition, EGCG is involved in RhoA GTPase transmission, resulting in reduced cell mobility, oxidative stress, and inflammation-related factors. A mouse myocardial infarction (MI) model was used to confirm the association between EGCG and EndMT in vivo. In the EGCG-treated group, ischemic tissue was regenerated by regulating proteins involved in the EndMT process, and cardioprotection was induced by positively regulating apoptosis and fibrosis of cardiomyocytes. Furthermore, EGCG can reactivate myocardial function due to EndMT inhibition. In summary, our findings confirm that EGCG is an impact activator controlling the cardiac EndMT process derived from ischemic conditions and suggest that supplementation with EGCG may be beneficial in the prevention of cardiovascular disease.

Cardiovascular diseases have been leading cause of death worldwide for many decades, and obesity has been acknowledged as a risk factor for cardiovascular diseases. In the present review, human epicardial adipose tissue-derived miRNAs reported to be differentially expressed under pathologic conditions are discussed and summarized. The results of the literature review indicate that some of the epicardial adipose tissue-derived miRNAs are believed to be cardioprotective, while some others show quite the opposite effects depending on the underlying pathologic conditions. Furthermore, they suggest that that the epicardial adipose tissue-derived miRNAs have great potential as both a diagnostic and therapeutic modality. Nevertheless, mainly due to highly limited availability of human samples, it is very difficult to make any generalized claims on a given miRNA in terms of its overall impact on the cardiovascular system. Therefore, further functional investigation of a given miRNA including, but not limited to, the study of its dose effect, off-target effects, and potential toxicity is required. We hope that this review can provide novel insights to transform our current knowledge on epicardial adipose tissue-derived miRNAs into clinically viable therapeutic strategies for preventing and treating cardiovascular diseases.

Endogenous neural stem cells (eNSCs) in the adult brain, which have the potential to self-renew and differentiate into functional, tissue-appropriate cell types, have raised new expectations for neurological disease therapy. Low-intensity focused ultrasound (LIFUS)-induced blood-brain barrier modulation has been reported to promote neurogenesis. Although these studies have reported improved behavioral performance and enhanced expression of brain biomarkers after LIFUS, indicating increased neurogenesis, the precise mechanism remains unclear. In this study, we evaluated eNSC activation as a mechanism for neurogenesis after LIFUS-induced blood-brain barrier modulation. We evaluated the specific eNSC markers, Sox-2 and nestin, to confirm the activation of eNSCs. We also performed 3'-deoxy-3'[ 18 F] fluoro-L-thymidine positron emission tomography ([ 18 F] FLT-PET) to evaluate the activation of eNSCs. The expression of Sox-2 and nestin was significantly upregulated 1 week after LIFUS. After 1 week, the upregulated expression decreased sequentially; after 4 weeks, the upregulated expression returned to that of the control group. [ 18 F] FLT-PET images also showed higher stem cell activity after 1 week. The results of this study indicated that LIFUS could activate eNSCs and induce adult neurogenesis. These results show that LIFUS may be useful as an effective treatment for patients with neurological damage or neurological disorders in clinical settings.

Background: This study explores the association of neutrophil-to-lymphocyte (NLR), monocyte-to-lymphocyte (MLR), and platelet-to-lymphocyte (PLR) ratios with the 3-month treatment response and persistence of tumor necrosis factor-alpha (TNF-α) blockers in patients with ankylosing spondylitis (AS)., Methods: This retrospective cohort study investigated 279 AS patients who were newly initiated on TNF-α blockers between April 2004 and October 2019 and 171 sex- and age-matched healthy controls. Response to TNF-α blockers was defined as a reduction in the Bath AS Disease Activity Index of ≥50% or 20 mm, and persistence referred to the time interval from the initiation to discontinuation of TNF-α blockers., Results: Patients with AS had significantly increased NLR, MLR, and PLR ratios as compared to controls. The frequency of non-response at 3 months was 3.7%, and TNF-α blockers' discontinuation occurred in 113 (40.5%) patients during the follow-up period. A high baseline NLR but not high baseline MLR and PLR showed an independently significant association with a higher risk of non-response at 3 months (OR = 12.3, p = 0.025) and non-persistence with TNF-α blockers (HR = 1.66, p = 0.01)., Conclusions: NLR may be a potential marker for predicting the clinical response and persistence of TNF-α blockers in AS patients.

Vascular calcification (VC) and osteoporosis are age-related diseases and significant risk factors for the mortality of elderly. VC and osteoporosis may share common risk factors such as renin-angiotensin system (RAS)-related hypertension. In fact, inhibitors of RAS pathway, such as angiotensin type 1 receptor blockers (ARBs), improved both vascular calcification and hip fracture in elderly. However, a sex-dependent discrepancy in the responsiveness to ARB treatment in hip fracture was observed, possibly due to the estrogen deficiency in older women, suggesting that blocking the angiotensin signaling pathway may not be effective to suppress bone resorption, especially if an individual has underlying osteoclast activating conditions such as estrogen deficiency. Therefore, it has its own significance to find alternative modality for inhibiting both vascular calcification and osteoporosis by directly targeting osteoclast activation to circumvent the shortcoming of ARBs in preventing bone resorption in estrogen deficient individuals. In the present study, a natural compound library was screened to find chemical agents that are effective in preventing both calcium deposition in vascular smooth muscle cells (vSMCs) and activation of osteoclast using experimental methods such as Alizarin red staining and Tartrate-resistant acid phosphatase staining. According to our data, citreoviridin (CIT) has both an anti-VC effect and anti-osteoclastic effect in vSMCs and in Raw 264.7 cells, respectively, suggesting its potential as an effective therapeutic agent for both VC and osteoporosis.

Organ-on-a-chip (OOAC) has attracted great attention during the last decade as a revolutionary alternative to conventional animal models. This cutting-edge technology has also brought constructive changes to the field of cardiovascular research. The cardiovascular system, especially the heart as a well-protected vital organ, is virtually impossible to replicate in vitro with conventional approaches. This made scientists assume that they needed to use animal models for cardiovascular research. However, the frequent failure of animal models to correctly reflect the native cardiovascular system necessitated a search for alternative platforms for preclinical studies. Hence, as a promising alternative to conventional animal models, OOAC technology is being actively developed and tested in a wide range of biomedical fields, including cardiovascular research. Therefore, in this review, the current literature on the use of OOACs for cardiovascular research is presented with a focus on the basis for using OOACs, and what has been specifically achieved by using OOACs is also discussed. By providing an overview of the current status of OOACs in cardiovascular research and its future perspectives, we hope that this review can help to develop better and optimized research strategies for cardiovascular diseases (CVDs) as well as identify novel applications of OOACs in the near future.

