Therapeutic Devices for Motor Symptoms in Parkinson's Disease: Current Progress and a Systematic Review of Recent Randomized Controlled Trials.

Background: Pharmacotherapy is the first-line treatment option for Parkinson's disease, and levodopa is considered the most effective drug for managing motor symptoms. However, side effects such as motor fluctuation and dyskinesia have been associated with levodopa treatment. For these conditions, alternative therapies, including invasive and non-invasive medical devices, may be helpful. This review sheds light on current progress in the development of devices to alleviate motor symptoms in Parkinson's disease. Methods: We first conducted a narrative literature review to obtain an overview of current invasive and non-invasive medical devices and thereafter performed a systematic review of recent randomized controlled trials (RCTs) of these devices. Results: Our review revealed different characteristics of each device and their effectiveness for motor symptoms. Although invasive medical devices are usually highly effective, surgical procedures can be burdensome for patients and have serious side effects. In contrast, non-pharmacological/non-surgical devices have fewer complications. RCTs of non-invasive devices, especially non-invasive brain stimulation and mechanical peripheral stimulation devices, have proven effectiveness on motor symptoms. Nearly no non-invasive devices have yet received Food and Drug Administration certification or a CE mark. Conclusion: Invasive and non-invasive medical devices have unique characteristics, and several RCTs have been conducted for each device. Invasive devices are more effective, while non-invasive devices are less effective and have lower hurdles and risks. It is important to understand the characteristics of each device and capitalize on these.

Involvement of Cathepsins in Innate and Adaptive Immune Responses in Periodontitis.

Periodontitis is an infectious disease whereby the chronic inflammatory process of the periodontium stimulated by bacterial products induces specific host cell responses. The activation of the host cell immune system upregulates the production of inflammatory mediators, comprising cytokines and proteolytic enzymes, which contribute to inflammation and bone destruction. It has been well known that periodontitis is related to systemic inflammation which links to numerous systemic diseases, including diabetes and arteriosclerosis. Furthermore, periodontitis has been reported in association with neurodegenerative diseases such as Alzheimer's disease (AD) in the brain. Regarding immune responses and inflammation, cathepsin B (CatB) plays pivotal role for the induction of IL-1ß, cathepsin K- (CatK-) dependent active toll-like receptor 9 (TLR9) signaling, and cathepsin S (CatS) which involves in regulating both TLR signaling and maturation of the MHC class II complex. Notably, both the production and proteolytic activities of cathepsins are upregulated in chronic inflammatory diseases, including periodontitis. In the present review, we focus on the roles of cathepsins in the innate and adaptive immune responses within periodontitis. We believe that understanding the roles of cathepsins in the immune responses in periodontitis would help to elucidate the therapeutic strategies of periodontitis, thus benefit for reduction of systemic diseases as well as neurodegenerative diseases in the global aging society.

Inhibition of the key metabolic pathways, glycolysis and lipogenesis, of oral cancer by bitter melon extract.

BACKGROUND: Metabolic reprogramming is one of the hallmarks of cancer which favours rapid energy production, biosynthetic capabilities and therapy resistance. In our previous study, we showed bitter melon extract (BME) prevents carcinogen induced mouse oral cancer. RNA sequence analysis from mouse tongue revealed a significant modulation in "Metabolic Process" by altering glycolysis and lipid metabolic pathways in BME fed group as compared to cancer group. In present study, we evaluated the effect of BME on glycolysis and lipid metabolism pathways in human oral cancer cells. METHODS: Cal27 and JHU022 cells were treated with BME. RNA and protein expression were analysed for modulation of glycolytic and lipogenesis genes by quantitative real-time PCR, western blot analyses and immunofluorescence. Lactate and pyruvate level was determined by GC/MS. Extracellular acidification and glycolytic rate were measured using the Seahorse XF analyser. Shotgun lipidomics in Cal27 and JHU022 cell lines following BME treatment was performed by ESI/ MS. ROS was measured by FACS. RESULTS: Treatment with BME on oral cancer cell lines significantly reduced mRNA and protein expression levels of key glycolytic genes SLC2A1 (GLUT-1), PFKP, LDHA, PKM and PDK3. Pyruvate and lactate levels and glycolysis rate were reduced in oral cancer cells following BME treatment. In lipogenesis pathway, we observed a significant reduction of genes involves in fatty acid biogenesis, ACLY, ACC1 and FASN, at the mRNA and protein levels following BME treatment. Further, BME treatment significantly reduced phosphatidylcholine, phosphatidylethanolamine, and plasmenylethanolamine, and reduced iPLA2 activity. Additionally, BME treatment inhibited lipid raft marker flotillin expression and altered its subcellular localization. ER-stress associated CHOP expression and generation of mitochondrial reactive oxygen species were induced by BME, which facilitated apoptosis. CONCLUSION: Our study revealed that bitter melon extract inhibits glycolysis and lipid metabolism and induces ER and oxidative stress-mediated cell death in oral cancer. Thus, BME-mediated metabolic reprogramming of oral cancer cells will have important preventive and therapeutic implications along with conventional therapies.

