After decades of research, stem cells have shown tremendous promise to treat a range of diseases, such as heart disease, diabetes, and neurodegenerative disease. However, many challenges remain in their transformation from bench to bedside, such as the potential risk of tumorigenicity from undifferentiated human induced pluripotent stem cells (hiPSC), the lack of large-scale culture systems for clinical treatment, and the inconvenience of cell therapy itself. "Cell sheet technology" and secretome therapy represent advances in these regards. With gradual breakthroughs in theory and technology, stem cell therapy will lead to a new medical revolution in the coming era.
The aging of a population structure is an inevitable path of demographic transition, as an inescapable result of decline in fertility rate and extension in life expectancy. Although demographic transition occurred earlier in Japan than in China, the two countries had similar patterns, both of which took a much shorter period of time than Western countries to complete demographic transition, as well as have been aging at a rapid speed that has rarely been seen in the world. Japan has the highest level of population aging in the world, and China has been experiencing a very fast pace of the population aging process and has the largest older population. Drawing upon data from World Population Prospects (2019), this paper compares changes in population aging in both China and Japan. Findings show that Japan's aging process is 30 years ahead of China, but China has been changing in a similar way as Japan. To be specific, both countries experienced four phases of the population aging process: accelerated development period, rapid development period, slow down period and high-level maintained period. In addition, both countries had a quick growing rate of population aging. It will take China 23 years and 10 years respectively for the aging rate increasing from 7% to 14% and then to 20%, while Japan took 24 and 11 years respectively, which is much shorter than developed countries in the West. Furthermore, China has a faster pace than Japan in population aging in the next 25 years. We found that from 2019-2044, China's aging rate, elderly dependency ratio, oldest-old coefficient and median age of population will increase 13.24 percent points, 24.21 percent points, 8.33 percent points, and 8.47 years, while the four indicators of Japan will increase 8.38 percent points, 22.52 percent points, 8.29 percent points, and 6.20 years, respectively.
The past decade has witnessed remarkable development in tissue engineering technologies and stem cells. Our lab has developed a novel technology ― "cell sheet technology" for tissue engineering. After the confluent cells are cultured on an innovative temperature-responsive culture dish, the cells can be harvested as an intact sheet by lowering temperature. We have successfully created multiple cell sheet-based tissues for therapies of a vast variety of diseases, in particular, myocardial diseases. On the other side, the discovery of human induced pluripotent stem cells (hiPSC) enables stable production of defined tissue-specific cell types and thus makes it possible to regenerate tissues or even organs for clinical application and in vitro drug screening/disease modeling. Recently, we have combined cell sheet technology and hiPSC-derived cardiac cells for fabrication of functional human cardiac tissues. This review summarizes ongoing challenges in this field and our progresses in solving issues, such as large scale culture of hiPSC-derived cardiac cells, elimination of undifferentiated iPSCs to decrease the risk of tumor formation as well as myocardial tissue fabrication technologies.
Stem cells are an undifferentiated cell population that has the ability to develop into many different cell types and also has the ability to repair damaged tissues in some cases. For a long time, the stem cell regenerative paradigm has been based on the assumption that progenitor cells play a critical role in tissue repair by means of their plasticity and differentiation potential. However, recent works suggest that the mechanism underlying the benefits of stem cell transplantation might relate to a paracrine modulatory effect rather than the replacement of affected cells at the site of injury. This paracrine modulatory effect derives from secretome which comprises a diverse host of growth factors, cytokines, chemokines, angiogenic factors, and exosomes which are extracellular vesicles that are produced in the endosomal compartment of most eukaryotic cells and are from about 30 to several hundred nanometers in diameter. The role of these factors is being increasingly recognized as key to the regulation of many physiological processes including leading endogenous and progenitor cells to sites of injury as well as mediating apoptosis, proliferation, migration, and angiogenesis. In reality, the immunomodulatory and paracrine role of these factors may mainly account for the therapeutic effects of stem cells and a number of in vitro and in vivo researches have proved limited stem cell engraftment at the site of injury. As a cell-free way for regenerative medicine therapies, stem cell secretome has shown great potential in a variety of clinical applications including prevention of cardiac disfunction, neurodegenerative disease, type 1 diabetes, hair loss, tumors, and joint osteoarthritis.
Wearable sensors have garnered considerable interest because of their great promise in terms of personalized health and disease management. Tears are a superior target for wireless, non-invasive wearable devices, and tear-based platforms have developed rapidly over the past decade. Although an increasing number of tear analytes have been found to be associated with multiple diseases, glucose still serves as a main target for tear-based wearable devices. There has been much investment and efforts to develop tear-based wearable biosensors, with contact lens-based and spring-like sensors flourishing commercially. Current efforts have moved past ocular and systematic disease markers to nutrients and chemicals. Moreover, tear-based wearable devices also have the potential to treat some ocular diseases. This review discusses aspects of tear-based wearable devices and it emphasizes that strict clinical validation is needed before such platforms enter the market. Multifunctional and theranostic strategies would further broaden their clinical use in the future.
