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Financial Management ; Hand ; Pilot Projects ; Rehabilitation ; Therapeutic Uses

Magnetic resonance-guided focused ultrasound (MRgFUS) is an emerging new technology with considerable potential to treat various neurological diseases. With refinement of ultrasound transducer technology and integration with magnetic resonance imaging guidance, transcranial sonication of precise cerebral targets has become a therapeutic option. Intensity is a key determinant of ultrasound effects. High-intensity focused ultrasound can produce targeted lesions via thermal ablation of tissue. MRgFUS-mediated stereotactic ablation is non-invasive, incision-free, and confers immediate therapeutic effects. Since the US Food and Drug Administration approval of MRgFUS in 2016 for unilateral thalamotomy in medication-refractory essential tremor, studies on novel indications such as Parkinson's disease, psychiatric disease, and brain tumors are underway. MRgFUS is also used in the context of blood-brain barrier (BBB) opening at low intensities, in combination with intravenously-administered microbubbles. Preclinical studies show that MRgFUS-mediated BBB opening safely enhances the delivery of targeted chemotherapeutic agents to the brain and improves tumor control as well as survival. In addition, BBB opening has been shown to activate the innate immune system in animal models of Alzheimer’s disease. Amyloid plaque clearance and promotion of neurogenesis in these studies suggest that MRgFUS-mediated BBB opening may be a new paradigm for neurodegenerative disease treatment in the future. Here, we review the current status of preclinical and clinical trials of MRgFUS-mediated thermal ablation and BBB opening, described their mechanisms of action, and discuss future prospects.
Alzheimer Disease ; Blood-Brain Barrier ; Brain ; Brain Neoplasms ; Essential Tremor ; High-Intensity Focused Ultrasound Ablation ; Immune System ; Magnetic Resonance Imaging ; Microbubbles ; Models, Animal ; Neurodegenerative Diseases ; Neurogenesis ; Parkinson Disease ; Plaque, Amyloid ; Sonication ; Therapeutic Uses ; Transducers ; Ultrasonography ; United States Food and Drug Administration

Spinal cord injury (SCI) causes axonal damage and demyelination, neural cell death, and comprehensive tissue loss, resulting in devastating neurological dysfunction. Neural stem/progenitor cell (NSPCs) transplantation provides therapeutic benefits for neural repair in SCI, and glial cell line-derived neurotrophic factor (GDNF) has been uncovered to have capability of stimulating axonal regeneration and remyelination after SCI. In this study, to evaluate whether GDNF would augment therapeutic effects of NSPCs for SCI, GDNF-encoding or mock adenoviral vector-transduced human NSPCs (GDNF-or Mock-hNSPCs) were transplanted into the injured thoracic spinal cords of rats at 7 days after SCI. Grafted GDNF-hNSPCs showed robust engraftment, long-term survival, an extensive distribution, and increased differentiation into neurons and oligodendroglial cells. Compared with Mock-hNSPC- and vehicle-injected groups, transplantation of GDNF-hNSPCs significantly reduced lesion volume and glial scar formation, promoted neurite outgrowth, axonal regeneration and myelination, increased Schwann cell migration that contributed to the myelin repair, and improved locomotor recovery. In addition, tract tracing demonstrated that transplantation of GDNF-hNSPCs reduced significantly axonal dieback of the dorsal corticospinal tract (dCST), and increased the levels of dCST collaterals, propriospinal neurons (PSNs), and contacts between dCST collaterals and PSNs in the cervical enlargement over that of the controls. Finally grafted GDNF-hNSPCs substantially reversed the increased expression of voltage-gated sodium channels and neuropeptide Y, and elevated expression of GABA in the injured spinal cord, which are involved in the attenuation of neuropathic pain after SCI. These findings suggest that implantation of GDNF-hNSPCs enhances therapeutic efficiency of hNSPCs-based cell therapy for SCI.
Animals ; Axons ; Cell Death ; Cell Movement ; Cell- and Tissue-Based Therapy ; Cicatrix ; Demyelinating Diseases ; gamma-Aminobutyric Acid ; Glial Cell Line-Derived Neurotrophic Factor ; Humans ; Hyperalgesia ; Myelin Sheath ; Neuralgia ; Neurites ; Neuroglia ; Neurons ; Neuropeptide Y ; Paraplegia ; Pyramidal Tracts ; Rats ; Regeneration ; Spinal Cord Injuries ; Spinal Cord ; Therapeutic Uses ; Transplants ; Voltage-Gated Sodium Channels