Endothelial-mesenchymal transition (EndMT) is a process by which endothelial cells (ECs) transition into mesenchymal cells (e.g., myofibroblasts and smooth muscle cells) and induce fibrosis of cells/tissues, due to ischemic conditions in the heart. Previously, we reported that echinochrome A (EchA) derived from sea urchin shells can modulate cardiovascular disease by promoting anti-inflammatory and antioxidant activity; however, the mechanism underlying these effects was unclear. We investigated the role of EchA in the EndMT process by treating human umbilical vein ECs (HUVECs) with TGF-β2 and IL-1β, and confirmed the regulation of cell migration, inflammatory, oxidative responses and mitochondrial dysfunction. Moreover, we developed an EndMT-induced myocardial infarction (MI) model to investigate the effect of EchA in vivo. After EchA was administered once a day for a total of 3 days, the histological and functional improvement of the myocardium was investigated to confirm the control of the EndMT. We concluded that EchA negatively regulates early or inflammation-related EndMT and reduces the myofibroblast proportion and fibrosis area, meaning that it may be a potential therapy for cardiac regeneration or cardioprotection from scar formation and cardiac fibrosis due to tissue granulation. Our findings encourage the study of marine bioactive compounds for the discovery of new therapeutics for recovering ischemic cardiac injuries.

NANOG plays a key role in cellular plasticity and the acquisition of the stem cell state during reprogramming, but its role in the regenerative process remains unclear. Here, we show that the induction of NANOG in neuronal cells is necessary for the physiological initiation of neuronal regeneration in response to ischemic stress. Specifically, we found that NANOG was preferentially expressed in undifferentiated neuronal cells, and forced expression of Nanog in neural progenitor cells (NPCs) promoted their self-renewing expansion both in ex-vivo slice cultures and in vitro limiting dilution analysis. Notably, the upstream region of the Nanog gene contains sequence motifs for hypoxia-inducible factor-1 alpha (HIF-1α). Therefore, cerebral neurons exposed to hypoxia significantly upregulated NANOG expression selectively in primitive (CD133 + ) cells, but not in mature cells, leading to the expansion of NPCs. Notably, up to 80% of the neuronal expansion induced by hypoxia was attributed to NANOG-expressing neuronal cells, whereas knockdown during hypoxia abolished this expansion and was accompanied by the downregulation of other pluripotency-related genes. Moreover, the number of NANOG-expressing neuronal cells were transiently increased in response to ischemic insult, predominantly in the infarct area of brain regions undergoing neurogenesis, but not in non-neurogenic loci. Together, these findings reveal a functional effect of NANOG-induction for the initiation of adaptive neuronal regeneration among heterogeneous NPC subsets, pointing to cellular plasticity as a potential link between regeneration and reprogramming processes., (© 2022. The Author(s).)

Background: To investigate the diagnostic performance of the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and monocyte-to-lymphocyte ratio (MLR) in the diagnosis of rheumatoid arthritis (RA) in subjects with undifferentiated inflammatory arthritis (UIA). Methods: This retrospective cohort study investigated 201 female patients with UIA (≥1 swollen joint) and 280 age-matched, healthy female controls. “Clinical RA” was defined based on the clinical judgment of a rheumatologist and “disease-modifying anti-rheumatic drugs (DMARDs) RA” was defined as a case of initiating DMARDs treatment within 6 months after the first visit. “Classified RA” was defined as fulfilling the 2010 classification criteria for RA. Receiver operating characteristics were used to determine the optimal cut-off value. Results: UIA patients had a significantly higher NLR, PLR, and MLR than the controls. Among the 201 UIA patients, 65 (32.3%), 63 (31.3%), and 61 (30.3%) subjects were classified as clinical RA, DMARDs RA, and classified RA, respectively. At a cut-off of 0.24, MLR showed moderate accuracy for the diagnosis of DMARDs RA (sensitivity, 65.1%; specificity, 62.3%; area under the curve [AUC], 0.701; p < 0.001). However, the diagnostic accuracies of NLR and PLR were low. Conclusions: MLR may be used as a complementary diagnostic indicator for RA diagnosis in patients with UIA.

Objective:  Blood blister-like aneurysms (BBAs) of the internal carotid artery (ICA) are challenging to treat. We assessed the clinical and radiologic outcomes in patients with ruptured BBAs of the ICA treated with wrap-clipping., Methods:  From November 2016 to January 2020, the clinical and radiologic data of patients with subarachnoid hemorrhage (SAH) caused by ICA BBAs who underwent wrap-clipping were retrospectively analyzed. The clinical outcomes were evaluated according to the modified Rankin Scale (mRS). Radiologic follow-up examinations included digital subtraction angiography (DSA), computed tomography angiography (CTA), and magnetic resonance angiography (MRA)., Results:  Seven patients were enrolled in this study. All BBAs were wrap-clipped successfully, including two BBAs that exhibited intraoperative bleeding and required balloon-assistance during surgery. All patients had favorable clinical outcomes during follow-up. Among the six patients who completed the radiologic follow-up visit, one patient presented ICA occlusion at the 6-month DSA follow-up, but no neurologic dysfunction was noted. We did not observe the progression of ICA stenosis in other patients., Conclusion:  All BBAs in this study were wrap-clipped successfully and completely occluded. Wrap-clipping is effective for BBAs of the ICA and has favorable clinical outcomes. A multicenter study with a large sample size and a longer radiologic follow-up is necessary., Competing Interests: None declared., (Thieme. All rights reserved.)