Pterostilbene, an active component of the dragon's blood extract, acts as an antidepressant in adult rats.

BACKGROUND: Hippocampal neurogenesis has been widely considered as one of the potential biological mechanisms for the treatment of depression caused by chronic stress. Many natural products have been reported to be beneficial for neurogenesis. OBJECTIVES: The present study is designed to investigate the effect of dragon's blood extract (DBE) and its biologically active compound, pterostilbene (PTE), on hippocampal neurogenesis. METHODS: The male Sprague-Dawley (SD) rats were used in this study, which were maintained on the normal, DBE and PTE diet groups for 4 weeks before dissection in the normal rat model and behavioral testing in the CUS depression rat model. Meanwhile, DMI-treated rats are subcutaneously injected with DMI (10 mg/kg, i.p.). RESULTS: Results revealed that DBE and PTE have the ability to promote hippocampal neurogenesis. DBE and PTE also promoted the proliferation of neural stem cells isolated from the brain of suckling rats. Oral administration of DBE and PTE induced the proliferation, migration, and differentiation of neural progenitor cells (NPCs) in chronic unexpected stressed (CUS) model rats, and improved the behavioral ability and alleviated depress-like symptoms of CUS rats. It was also observed that PTE treatment significantly induced the expression of neurogenesis-related factors, including BDNF, pERK, and pCREB. CONCLUSION: Oral administration of PTE could affect neurogenesis and it is likely to be achieved via BDNF/ERK/CREB-associated signaling pathways.

Hyperbaric Oxygen Therapy as Concurrent Treatment with Systemic Steroids for Idiopathic Sudden Sensorineural Hearing Loss: A Comparison of Three Different Steroid Treatments.

We analyzed 356 patients with idiopathic sudden sensorineural hearing loss treated with hyperbaric oxygen therapy and systemic steroids (n = 161), systemic steroids alone (n = 160), or intratympanic and systemic steroids (n = 35). The main outcome measure was the hearing recovery rate. The effect of other variables, including the initial averaged 5-frequency hearing level, patient age, interval between the onset of symptoms and treatment, presence of vertigo as a complication, presence of diabetes mellitus, smoking history, and presence of hypertension, on the hearing recovery rate was also evaluated. The overall hearing recovery rate was significantly higher for the patients treated with hyperbaric oxygen therapy and systemic steroids than for those treated with systemic steroids alone (p < 0.001) or systemic and intratympanic steroids (p < 0.001). The presence of vertigo negatively affected hearing recovery. Our findings suggest that hyperbaric oxygen therapy confers a significant additional therapeutic benefit when used in combination with steroid therapy for idiopathic sudden sensorineural hearing loss.

The Critical Role of IL-10 in the Antineuroinflammatory and Antioxidative Effects of Rheum tanguticum on Activated Microglia.