BACKGROUND AND OBJECTIVES: Most studies in cardiac regeneration have explored bone marrow mesenchymal stem cells (BM-MSC) with variable therapeutic effects. Amniotic fluid MSC (AF-MSC) having extended self-renewal and multi-potent properties may be superior to bone marrow MSC (BM-MSC). However, a comparison of their cardiomyogenic potency has not been studied yet.METHODS: The 5-azacytidine (5-aza) treated AF-MSC and BM-MSC were evaluated for the expression of GATA-4, Nkx2.5 and ISL-1 transcripts and proteins by quantitative RT-PCR and Western blotting, respectively as well as for the expression of cardiomyogenic differentiation markers cardiac troponin-T (cTNT), beta myosin heavy chain (βMHC) and alpha sarcomeric actinin (ASA) by immunocytochemistry.RESULTS: The AF-MSC as compared to BM-MSC had significantly higher expression of GATA-4 (183.06±29.85 vs. 9.80±0.05; p<0.01), Nkx2.5 (8.3±1.4 vs. 1.82±0.32; p<0.05), and ISL-1 (39.59±4.05 vs. 4.36±0.39; p<0.01) genes as well as GATA-4 (2.01±0.5 vs. 0.6±0.1; p<0.05), NKx2.5 (1.9±0.14 vs. 0.8±0.2; p<0.01) and ISL-1 (1.7±0.3 vs. 0.9±0.1; p<0.05) proteins. The AF-MSC also had significantly elevated expression of cTNT (5.0×10⁴±0.6×10⁴ vs. 3.5 ×10⁴±0.8×10⁴; p<0.01), β-MHC (15.7×10⁴±0.9×10⁴ vs. 8.2×10⁴±0.6×10⁴; p<0.01) and ASA (18.6×10⁴±4.9×10⁴ vs. 13.1×10⁴±3.0×10⁴; p<0.05) than BM-MSC.CONCLUSIONS: Our data suggest that AF-MSC have greater cardiomyogenic potency than BM-MSC, and thus may be a better source of MSC for therapeutic applications in cardiac regenerative medicine.
Actinin ; Amniotic Fluid ; Antigens, Differentiation ; Azacitidine ; Blotting, Western ; Bone Marrow ; Female ; Humans ; Immunohistochemistry ; Mesenchymal Stromal Cells ; Regeneration ; Regenerative Medicine ; Therapeutic Uses ; Troponin T ; Ventricular Myosins

BACKGROUND: Beta-carotene (BC) is a carotenoid which exerts anti-cancer effects in several types of cancer, including colorectal cancer. Epigenetic modifications of genes, such as histone deacetylation and DNA hypermethylation, have also been detected in various types of cancer. To understand the molecular mechanism underlying cancer preventive and therapeutic effects of BC, microRNAs (miRNAs), histone acetylation, and global DNA methylation in colon cancer stem cells (CSCs) were investigated.METHODS: HCT116 colon cancer cells positive for expression of CD44 and CD133 were sorted by flow cytometry and used in subsequent experiments. Cell proliferation was examined by the MTT assay and self-renewal capacity was analyzed by the sphere formation assay. The miRNA sequencing array was used to detect miRNAs regulated by BC. Histone acetylation levels were measured by the Western blot analysis. mRNA expression of DNA methyltransferases (DNMTs) was examined by qPCR and global DNA methylation levels were determined by enzyme-linked immunosorbent assay.RESULTS: Treatment of CD44⁺CD133⁺ colon CSCs with BC caused a reduction in both cell proliferation and sphere formation. Analysis of the miRNA sequencing array showed that BC regulated expression of miRNAs associated with histone acetylation. Histone H3 and H4 acetylation levels were elevated by BC treatment. In addition, BC treatment down-regulated DNMT3A mRNA expression and global DNA methylation in colon CSCs.CONCLUSIONS: These results suggest that BC regulates epigenetic modifications for its anti-cancer effects in colon CSCs.
Acetylation ; beta Carotene ; Blotting, Western ; Cell Proliferation ; Colon ; Colonic Neoplasms ; Colorectal Neoplasms ; DNA Methylation ; DNA ; Enzyme-Linked Immunosorbent Assay ; Epigenomics ; Flow Cytometry ; Histones ; Methyltransferases ; MicroRNAs ; RNA, Messenger ; Stem Cells ; Therapeutic Uses

