Publications by authors named "Shinn-Zong Lin"

294 Publications

Telomeres and Cancer.

Life (Basel) 2021 Dec 16;11(12). Epub 2021 Dec 16.

Buddhist Tzu Chi Bioinnovation Center, Tzu Chi Foundation, Hualien 970, Taiwan.

Telomeres cap the ends of eukaryotic chromosomes and are indispensable chromatin structures for genome protection and replication. Telomere length maintenance has been attributed to several functional modulators, including telomerase, the shelterin complex, and the CST complex, synergizing with DNA replication, repair, and the RNA metabolism pathway components. As dysfunctional telomere maintenance and telomerase activation are associated with several human diseases, including cancer, the molecular mechanisms behind telomere length regulation and protection need particular emphasis. Cancer cells exhibit telomerase activation, enabling replicative immortality. Telomerase reverse transcriptase (TERT) activation is involved in cancer development through diverse activities other than mediating telomere elongation. This review describes the telomere functions, the role of functional modulators, the implications in cancer development, and the future therapeutic opportunities.
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http://dx.doi.org/10.3390/life11121405DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8704776PMC
December 2021

Complete Restoration of Motor Function in Acute Cerebral Stroke Treated with Allogeneic Human Umbilical Cord Blood Monocytes: Preliminary Results of a phase I Clinical Trial.

Cell Transplant 2021 Jan-Dec;30:9636897211067447

Department of Neurosurgery, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien.

Stem cell therapy has been explored for the treatment of cerebral stroke. Several types of stem cells have been investigated to ensure the safety and efficacy in clinical trials.Cryopreserved umbilical cord blood (UCB) mononuclear cells (MNCs) obtained from healthy donors have a more stabilized quality, thereby ensuring a successful therapy. A phase I study was conducted on patients aged 45-80 years who sustained acute ischemic stroke. An UCB unit was obtained from a public cord blood bank based on ABO/Rh blood type, HLA matching score (6/6), and cell dose (total MNC count of 0.5-5 × 10 cells/kg). In addition, to facilitate blood brain barrier penetration of UCB, 4 doses of 100 mL mannitol was administered intravenously after 30 min after UCB transplantation and every 4 h thereafter. The primary outcomes were the number of disease (GVHD) within 100 days after transfusion. The secondary outcomes were changes in the National Institutes of Health Stroke Scale (NIHSS), Barthel index, and Berg Balance Scale scores. A 46-year-old male patient with identical ABO/Rh blood type, HLA matching score of 6/6, and MNC count of 2.63 × 10 cells/kg was enrolled. The patient did not present with serious AEs or GVHD during the 12-month study period. The patient's NIHSS score decreased from 9 to 1. Moreover, the Berg Balance Scale score increased from 0 to 48 and the Barthel index score from 0 to 90. This preliminary study showed that an adult patient with hemiplegia due to ischemic stroke completely recovered within 12 months after receiving allogeneic UCB therapy.
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http://dx.doi.org/10.1177/09636897211067447DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8728774PMC
December 2021

Granulocyte Colony-Stimulating Factor for Treatment of Patients with Chronic Traumatic Brain Injury: A Preliminary Pre-Post Study.

Brain Sci 2021 Oct 29;11(11). Epub 2021 Oct 29.

Department of Neurosurgery, Hualien Tzu Chi Hospital/Tzu Chi University, Hualien 970, Taiwan.

Chronic traumatic brain injury (TBI) can cause permanent disability and thereby negatively affect patients, families, and society. Currently, there is no effective treatment for patients with chronic TBI. One possible option is granulocyte colony-stimulating factor (G-CSF), which has potential neuroregenerative and neuroprotective effects through its ability to mobilize hematopoietic stem cells and increase neurogenic growth factor levels. Previous studies have shown that G-CSF administration is safe for patients with neurological diseases such as stroke and dementia. The present study aimed to explore the safety and efficacy of G-CSF use in patients with chronic TBI.

Methods: 38 patients with chronic TBI were administered 3-day rounds of G-CSF (10 μg/kg per day) once a month for 6 months. These patients were clinically evaluated using the modified Rankin scale (mRS) and Karnofsky Performance Score (KPS). Laboratory measures of the leucocyte counts and differential count percentage were also assessed.

Results: At the 6-month follow-up, further assessment showed that patients tolerated the treatment well with only mild and transient side effects being observed. Further clinical evaluation showed significant improvements in mRS and KPS after G-CSF treatment. Laboratory results also confirmed the action of the medication, with increased leukocytosis and band forms.

Conclusions: The results suggest that 6-month chronic G-CSF treatment is safe for patients with chronic TBI and may provide clinical benefits and neurological improvements. The adverse effects of the treatment, however, are transient and usually tolerable. Thus, these preliminary findings suggest that future clinical trials of G-CSF use in patients with chronic TBI are warranted.
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http://dx.doi.org/10.3390/brainsci11111441DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8615826PMC
October 2021

Coactivation of GSK3β and IGF-1 Attenuates Amyotrophic Lateral Sclerosis Nerve Fiber Cytopathies in SOD1 Mutant Patient-Derived Motor Neurons.

Cells 2021 10 16;10(10). Epub 2021 Oct 16.

Bioinnovation Center, Buddhist Tzu Chi Medical Foundation, Hualien 97002, Taiwan.

Amyotrophic lateral sclerosis (ALS) is a progressive nervous system disease that causes motor neuron (MN) degeneration and results in patient death within a few years. To recapitulate the cytopathies of ALS patients' MNs, mutant and corrected isogenic-induced pluripotent stem cell (iPSC) lines were established. Two mutant ALS ( and ), two mutant corrected ( and ), and one sporadic ALS iPSC lines were directed toward MNs. After receiving ~90% purity for MNs, we first demonstrated that mutant ALS MNs recapitulated ALS-specific nerve fiber aggregates, similar to ALS MNs in a previous study. Moreover, we found that both mutant MNs showed ALS-specific neurite degenerations and neurotransmitter-induced calcium hyperresponsiveness. In a small compound test using these MNs, we demonstrated that gastrodin, a major ingredient of , showed therapeutic effects that decreased nerve fiber cytopathies and reverse neurotransmitter-induced hyperresponsiveness. The therapeutic effects of gastrodin applied not only to ALS MNs but also to sporadic ALS MNs and ALS mice. Moreover, we found that coactivation of the GSK3β and IGF-1 pathways was a mechanism involved in the therapeutic effects of gastrodin. Thus, the coordination of compounds that activate these two mechanisms could reduce nerve fiber cytopathies in ALS MNs. Interestingly, the therapeutic role of GSK3β activation on ALS MNs in the present study was in contrast to the role previously reported in research using cell line- or transgenic animal-based models. In conclusion, we identified in vitro ALS-specific nerve fiber and neurofunctional markers in MNs, which will be useful for drug screening, and we used an iPSC-based model to reveal novel therapeutic mechanisms (including GSK3β and IGF-1 activation) that may serve as potential targets for ALS therapy.
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http://dx.doi.org/10.3390/cells10102773DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8535155PMC
October 2021

Differentiation of Human Pluripotent Stem Cells Into Specific Neural Lineages.