Rheum tanguticum Maxim. ex Balf. (Rt), a traditional Tibetan medicine, is known to exert various bioactivities, including anti-inflammatory and antioxidative activities. The present study was conducted to investigate anti-inflammatory and antioxidative effects of Rt on activated microglia. Rt (10 µg/ml) significantly inhibited the mean protein level of interleukin-1ß (IL-1ß) in the organotypic hippocampal slice cultures following treatment with chromogranin A (CGA, 10 nM) and pancreastatin (10 nM), endogenous microglial activators present in senile plaques. Rt also significantly inhibited the expression and production of inflammatory and oxidative molecules, including IL-1ß, tumor necrosis factor-α, and nitric oxide, by cultured microglia after treatment with CGA. These effects of Rt are considered to be mediated by the secretion of interleukin-10 (IL-10) from microglia, because neutralizing antibodies against IL-10 significantly canceled these effects. To explore the causative components of Rt responsible for inducing the secretion of IL-10, the effects of seven components of Rt on the IL-10 expression in microglia were examined. Among them, aloe-emodin (10 µM) and (+)-catechin (30 µM) were able to induce the secretion of IL-10 from cultured microglia. Therefore, aloe-emodin and (+)-catechin are deemed responsible for the antineuroinflammatory and antioxidative effects of Rt through the secretion of IL-10 from microglia. Accordingly, Rt is considered potentially useful for the treatment of AD.

Brazilian Green Propolis Prevents Cognitive Decline into Mild Cognitive Impairment in Elderly People Living at High Altitude.

BACKGROUND: Systemic inflammation is known as a risk factor of cognitive decline. OBJECTIVE: To investigate the effects of propolis on cognitive decline and systemic inflammation in elderly people living at high altitude. METHODS: Sixty participants (average 72.8 years) living at altitude (2,260 meters) were randomized to receive propolis (0.83 g, n = 30) or placebo (n = 30) for 24 months. Cognitive outcomes were assessed using MMSE and serum cytokine levels were measured for 24 months in a double-blind study. RESULTS: MMSE scores were 26.17 at baseline and 23.87 at 24 months in placebo group. Compared to placebo group, improvements of MMSE scores were significant in propolis-treated subjects (p = 0.007) with a response emerging over time (time points×group interaction, p = 0.016). In addition, the serum IL-1ß and IL-6 levels were significantly different across treatments (p < 0.0001) showing upward and downward trends in placebo- and propolis-treated subjects, respectively (p < 0.0001). Serum levels of TNF-α were not significantly different across treatment (p = 0.0528) but with a response emerging over time (time points×group interaction, p = 0.016). In contrast, serum levels of TGFß1 were significantly different across treatments (p < 0.0001) showing downward and upward trends in placebo- and propolis-treated subjects, respectively. Serum levels of IL-10 were significant for the effect of groups (p = 0.0411). Furthermore, MMSE scores correlated with the decrease in IL-1ß and the increase in TGFß1 in serum. CONCLUSION: Elderly people living at high altitude developed to MCI in 24 months with exacerbation of systemic inflammation. Ingestion of propolis (>12 months) protected against cognitive decline after systemic inflammation was reduced.

Boi-ogi-to (TJ-20), a Kampo Formula, Suppresses the Inflammatory Bone Destruction and the Expression of Cytokines in the Synovia of Ankle Joints of Adjuvant Arthritic Rats.

TJ-20 is a formula consisting of 6 herbs that has been used in the clinical treatment of rheumatoid arthritis (RA) in China and Japan for centuries. However, scientific evidence of the effects of TJ-20 has not been established. In the present study, we focused on the therapeutic effects and investigated the main function of TJ-20 on adjuvant arthritis (AA), an animal model of RA, which was induced with complete Freund's adjuvant (CFA). TJ-20 was administered orally at 600 mg/kg once a day from 0, 7, and 10 days to 8 weeks after the CFA treatment. TJ-20 significantly ameliorated inflammatory progression and bone destruction in AA in a time-dependent manner. Furthermore, TJ-20 significantly reduced the increased changes in a number of macrophages and helper T cells. Moreover, TJ-20 suppressed the expression of TNF-α whereas it augmented the expression of IL-10 and attenuated Th1 cells responses in the synovia of the ankle joint. Therefore, TJ-20 regulated the expression of proinflammatory and anti-inflammatory cytokines in macrophages and Th1/Th2 balance in the synovia of ankle joints in AA rats. These results suggest the positive anti-inflammatory effect of TJ-20 and provide a scientific basis for the clinical use of TJ-20 for RA.