Background and Objectives: We investigated whether nutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphoycte ratio (PLR), and monocyte-to-lymphocyte ratio (MLR) are associated with the presence of osteoporosis (OP) and vertebral fractures in patients with rheumatoid arthritis (RA). Materials and Methods: This retrospective cohort study included 413 postmenopausal patients with RA and 200 healthy controls who underwent dual-energy X-ray absorptiometry (DEXA) between January 2005 and December 2017. DEXA examination data were defined as the index date, and all laboratory values were measured within one month from the index date. OP was defined as a T-score < −2.5, and incident vertebral fractures were defined as the first occurrence of non-traumatic fractures after the index date. NLR, PLR, and MLR measures were dichotomized by a median split (low vs. high). Results: The median NLR, PLR, and MLR in RA patients were significantly higher than those in controls. The frequencies of OP of the lumbar spine, hip, and either site in postmenopausal patients with RA were 24.7%, 15.5%, and 32%, respectively, and were significantly higher than those in controls. After adjusting for confounding factors, a high baseline NLR was significantly associated with OP at either site (OR = 1.61, p = 0.041). In addition, high baseline NLR (OR = 2.11, p = 0.025) and PLR (OR = 2.3, p = 0.011) were related with the presence OP at hip. During the follow-up period, 53 (12.8%) patients with RA developed vertebral fractures incidentally. In multivariable Cox regression models, a high baseline NLR (HR = 4.72, p < 0.001), PLR (HR = 1.96, p = 0.024), and MLR (HR = 2.64, p = 0.002) were independently associated with a higher risk of incidental vertebral fractures. Conclusions: Our data suggest that NLR, PLR, and MLR can be used as potential markers of systemic bone loss among individuals with RA.

Direct lineage conversion holds great promise in the regenerative medicine field for restoring damaged tissues using functionally engineered counterparts. However, current methods of direct lineage conversion, even those using virus-mediated transgenic expression of tumorigenic factors, are extremely inefficient (~25%). Thus, advanced methodologies capable of revolutionizing efficiency and addressing safety concerns are key to clinical translation of these technologies. Here, we propose an extracellular vesicle (EV)-guided, nonviral, direct lineage conversion strategy to enhance transdifferentiation of fibroblasts to induced cardiomyocyte-like cells (iCMs). The resulting iCMs have typical cardiac Ca 2+ transients and electrophysiological features and exhibit global gene expression profiles similar to those of cardiomyocytes. This is the first demonstration of the use of EVs derived from embryonic stem cells undergoing cardiac differentiation as biomimetic tools to induce cardiac reprogramming with extremely high efficiency (>60%), establishing a general, more readily accessible platform for generating a variety of specialized somatic cells through direct lineage conversion.

Background and Objectives: It is crucial to prevent osteoporosis in patients receiving long-term glucocorticoid (GC) treatment. This study aimed to investigate the frequency and associated factors of preventive care for glucocorticoid-induced osteoporosis (GIOP) in Korea. Materials and Methods: Using the Korean National Health Insurance Service database, we identified 37,133 individuals aged ≥ 20 years who commenced long-term (≥90 days) oral GC between 2011 and 2012. High-quality GIOP preventive care was defined as either a bone mineral density (BMD) test, calcium and/or vitamin D supplementation, or prescription osteoporosis medications within 6 months of GC initiation. Multivariable logistic regression models were used to calculate odds ratios (ORs) for associated factors for high-quality GIOP preventive care. Results: The mean age was 49.8 years, and 18,476 (49.8%) patients were female. The frequency of high-quality GIOP preventive care was only 3.68% (BMD test, 1.46%; osteoporosis medications, 1.65%; calcium/vitamin D, 1.63%). Increasing age (OR = 2.53, p < 0.001; 40-49 years, OR = 3.99, p < 0.001; 50-59 years, OR = 5.17, p < 0.001; 60-69 years, OR = 8.07, p < 0.001; ≥70 years, respectively), systemic autoimmune disease (OR = 3.08, p < 0.001), rural residence (OR = 1.19, p = 0.046), concomitant hyperthyroidism (OR = 1.58, p = 0.007), and malignancy (OR = 1.59, p < 0.001) were significantly associated with a higher likelihood of receiving high-quality GIOP preventive care. Male sex (OR = 0.26, p < 0.001) and GC prescription in primary care clinics and nursing hospitals (OR = 0.66, p < 0.001) were associated with a lower rate of high-quality GIOP preventive care. Conclusions: Most Korean patients treated with GC did not receive appropriate preventive care for GIOP in real-world practice. More efforts are needed by clinicians to prevent, screen, and treat GIOP.

Although the optimal therapy for myocardial infarction includes reperfusion to restore blood flow to the ischemic area, myocardial injury after ischemia/reperfusion usually leads to an inflammatory response, oxidative stress, and cardiomyocyte apoptosis. In this study, rat adipose-derived stem cells were differentiated into low-thermogenic beige adipocytes (LBACs) and high-thermogenic beige adipocytes (HBACs) to study the different cardioprotective effects of heterogeneous expression of brown adipocytes. We found that antioxidant and antiapoptotic factors in H9c2 cardiomyocytes were upregulated by high levels of secreted FGF21 in HBAC conditioned medium (HBAC-CM), whereas FGF21 in HBAC-CM did not affect antioxidative or antiapoptotic cell death in H9c2 cardiomyocytes with Nrf2 knockdown. These results show that NRF2 mediates antioxidative and antiapoptotic effects through the HBAC-secreted factor FGF21. Consistent with this finding, the expression of antioxidant and antiapoptotic genes was upregulated by highly secreted FGF21 after HBAC-CM treatment compared to LBAC-CM treatment in H9c2 cardiomyocytes via NRF2 activation. Furthermore, HBAC-CM significantly attenuated ischemic rat heart tissue injury via NRF2 activation. Based on these findings, we propose that HBAC-CM exerts beneficial effects in rat cardiac ischemia/reperfusion injury by modulating NRF2 and has potential as a promising therapeutic agent for myocardial infarction.