Cell Transplant 2021 Jan-Dec;30:9636897211017829

Department of Chinese Medicine, Hualien Tzu Chi Hospital, Hualien, Taiwan.

Human pluripotent stem cells (hPSCs) are sources of several somatic cell types for human developmental studies, in vitro disease modeling, and cell transplantation therapy. Improving strategies of derivation of high-purity specific neural and glial lineages from hPSCs is critical for application to the study and therapy of the nervous system. Here, we will focus on the principles behind establishment of neuron and glia differentiation methods according to developmental studies. We will also highlight the limitations and challenges associated with the differentiation of several "difficult" neural lineages and delay in neuronal maturation and functional integration. To overcome these challenges, we will introduce strategies and novel technologies aimed at improving the differentiation of various neural lineages to expand the application potential of hPSCs to the study of the nervous system.
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http://dx.doi.org/10.1177/09636897211017829DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8529300PMC
October 2021

Intracerebral transplantation of autologous adipose-derived stem cells for chronic ischemic stroke: A phase I study.

J Tissue Eng Regen Med 2022 Jan 21;16(1):3-13. Epub 2021 Oct 21.

Department of Neurosurgery, Bioinnovation Center, Tzu Chi Foundation, Buddhist Tzu Chi General Hospital, Tzu Chi University, Hualien, Taiwan, ROC.

Current therapy does not provide significant benefits for patients with chronic stroke. Pre-clinical studies suggested that autologous adipose-derived stem cells have benefits for the treatment of chronic stroke. This Phase I open-label study was conducted to demonstrate the safety and efficacy of autologous adipose-derived stem cells (GXNPC1) in chronic stroke. Three patients with chronic stroke were treated with stereotactic implantation of autologous adipose-derived stem cells (1 × 10 cells). The primary endpoints of safety evaluation included adverse events, over a 6 months post-implantation period. The secondary endpoints included improvements in neurological functions. Evolutional change of brain parenchyma was also followed with magnetic resonance imaging (MRI). All three participants improved significantly at 6 months follow-up. The extent of improvement from pre-treatment was: National Institutes of Health Stroke Scale improved 5-15 points, Barthel Index: 25-50 points, Berg balance scale 0-21 points and Fugl-Meyer modified sensation 3-28 points. All three patients had signal change along the implantation tract on MRI one month after surgery. There is no related safety issue through 6 months observation. Clinical measures of neurological symptoms of these patients with chronic stroke improved at 6 months without adverse effects after implantation of autologous adipose-derived stem cells (GXNPC1), which might be correlated with post-implantation changes on brain MRI. Clinical Trial Registration-URL: https://clinicaltrials.gov/ct2/show/NCT02813512?term=ADSC&cond=Stroke&cntry=TW&draw=2&rank=1 Unique identifier: NCT02813512.
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http://dx.doi.org/10.1002/term.3256DOI Listing
January 2022

Effect of deep brain stimulation on brain network and white matter integrity in Parkinson's disease.

CNS Neurosci Ther 2022 01 12;28(1):92-104. Epub 2021 Oct 12.

Department of Neurosurgery, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan.

Aims: The effects of subthalamic nucleus (STN)-deep brain stimulation (DBS) on brain topological metrics, functional connectivity (FC), and white matter integrity were studied in levodopa-treated Parkinson's disease (PD) patients before and after DBS.

Methods: Clinical assessment, resting-state functional MRI (rs-fMRI), and diffusion tensor imaging (DTI) were performed pre- and post-DBS in 15 PD patients, using a within-subject design. The rs-fMRI identified brain network topological metric and FC changes using graph-theory- and seed-based methods. White matter integrity was determined by DTI and tract-based spatial statistics.

Results: Unified Parkinson's Disease Rating Scale III (UPDRS- III) scores were significantly improved by 35.3% (p < 0.01) after DBS in PD patients, compared with pre-DBS patients without medication. Post-DBS PD patients showed a significant decrease in the graph-theory-based degree and cost in the middle temporal gyrus and temporo-occipital part-Right. Changes in FC were seen in four brain regions, and a decrease in white matter integrity was seen in the left anterior corona radiata. The topological metrics changes were correlated with Beck Depression Inventory II (BDI-II) and the FC changes with UPDRS-III scores.

Conclusion: STN-DBS modulated graph-theoretical metrics, FC, and white matter integrity. Brain connectivity changes observed with multi-modal imaging were also associated with postoperative clinical improvement. These findings suggest that the effects of STN-DBS are caused by brain network alterations.
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http://dx.doi.org/10.1111/cns.13741DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8673709PMC
January 2022

Peiminine Reduces ARTS-Mediated Degradation of XIAP by Modulating the PINK1/Parkin Pathway to Ameliorate 6-Hydroxydopamine Toxicity and α-Synuclein Accumulation in Parkinson's Disease Models In Vivo and In Vitro.

Int J Mol Sci 2021 Sep 23;22(19). Epub 2021 Sep 23.

Graduate Institute of Biomedical Sciences, China Medical University, Taichung 40402, Taiwan.

Parkinson's disease (PD) is a degenerative disease that can cause motor, cognitive, and behavioral disorders. The treatment strategies being developed are based on the typical pathologic features of PD, including the death of dopaminergic (DA) neurons in the substantia nigra of the midbrain and the accumulation of α-synuclein in neurons. Peiminine (PMN) is an extract of Miq that has antioxidant and anti-neuroinflammatory effects. We used and SH-SY5Y cell models of PD to evaluate the neuroprotective potential of PMN and address its corresponding mechanism of action. We found that pretreatment with PMN reduced production and DA neuron degeneration caused by exposure to 6-hydroxydopamine (6-OHDA), and therefore significantly improved the DA-mediated food-sensing behavior of 6-OHDA-exposed worms and prolonged their lifespan. PMN also diminished the accumulation of α-synuclein in transgenic worms and transfected cells. In our study of the mechanism of action, we found that PMN lessened ARTS-mediated degradation of X-linked inhibitor of apoptosis (XIAP) by enhancing the expression of PINK1/parkin. This led to reduced 6-OHDA-induced apoptosis, enhanced activity of the ubiquitin-proteasome system, and increased autophagy, which diminished the accumulation of α-synuclein. The use of small interfering RNA to down-regulate parkin reversed the benefits of PMN in the PD models. Our findings suggest PMN as a candidate compound worthy of further evaluation for the treatment of PD.
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http://dx.doi.org/10.3390/ijms221910240DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8549710PMC
September 2021

Intramyocardial injection of human adipose-derived stem cells ameliorates cognitive deficit by regulating oxidative stress-mediated hippocampal damage after myocardial infarction.