Overexpression of Cathepsin E Interferes with Neuronal Differentiation of P19 Embryonal Teratocarcinoma Cells by Degradation of N-cadherin.

Cathepsin E (CatE), an aspartic protease, has a limited distribution in certain cell types such as gastric cells. CatE is not detectable in the normal brain, whereas it is increasingly expressed in damaged neurons and activated microglia of the pathological brain. Neurons expressing high levels of CatE showed apparent morphological changes, including a marked shrinkage of the cytoplasmic region and beading of neurites, suggesting neuronal damage. The intracellular level of CatE in neurons is strictly regulated at both transcriptional and translational levels. Although the up-regulation of CatE may cause pathological changes in neurons, little information is available about the precise outcome of the increased expression of CatE in neurons. In this study, we have attempted to clarify the outcome of up-regulated CatE gene expression in neurons using the P19 cell neuronal differentiation after the overexpression of CatE. We unexpectedly found that the overexpression of CatE interfered with neuronal differentiation of P19 cells through an impairment of cell aggregate formation. Pepstatin A, an aspartic protease inhibitor, restored the impaired cell aggregation of P19/CatE cells. The small number of P19 cells differentiated into neurons had abnormal morphology characterized by their fusiform cell bodies with short processes. Furthermore, CatE proteolytically cleaved the extracellular domain of N-cadherin. These observations suggest that the overexpression of CatE interferes with neuronal differentiation of P19 cells through an impairment of cell aggregate formation, possibly through proteolytic degradation of N-cadherin.

The Neuroprotective Effects of Ratanasampil on Oxidative Stress-Mediated Neuronal Damage in Human Neuronal SH-SY5Y Cells.

We previously found that Ratanasampil (RNSP), a traditional Tibetan medicine, improves the cognitive function of mild-to-moderate AD patients living at high altitude, as well as learning and memory in an AD mouse model (Tg2576); however, mechanism underlying the effects of RNSP is unknown. In the present study, we investigated the effects and molecular mechanisms of RNSP on oxidative stress-induced neuronal toxicity using human neuroblastoma SH-SY5Y cells. Pretreatment with RNSP significantly ameliorated the hydrogen peroxide- (H2O2-) induced cytotoxicity of SH-SY5Y cells in a dose-dependent manner (up to 60 µg/mL). Furthermore, RNSP significantly reduced the H2O2-induced upregulation of 8-oxo-2'-deoxyguanosine (8-oxo-dG, the oxidative DNA damage marker) but significantly reversed the expression of repressor element-1 silencing transcription factor (REST) from H2O2 associated (100 µM) downregulation. Moreover, RNSP significantly attenuated the H2O2-induced phosphorylation of p38 mitogen-activated protein kinase (MAPK) and extracellular signal-regulated kinase 1/2 (ERK 1/2) in SH-SY5Y cells. These observations strongly suggest that RNSP may protect the oxidative stress-induced neuronal damage that occurs through the properties of various antioxidants and inhibit the activation of MAPKs. We thus provide the principle molecular mechanisms of the effects of RNSP and indicate its role in the prevention and clinical management of AD.

Microglial cathepsin B contributes to the initiation of peripheral inflammation-induced chronic pain.

