Effects of transcranial direct current stimulation alone and in combination with rehabilitation therapies on gait and balance among individuals with Parkinson's disease: a systematic review and meta-analysis.

BACKGROUND: Parkinson's disease (PD) is a neurogenerative disorder implicated in dysfunctions of motor functions, particularly gait and balance. Transcranial direct current stimulation (tDCS) is a noninvasive brain stimulation offered as a potential adjuvant therapy for PD. This systematic review and meta-analysis were conducted to identify whether tDCS alone and combined with additional rehabilitation therapies improve gait and balance among individuals with PD. METHODS: We searched PubMed, Embase, Web of Science, and relevant databases for eligible studies from inception to December 2022. Studies with a comparative design investigating the effects of tDCS on motor functions, including gait and balance among individuals with PD, were included. A meta-analysis was performed for each outcome using a random effects model for subgroup analysis and pooling of overall effect sizes. RESULTS: A total of 23 studies were included in the meta-analysis. The pooled results revealed that tDCS has moderate overall effects on gait, measured by gait speed (standardized mean deviation [SMD] = 0.238; 95% confidence interval [CI] - 0.026 to 0.502); stride length (SMD = 0.318; 95% CI - 0.015 to 0.652); cadence (SMD = - 0.632; 95% CI - 0.932 to - 0.333); freezing of gait questionnaire scores (SMD = - 0.360; 95% CI - 0.692 to - 0.027); step length (SMD = 0.459; 95% CI - 0.031 to 0.949); walking time (SMD = - 0.253; 95% CI - 0.758 to 0.252); stride time (SMD = - 0.785; 95% CI: - 1.680 to 0.111); double support time (SMD = 1.139; 95% CI - 0.244 to 0.523); and balance, measured by timed up and go (TUG) test (SMD = - 0.294; 95% CI - 0.516 to - 0.073), Berg balance scale (BBS) scores (SMD = 0.406; 95% CI - 0.059 to 0.87), and dynamic gait index (SMD = 0.275; 95% CI - 0.349 to 0.898). For the subgroup analysis, gait and balance demonstrated moderate effect sizes. However, only cadence, stride time, and TUG indicated a significant difference between real and sham tDCS (P = 0.027, P = 0.002, and P = 0.023, respectively), whereas cadence and BBS (P < 0.01 and P = 0.045, respectively) significantly differed after real tDCS plus other therapies rather than after sham tDCS plus other therapies. CONCLUSIONS: Our results indicated that tDCS is significantly associated with gait and balance improvements among individuals with PD. The findings of this study provide more proof supporting the effectiveness of tDCS, encouraging tDCS to be utilized alone or in combination with other therapies in clinical practice for PD rehabilitation.

Laser-light cueing shoes with integrated foot pressure and inertial sensing for investigating the impact of visual cueing on gait characteristics in Parkinson's disease individuals.

Gait disorders are a fundamental challenge in Parkinson's disease (PD). The use of laser-light visual cues emitted from shoes has demonstrated effective in improving freezing of gait within less restrictive environments. However, the effectiveness of shoes-based laser-light cueing may vary among individuals with PD who have different types of impairments. We introduced an innovative laser-light visual shoes system capable of producing alternating visual cues for the left and right feet through one-side cueing at a time, while simultaneously recording foot inertial data and foot pressures. The effects of this visual cueing system on gait patterns were assessed in individuals with PD, both those with well-gait and those with worse-gait. Our device successfully quantified gait characteristics, including the asymmetry in the center of pressure trajectory, in individuals with PD. Furthermore, visual cueing prolonged stride times and increased the percentage of stance phase, while concurrently reducing stride length in PD individuals with well-gait. Conversely, in PD individuals with worse-gait, visual cueing resulted in a decreased freeze index and a reduction in the proportion of intervals prone to freezing episodes. The effects of visual cueing varied between PD individuals with well-gait and those with worse-gait. Visual cueing slowed down gait in the well-gait group while it appeared to mitigate freezing episodes in worse-gait group. Future researches, including enhancements to extend the projection distance of visual cues and clinical assessments conducted in real-world settings, will help establish the clinical utility of our proposed visual cueing system.