J Mol Med (Berl) 2021 12 11;99(12):1815-1827. Epub 2021 Oct 11.

Bioinnovation Center, Tzu Chi Foundation, Department of Neurosurgery, Buddhist Tzu Chi General Hospital, Tzu Chi University, No.707, Sec. 3, Chung Yang Rd. 970, Hualien, Taiwan.

Cognitive impairment is a serious side effect of post-myocardial infarction (MI) course. We have recently demonstrated that human adipose-derived stem cells (hADSCs) ameliorated myocardial injury after MI by attenuating reactive oxygen species (ROS) levels. Here, we studied whether the beneficial effects of intramyocardial hADSC transplantation can extend to the brain and how they may attenuate cognitive dysfunction via modulating ROS after MI. After coronary ligation, male Wistar rats were randomized via an intramyocardial route to receive either vehicle, hADSC transplantation (1 × 10 cells), or the combination of hADSCs and 3-Morpholinosydnonimine (SIN-1, a peroxynitrite donor). Whether hADSCs migrated into the hippocampus was assessed by using human-specific primers in qPCR reactions. Passive avoidance test was used to assess cognitive performance. Postinfarction was associated with increased oxidative stress in the myocardium, circulation, and hippocampus. This was coupled with decreased numbers of dendritic spines as well as a significant downregulation of synaptic plasticity consisting of synaptophysin and PSD95. Step-through latency during passive avoidance test was impaired in vehicle-treated rats after MI. Intramyocardial hADSC injection exerted therapeutic benefits in improving cardiac function and cognitive impairment. None of hADSCs was detected in rat's hippocampus at the 3rd day after intramyocardial injection. The beneficial effects of hADSCs on MI-induced histological and cognitive changes were abolished after adding SIN-1. MI-induced ROS attacked the hippocampus to induce neurodegeneration, resulting in cognitive deficit. The remotely intramyocardial administration of hADSCs has the capacity of improved synaptic neuroplasticity in the hippocampus mediated by ROS, not the cell engraftment, after MI. KEY MESSAGES: Human adipose-derived stem cells (hADSCs) ameliorated injury after myocardial infarction by attenuating reactive oxygen species (ROS) levels. Intramyocardial administration of hADSCs remotely exerted therapeutic benefits in improving cognitive impairment after myocardial infarction. The improved synaptic neuroplasticity in the hippocampus was mediated by hADSC-inhibiting ROS, not by the stem cell engraftment.
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http://dx.doi.org/10.1007/s00109-021-02135-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8599314PMC
December 2021

Endometriosis Is Associated with an Increased Risk of Coronary Artery Disease in Asian Women.

J Clin Med 2021 Sep 15;10(18). Epub 2021 Sep 15.

Department of Obstetrics and Gynecology, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Tzu Chi University, Hualien 970, Taiwan.

Endometriosis is a common systemic chronic inflammatory disease. Inflammation is the key mechanism responsible for the development of endothelial dysfunction and atherosclerosis. We aimed to investigate the risk of coronary artery disease (CAD) among Asian women with endometriosis. This retrospective population-based cohort study included patients with endometriosis diagnosed from 2000 to 2012 and registered in the Longitudinal Health Insurance Database, Taiwan. The comparison cohort (those without endometriosis) were selected (1:4) by matching the age frequency and the index year. We followed up the patients until the diagnosis of CAD (ICD-9-CM codes: 410-414, A270, and A279), withdrawal from the National Health Insurance system, death, or the end of the study. We used a multivariable-adjusted Cox proportional hazard model for evaluating the risk of CAD. We included 19,454 patients with endometriosis and 77,816 women as a comparison group. The mean age of the women at the diagnosis of endometriosis was 37.4 years. A total of 3245 women developed CAD in both groups during a median follow-up of 7 years. The incidence of CAD was higher in women with endometriosis than in those without (5.96 vs. 4.38 per 10,000 person-years; adjusted hazard ratio [95% confidence interval], 1.34 [1.22-1.47]). In conclusion, Asian women with endometriosis had a significantly higher risk of CAD. Further large-scale studies are needed to elucidate the cause-effect relationship between endometriosis and CAD.
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http://dx.doi.org/10.3390/jcm10184173DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8472678PMC
September 2021

N-butylidenephthalide ameliorates high-fat diet-induced obesity in mice and promotes browning through adrenergic response/AMPK activation in mouse beige adipocytes.

Biochim Biophys Acta Mol Cell Biol Lipids 2021 12 3;1866(12):159033. Epub 2021 Sep 3.

Buddhist Tzu Chi Bioinnovation Center, Buddhist Tzu Chi Medical Foundation, Hualien 970, Taiwan; Department of Pathology, Hualien Tzu Chi Hospital and Tzu Chi University, Hualien 970, Taiwan. Electronic address:

Thermogenesis (non-exercise activity) in brown adipose tissue (BAT) promotes energy expenditure because of its higher number of mitochondria than white adipose tissue (WAT). The main function of thermogenesis in BAT can counteract obesity through the dissipation of calories as heat. N-butylidenephthalide (BP) is a natural derivative from Angelica sinensis, a Chinese herb that has been used for thousands of years. In this report, we demonstrated that BP improved the metabolic profiles of mice with high fat diet-induced obesity (DIO) by preventing weight gain, improving serum blood parameters, enhancing energy expenditure, stimulating white fat browning, and reversing hepatic steatosis. Further investigations demonstrated that BP administration upregulated the mRNA expression of beige (CD137, TMEM26) and brown fat selected genes (UCP1, PRDM16, PGC-1α, PPARγ) in white adipose tissues. In vitro studies, BP treatment increased multilocular lipid droplet levels, induced β-adrenergic receptor (cAMP/PKA) and AMP-activated protein kinase (AMPK) signaling (AMPK/acetyl-CoA carboxylase/SIRT1), and increased oxygen consumption in murine differentiated beige adipocytes, and the effects of BP were blocked by an AMPK inhibitor. BP promoted the interaction of AMPK with PGC-1α in beige adipocytes. Our findings provide novel insights into the application of BP in regulating energy metabolism and suggest its utility for clinical use in the treatment of obesity and related diseases.
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http://dx.doi.org/10.1016/j.bbalip.2021.159033DOI Listing
December 2021

3-N-butylphthalide protects against high-fat-diet-induced obesity in C57BL/6 mice and increases metabolism in lipid-accumulating cells.