Interleukin (IL)-1ß and IL-18 play critical roles in the induction of chronic pain hypersensitivity. Their inactive forms are activated by caspase-1. However, little is known about the mechanism underlying the activation of pro-caspase-1. There is increasing evidence that cathepsin B (CatB), a typical lysosomal cysteine protease, is involved in the pro-caspase-1 activation and the subsequent maturation of IL-1ß and IL-18. In this context, CatB is considered to be an important molecular target to control chronic pain. However, no information is currently available about the role of CatB in chronic pain hypersensitivity. We herein show that CatB deficiency or the intrathecal administration of CA-074Me, a specific CatB inhibitor, significantly inhibited the induction of complete Freund's adjuvant-induced tactile allodynia in mice without affecting peripheral inflammation. In contrast, CatB deficiency did not affect the nerve injury-induced tactile allodynia. Furthermore, CatB deficiency or CA-074Me treatment significantly inhibited the maturation and secretion of IL-1ß and IL-18 by cultured microglia following treatment with the neuroactive glycoprotein chromogranin A (CGA), but not with ATP. Moreover, the IL-1ß expression in spinal microglia and the induction of tactile allodynia following the intrathecal administration of CGA depended on CatB, whereas those induced by the intrathecal administration of ATP or lysophosphatidic acid were CatB independent. These results strongly suggest that CatB is an essential enzyme for the induction of chronic inflammatory pain through its activation of pro-caspase-1, which subsequently induces the maturation and secretion of IL-1ß and IL-18 by spinal microglia. Therefore, CatB-specific inhibitors may represent a useful new strategy for treating inflammation-associated pain.

Nitrogen monoxide adsorption on Pt4 clusters coated on gamma-Al2O3 (111) surface.

The nitrogen monoxide (NO) adsorption on platinum tetramer (Pt4) clusters supported on gamma alumina (gamma-Al2O3) with surface index (111) was investigated by using ab-initio calculation based on density functional theory. The Pt4 geometries used in this study are tetrahedron and planar rhombus. The adsorption of Pt4 on gamma-Al2O3 (111) surface in tetrahedron configuration is energetically more favorable as compared to that of the planar rhombus. However, it was found that NO molecule adheres strongly to Pt4 with planar configuration on gamma-Al2O3(111) surface. In addition, the NO adsorption calculation on the isolated Pt4 clusters also shows similar preference to planar configuration. The local density of states (LDOS) reveals that the difference in reactivity comes from the different hybridization strengths between the electronic states of nitrogen atom and those of platinum tetramers. The results are in good agreement with the experiments which show similar tendency for CO and N2O reactivity to gas-phase platinum clusters.

Phosphatidylserine-containing liposomes suppress inflammatory bone loss by ameliorating the cytokine imbalance provoked by infiltrated macrophages.

Phosphatidylserine (PS)-containing liposomes (PSLs) strongly inhibit inflammatory bone loss in adjuvant arthritic (AA) rats. This effect was attributed to the inhibition of osteoclastogenesis through the secretion of prostaglandin E(2) and transforming growth factor-ß1 by osteoclast precursors after the phagocytosis of PSLs. However, infiltrated macrophages are considered to secrete anti-inflammatory mediators after phagocytosis of PSLs, which also contribute to inhibiting osteoclastogenesis. In the present study, we have attempted to elucidate the effects of PSLs on the phenotype of infiltrated macrophages during inflammatory bone loss. In AA rats, the ankle joints swelled with the infiltration of both macrophages and helper T cells into the synovium after a complete Freund's adjuvant injection. In the ankle joints of AA rats, approximately half of the infiltrated macrophages underwent a phenotypic change from interleukin (IL)-1ß-producing to IL-10-producing cells after the phagocytosis of PSLs. In lipopolysaccharide (LPS)-stimulated macrophages, PSLs also significantly decreased IL-1ß production, but increased IL-10 production. Moreover, PSLs inhibited the rapid activation of p38 mitogen-activated protein kinases (MAPK) and nuclear factor (NF)-κB, but enhanced the delayed activation of extracellular signal-regulated kinase (ERK) in LPS-stimulated macrophages. PSL-induced different influence on the activities of p38 MAPK and ERK is a likely underlying mechanism for phenotypic change of infiltrated macrophages after the phagocytosis of PSLs. This phenotypic change may be responsible for a significant decrease in the mean mRNA level of the receptor activator of NF-κB (RANK) and the RANK ligand (RANKL) in the ankle joint of PSL-treated AA rats, resulting in the inhibition of inflammatory bone loss.

Phosphatidylserine-containing liposomes inhibit the differentiation of osteoclasts and trabecular bone loss.