Vascular occlusive disease is a chronic disease with significant morbidity and mortality. Although a variety of therapies and medications have been developed, the likelihood of disease re-emergence is high and this can be life-threatening. Based on a previous screening experiment related to vascular obstructive diseases using 34 types of essential oils, cold-pressed oil (CpO) from Citrus aurantifolia (lime) has been demonstrated to have the best effect for the inhibition of vascular smooth muscle cells (VSMCs) proliferation. The aim of the present study was to evaluate the effect of lime CpO on the pathological changes of VSMCs. To determine this, the effect of lime CpO on VSMC proliferation, a major cause of vascular disease, was investigated. To determine the safe concentration interval for toxicity of CpO during VSMC culture, a dilution of 1x10 -5 was determined using Cell Counting Kit-8 assay, which was confirmed to be non-toxic using a lactate dehydrogenase assay. To examine the effect of lime CpO in cellular signaling pathways, changes in phosphorylation of both the PI3K/AKT/mTOR and extracellular signal-regulated MEK/ERK signaling pathways with serum were investigated. Furthermore, lime CpO with FBS also significantly decreased the expression levels of the cell cycle regulators cyclin D1 and proliferating cell nuclear antigen. Additionally, lime CpO with FBS significantly inhibited the sprouting of VSMCs in an ex vivo culture system. These results suggested that lime CpO inhibited the abnormal proliferation of VSMCs and can be developed as a nature-based therapeutic agent for obstructive vascular disease., Competing Interests: The authors declare that they have no competing interests., (Copyright: © Song et al.)

Systemic sclerosis (SSc) is a chronic autoimmune disease characterized by fibrosis of the skin and internal organs. Despite the recent advances in the pathogenesis and treatment of SSc, effective therapies for fibrosis caused by SSc have not yet been established. In this study, we investigated the potential role of mirodenafil, a potent phosphodiesterase 5 (PDE5) inhibitor, in the treatment of fibrosis in SSc. We used a bleomycin (BLM)-induced SSc mouse model to mimic the typical features of fibrosis in human SSc and examined the dermal thickness to assess the degree of skin fibrosis after staining with hematoxylin and eosin or Masson's trichrome stains. The effect of mirodenafil on the expression of profibrotic genes was also analyzed by treating fibroblasts with transforming growth factor (TGF)-β and mirodenafil. We showed that mirodenafil ameliorated dermal fibrosis and downregulated the protein levels of fibrosis markers including COL1A1 and α-SMA in the BLM-induced SSc mouse model. Further, using mouse embryonic fibroblasts and human lung fibroblasts, we demonstrated that the expression of collagen and profibrotic genes was reduced by treatment with mirodenafil. Finally, we showed that mirodenafil inhibited TGF-β-induced phosphorylation of Smad2/3 in fibroblasts, which suggested that this drug may ameliorate fibrosis by suppressing the TGF-β/Smad signaling pathway. Our findings suggest that mirodenafil possesses a therapeutic potential for treating fibrosis in SSc., Competing Interests: No potential conflict of interest was reported by the author(s)., (© 2021 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.)

Recently published clinical trials involving the use of adipose-derived stem cells (ADSCs) indicated that approximately one-third of the studies were conducted on musculoskeletal disorders (MSD). MSD refers to a wide range of degenerative conditions of joints, bones, and muscles, and these conditions are the most common causes of chronic disability worldwide, being a major burden to the society. Conventional treatment modalities for MSD are not sufficient to correct the underlying structural abnormalities. Hence, ADSC-based cell therapies are being tested as a form of alternative, yet more effective, therapies in the management of MSDs. Therefore, in this review, MSDs subjected to the ADSC-based therapy were further categorized as arthritis, craniomaxillofacial defects, tendon/ligament related disorders, and spine disorders, and their brief characterization as well as the corresponding conventional therapeutic approaches with possible mechanisms with which ADSCs produce regenerative effects in disease-specific microenvironments were discussed to provide an overview of under which circumstances and on what bases the ADSC-based cell therapy was implemented. Providing an overview of the current status of ADSC-based cell therapy on MSDs can help to develop better and optimized strategies of ADSC-based therapeutics for MSDs as well as help to find novel clinical applications of ADSCs in the near future.

Neurodegenerative disease is a brain disorder caused by the loss of structure and function of neurons that lowers the quality of human life. Apart from the limited potential for endogenous regeneration, stem cell-based therapies hold considerable promise for maintaining homeostatic tissue regeneration and enhancing plasticity. Despite many studies, there remains insufficient evidence for stem cell tracing and its correlation with endogenous neural cells in brain tissue with three-dimensional structures. Recent advancements in tissue optical clearing techniques have been developed to overcome the existing shortcomings of cross-sectional tissue analysis in thick and complex tissues. This review focuses on recent progress of stem cell treatments to improve neurodegenerative disease, and introduces tissue optical clearing techniques that can implement a three-dimensional image as a proof of concept. This review provides a more comprehensive understanding of stem cell tracing that will play an important role in evaluating therapeutic efficacy and cellular interrelationship for regeneration in neurodegenerative diseases., Competing Interests: Conflict-of-interest statement: The authors declare no conflicts of interest for this article., (©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.)

The acute demise of stem cells following transplantation significantly compromises the efficacy of stem cell-based cell therapeutics for infarcted hearts. As the stem cells transplanted into the damaged heart are readily exposed to the hostile environment, it can be assumed that the acute death of the transplanted stem cells is also inflicted by the same environmental cues that caused massive death of the host cardiac cells. Pyroptosis, a highly inflammatory form of programmed cell death, has been added to the list of important cell death mechanisms in the damaged heart. However, unlike the well-established cell death mechanisms such as necrosis or apoptosis, the exact role and significance of pyroptosis in the acute death of transplanted stem cells have not been explored in depth. In the present study, we found that M1 macrophages mediate the pyroptosis in the ischemia/reperfusion (I/R) injured hearts and identified miRNA-762 as an important regulator of interleukin 1β production and subsequent pyroptosis. Delivery of exogenous miRNA-762 prior to transplantation significantly increased the post-transplant survival of stem cells and also significantly ameliorated cardiac fibrosis and heart functions following I/R injury. Our data strongly suggest that suppressing pyroptosis can be an effective adjuvant strategy to enhance the efficacy of stem cell-based therapeutics for diseased hearts.