Biomed Pharmacother 2021 Jul 10;139:111687. Epub 2021 May 10.

Buddhist Tzu Chi Bioinnovation Center, Buddhist Tzu Chi Medical Foundation, Hualien 970, Taiwan; Department of Pathology, Hualien Tzu Chi Hospital and Tzu Chi University, Hualien 970, Taiwan. Electronic address:

Obesity is one of the world's largest health problems, and 3-N-butylphthalide (NBP), a bioactive compound in celery, has been used in dieting and weight management programs. In this study, NBP prevented high-fat-diet-induced weight gain, reduced the food efficiency ratio, altered the blood biochemical profile, and reduced the obesity-related index. NBP reduced adiposity, white fat depots, liver weight, and hepatic steatosis in obese mice. NBP ameliorated the diabetic state by decreasing glucose levels and improving glucose and insulin tolerance. NBP increased uncoupling protein-1 expression in white adipose tissue and upregulated thermogenesis by enhancing mitochondrial respiration. NBP inhibited white adipocyte development by prohibiting lipid accumulation in human adipose-derived stem cells. NBP increased free fatty acid uptake and the oxygen consumption rate in beige adipocytes. Our results suggest that NBP could be used as functional natural supplement against obesity and its associated disorders.
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http://dx.doi.org/10.1016/j.biopha.2021.111687DOI Listing
July 2021

-Butylidenephthalide Modulates Autophagy to Ameliorate Neuropathological Progress of Spinocerebellar Ataxia Type 3 through mTOR Pathway.

Int J Mol Sci 2021 Jun 13;22(12). Epub 2021 Jun 13.

Department of Life Science, Graduate Institute of Biotechnology, National Dong-Hwa University, Hualien 97447, Taiwan.

Spinocerebellar ataxia type 3 (SCA3), a hereditary and lethal neurodegenerative disease, is attributed to the abnormal accumulation of undegradable polyglutamine (polyQ), which is encoded by mutated ataxin-3 gene (). The toxic fragments processed from mutant can induce neuronal death, leading to the muscular incoordination of the human body. Some treatment strategies of SCA3 are preferentially focused on depleting the abnormal aggregates, which led to the discovery of small molecule -butylidenephthalide (-BP). -BP-promoted autophagy protected the loss of Purkinje cell in the cerebellum that regulates the network associated with motor functions. We report that the -BP treatment may be effective in treating SCA3 disease. -BP treatment led to the depletion of mutant with the expanded polyQ chain and the toxic fragments resulting in increased metabolic activity and alleviated atrophy of SCA3 murine cerebellum. Furthermore, -BP treated animal and HEK-293 cell models could consistently show the depletion of aggregates through mTOR inhibition. With its unique mechanism, the two autophagic inhibitors Bafilomycin A1 and wortmannin could halt the -BP-induced elimination of aggregates. Collectively, -BP shows promising results for the treatment of SCA3.
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http://dx.doi.org/10.3390/ijms22126339DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8231882PMC
June 2021

Chinese herbs and acupuncture to improve cognitive function in Alzheimer's disease.

Tzu Chi Med J 2021 Apr-Jun;33(2):122-127. Epub 2021 Feb 6.

Bioinnovation Center, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan.

Alzheimer's disease (AD) is a neurodegenerative disease with a variety of causes. Traditional Chinese medicine (TCM), which includes the two main approaches of acupuncture and herbal medication, views the human body as a self-controlled system network. Fundamental theories, including "qi," the five elements, and the theory of viscera, form the basis for classification. Diseases in humans are considered to be caused by an imbalance of "yang qi" and "yin qi" that lead to the nonhomeostasis of organs. Acupuncture is derived from 12 main meridians and 365 acupuncture points characterized by "blood and qi." Needling of different positions corresponds to specific disease treatments to increase qi. Treatment with Chinese herbal medicines is based on syndrome differentiation characterized as "Zheng" which differs from the cause orientation approach of Western medicine. In this article, we review basic and clinical research studies that describe TCM herbs and acupuncture for the treatment of AD. Moreover, we propose that these two approaches be integrated to improve the outcomes for AD patients.
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http://dx.doi.org/10.4103/tcmj.tcmj_51_20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8059467PMC
February 2021

Use of bladder antimuscarinics is associated with an increased risk of dementia: a retrospective population-based case-control study.

Sci Rep 2021 03 1;11(1):4827. Epub 2021 Mar 1.

Department of Obstetrics and Gynecology, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Tzu Chi University, No. 707, Chung-Yang Rd., Sec. 3, Hualien, Taiwan, ROC.

The association between bladder antimuscarinic use and dementia development is unclear. We used data from the Taiwan National Health Insurance Research Database to determine the association between the exposure dose and duration of bladder antimuscarinics and the subsequent dementia risk. We enrolled participants aged 55 years or more and defined a dementia cohort (International Classification of Diseases, Ninth Revision, Clinical Modification codes 290, 294.1, and 331.0). We used a propensity score matching method, and randomly enrolled two controls without dementia. We evaluated dementia risk with respect to the exposure dose and duration of treatment with seven bladder antimuscarinics (oxybutynin, propiverine, tolterodine, solifenacin, trospium, darifenacin, and fesoterodine) used for at least 1 year before the index date, after adjusting for age, sex, comorbidities, and medications. The dementia risk was 2.46-fold (95% confidence interval: 2.22-2.73) higher in Taiwanese patients who used bladder antimuscarinics for ≥ 1 year than in those who were not exposed to this treatment. The risk proportionally increased with increasing doses of antimuscarinics for less than 4 years. Taiwanese patients aged 55 years or more on bladder antimuscarinics exhibited a higher risk of dementia. Additional studies in other countries are required to determine whether this result is valid worldwide.
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http://dx.doi.org/10.1038/s41598-021-84229-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7921664PMC
March 2021

Diabetes mellitus risk after hysterectomy: A population-based retrospective cohort study.

Medicine (Baltimore) 2021 Jan;100(4):e24468

Institute of Medical Sciences.