The butanol extract of Asparagus cochinchinensis roots fermented with Weissella cibaria (BAW) effectively prevents inflammation and remodeling of airway in the ovalbumin (OVA)-induced asthma model. To characterize biomarkers that can predict the anti-asthmatic effects induced by BAW treatment, we measured the alteration of endogenous metabolites in the serum of OVA-induced asthma mice after administration of low concentration BAW (BAWLo, 250 mg/kg) and high concentration BAW (BAWHi, 500 mg/kg) using ¹H nuclear magnetic resonance (¹H-NMR) spectral data. The number of immune cells and serum concentration of IgE as well as thickness of the respiratory epithelium and infiltration of inflammatory cells in the airway significantly recovered in the OVA+BAW treated group as compared to the OVA+Vehicle treated group. In the metabolic profile analysis, the pattern recognition showed completely separate clustering of serum analysis parameters between the OVA+Vehicle and OVA+BAW treated groups. Of the total endogenous metabolites, 19 metabolites were upregulated or downregulated in the OVA+Vehicle treated group as compared to the Control treated group. However, only 4 amino acids (alanine, glycine, methionine and tryptophan) were significantly recovered after BAWLo and BAWHi treatment. This study provides the first results pertaining to metabolic changes in the asthma model mice treated with OVA+BAW. Additionally, these findings show that 4 metabolites can be used as one of biomarkers to predict the anti-asthmatic effects.
Amino Acids ; Animals ; Asthma ; Biomarkers ; Fermentation ; Glycine ; Immunoglobulin E ; Inflammation ; Magnetic Resonance Spectroscopy ; Metabolome ; Metabolomics ; Methionine ; Mice ; Ovalbumin ; Respiratory Mucosa ; Therapeutic Uses ; Weissella

BACKGROUND: Management of atopic dermatitis (AD) involves the regular use of emollients together with topical steroids or calcineurin inhibitors for acute flares. However, the long-term use of oral medications in young children may have certain limitations. Wet wrap dressing (WWD) is an interesting alternative therapy for the short-term control of severe or refractory flares, thus avoiding the use of systemic treatments. OBJECTIVE: This study aimed to compare the efficacy between WWD and topical steroid agents and to control and estimate the utility of WWD in pediatric AD. METHODS: A total of 40 patients with mild-to-severe AD (eczema area and severity index of ≥3) aged <13 years were included in this study. Twenty patients were treated with WWD using two layers of cotton bandages or garments (Tubifast™), and the remaining were applied with topical steroid agents without cotton bandages. Improvement in severity of atopic dermatitis was evaluated using the eczema area and severity index (EASI). Improvement in skin barrier dysfunction was evaluated by measuring the transepidermal water loss (TEWL). We compared the two groups after 1 week of treatment using analysis of covariance and t-test. Furthermore, we surveyed the study groups using a questionnaire to estimate the utility of WWD and its adverse effects as well as to evaluate subjective outcomes of WWD. RESULTS: There were significant reductions in the mean EASI (−6.3, 95% confidence interval [CI]: −7.5 to −5.1, p=0.013) and TEWL (−26.7, 95% CI: −31.2 to −22.3, p=0.002) after 1 week of WWD treatment compared with the mean EASI (−4.0, 95% CI: −5.2 to −2.9) and TEWL (−15.4, 95% CI: −19.8 to −10.9) of the control group. Results of patient self-assessment and scores in the visual analogue scale (VAS) for pruritus were improved in both groups, but the differences were not statistically significant. Usefulness of WWD as an alternative therapy for the conventional therapy was satisfactory. CONCLUSION: This study is meaningful in that it estimates both the subjective and objective efficacy of WWD. In view of these findings, WWD showed superior therapeutic effects than conventional steroid application in the treatment of AD in children, with good compliance of patients and parent-caregivers.
Bandages ; Calcineurin Inhibitors ; Child ; Clothing ; Compliance ; Dermatitis, Atopic ; Eczema ; Emollients ; Humans ; Pruritus ; Self-Assessment ; Skin ; Steroids ; Therapeutic Uses ; Water