Objective: High disease activity of ankylosing spondylitis (AS) is associated with poor sleep quality The purpose of this study was to identify which of the representative tools for evaluating the disease activity of AS best reflect the quality of sleep., Methods: A total of 107 AS patients were enrolled in the study and the sleep quality was assessed using the Pittsburgh Sleep Quality Index (PSQI) Age, sex, concomitant medication, erythrocyte sedimentation rate (ESR), serum C-reactive protein (CRP) level, Beck Depression Inventory second edition (BDI-II), Bath ankylosing spondylitis disease activity index (BASDAI), ankylosing spondylitis disease activity score (ASDAS)-ESR, ASDAS-CRP, pain visual analog scale, Insomnia Severity Index (ISI), and Epworth Sleepiness Scale (ESS) were analyzed as covariates., Results: Overall, 65% (70/107) of subjects reported poor sleep quality (PSQI>5) There was a positive correlation between the sleep quality and disease activity as measured by the BASDAI, ASDAS-ESR, and ASDAS-CRP In addition, the BASDAI demonstrated good correlations with ISI, ESS, and BDI-II, respectively However, only BASDAI showed reliable correlation with PSQI among the disease activity parameters of AS (adjusted odd ratio 5.36, p=0.023)., Conclusion: BASDAI is the most reliable parameter of disease activity associated with the sleep quality in patients with AS., (Copyright © 2021 by The Korean College of Rheumatology. All rights reserved.)

Extracellular vesicles (EVs) are cell derivatives containing diverse cellular molecules, have various physiological properties and are also present in stem cells used for regenerative therapy. We selected a "multiplexed target" that demonstrates multiple effects on various cardiovascular cells, while functioning as a cargo of EVs. We screened various microRNAs (miRs) and identified miR-210 as a candidate target for survival and angiogenic function. We confirmed the cellular and biological functions of EV-210 (EVs derived from ASC miR-210 ) secreted from adipose-derived stem cells (ASCs) transfected with miR-210 (ASC miR-210 ). Under hypoxic conditions, we observed that ASC miR-210 inhibits apoptosis by modulating protein tyrosine phosphatase 1B (PTP1B) and death-associated protein kinase 1 (DAPK1). In hypoxic endothelial cells, EV-210 exerted its angiogenic capacity by inhibiting Ephrin A (EFNA3). Furthermore, EV-210 enhanced cell survival under the control of PTP1B and induced antiapoptotic effects in hypoxic H9c2 cells. In cardiac fibroblasts, the fibrotic ratio was reduced after exposure to EV-210, but EVs derived from ASC miR-210 did not communicate with fibroblasts. Finally, we observed the functional restoration of the ischemia/reperfusion-injured heart by maintaining the intercommunication of EVs and cardiovascular cells derived from ASC miR-210 . These results suggest that the multiplexed target with ASC miR-210 is a useful tool for cardiovascular regeneration.

Due to the shortage of phosphate and the eutrophication caused by phosphorus pollution, it is urgent to recover phosphate from wastewater. Given their high adsorption capacity and convenient separation from water to which a magnetic field is applied, ferrite composites have received increasing attention for phosphate recovery. In this study, Spinel La@MgFe 2 O 4 was prepared using a one-step co-precipitation method. La 3+ loading on grain boundary defects of MgFe 2 O 4 , and phosphorus absorption capacity were examined using X-ray diffraction (XRD), Fourier-transform infrared spectrometry (FTIR), X-ray photoelectron spectroscopy (XPS), and vibrating sample magnetometry (VSM). The structure of La@MgFe 2 O 4 involved La 3+ loading on grain boundary defects of MgFe 2 O 4 in the form of La(OH) 3 . The addition of La changed the crystallinity and morphology of MgFe 2 O 4 , which greatly improved the capacity of MgFe 2 O 4 for phosphorus adsorption. Saturation magnetization remained at 14 emu·g -1 , which was easily separated from water using an external magnetic field. The maximum adsorption capacity was 143.156 mg·g -1 at pH 6 and 10℃, which was comparable to that achieved at 25℃. Kinetic observations showed that a low phosphorus concentration (10 mg·L -1 ) could result in extremely low phosphorus adsorption by La@MgFe 2 O 4 after 30 min. The adsorption mechanism shows that phosphorus is removed through ligand exchange and the formation of inner spherical complexes. La@MgFe 2 O 4 has highly selective adsorption with respect to phosphate, and the adsorbent can be reused many times after desorption. Based on addition of 1 g·L -1 of La@MgFe 2 O 4 in the treatment of low temperature municipal wastewater in Northern China, phosphate concentrations could be reduced to less than 0.5 mg·L -1 an hour, offering a promising means of phosphate adsorption even in cold regions.

Human adipose-derived stem cells (hASCs) can be isolated from fat tissue and have attracted interest for their potential therapeutic applications in metabolic disease. hASCs can be induced to undergo adipogenic differentiation in vitro by exposure to chemical agents or inductive growth factors. We investigated the effects and mechanism of differentiating hASC-derived white adipocytes into functional beige and brown adipocytes with isoliquiritigenin (ILG) treatment. Here, we showed that hASC-derived white adipocytes could promote brown adipogenesis by expressing both uncoupling protein 1 (UCP1) and PR/SET Domain 16 (PRDM16) following low-dose ILG treatments. ILG treatment of white adipocytes enhanced the expression of brown fat-specific markers, while the expression levels of c-Jun N-terminal kinase (JNK) signaling pathway proteins were downregulated. Furthermore, we showed that the inhibition of JNK phosphorylation contributed to white adipocyte differentiation into beige adipocytes, which was validated by the use of SP600125. We identified distinct regulatory effects of ILG dose responses and suggested that low-dose ILG induced the beige adipocyte potential of hASCs via JNK inhibition.

Macrophages are re-educated and polarized in response to myocardial infarction (MI). The M2 anti-inflammatory phenotype is a known dominator of late stage MI. Mesenchymal stem cells (MSCs) represent a promising tool for cell therapy, particularly heart related diseases. In general, MSCs induce alteration of the macrophage subtype from M1 to M2, both in vitro and in vivo. We conjectured that hypoxic conditions can promote secretome productivity of MSCs. Hypoxia induces TGF-β1 expression, and TGF-β1 mediates M2 macrophage polarization for anti-inflammation and angiogenesis in infarcted areas. We hypothesized that macrophages undergo advanced M2 polarization after exposure to MSCs in hypoxia. Treatment of MSCs derived hypoxic conditioned medium (hypo-CM) promoted M2 phenotype and neovascularization through the TGF-β1/Smad3 pathway. In addition, hypo-CM derived from MSCs improved restoration of ischemic heart, such as attenuating cell apoptosis and fibrosis, and ameliorating microvessel density. Based on our results, we propose a new therapeutic method for effective MI treatment using regulation of macrophage polarization. [BMB Reports 2020; 53(11): 600-604].