China has initiated the special security project for rare diseases from the national strategic level since 2018. Chinese government has formulated China's First List of Rare Diseases (121 diseases included), established Expert Committee of Diagnosis, Treatment and Security of Rare Diseases and China Alliance of Rare Diseases. The government also encouraged all the provinces to include the security plan and strategies of rare diseases into key work and promoted the establishment of rare diseases clinical research center and the formulation of diagnosis and treatment guidelines. All these actions led to the further improvement of scientific research ability and diagnosis and treatment ability. In terms of the treatment drug of the 121 diseases in China's First List of Rare Diseases, 83 of them are on the market in China and 50 have been included in the national medical insurance accompanied with the tax reduction policy on rare diseases drug and several charity foundations and enterprise donation programs were developed so that drug availability and accessibility for patients are increased. However, there is no clear definition and corresponding coding of rare diseases; the economic burden of most rare diseases could not be calculated accurately because of the difficulty in diagnosis and misclassification. Regarding the service provision system, social security system of rare diseases in China needs further improvement because of the rather few kinds of rare diseases involved in the screening, low level of diagnostic ability, rather few rehabilitation programs and the lack of social caring and knowledge training. It is necessary for China to provide comprehensive and well-rounded health care and social caring for rare diseases patients. Since the formulation and implementation conditions of the policy are different among different regions, the pilot should be carried out first in regions with desired qualifications when China is formulating the rare diseases policy and then a mature national plan should be developed.
Cordycepin, a derivative of nucleoside adenosine, is one of the active ingredients extracted from the fungi of genus Cordyceps, which have been used for traditional herbal remedies. In this study, we examined the effect of cordycepin on the proliferation and apoptosis of human bladder cancer T24 cells and its mechanism of action. Cordycepin treatment significantly reduced the cell survival rate of T24 cells in a concentration-dependent manner, which was associated with the induction of apoptosis. Cordycepin activated caspase-8 and -9, which are involved in the initiation of extrinsic and intrinsic apoptosis pathways, respectively, and also increased caspase-3 activity, a typical effect caspase, subsequently leading to poly (ADP-ribose) polymerase cleavage. Additionally, cordycepin increased the Bax/Bcl-2 ratio and truncation of Bid, and destroyed the integrity of mitochondria, which contributed to the cytosolic release of cytochrome c. Moreover, cordycepin effectively inactivated the phosphoinositide 3-kinase (PI3K)/Akt signaling pathway, while LY294002, a PI3K/Akt inhibitor, increased the apoptosis-inducing effect of cordycepin. Cordycepin further enhanced the intracellular levels of reactive oxygen species (ROS), while the addition of N-acetyl cysteine (NAC), a ROS inhibitor, significantly diminished cordycepin-induced mitochondrial dysfunction and growth inhibition, and also blocked the inactivation of PI3K/Akt signaling pathway. Furthermore, the presence of NAC significantly attenuated the enhanced apoptotic cell death and reduction of cell viability by treatment with cordycepin and LY294002. Collectively, the data indicate that cordycepin induces apoptosis through the activation of extrinsic and intrinsic apoptosis pathways and the ROS-dependent inactivation of PI3K/Akt signaling in human bladder cancer T24 cells.
Histone acetylation has recently been implicated in gene transcription and estradiol (E2) actions in the hypothalamus. This study aims to determine the involvement of histone acetylation in mediating E2-induced luteinizing hormone (LH) surge to understand the mechanism underlying LH surge dysfunction in female reproductive aging. Young and middle-aged female rats were ovariectomized (OVX) and treated with hormone or oil once per day for two days. At the time of the expected LH surge, blood samples were taken for LH assay. The anterior and posterior hypothalami were dissected, histone H3/H4 acetylation and histone deacetylases (HDACs) 4, -5, -10 and -11 protein expressions were measured using Western blotting. Our results show that in the young females, E2 markedly increased histone H3 acetylation while significantly reducing HDAC10 protein expression in the anterior hypothalamus. Notably, E2-induced alterations of histone H3 acetylation and HDAC10 in the anterior hypothalamus were absent in middle-aged females, associated with a reduced LH release. However, age alters histone H4 acetylation in both the anterior and posterior hypothalamus and significantly increased HDAC 4 and -5 protein expression in the anterior hypothalamus. Taken together, these data suggest that histone H3 acetylation in the anterior hypothalamus may mediate E2 regulation of LH surge and the process possibly through decreasing HDAC10. The missed responsiveness of histone H3 acetylation and HDAC10 expression to E2 in the anterior hypothalamus may contribute to LH surge failure that occurs in female reproductive aging.