Myoelectric, Myo-Oxygenation, and Myotonometry Changes during Robot-Assisted Bilateral Arm Exercises with Varying Resistances.

Robot-assisted bilateral arm training has demonstrated its effectiveness in improving motor function in individuals post-stroke, showing significant enhancements with increased repetitions. However, prolonged training sessions may lead to both mental and muscle fatigue. We conducted two types of robot-assisted bimanual wrist exercises on 16 healthy adults, separated by one week: long-duration, low-resistance workouts and short-duration, high-resistance exercises. Various measures, including surface electromyograms, near-infrared spectroscopy, heart rate, and the Borg Rating of Perceived Exertion scale, were employed to assess fatigue levels and the impacts of exercise intensity. High-resistance exercise resulted in a more pronounced decline in electromyogram median frequency and recruited a greater amount of hemoglobin, indicating increased muscle fatigue and a higher metabolic demand to cope with the intensified workload. Additionally, high-resistance exercise led to increased sympathetic activation and a greater sense of exertion. Conversely, engaging in low-resistance exercises proved beneficial for reducing post-exercise muscle stiffness and enhancing muscle elasticity. Choosing a low-resistance setting for robot-assisted wrist movements offers advantages by alleviating mental and physiological loads. The reduced training intensity can be further optimized by enabling extended exercise periods while maintaining an approximate dosage compared to high-resistance exercises.

Laser-light Visual Cueing Shoes with Foot Pressures and Inertial Sensing for Individuals with Parkinson's Disease.

Gait disorder is a core problem in individuals with Parkinson's disease (PD), including bradykinesia, shuffling steps, festinating gait, and freeze of gait (FOG). Laser-light visual cueing has been demonstrated to be efficient in the mediation of gaits and the reduction in number of FOG episodes. However, previous approaches commonly adopted independent controls of visual cueing on left and right sides which was prone to produce two cues while individual was not in normal walking. In this study, we developed laser-light visual shoes which produced interlaced visual cues for left and right feet in a manner of one-side cueing at a time, solving the aforementioned problem. With parallel measurement of foot inertial data and foot pressures in each shoe, our results showed that the proposed visual cueing made PD individuals in the on-medication condition walk with a longer stance and swing times, that is, they walked more carefully and stable. The proposed approach can also be used to study kinematic and kinetic characteristics of gaits in the off-medication condition to clarify the mediation of visual cueing on motor control of PD individuals.Clinical Relevance- This demonstrates the effect of laser-light visual cueing on gaits in individuals with Parkinson's disease.

Event-related brain potentials reveal enhancing and compensatory mechanisms during dual neurocognitive and cycling tasks.

BACKGROUND: Various neurocognitive tests have shown that cycling enhances cognitive performance compared to resting. Event-related potentials (ERPs) elicited by an oddball or flanker task have clarified the impact of dual-task cycling on perception and attention. In this study, we investigate the effect of cycling on cognitive recruitment during tasks that involve not only stimulus identification but also semantic processing and memory retention. METHODS: We recruited 24 healthy young adults (12 males, 12 females; mean age = 22.71, SD = 1.97 years) to perform three neurocognitive tasks (namely color-word matching, arithmetic calculation, and spatial working memory) at rest and while cycling, employing a within-subject design with rest/cycling counterbalancing. RESULTS: The reaction time on the spatial working memory task was faster while cycling than at rest at a level approaching statistical significance. The commission error percentage on the color-word matching task was significantly lower at rest than while cycling. Dual-task cycling while responding to neurocognitive tests elicited the following results: (a) a greater ERP P1 amplitude, delayed P3a latency, less negative N4, and less positivity in the late slow wave (LSW) during color-word matching; (b) a greater P1 amplitude during memory encoding and smaller posterior negativity during memory retention on the spatial working memory task; and (c) a smaller P3 amplitude, followed by a more negative N4 and less LSW positivity during arithmetic calculation. CONCLUSION: The encoding of color-word and spatial information while cycling may have resulted in compensatory visual processing and attention allocation to cope with the additional cycling task load. The dual-task cycling and cognitive performance reduced the demands of semantic processing for color-word matching and the cognitive load associated with temporarily suspending spatial information. While dual-tasking may have required enhanced semantic processing to initiate mental arithmetic, a compensatory decrement was noted during arithmetic calculation. These significant neurocognitive findings demonstrate the effect of cycling on semantic-demand and memory retention-demand tasks.