Abstract: We explored whether hysterectomy with or without bilateral oophorectomy was associated with the increasing incidence of diabetes mellitus (DM) in an East Asian population. This was a retrospective population-based cohort study that analyzed DM risk in Taiwanese women, using a health insurance research database of 1998 to 2013 containing nearly 1 million people. We identified 7088 women aged 30 to 49 years who had undergone hysterectomy with or without oophorectomy. The comparison group included 27,845 women without a hysterectomy who were randomly selected from the population and matched to women in the hysterectomy group by age (exact year) and year of the surgery. DM comorbidities were identified. The incidence and hazard ratios for DM were calculated with Cox proportional hazard regression models. The median ages of patients in the hysterectomy and comparison groups were both approximately 44 years. After a median 7.1 years of follow-up, the incidence of DM was 40% higher in the hysterectomized women as compared with the comparisons (9.12 vs 6.78/1000 person-years, P < .001), with an adjusted hazard ratio (aHR) of 1.37 (95% confidence interval [CI] = 1.23 -1.52). However, the DM risk was not increased in the women with hysterectomy plus oophorectomy (aHR=1.28, 95% CI = 0.93-1.76). Furthermore, among women aged 30 to 39 years, 40 to 49 years, the risk in hysterectomized women was higher than the comparisons (aHR = 1.75, 95% CI = 1.27-2.41; aHR = 1.33, 95% CI = 1.19-1.49, respectively). Our study provides essential and novel evidence for the association between hysterectomy and DM risk in women aged 30 to 49 years, which is relevant to these women and their physicians. Physicians should be aware of the increased DM risk associated with hysterectomy and take this into consideration when evaluating a patient for a hysterectomy. The current results might help gynecologists prevent DM and encourage diagnostic and preventive interventions in appropriate patients.
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http://dx.doi.org/10.1097/MD.0000000000024468DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7850756PMC
January 2021

Hysterectomies are associated with an increased risk of osteoporosis and bone fracture: A population-based cohort study.

PLoS One 2020 1;15(12):e0243037. Epub 2020 Dec 1.

Department of Obstetrics and Gynecology, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, and Tzu Chi University, Hualien, Taiwan.

Aim: This study investigated the risk of osteoporosis or bone fractures (vertebrae, hip and others) in hysterectomized women in Taiwan.

Materials And Methods: This is a retrospective population-based cohort study from 2000 to 2013. Women aged ≥30 years who underwent hysterectomy between 2000 and 2012 were included in this study. The comparison group was randomly selected from the database with a 1:4 matching with age and index year. Incidence rate and hazard ratios of osteoporosis and bone fracture between hysterectomized women and the comparison group were calculated. Cox proportional hazard regressions were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs).

Results: We identified 9,189 hysterectomized women and 33,942 age-matched women without a hysterectomy. All women were followed for a median time of about 7 years. The adjusted hazard ratio (aHR) of subsequent osteoporosis or bone fracture was higher in the hysterectomy women (2.26, 95% confidence interval [CI] = 2.09-2.44) than in the comparison group. In the subgroup analysis, oophorectomy and estrogen therapy increase the risk of osteoporosis or fracture in both groups. Regarding the fracture site, the aHR of vertebral fracture (4.92, 95% CI = 3.78-6.40) was higher in the hysterectomized women than in the comparison group. As follow-up time increasing, the aHR of vertebral fracture in hysterectomized women were 4.33 (95% CI = 2.99-6.28), 3.89 (95% CI = 2.60-5.82) and 5.42 (95% CI = 2.66-11.01) for <5, 5-9 and ≥9 years of follow-up, respectively.

Conclusions: In conclusion, we found that hysterectomized women might be associated with increased risks of developing osteoporosis or bone fracture.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0243037PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7707488PMC
January 2021

Association of laparoscopy and laparotomy with adverse fetal outcomes: a retrospective population-based case-control study.

Surg Endosc 2021 11 13;35(11):6048-6054. Epub 2020 Oct 13.

Department of Obstetrics and Gynecology, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, and Tzu Chi University, No. 707, Chung-Yang Rd., Sec. 3, Hualien, Taiwan.

Background: This study aimed to evaluate fetal adverse outcomes of laparoscopy and laparotomy in pregnant women to determine the safety of these surgical approaches.

Methods: This was a retrospective nationwide case-control study of women who became pregnant for the first time between 2000 and 2012 in Taiwan. The case (with adverse fetal outcomes) and control groups comprised 208,604 and 417,124 participants, respectively. Participants who underwent appendectomy, cholecystectomy, ovarian cystectomy, or myomectomy were treated with either laparoscopy or laparotomy. A conditional logistic regression model was used to calculate the odds ratios (ORs) for adverse fetal outcomes.

Results: The laparotomy and laparoscopy groups comprised 632 and 536 patients, respectively. Women who underwent laparoscopy had a significantly higher risk of adverse fetal outcomes (adjusted OR [AOR] = 2.33; 95% CI 1.66-2.99) than those who underwent laparotomy. Adverse fetal outcomes were found to be significantly associated with laparoscopy among women aged 20-39 years (AOR = 2.30; 95% CI 1.70-3.31). Regarding surgical indication, unlike laparotomy, laparoscopic cholecystectomy and appendectomy were not associated with adverse fetal outcomes. However, laparoscopic myomectomy and ovarian surgeries were associated with a higher incidence of adverse fetal outcomes than the laparotomy group (AOR = 2.29 [95% CI 1.57-3.35, p < 0.0001] and AOR = 2.52 [95% CI 1.58-4.04, p = 0.0001], respectively).

Conclusions: Pregnant women who underwent laparoscopic surgery experienced significantly more adverse fetal outcomes than those who underwent laparotomy. Therefore, pregnant women undergoing either laparotomy or laparoscopy should be informed of the risk of adverse fetal outcomes.
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http://dx.doi.org/10.1007/s00464-020-08094-2DOI Listing
November 2021

Transplantation of Adipose-Derived Stem Cells Alleviates Striatal Degeneration in a Transgenic Mouse Model for Multiple System Atrophy.

Cell Transplant 2020 Jan-Dec;29:963689720960185

Department of Life Science and Graduate Institute of Biotechnology, 63373National Dong Hwa University, Hualien, Taiwan, R.O.C.

Patients with multiple system atrophy (MSA), a progressive neurodegenerative disorder of adult onset, were found less than 9 years of life expectancy after onset. The disorders include bradykinesia and rigidity commonly seen in Parkinsonism disease and additional signs such as autonomic dysfunction, ataxia, or dementia. In clinical treatments, MSA poorly responds to levodopa, the drug used to remedy Parkinsonism disease. The exact cause of MSA is still unknown, and exploring a therapeutic solution to MSA remains critical. A transgenic mouse model was established to study the feasibility of human adipose-derived stem cell (ADSC) therapy in vivo. The human ADSCs were transplanted into the striatum of transgenic mice via intracerebral injection. As compared with sham control, we reported significantly enhanced rotarod performance of transgenic mice treated with ADSC at an effective dose, 2 × 10 ADSCs/mouse. Our ex vivo feasibility study supported that intracerebral transplantation of ADSC might alleviate striatal degeneration in MSA transgenic mouse model by improving the nigrostriatal pathway for dopamine, activating autophagy for α-synuclein clearance, decreasing inflammatory signal, and further cell apoptosis, improving myelination and cell survival at caudate-putamen.
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http://dx.doi.org/10.1177/0963689720960185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7784590PMC
August 2021

Host pre-conditioning improves human adipose-derived stem cell transplantation in ageing rats after myocardial infarction: Role of NLRP3 inflammasome.