Alterations of the transmural gradient of repolarization may contribute to the increase of transmural dispersion of repolarization and ventricular arrhythmias. The transmural gradient of repolarization may play an important role in sudden death associated with left ventricular epicardial pacing. To investigate the changes of transmural gradient dispersion of ventricular repolarization with different pacing sites in heart failure (HF) canines, 8 mongrel dogs were randomized into healthy group and HF group (n = 4). We mapped the monophasic action potential duration (MAPD) in the subendocardial, subepicardial and mid-myocardial layers of the left ventricle (LV) in canines of healthy and HF groups during right atrium (RA) pacing, right ventricular apical endocardial (RV Endo ) pacing, left ventricular lateral epicardial (LV Epi ) pacing and biventricular (Biv) pacing respectively. The results showed that in the healthy group, the MAPDs were significantly different among the three layers during RA pacing (all P < 0.05). The MAPD was longer in the mid-myocardial layer compared with those in the subepicardial and subendocardial layers during RV Endo , LV Epi or Biv pacing (P < 0.05). However, there was no significant difference in MAPD between the subendocardial and subepicardial layers during RV Endo , LV Epi or Biv pacing (P > 0.05). In the HF group, the MAPDs in all three layers were prolonged compared with those in the same locations in the healthy group (all P < 0.05). However, there were no differences in MAPD among the three layers during RA, RV Endo , LV Epi or Biv pacing (all P > 0.05). By MAP recording with our new mapping electrode, we found a transmural MAPD gradient among the three layers of the LV during RA pacing and the gradient between the subendocardial and subepicardial layers vanished during RV Endo , LV Epi or Biv pacing in healthy dogs. In contrast, there was no transmural MAPD gradient during RA, RV Endo , LV Epi or Biv pacing in HF dogs. These results are helpful to understand the mechanism of ventricular arrhythmias in patients with HF.

Background: Although low-intensity pulsed ultrasound has been reported to be potential cartilage regeneration, there still unresolved treatment due to cartilage fibrosis and degeneration by a lack of rapid and high-efficiency treatment. The purpose of this study was to investigate the effect of a combination therapy of focused acoustic force and stem cells at site for fast and efficient healing on cartilage regeneration., Methods: Using a rat articular cartilage defects model, one million adipose tissue-derived stem cells (ASCs) were injected into the defect site, and low-intensity focused ultrasound (LOFUS) in the range of 100-600 mV was used for 20 min/day for 2 weeks. All experimental groups were sacrificed after 4 weeks in total. The gross appearance score and hematoxylin and eosin (H&E), Alcian blue, and Safranin O staining were used for measuring the chondrogenic potential. The cartilage characteristics were observed, and type II collagen, Sox 9, aggrecan, and type X collagen were stained with immunofluorescence. The results of the comprehensive analysis were calculated using the Mankin scoring method., Results: The gross appearance scores of regenerated cartilage and chondrocyte-like cells in H&E images were higher in LOFUS-treated groups compared to those in negative control or ASC-treated groups. Safranin O and Alcian blue staining demonstrated that the 100 and 300 mV LOFUS groups showed greater synthesis of glycosaminoglycan and proteoglycan. The ASC + LOFUS 300 mV group showed positive regulation of type II collagen, Sox 9 and aggrecan and negative regulation of type X collagen, which indicated the occurrence of cartilage regeneration based on the Mankin score result., Conclusion: The combination therapy, which involved treatment with ASC and 300 mV LOFUS, quickly and effectively reduced articular cartilage defects.

Osteoarthritis (OA) is a common joint disease that results from the disintegration of joint cartilage and the underlying bone. Because cartilage and chondrocytes lack the ability to self-regenerate, efforts have been made to utilize stem cells to treat OA. Although various methods have been used to differentiate stem cells into functional chondrocytes, the currently available methods cannot induce stem cells to undergo differentiation into chondrocyte-like cells without inducing characteristics of hypertrophic chondrocytes, which finally lead to cartilage disintegration and calcification. Therefore, an optimized method to differentiate stem cells into chondrocytes that do not display undesired phenotypes is needed. This study focused on differentiating adipose-derived stem cells (ASCs) into functional chondrocytes using a small molecule that regulated the expression of Sox9 as a key factor in cartilage development and then explored its ability to treat OA. We selected ellipticine (ELPC), which induces chondrocyte differentiation of ASCs, using a GFP-Sox9 promoter vector screening system. An in vivo study was performed to confirm the recovery rate of cartilage regeneration with ASC differentiation into chondrocytes by ELPC in a collagenase-induced animal model of OA. Taken together, these data indicate that ellipticine induces ASCs to differentiate into mature chondrocytes without hypertrophic chondrocytes in vitro and in vivo, thus overcoming a problem encountered in previous studies. These results indicate that ELPC is a novel chondrocyte differentiation-inducing drug that shows potential as a cell therapy for OA.