Liposomes containing phosphatidylserine (PS) are engulfed by phagocytes including macrophages, microglia, and dendritic cells. PS liposomes (PSLs) mimic the effects of apoptotic cells on these phagocytes to induce the secretion of anti-inflammatory molecules and to inhibit the maturation of dendritic cells. However, the effects of PSLs on osteoclasts, which are also differentiated from the common myeloid precursors, remain to be determined. This study investigated the effects of PSLs on the osteoclastogenesis. In the rat bone marrow culture system, osteoclast precursors phagocytosed PSLs to secrete TGF-beta1 and PGE(2), which in turn inhibited osteoclastogenesis through the downregulation of receptor activator for NF-kappaB ligand, receptor activator of NF-kappaB, ICAM-1, and CD44. Consistent with these in vitro observations, i.m. injection of PSLs significantly increased the plasma level of TGF-beta1 and PGE(2) and decreased the expression of receptor activator for NF-kappaB ligand, receptor activator of NF-kappaB, and ICAM-1 in the skeletal tissues of ankle joints of rats with adjuvant arthritis (AA). A quantitative analysis using microcomputed tomography revealed that PSLs as well as TGF-beta1 together with PGE(2) significantly inhibited AA-induced trabecular bone loss. These observations strongly suggest that PSLs generate TGF-beta1 and PGE(2) release, leading to inhibit osteoclastogenesis and AA-induced trabecular bone loss. Because PS is a component of the cell membrane, PSLs therefore can be a potentially effective pharmacological intervention against abnormal bone loss, such as osteoporosis without deleterious side effects.

Age-dependent responses of glial cells and leptomeninges during systemic inflammation.

Systemic inflammation causes the age-dependent differential glial responses, but little is known about how age influences the barrier function of leptomeninges during systemic inflammation. This study was conducted to elucidate the relationship between the glial responses and the levels of tight junction proteins, occludin and ZO-1, in adjuvant arthritis (AA) rats. In young AA rats, microglia and astrocytes localized to the proximity of the leptomeninges expressed interleukin (IL)-10 and transforming growth factor (TGF)-beta1. The level of occludin significantly increased. In middle-aged AA rats, however, glial cells expressed IL-1beta and prostaglandin E(2) (PGE(2))-synthesizing enzymes. Furthermore, occludin and ZO-1 significantly decreased, resulting in the increased permeability of leptomeninges. In the cultured leptomeningeal cells, IL-1beta and PGE(2) caused a marked loss of occludin and ZO-1, respectively. Pretreatment with IL-10 and TGF-beta1 significantly antagonized their effects. These findings establish that age strongly influences the barrier functions of the leptomeninges through the age-dependent differential glial responses during systemic inflammation.

Leptomeningeal cells activate microglia and astrocytes to induce IL-10 production by releasing pro-inflammatory cytokines during systemic inflammation.

The leptomeninges covering the surface of the brain parenchyma play the physical role at the cerebrospinal fluid-blood barrier. We report here that leptomeningeal cells may transduce peripheral proinflammatory signals to the central anti-inflammatory response through the activation of glial cells in the brain parenchyma. After adjuvant injection, both microglia and astrocytes in the cerebral cortex localized in the proximity of the leptomeninges were activated. The protein levels of tumor necrosis factor-alpha (TNF-alpha) and interleukin-10 (IL-10) in the cortical extracts were significantly increased at different time after adjuvant injection. The TNF-alpha immunoreactivity was most prominent in the leptomeninges covering astrocytes. On the other hand, the IL-10 immunoreactivity was observed in both activated microglia and astrocytes localized along the leptomeninges. Cultured leptomeningeal cells covering the cerebral cortex released TNF-alpha which was significantly increased by lipopolysaccharide (LPS). Upon stimulation with LPS, cultured leptomeningeal cells also secreted interleukin-1beta and interleukin-6 with differential time-courses. When primary cultured rat astrocytes and microglia were treated with the conditioned medium of LPS-activated cultured leptomeningeal cells, the immunoreactivity of IL-10 was markedly increased. These observations strongly suggest that leptomeningeal cells release pro-inflammatory cytokines to activate both microglia and astrocytes during systemic inflammation. The activated astrocytes and microglia may in turn regulate anti-inflammatory response in the brain by providing IL-10.