J Cell Mol Med 2020 11 6;24(21):12272-12284. Epub 2020 Oct 6.

Bioinnovation Center, Tzu Chi Foundation, Hualien City, Taiwan.

Functional decline of stem cell transplantation in ageing hosts is well documented. The mechanism for this is poorly understood, although it is known that advancing age does not provide an optimal milieu for exogenous stem cells to survive, engraft and differentiate. We showed that n-butylidenephthalide improved human adipose-derived stem cell (hADSC) engraftment via attenuating the production of reactive oxygen species (ROS). It remained unclear whether pre-treated hosts with n-butylidenephthalide can rejuvenate the ageing heart and improve hADSC engraftment by regulating the ROS/NLRP3 inflammasome-mediated cardiac fibrosis after myocardial infarction. One hour after coronary ligation, hADSCs were transplanted into the hearts of young and ageing Wistar rats that were pre-treated with or without n-butylidenephthalide for 3 days. At day 3 after infarction, myocardial infarction was associated with an increase in ROS levels and NLRP3 inflammasome activity with age. hADSC transplant effectively provided a significant decrease in ROS levels, NLRP3 inflammasome activity, IL-1β levels and cardiac fibrosis in either young or old infarcted rats. However, the beneficial effects of hADSCs were greater in young compared with old rats in terms of NLRP3 inflammasome activity. The infarcted ageing rats pre-conditioned by n-butylidenephthalide improved engraftment and differentiation of hADSCs and additionally attenuated cardiac fibrosis compared with hADSCs alone. The anti-inflammation effects of n-butylidenephthalide were reversed by SIN-1. In conclusions, the increased NLRP3 inflammasome activity plays the pathogenesis of ageing-related functional hADSC decline in the ageing hosts. n-butylidenephthalide-pre-treated ageing hosts reversibly ameliorate the harsh microenvironments, improve stem cell engraftment and attenuate cardiac fibrosis after myocardial infarction.
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http://dx.doi.org/10.1111/jcmm.15403DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7686984PMC
November 2020

First insights on value-based healthcare of elders using ICHOM older person standard set reporting.

BMC Geriatr 2020 09 9;20(1):335. Epub 2020 Sep 9.

Aging and Health Research Center, National Yang Ming University, Taipei, Taiwan.

Background: Clinical guidelines for specific conditions fragment care provision for elders. The International Consortium for Health Outcomes Measurement (ICHOM) has developed a global standard set of outcome measures for comprehensive assessment of older persons. The goal of this study was to report value-based health metrics in Taiwan using this ICHOM toolset.

Methods: The cross-sectional study of baseline data excerpted from a prospective longitudinal cohort, which recruited people ≥65 years old with ≥3 chronic medical conditions between July and December 2018. All participants received measurements of physical performance, anthropometric characteristics, health-related behaviors, Charlson Comorbidity Index, and Montreal Cognitive Assessment. The ICHOM toolset comprises three tiers: 1 includes frailty and having chosen a preferred place of death; 2 includes polypharmacy, falls, and participation in decision-making; and 3 includes loneliness, activities of daily living, pain, depression, and walking speed. These items were converted into a 0-10 point value-based healthcare score, with high value-based health status defined as ≥8/10 points.

Results: Frequencies of individual ICHOM indicators were: frail 11.7%, chose preferred place of death 14.4%, polypharmacy 31.5%, fell 17.1%, participated in decision-making 81.6%, loneliness 26.8%, limited activities of daily living 22.4%, pain 10.4%, depressed mood 13.0%, and slowness 38.5%. People with high disease burden (OR 0.40, 95% CI 0.21-0.76, p = 0.005) or cognitive impairment (OR 0.49, 95%CI 0.27-0.87, p = 0.014) were less likely to have high value-based healthcare status.

Conclusions: The ICHOM Standard Set Older Person health outcome measures provide an opportunity to shift from a disease-centric medical paradigm to whole person-focused goals. This study identified advanced age, chronic disease burden and cognitive impairment as important barriers to achieving high value-based healthcare status.
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http://dx.doi.org/10.1186/s12877-020-01734-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7487791PMC
September 2020

Clinical Application Potential of Small Molecules that Induce Brown Adipose Tissue Thermogenesis by Improving Fat Metabolism.

Cell Transplant 2020 Jan-Dec;29:963689720927394

63136Hualien Tzu Chi Hospital, Hualien, Taiwan.

Mammalian fat comprises white and brown adipose tissue (WAT and BAT, respectively). WAT stores energy, whereas BAT is used for thermogenesis. In recent years, the incidence of obesity and its associated disorders have increased tremendously. Considering the thermogenic capacity and decreased levels of BAT with increasing age, BAT can be used as a suitable therapeutic target for the treatment of obesity and diabetes. In several studies, using positron emission tomography and computed tomography images, adult humans have been shown to have functional BAT in interscapular fat. Results of these basic research studies on BAT have shed light on the new components of transcriptional regulation and the role of hormones in stimulating BAT growth and differentiation. In this review article, we have summarized the thermogenic regulators identified in the past decades by focusing on peroxisome proliferator-activated receptor gamma/uncoupling protein 1 activators, branched-chain amino acids, fatty acids (lipokine), and adenosine monophosphate-activated protein kinase mediators. We have also presented the progress of a few ongoing clinical trials aimed at the treatment of obesity and its associated metabolic disorders. The main purpose of this review was to provide a comprehensive introduction to the latest knowledge of the representative thermogenic regulators for the treatment of obesity. The fat combustion capacity of BAT may have great potential and can be considered as a suitable target for the therapeutic application of drugs from bench-to-bed treatment of obesity and the associated diseases.
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http://dx.doi.org/10.1177/0963689720927394DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7563884PMC
July 2021

Aspirin associated with a decreased incidence of uterine cancer: A retrospective population-based cohort study.

Medicine (Baltimore) 2020 Jul;99(31):e21446

Department of Obstetrics and Gynecology, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, and Tzu Chi University.