Although there have been reports of promising results regarding the transplantation of mesenchymal stem cells (MSCs) for neurodegenerative diseases through the use of neuronal differentiation or control of the microenvironment, traditional surgical transplantation methods like parenchymal or intravenous injection have limitations such as secondary injuries in the brain, infection, and low survival rate of stem cells in the target site. Focused ultrasound (FUS) treatment is an emerging modality for the treatment of brain diseases, including neurodegenerative disorders. The various biological effects of FUS treatment have been investigated; therefore, the goal is now to improve the delivery efficiency and function of MSCs by capitalizing on the advantages of FUS. In this study, we demonstrated that FUS increases MSC transplantation into brain tissue by >2-fold, and that this finding might be related to the activation of intercellular adhesion molecule-1 in endothelial and subendothelial cells and vascular adhesion molecule-1 in endothelial cells., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Abelmoschus manihot (L.) Medic flower is a medicinal plant for the treatment of diseases in China. The present study was carried out to scientifically validate the gastroprotective activity and clarify the possible mechanism of the total flavones from Abelmoschus manihot (L.) Medic flower is a medicinal plant for the treatment of diseases in China. The present study was carried out to scientifically validate the gastroprotective activity and clarify the possible mechanism of the total flavones from., Methods: Gastric ulcer was induced in mice by oral administration of ethanol. The gastroprotective activity of TFA was evaluated by the gastric ulcer index and histological examinations. The gastric tissue was collected in the form of homogenate. The level of malondialdehyde (MDA) and glutathione (GSH), the activity of superoxide dismutase (SOD), and protein content were measured. Western blotting for the expression of Bax, Bcl-2, TNF- α , and NF- κ B(p65) was also carried out. The effect of TFA was compared with that of standard antiulcer drug omeprazole (100 mg/kg)., Results: This gastroprotective effect of TFA could be attributed to the increase in the activity of SOD and GSH and decrease in the levels of MDA and also decrease in the levels of Bax, TNF- α , and NF- κ B(p65) was also carried out. The effect of TFA was compared with that of standard antiulcer drug omeprazole (100 mg/kg)., Conclusion: The findings of this study demonstrated that TFA could significantly attenuate ethanol-induced gastric injury via antioxidative, anti-inflammatory, and antiapoptotic effects., Competing Interests: The authors declare that there are no conflicts of interest regarding the publication of this article., (Copyright © 2020 Jun Zhang et al.)

Background: The efficacy of interstitial vascular fraction (SVF) transplantation in the treatment of heart disease has been proven in a variety of in vivo studies. In a previous study, we found that bone marrow-derived mesenchymal stem cells (BM-MSCs) altered their expression of several cardiomyogenic factors under hypoxic conditions., Methods: We hypothesized that hypoxia may also induce obtained adipose-derived adherent stromal cells (ADASs) from SVFs and adipose-derived stem cells (ASCs) to differentiate into cardiomyocytes and/or cells with comparable phenotypes. We examined the differentiation markers of cell lineages in ADASs and ASCs according to time by hypoxic stress and found that only ADASs expressed cardiomyogenic markers within 24 h under hypoxic conditions in association with the expression of hypoxia-inducible factor 1-α (HIF-1α)., Results: Differentially secreted proteins in a conditioned medium (CM) from ASCs and ADASs under normoxic or hypoxic conditions were detected using an antibody assay and may be associated with a dramatic increase in the expression of cardiomyogenic markers in only ADASs. Furthermore, the cardiomyogenic factors were expressed more rapidly in ADASs than in ASCs under hypoxic conditions in association with the expression of HIF-1α, and angiogenin, fibroblast growth factor-19 (FGF-19) and/or macrophage inhibitory factor (MIF) are related., Conclusions: These results provide new insights into the applicability of ADASs preconditioned by hypoxic stress in cardiac diseases.

Cardiac fibrosis is a common precursor to ventricular dysfunction and eventual heart failure, and cardiac fibrosis begins with cardiac fibroblast activation. Here we have demonstrated that the TGF-β signaling pathway and Wnt signaling pathway formed a transactivation circuit during cardiac fibroblast activation and that miR-384-5p is a key regulator of the transactivation circuit. The results of in vitro study indicated that TGF-β activated an auto-positive feedback loop by increasing Wnt production in cardiac fibroblasts, and Wnt neutralizing antibodies disrupted the feedback loop. Also, we demonstrated that miR-384-5p simultaneously targeted the key receptors of the TGF-β/Wnt transactivation circuit and significantly attenuated both TGF-β-induced cardiac fibroblast activation and ischemia-reperfusion-induced cardiac fibrosis. In addition, small molecule that prevented pro-fibrogenic stimulus-induced downregulation of endogenous miR-384-5p significantly suppressed cardiac fibroblast activation and cardiac fibrosis. In conclusion, modulating a key endogenous miRNA targeting multiple components of the TGF-β/Wnt transactivation circuit can be an effective means to control cardiac fibrosis and has great therapeutic potential.

Dysregulation of cellular energy metabolism is closely linked to cancer development and progression. Calorie or glucose restriction (CR or GR) inhibits energy-dependent pathways, including IGF-1/PI3K/Akt/mTOR, in cancer cells. However, alterations in proton dynamics and reversal of the pH gradient across the cell membrane, which results in intracellular alkalinization and extracellular acidification in cancer tissues, have emerged as important etiopathogenic factors. We measured glucose, lactate, and ATP production after GR, plant-derived CR-mimetic curcumin treatment, and curcumin plus GR in human hepatoma cells. Intracellular pH regulatory effects, in particular, protein-protein interactions within mTOR complex-1 and its structural change, were investigated. Curcumin treatment or GR mildly inhibited Na+/H+ exchanger-1 (NHE1). vATPase, monocarboxylate transporter (MCT)-1, and MCT4 level. Combination treatment with curcumin and GR further enhanced the inhibitory effects on these transporters and proton-extruding enzymes, with intracellular pH reduction. ATP and lactate production decreased according to pH change. Modeling of mTOR protein revealed structural changes upon treatments, and curcumin plus GR decreased binding of Raptor and GβL to mTOR, as well as of Rag A and Rag B to Raptor. Consequently, 4EBP1 phosphorylation was decreased and cell migration and proliferation were inhibited in a pH-dependent manner. Autophagy was increased by curcumin plus GR. In conclusion, curcumin treatment combined with GR may be a useful supportive approach for preventing intracellular alkalinization and cancer progression.

Cutaneous wounds can present significant clinical problems because of abnormal healing after deep dermal damage. Despite technical advances in wound care, there are still unmet needs that result from inefficient treatment. In this study, we aimed to improve skin wound healing using a contractibility band with static magnetic field (SMF), termed a magnetic band (Mb). To examine the effect of the Mb on wound healing, full-thickness 15 × 35 mm excision wounds were surgically created on the dorsum of rats. An elastic and contractile band (nontreatment), or one neodymium magnet (Nd-1) or two magnets with an elastic and contractile band (Nd-2) were topically applied to the wound daily and the wound size was measured from day 1 to 7 after surgery. Nd-2 showed a significant (95%) reduction in the wound size on day 3. Histological analysis showed that proinflammatory cytokine levels were diminished by Nd-2, and granulation tissue and microvessels were increased compared with those in the sham group. During Mb-induced wound healing, apoptosis was significantly reduced and matrix remodeling-related factors were initially regulated. The results suggest that combination therapy comprising an SMF and an elastic and contractile band could be a promising tool to heal cutaneous wounds rapidly.