CRISPR editing demonstrates rs10490924 raised oxidative stress in iPSC-derived retinal cells from patients with ARMS2/HTRA1-related AMD.

Genome-wide association studies (GWAS) have identified genetic risk loci for age-related macular degeneration (AMD) on the chromosome 10q26 (Chr10) locus and are tightly linked: the A69S (G>T) rs10490924 single-nucleotide variant (SNV) and the AATAA-rich insertion-deletion (indel, del443/ins54), which are found in the age-related maculopathy susceptibility 2 (ARMS2) gene, and the G512A (G>A) rs11200638 SNV, which is found in the high-temperature requirement A serine peptidase 1 (HTRA1) promoter. The fourth variant is Y402H complement factor H (CFH), which directs CFH signaling. CRISPR manipulation of retinal pigment epithelium (RPE) cells may allow one to isolate the effects of the individual SNV and thus identify SNV-specific effects on cell phenotype. Clustered regularly interspaced short palindromic repeats (CRISPR) editing demonstrates that rs10490924 raised oxidative stress in induced pluripotent stem cell (iPSC)-derived retinal cells from patients with AMD. Sodium phenylbutyrate preferentially reverses the cell death caused by ARMS2 rs10490924 but not HTRA1 rs11200638. This study serves as a proof of concept for the use of patient-specific iPSCs for functional annotation of tightly linked GWAS to study the etiology of a late-onset disease phenotype. More importantly, we demonstrate that antioxidant administration may be useful for reducing reactive oxidative stress in AMD, a prevalent late-onset neurodegenerative disorder.

The Executive-Function-Related Cognitive-Motor Dual Task Walking Performance and Task Prioritizing Effect on People with Parkinson's Disease.

To safely walk in a community environment requires dual cognitive-walking ambulation ability for people with Parkinson's disease (PD). A past study showed inconsistent results on cognitive-walking performance for PD patients, possibly due to the various cognitive tasks used and task priority assignment. This study designed cognitive-walking tests that used executive-related cognitive tasks to evaluate patients with early-stage Parkinson's disease who did not have obvious cognitive deficits. The effect of assigning task prioritization was also evaluated. Sixteen individuals with PD (PD group) and 16 individuals without PD (control group) underwent single cognitive tests, single walking tests, dual walking tests, and prioritizing task tests. Three types of cognitive, spatial memory, Stroops, and calculation tasks were employed. The cognitive performance was evaluated by response time, accuracy, and speed-accuracy trade off composite score. The walking performance was evaluated by the temporal spatial gait characteristics and variation in gait. The results showed that the walking performance of the PD group was significantly worse than the control group in both single and dual walking conditions. The group difference in cognitive performance was shown in composite score under the dual calculation walking task but not under the single task. While assigning priority to walking, no group difference in walking was observed but the response accuracy rate of PD groups declined. This study concluded that the dual task walking test could sharpen the cognitive deficits for early-stage PD patients. The task priority assignment might not be recommended while testing gait deficits since it decreased the ability to discriminate group differences.

HIF2α activation and mitochondrial deficit due to iron chelation cause retinal atrophy.