Aspirin (ASA) exerts an anti-tumor effect via the COX pathway. Clinical studies on the chemopreventive effects of ASA on uterine cancer (UC) remain inconsistent. We used population-based retrospective cohort study to evaluate the UC in ASA users in Taiwanese women. From insurance claims data, we identified 23,342 women received ASA treatment between 2000 and 2010 and a comparison group of same sample size randomly selected from the same database matched by the propensity score. The incidence of UC in the ASA cohort was 10% of that in the comparison group (0.28 vs 2.73 per 10,000 person-years). The Poisson regression analysis estimated adjusted incidence rate ratio (IRR) was 0.10 (95% confidence interval (CI) = 0.09-0.11) for ASA users relatives to comparisons after controlling for covariates. The UC incidence in ASA users decreased with age, from 0.61 per 10,000 person-years in the 20 to 39 years old (adjusted IRR = 0.21, 95% CI = 0.15-0.29) to 0.21 per 10,000 person-years in the 65 to 80 years old (adjusted IRR = 0.15, 95% CI = 0.12-0.16). The incidence was higher in longer term users. Hormone therapy of estradiol was associated with the increase of UC risk in both cohorts, but less in ASA users than comparisons (1.34 vs 4.75 per 10,000 person-years). This study suggests that ASA use was associated with a decreased risk of UC. Further prospective randomized clinical trials are warranted to confirm the association.
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http://dx.doi.org/10.1097/MD.0000000000021446DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7402752PMC
July 2020

The application of stem cell therapy and brown adipose tissue transplantation in metabolic disorders.

Cytotherapy 2020 10 17;22(10):521-528. Epub 2020 Jul 17.

Graduate Institute of Biomedical Science, China Medical University, Taichung, Taiwan; Center for Translational Medicine, China Medical University and Hospital, Taichung, Taiwan. Electronic address:

The discovery of brown fat in adult humans has led to increased research of the thermogenic function of this tissue in various metabolic diseases. In addition, high levels of brown fat have been correlated with lower body mass index values. Therefore, increasing brown fat mass and/or activity through methods such as the browning of white fat is considered a promising strategy to prevent and treat obesity-associated diseases. Cell-based approaches using mesenchymal stromal cells and brown adipose tissue (BAT) have been utilized to directly increase BAT mass/activity through cell and tissue implantation into animals. In addition, recent studies evaluating the transplantation of human embryonic stem cells and induced pluripotent stem (iPS) cells have shown promising results in terms of positive metabolic function. In this comprehensive review, we provide a summary of the research over the past 10 years with regard to stem cell therapy and brown fat tissue transplantation for the effective treatment of metabolic syndrome. Recent advancements in stem cell methods have allowed for the production of brown adipocytes from human iPS cells, which represent an unlimited source of cellular material with which to study adipocyte development. In addition, this process is expected to be used to further explore drug- and cell-based therapies to treat obesity-related metabolic complications.
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http://dx.doi.org/10.1016/j.jcyt.2020.06.004DOI Listing
October 2020

Enhanced Bone Formation in Osteoporotic Mice by a Novel Transplant Combined with Adipose-derived Stem Cells and Platelet-rich Fibrin Releasates.

Cell Transplant 2020 Jan-Dec;29:963689720927398

School of Veterinary Medicine, National Taiwan University, Taipei, Taiwan.

Osteoporotic fracture is the main complication of osteoporosis (OP) and accounts for millions of injuries annually. Local intervention by intra-marrow injection has been a good option for preventing osteoporotic bone loss when the osteoporotic femoral fracture has been treated. In this study, tail vein transplantations were examined to evaluate the cell-based therapeutic approach for treating OP with adipose-derived stem cells (ADSCs) and platelet-rich fibrin releasates (PRFr) in an ovariectomized (OVX) mice model. Thirty-six 12-wk-old female ICR mice were randomly divided into six groups: untreated control; sham-operated; OVX-control; OVX-ADSCs; OVX-PRFr; and OVX-ADSCs+PRFr. Starting 8 wk after ovariectomy, the OVX mice received tail vein injections once each week for four consecutive weeks, then were evaluated radiographically and histopathologically 8 wk after the first injection. We also assessed changes to bone trabeculae in the proximal tibial growth plate. In OVX mice treated with ADSCs or PRFr alone, or with a combination of ADSCs and PRFr, the trabecular bone mineral density (BMD), bone volume ratios (BV/TV), and numbers (Tb.N) in the proximal tibia areas were significantly higher than that in the OVX-control group. Significant differences between OVX-treated mice and OVX controls were found for trabecular separation, but not for trabecular thickness. These results indicate that ADSCs or PRFr treatment enhances bone microarchitecture in OP. The treatment of bone loss of OVX mice with ADSCs+PRFr induced greater bone consolidation with bone tissue production ( < 0.01) when compared to the others. Thus, we conclude that the transplantation of ADSCs combined with PRFr might provide an alternative strategy for the treatment of various bone disorders in OP with an unlimited source of cells and releasates.
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http://dx.doi.org/10.1177/0963689720927398DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7563809PMC
June 2021

Maackiain Ameliorates 6-Hydroxydopamine and Pathologies by Modulating the PINK1/Parkin Pathway in Models of Parkinson's Disease in and the SH-SY5Y Cell Line.

Int J Mol Sci 2020 Jun 23;21(12). Epub 2020 Jun 23.

Graduate Institute of Biomedical Sciences, China Medical University, Taichung 40402, Taiwan.

The movement disorder Parkinson's disease (PD) is the second most frequently diagnosed neurodegenerative disease, and is associated with aging, the environment, and genetic factors. The intracellular aggregation of α-synuclein and the loss of dopaminergic neurons in the substantia nigra pars compacta are the pathological hallmark of PD. At present, there is no successful treatment for PD. Maackiain (MK) is a flavonoid extracted from dried roots of Aiton. MK has emerged as a novel agent for PD treatment that acts by inhibiting monoamine oxidase B. In this study, we assessed the neuroprotective potential of MK in and investigated possible mechanism of this neuroprotection in the human SH-SY5Y cell line. We found that MK significantly reduced dopaminergic neuron damage in 6-hydroxydopamine (6-OHDA)-exposed worms of the BZ555 strain, with corresponding improvements in food-sensing behavior and life-span. In transgenic worms of strain NL5901 treated with 0.25 mM MK, the accumulation of α-synuclein was diminished by 27% ( < 0.01) compared with that in untreated worms. Moreover, in worms and the SH-SY5Y cell line, we confirmed that the mechanism of MK-mediated protection against PD pathology may include blocking apoptosis, enhancing the ubiquitin-proteasome system, and augmenting autophagy by increasing expression. The use of small interfering RNA to downregulate parkin expression in vivo and in vitro could reverse the benefits of MK in PD models. MK may have considerable therapeutic applications in PD.
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http://dx.doi.org/10.3390/ijms21124455DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352553PMC
June 2020

Liposome Consolidated with Cyclodextrin Provides Prolonged Drug Retention Resulting in Increased Drug Bioavailability in Brain.

Int J Mol Sci 2020 Jun 21;21(12). Epub 2020 Jun 21.

Department of Life Science, National Dong Hwa University, No. 1, Sec. 2, Da Hsueh Rd., Shou-Feng, Hualien 974301, Taiwan.