The retinoid-interferon-induced mortality-19 (GRIM-19) gene has been identified as a negative regulator associated with tumor development. The current study created a model of an orthotopically implanted hepatocarcinoma tumor to verify the inhibitory effect of GRIM-19 in vivo. After treatment with GRIM-19 carried by attenuated Salmonella, transplanted tumors were measured with an Imaging System. The expression of GRIM-19, Stat3/p-Stat3, cyclinD1, CDK4, PCNA, Bax/Bcl-2, cleaved caspase-9/3, VEGF, and MMP-2/9 was determined using immunohistochemistry and Western blot analysis. The cell cycle was assessed using flow cytometry (FCM). Apoptosis was determined using FCM and a TUNEL assay. Results indicated that GRIM-19 overexpression resulted in inhibition of peritoneal metastasis, induction of cell cycle arrest, and apoptosis in vivo. In addition, the expression of Stat3/p-Stat3 was down-regulated by GRIM-19. These results suggest that GRIM-19 overexpression could suppress the growth of orthotopically implanted hepatocarcinoma tumors by reversing the regulation of the Stat3 signaling pathway. This approach could potentially be a powerful treatment for hepatocarcinoma.
There is little information regarding the use of a combination of the albumin-bilirubin (ALBI) grade and the fibrosis-4 index (FIB-4) in predicting hepatocellular carcinoma (HCC) patient outcomes after liver resection. In this study, we aimed to analyze the predictive ability of a combination of the ALBI grade and the FIB-4 score (ALBI-FIB-4) for HCC patients within the Milan criteria after liver resection. The data of HCC patients within the Milan criteria who underwent liver resection between 2011 and 2019 at our center were reviewed (n = 544). Patients with an FIB-4 index > 3.25 were considered to have a high FIB-4 index and were given a score of 1, whereas patients with an FIB-4 index ≤ 3.25 were considered to have a low FIB-4 index and were given a score of 0. The ALBI-FIB-4 score was a summary score that combined the ALBI grade and the score based on the FIB-4 index. During the follow-up period, 279 patients experienced recurrence, and 175 patients died. Multivariate analysis showed that tumor size, the presence of multiple tumors, the presence of microvascular invasion and the ALBI-FIB-4 score were four independent risk factors for both postoperative recurrence-free survival (RFS) and overall survival (OS). The 5-year RFS of patients with high ALBI-FIB-4 scores of 1, 2, and 3 were 55.0%, 44.2% and 35.3%, respectively (p = 0.004). The 5-year OS rates of patients with high ALBI-FIB-4 scores of 1, 2, and 3 were 72.9%, 66.4% and 54.8%, respectively (p = 0.011). The ALBI-FIB-4 score may be a surrogate marker for predicting the prognosis of patients with HCC after liver resection. A high ALBI-FIB-4 score was associated with a high incidence of postoperative recurrence and mortality.
A growing number of studies show that breastfeeding is the best source of nutrition for infants and young children and one of the most effective measures to ensure the healthy growth and development of children. However, a study from the China Development Research Fund found that the rate of exclusive breastfeeding among Chinese infants within six months of birth is only 29%, a rate that is lower than that in other countries and regions of the world. Other data provided by the World Bank shows that the rate of exclusive breastfeeding in China declined from 1998 to 2013 and that it increased slightly by 2018, but it was still lower than the global average. Compared to other Asian countries, the exclusive breastfeeding rate in China is also low. Establishing a sound breastfeeding support system and creating a breastfeeding environment with full support for mothers of infants is a way to effectively improve the state of breastfeeding in China, to ensure the healthy growth of children, and to achieve the goals of Healthy China 2030.
We conducted a study to try to plot the lesions of melanocytic nevus and malignant melanoma on the palm and fingers, and compared them to identify the different distribution pattern of both lesions. Data on 8 patients with melanomas (4 male and 4 female) and 26 patients with melanocytic nevus (6 male and 20 female) of palm and finger pulp who visited Wakayama Medical University Hospital between 1986 and 2018 was retrospectively collected. We found that all of the 8 lesions of melanoma were located on the finger pulps and distal to the 'distal transverse crease' of the palm, and that melanomas were not present proximal to the transverse crease. On the other hand, melanocytic nevus was present in the proximal area to the distal transverse crease of the palm more frequently than melanomas (50.0% vs. 0%), and there was statistically significant difference (p = 0.011 by Fisher's exact probability test). From these observations, our findings may reveal the contribution of mechanical stress to the cause of palmar melanoma, and may facilitate clinical differentiation between malignant melanoma and melanocytic nevus by the localization. Further studies with increased number of patients are needed to validate the finding.
Accidental awareness during general anaesthesia may cause many intraoperative discomforts and bring further moderate to severe long-term symptoms including flashbacks, nightmares, hyperarousal or post-traumatic stress disorder. The incidence of awareness varied from 0.017% to 4% among studies. The relatively reliable incidence of intraoperative awareness with postoperative recall is 0.02%. The reason causing awareness was unclear. Insufficient anaesthetic dosing was thought as the principal cause. Even awareness was not comprehensively understood, some endeavors have been raised to prevent or reduce it, including i) Reducing the insufficient anaesthetic dosing induced by negligence; ii) Providing close clinical observation and clinical parameters from the monitor such as bispectral index or electroencephalogram, as well as isolated forearm technique and passive brain-computer interface may bring some effects sometimes. Because current studies still have some flaws, further trials with new detecting approach, superior methodology and underlying aetiology are needed to unfasten the possible factors causing awareness.