Iron accumulation causes cell death and disrupts tissue functions, which necessitates chelation therapy to reduce iron overload. However, clinical utilization of deferoxamine (DFO), an iron chelator, has been documented to give rise to systemic adverse effects, including ocular toxicity. This study provided the pathogenic and molecular basis for DFO-related retinopathy and identified retinal pigment epithelium (RPE) as the target tissue in DFO-related retinopathy. Our modeling demonstrated the susceptibility of RPE to DFO compared with the neuroretina. Intriguingly, we established upregulation of hypoxia inducible factor (HIF) 2α and mitochondrial deficit as the most prominent pathogenesis underlying the RPE atrophy. Moreover, suppressing hyperactivity of HIF2α and preserving mitochondrial dysfunction by α-ketoglutarate (AKG) protects the RPE against lesions both in vitro and in vivo. This supported our observation that AKG supplementation alleviates visual impairment in a patient undergoing DFO-chelation therapy. Overall, our study established a significant role of iron deficiency in initiating DFO-related RPE atrophy. Inhibiting HIF2α and rescuing mitochondrial function by AKG protect RPE cells and can potentially ameliorate patients' visual function.

Deep Neural Network for the Detections of Fall and Physical Activities Using Foot Pressures and Inertial Sensing.

Fall detection and physical activity (PA) classification are important health maintenance issues for the elderly and people with mobility dysfunctions. The literature review showed that most studies concerning fall detection and PA classification addressed these issues individually, and many were based on inertial sensing from the trunk and upper extremities. While shoes are common footwear in daily off-bed activities, most of the aforementioned studies did not focus much on shoe-based measurements. In this paper, we propose a novel footwear approach to detect falls and classify various types of PAs based on a convolutional neural network and recurrent neural network hybrid. The footwear-based detections using deep-learning technology were demonstrated to be efficient based on the data collected from 32 participants, each performing simulated falls and various types of PAs: fall detection with inertial measures had a higher F1-score than detection using foot pressures; the detections of dynamic PAs (jump, jog, walks) had higher F1-scores while using inertial measures, whereas the detections of static PAs (sit, stand) had higher F1-scores while using foot pressures; the combination of foot pressures and inertial measures was most efficient in detecting fall, static, and dynamic PAs.

CRISPR Manipulations in Stem Cell Lines.

Insights into genome engineering in cells have allowed researchers to cultivate and modify cells as organoids that display structural and phenotypic features of human diseases or normal health status. The generation of targeted mutants is a crucial step toward studying the biomedical effect of genes of interest. Modified organoids derived from patients' tissue cells are used as models to study diseases and test novel drugs. CRISPR-Cas9 technology has contributed to an explosion of advances that have the ability to edit genomes for the study of monogenic diseases and cancers. The generation of such mutants in human induced pluripotent stem cells (iPSCs) is of utmost importance as these cells carry the potential to be differentiated into any cell lineage. We describe recent developments that are broadening our understanding and extend DNA specificity, product selectivity, and fundamental capabilities. Furthermore, fundamental capabilities and remarkable advancements in basic research, biotechnology, and therapeutics development in cell engineering are detailed within this chapter. Using the CRISPR/Cas9 nuclease system for induction of targeted double-strand breaks, gene editing of target loci in iPSCs can be achieved with high efficiency. This chapter includes detailed protocols for the preparation of reagents to target loci of interest and transfection to genotype single cell-derived iPSC clones. Furthermore, we provide a protocol for the convenient generation of ribonucleoprotein (RNP) delivered directly to cells.

Metabolite Extraction from RPE Cells and Retinas Related to Retinitis Pigmentosa.

The application of metabolomics in ophthalmology helps to identify new biomarkers and elucidate disease mechanisms in different eye diseases, as well as aiding in the development of potential treatment options. Extracting metabolites successfully is essential for potential further analysis using mass spectrometry. In this chapter, we describe how to extract metabolites from a variety of sources including (1) cells on a dish, (2) cell culture medium, and (3) tissues in vivo with and without stable isotope tracers. Samples prepared using this protocol are suitable for a range of downstream mass spectrometry analyses and are stable in solvent for weeks at -80 °C.

CRISPR-Mediated Genome Engineering in Cell Lines.