Although butylidenephthalide (BP) is an efficient anticancer drug, its poor bioavailability renders it ineffective for treating drug-resistant brain tumors. However, this problem is overcome through the use of noninvasive delivery systems, including intranasal administration. Herein, the bioavailability, drug stability, and encapsulation efficiency (EE, up to 95%) of BP were improved by using cyclodextrin-encapsulated BP in liposomal formulations (CDD1). The physical properties and EE of the CDD1 system were investigated via dynamic light scattering, transmission electron microscopy, UV-Vis spectroscopy, and nuclear magnetic resonance spectroscopy. The cytotoxicity was examined via MTT assay, and the cellular uptake was observed using fluorescence microscopy. The CDD1 system persisted for over 8 h in tumor cells, which was a considerable improvement in the retention of the BP-containing cyclodextrin or the BP-containing liposomes, thereby indicating a higher BP content in CDD1. Nanoscale CDD1 formulations were administered intranasally to nude mice that had been intracranially implanted with temozolomide-resistant glioblastoma multiforme cells, resulting in increased median survival time. Liquid chromatography-mass spectrometry revealed that drug biodistribution via intranasal delivery increased the accumulation of BP 10-fold compared to oral delivery methods. Therefore, BP/cyclodextrin/liposomal formulations have potential clinical applications for treating drug-resistant brain tumors.
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http://dx.doi.org/10.3390/ijms21124408DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352271PMC
June 2020

Regenerative Potential of Platelet-Rich Fibrin Releasate Combined with Adipose Tissue-Derived Stem Cells in a Rat Sciatic Nerve Injury Model.

Cell Transplant 2020 Jan-Dec;29:963689720919438

Bioinnovation Center, Tzu Chi Foundation, Hualien, Taiwan.

Sciatic nerve injuries, not uncommon in trauma with a limited degree of functional recovery, are considered a persistent clinical, social, and economic problem worldwide. Accumulating evidence suggests that stem cells can promote the tissue regeneration through various mechanisms. The aim of the present study was to investigate the role of adipose tissue-derived stem cells (ADSCs) and combine with platelet-rich fibrin releasate (PRFr) in the regeneration of sciatic nerve injury in rats. Twenty-four Sprague-Dawley rats were randomly assigned to four groups, a blade was used to transect the left hindlimb sciatic nerve, and silicon tubes containing one of the following (by injection) were used to bridge the nerve proximal and distal ends (10-mm gap): group 1: untreated controls; group 2: PRFr alone; group 3: ADSCs alone; group 4: PRFr + ADSCs-treated. Walking function was assessed in horizontal rung ladder apparatus to compare the demands of the tasks and test sensitivity at 1-mo interval for a total of 3 mo. The gross inspection and histological examination was performed at 3 mo post transplantation. Overall, PRFr + ADSCs-treated performed better compared with PRFr or ADSCs injections alone. Significant group differences of neurological function were observed in ladder rung walking tests in all treated groups compared to that of untreated controls ( < 0.05). This injection approach may provide a successfully employed technique to target sciatic nerve defects in vivo, and the combined strategy of ADSCs with PRFr appears to have a superior effect on nerve repair.
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http://dx.doi.org/10.1177/0963689720919438DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7586258PMC
June 2021

Age-stratified differences of physical capacity in rural community-dwelling Taiwanese older women: A cross-sectional study.

Arch Gerontol Geriatr 2020 Sep - Oct;90:104123. Epub 2020 May 22.

Center for Aging and Health, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan; Aging and Health Research Center, National Yang Ming University, Taipei, Taiwan; Department of Geriatric Medicine, National Yang Ming University School of Medicine, Taipei, Taiwan. Electronic address:

Objectives: Physical capacity decline may precede physical disability. We explored age-related physical capacity decline among rural community-dwelling Taiwanese older women to provide reference values and to identify indicators of early-onset decline in physical capacity.

Methods: Older women aged 65-96 were recruited from rural community centers. Physical capacity was measured by handgrip strength (HS), gait speed (GS), five-times-sit-to-stand (5xSTS), timed up and go (TUG), and the Berg balance scale (BBS). Participants were stratified into four age groups: 65-69, 70-74, 75-79, and ≥80 years.

Results: Of 137 participants, 61 % exhibited poor 5xSTS, 34-49 % showed low HS, poor TUG and BBS, and 26 % had slow GS. The mean values in GS, HS, 5xSTS, TUG, and BBS were 1.02 m/s, 17.8 kg, 14.5 s, 12.6 s, and 50 points, respectively. Abnormal mean values were first noted at age 70-74 years for 5xSTS, age 75-79 years for HS, TUG, and BBS, and age ≥80 years for GS. Also, more than half the participants exhibited the first poor 5xSTS at age 70-74 years; the first poor HS and TUG at age 75-79 years; and lastly, the first poor BBS and GS at age ≥80 years. At age 65-69 years, 14-41 % of participants reported poor performance in all measures except for GS.

Conclusions: Low HS and poor 5xSTS and TUG performance were more common and had earlier onset than slow GS. More attention should be directed toward the 5xSTS, TUG, and HS in rural community-dwelling Taiwanese older women.
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http://dx.doi.org/10.1016/j.archger.2020.104123DOI Listing
December 2020

Identifying Therapeutic Targets for Spinocerebellar Ataxia Type 3/Machado-Joseph Disease through Integration of Pathological Biomarkers and Therapeutic Strategies.

Int J Mol Sci 2020 Apr 26;21(9). Epub 2020 Apr 26.

Bioinnovation Center, Buddhist Tzu Chi Medical Foundation, Hualien 97002, Taiwan.

Spinocerebellar ataxia type 3/Machado-Joseph disease (SCA3/MJD) is a progressive motor disease with no broadly effective treatment. However, most current therapies are based on symptoms rather than the underlying disease mechanisms. In this review, we describe potential therapeutic strategies based on known pathological biomarkers and related pathogenic processes. The three major conclusions from the current studies are summarized as follows: (i) for the drugs currently being tested in clinical trials; a weak connection was observed between drugs and SCA3/MJD biomarkers. The only two exceptions are the drugs suppressing glutamate-induced calcium influx and chemical chaperon. (ii) For most of the drugs that have been tested in animal studies, there is a direct association with pathological biomarkers. We further found that many drugs are associated with inducing autophagy, which is supported by the evidence of deficient autophagy biomarkers in SCA3/MJD, and that there may be more promising therapeutics. (iii) Some reported biomarkers lack relatively targeted drugs. Low glucose utilization, altered amino acid metabolism, and deficient insulin signaling are all implicated in SCA3/MJD, but there have been few studies on treatment strategies targeting these abnormalities. Therapeutic strategies targeting multiple pathological SCA3/MJD biomarkers may effectively block disease progression and preserve neurological function.
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http://dx.doi.org/10.3390/ijms21093063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7246822PMC
April 2020
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