Rosmarinic acid (RA) is a natural polyphenolic compound that exists in many medicinal species of Boraginaceae and Lamiaceae. The previous studies have revealed that RA had therapeutic effects on hepatocellular carcinoma (HCC) in the H22-xenograft models by inhibiting the inflammatory cytokines and NF-κB p65 pathway in the tumor microenvironment. However, its molecular mechanisms of immunoregulation and pro-apoptotic effect in HCC have not been fully explored. In the present study, RA at 75, 150, and 300 mg/kg was given to H22 tumor-bearing mice via gavage once a day for 10 days. The results showed that RA can effectively inhibit the tumor growth through regulating the ratio of CD4⁺/CD8⁺ and the secretion of interleukin (IL)-2 and interferon-γ, inhibiting the expressions of IL-6, IL-10 and signal transducer and activator of transcription 3, thereby up-regulating Bax and Caspase-3 and down-regulating Bcl-2. The underlying mechanisms involved regulation of immune response and induction of HCC cell apoptosis. These results may provide a more comprehensive perspective to clarify the anti-tumor mechanism of RA in HCC.
Animals ; Apoptosis ; Boraginaceae ; Carcinoma, Hepatocellular ; Caspase 3 ; Cytokines ; Interleukin-10 ; Interleukin-6 ; Interleukins ; Lamiaceae ; Mice ; STAT3 Transcription Factor ; Therapeutic Uses ; Tumor Microenvironment

PURPOSE: The use of platelet-rich plasma (PRP) for the treatment of nonhealing ulcers is a relatively new technique. Although it seems to result in a satisfying level of healing and low complication rates, data regarding its effectiveness remain sparse. This study aims to evaluate the potential therapeutic effects of PRP on chronic nonhealing ulcers. MATERIALS AND METHODS: This was a prospectively designed study comparing outcomes between patients treated with PRP (Group A, n=15) and patients treated conventionally (Group B, n=12) for different types of nonhealing ulcers. In Group A, PRP was produced from the patients’ own peripheral blood samples and was applied on the ulcer once every week. In Group B, patients were treated conventionally, without applying PRP. The total treatment period was 5 weeks. RESULTS: Both groups were similar regarding age, sex, comorbidities, and time of treatment. In Group A, patients showed a nonsignificant reduction of 4.5 mm2 in ulcer area (P=0.190) and a reduction of more than 1 mm in depth (P=0.0006), while Group B showed an increase of 108±80.5 mm2 in ulcer area after 5 weeks (P=0.016). The healing rate (HR) in Group A was stable and positive throughout the treatment period, while HR in Group B was initially negative but became positive after the 3rd week. CONCLUSION: PRP application once a week promotes the healing of chronic ulcers. It improves the ulcer’s depth and HR, although its effect on ulcer area seems to be nonsignificant. However, larger comparative series are still needed to confirm these findings.
Comorbidity ; Humans ; Platelet-Rich Plasma ; Prospective Studies ; Regeneration ; Therapeutic Uses ; Ulcer

PURPOSE: Relaxin (RLX) is a transforming growth factor-β1 (TGF-β1) antagonist that is believed to function as a potent collagen re-arranger and a major suppressor of extracellular matrix components. Adenoviruses (Ads) are accepted vectors for cancer gene therapy. However, repeated treatments of Ad are limited by short-term biological activity in vivo. The efficacy of sustained RLX expression to scar remodeling was assessed using an injectable alginate gel-matrix system. MATERIALS AND METHODS: Pig scar tissue was treated with relaxin-expressing Ad loaded in alginate gel (gel/Ad-RLX). Surface areas, color, and pliability of scars were compared, and various factors influencing scar formation and collagen arrangement were analyzed. RESULTS: Gel/Ad-RLX decreased scar size, color index, and pliability. Immunohistochemistry showed decreased levels of major extracellular matrix proteins in the gel/Ad-RLX-treated group. Furthermore, treatment with gel/Ad-RLX reduced expression of tissue inhibitor of metalloproteinase-1 and alpha-smooth muscle actin and markedly increased expression of matrix metalloproteinase-1 in pig scar tissues. Gel/Ad-RLX also significantly downregulated TGF-β1 and upregulated TGF-β3 mRNAs in pig scar tissues. CONCLUSION: These results support a prominent role for RLX in scar remodeling and suggest that gel/Ad-RLX may have therapeutic effects on scar formation.
Actins ; Adenoviridae ; Cicatrix ; Collagen ; Extracellular Matrix ; Extracellular Matrix Proteins ; Genes, Neoplasm ; Genetic Therapy ; Immunohistochemistry ; Matrix Metalloproteinase 1 ; Pliability ; Relaxin ; RNA, Messenger ; Therapeutic Uses ; Tissue Inhibitor of Metalloproteinase-1