Background: Compared with pharmaceuticals, natural medicines are gaining acceptance as countermeasures against radiation injury because of their distinct characteristics, specifically low toxicity and multi-target effects., Methods: The ability of a traditional Chinese medicine, Acanthopanax senticosus (AS), to reduce radiation injury following exposure of the heads of mice to 4?Gy low-linear energy transfer (LET) radiation was assessed histologically, behaviorally and metabolically''., Results: Irradiated mice administered AS extract showed improved learning ability and central nervous system (CNS) function. AS extract effectively controlled nerve cell swelling, protein loss, and necrotic tissue liquefaction that was observed in the irradiated mouse brain. Metabolomics data demonstrated that treatment with AS extract resulted in significant quantitative changes of 16 classes of cerebral metabolites in the prefrontal cortex (PFC) of irradiated mice. Using a principal component analysis (PCA), three principal components, F1, F2 and F3, were identified as related to brain energy metabolism, brain tissue development, and brain glutamate cycle, respectively. In addition, the F2 and F3 scores of the AS-treated group of mice were higher compared to mice that were treated with Venlafaxine. Furthermore, the efficiency of balancing the glutamate cycle that the AS-treated group achieved was two times greater than that of the mice treated with Venlafaxine., Conclusions: AS is a promising approach to reduce radiation-induced brain injury. Further studies are warranted to examine the potential of AS to reduce the side effects caused by chemotherapeutics., (Copyright © 2018. Published by Elsevier Masson SAS.)

Pathologic proliferation and migration of vascular smooth muscle cells (VSMCs) exacerbate cardiovascular disease. MicroRNAs (miRNAs), as endogenous inhibitors of protein synthesis, are expected to modulate pathologic proliferation of VSMCs. Here we report that both platelet-derived growth factor receptor (PDGFR) targeting miR-9 and a small molecule that increases miR-9 can inhibit the serum-induced proliferation of VSMCs. First, based on miRNA-target prediction databases and empirical data, we have selected miR-9 as a potent anti-proliferative miRNA in VSMCs. Further examination indicated that miR-9 directly targets PDGFR disrupting downstream signaling cascades, and this resulted in inhibition of VSMC proliferation and migration. Exogenous delivery of miR-9 inhibited VSMC proliferation in vitro, and a small molecule that increased miR-9 expression also inhibited neointima formation following balloon injury in vivo . We provide evidence of miRNA-mediated modulation of VSMC proliferation and further demonstrate that small molecule-mediated regulation of miRNA targeting a key regulator of VSMC proliferation is a viable therapeutic strategy for treating vascular disease involving pathologic VSMC proliferation such as restenosis., Competing Interests: CONFLICTS OF INTEREST The authors indicate no potential conflicts of interest.

In recent years, stem cell-related therapies have been widely applied for treating neurodegenerative disease. Despite their potential, stem cell tracking and imaging techniques for the evaluation of in vivo proof-of-concept (PoC) therapies have not been sufficiently represented in the research area. This review summarizes the recent approaches that have been used for tracking and imaging engrafted stem cells in vivo. Furthermore, we introduce tissue clearing technology that can be applied to develop three-dimensional in vivo experiments. Monitoring stem cell survival and migration and graft-host relationships is a useful strategy to evaluate the therapeutic efficacy of regenerative medicine approaches in neurodegenerative disease., Competing Interests: The authors declare that they have no conflict of interests.

The restoration of damaged articular cartilage is a long-pursued goal in regenerative medicine. Chondrocyte-specific differentiation of mesenchymal stem cells (MSCs) may be an effective means of repairing damaged cartilage. We identified small molecule 6 with sulfonamide as an agent that promotes specific chondrogenic differentiation of human adipose-derived MSCs (hASCs). Unlike other chondrogenic differentiation media composed of various defined components, simply adding compound 6 into culture medium was sufficient to induce chondrogenesis in this study. In an animal osteoarthritis model, both the small molecule 6 and the 6-treated hASCs exhibited enhanced recovery of injured articular cartilage. This work provides new insight into MSC differentiation induced by small molecules and potential new therapeutic approaches for articular cartilage injury., (Copyright © 2016. Published by Elsevier Ltd.)

Purpose: To detect differences between the values of dynamic coracohumeral distance (CHD) measured using ultrasonography (USG) in different shoulder rotations and to investigate its correlation with subscapularis tear., Methods: We prospectively enrolled consecutive patients (n = 168) who were scheduled to have arthroscopic rotator cuff repair. Patients with a history of previous shoulder surgery or shoulder fracture and patients with external rotation less than 30° were excluded from the study. Dynamic CHD was measured using USG in 3 different shoulder positions: external rotation, neutral and internal rotation. We evaluated the intrarater reliability with 3 times repetition of measurement. Patients were divided into 1 of 3 groups according to arthroscopic findings: intact subscapularis, partial-thickness tear, and full-thickness tear of the subscapularis. The control group (n = 23) included patients without rotator cuff tears from the outpatient clinic. Subgroup analysis-according to the presence of dynamic subcoracoid stenosis, defined as a CHD less than 6 mm measured in internal rotation-was performed to find the clinical effect of dynamic subcoracoid stenosis., Results: A partial-thickness tear of the subscapularis tendon was present in 60 patients (35.7%) and a full-thickness tear in 26 patients (15.4%) among 168 patients. The CHD was maximum in external rotation and the narrowest in internal rotation. There were no statistical differences in the CHDs between groups with different subscapularis tear status. According to the presence of dynamic subcoracoid stenosis, patients with dynamic subcoracoid stenosis had a significantly higher incidence of partial-thickness subscapularis tear than those without stenosis (P = .022)., Conclusions: The CHD values were narrowest in shoulder internal rotation, which is thought to be the pathogenic position. We could not confirm the correlation between CHD and subscapularis tear. However, patients who have dynamic subcoracoid stenosis had significantly higher incidence of subscapularis tear than others without dynamic stenosis., Level of Evidence: Level II, prospective prognostic cohort study., (Copyright © 2016 Arthroscopy Association of North America. Published by Elsevier Inc. All rights reserved.)