A specific targeting nuclease is a powerful tool for mediating genome alternative expression with high precision. The RNA sequence-guided Cas9 nuclease from the microbial clustered regularly interspaced short palindromic repeats (CRISPR) adaptive immune system can be used to facilitate genome engineering in cells by using a 20-nt targeting sequence. In this chapter, we describe a set of tools for Cas9-mediated genome editing via non-homologous end joining (NHEJ) or homology-directed repair (HDR) in the generation of modified cell lines for downstream functional studies. This protocol provides experimentally derived guidelines for the selection of target sites, evaluation of cleavage efficiency, and analysis of off-target activity. Beginning with target design, we will cover gene modifications and modified clonal cell lines.

Effects of robotic priming of bilateral arm training, mirror therapy, and impairment-oriented training on sensorimotor and daily functions in patients with chronic stroke: study protocol of a single-blind, randomized controlled trial.

BACKGROUND: Combining robotic therapy (RT) with task-oriented therapy is an emerging strategy to facilitate motor relearning in stroke rehabilitation. This study protocol will compare novel rehabilitation regimens that use bilateral RT as a priming technique to augment two task-oriented therapies: mirror therapy (MT) and bilateral arm training (BAT) with a control intervention: RT combined with impairment-oriented training (IOT). METHODS: This single-blind, randomized, comparative efficacy study will involve 96 participants with chronic stroke. Participants will be randomized into bilateral RT+MT, bilateral RT+BAT, and bilateral RT+IOT groups and receive 18 intervention sessions (90 min/day, 3 d/week for 6 weeks). The outcomes will include the Fugl-Meyer Assessment, Stroke Impact Scale version 3.0, Medical Research Council scale, Revised Nottingham Sensory Assessment, ABILHAND Questionnaire, and accelerometer and will be assessed at baseline, after treatment, and at the 3-month follow-up. Analysis of covariance and the chi-square automatic interaction detector method will be used to examine the comparative efficacy and predictors of outcome, respectively, after bilateral RT+MT, bilateral RT+BAT, and bilateral RT+IOT. DISCUSSION: The findings are expected to contribute to the research and development of robotic devices, to update the evidence-based protocols in postacute stroke care programs, and to investigate the use of accelerometers for monitoring activity level in real-life situations, which may in turn promote home-based practice by the patients and their caregivers. Directions for further studies and empirical implications for clinical practice will be further discussed in upper-extremity rehabilitation after stroke. TRIAL REGISTRATION: This trial was registered December 12, 2018, at www. CLINICALTRIALS: gov ( NCT03773653 ).

Effects of Lower Limb Cycling Training on Different Components of Force and Fatigue in Individuals With Parkinson's Disease.

The strength of lower extremity is important for individuals to maintain balance and ambulation functions. The previous studies showed that individuals with Parkinson's disease suffered from fatigue and strength loss of central origin. The purpose of this study was to investigate the effect of lower extremities' cycling training on different components of force and fatigue in individuals with Parkinson's disease. Twenty-four individuals (13 males, 11 females, mean age: 60.58 ± 8.21 years) diagnosed with idiopathic Parkinson's disease were randomized into training and control groups. The maximum voluntary contraction (MVC) force, voluntary activation level (VA), and twitch force of knee extensors were measured using a custom-made system with surface electrical stimulation. The general, central, and peripheral fatigue indexes (GFI, CFI, and PFI) were calculated after a fatiguing cycling protocol. Subjects received 8 weeks of low resistance cycling training (training group) or self-stretching (control group) programs. Results showed that MVC, VA, and twitch force improved (p < 0.05) only in the training group. Compared to the baseline, central fatigue significantly improved in the training group, whereas peripheral fatigue showed no significant difference in two groups. The cycling training was beneficial for individuals with Parkinson's disease not only in muscle strengthening but also in central fatigue alleviation. Further in-depth investigation is required to confirm the effect of training and its mechanism on central fatigue.

Long-term vitamin A supplementation in a preclinical mouse model for RhoD190N-associated retinitis pigmentosa.

Retinitis pigmentosa (RP) is caused by one of many possible gene mutations. The National Institutes of Health recommends high daily doses of vitamin A palmitate for RP patients. There is a critical knowledge gap surrounding the therapeutic applicability of vitamin A to patients with the different subtypes of the disease. Here, we present a case report of a patient with RP caused by a p.D190N mutation in Rhodopsin (RHO) associated with abnormally high quantitative autofluorescence values after long-term vitamin A supplementation. We investigated the effects of vitamin A treatment strategy on RP caused by the p.D190N mutation in RHO by exposing Rhodopsin p.D190N (RhoD190N/+) and wild-type (WT) mice to experimental vitamin A-supplemented and standard control diets. The patient's case suggests that the vitamin A treatment strategy should be further studied to determine its effect on RP caused by p.D190N mutation in RHO and other mutations. Our mouse experiments revealed that RhoD190N/+ mice on the vitamin A diet exhibited higher levels of autofluorescence and lipofuscin metabolites compared to WT mice on the same diet and isogenic controls on the standard control diet. Vitamin A supplementation diminished photoreceptor function in RhoD190N/+ mice while preserving cone response in WT mice. Our findings highlight the importance of more investigations into the efficacy of clinical treatments like vitamin A for patients with certain genetic subtypes of disease and of genotyping in the precision care of inherited retinal degenerations.

Effects of ankle continuous passive motion on soleus hypertonia in individuals with cerebral palsy: A case series.

BACKGROUND: Continuous passive motion device (CPM) provides repetitive movement over extended periods of time for those who have low functional ability. The purpose of this research was to evaluate the effects of a four-week program of continuous passive motion of the ankle joint on the changes in soleus hypertonia in individuals with cerebral palsy who suffered from life-long hypertonia. METHODS: A single group, repeated-measures study was conducted. Eight individuals (7 males and 1 female with a mean age of 21.8 ± 8.5 years) with spastic cerebral palsy underwent bilateral ankle CPM for 1 h a day, 5 days a week, for 4 weeks. The outcome measures included the Modified Ashworth Scale (MAS) score, passive range of motion (PROM) of the ankle, the ratio of maximum H reflex to maximum soleus M-response (H/M ratio), and post-activation depression (PAD). All outcomes were measured before and after the intervention. A paired t-test was used to examine treatment effects pre-versus post-intervention. RESULTS: Paired t-tests showed that the CPM program significantly decreased the MAS score (p = 0.006), decreased the maximum H/M ratio (p=0.001), improved PAD (p = 0.003, p = 0.040, and p = 0.032 at 0.2 Hz, 1 Hz, and 2 Hz, respectively), and increased the passive ankle range of motion (p = 0.049). CONCLUSION: Ankle CPM not only reduced soleus hypertonia but also improved the PROM in individuals with cerebral palsy. The results of this study show ankle CPM to be an effective intervention for individuals with cerebral palsy.

The Effect and Dose-Response of Functional Electrical Stimulation Cycling Training on Spasticity in Individuals With Spinal Cord Injury: A Systematic Review With Meta-Analysis.

Background: To investigate the effect and dose-response of functional electrical stimulation cycling (FES-cycling) training on spasticity in the individuals with spinal cord injury (SCI). Method: Five electronic databases [PubMed, Scopus, Medline (Proquest), Embase, and Cochrane Central Register of Controlled Trials (CENTRAL)] were searched before September 2021. The human trials and studies of English language were only included. Two authors independently reviewed and extracted the searched studies. The primary outcome measure was spasticity assessed by Modified Ashworth Scale or Ashworth Scale for lower limbs. The secondary outcome measures were walking abilities, such as 6 Min Walk Test (6MWT), Timed Up and Go (TUG), and lower limbs muscle strength (LEMS). A subgroup analysis was performed to investigate the efficacious threshold number of training sessions. A meta-regression analysis was used to examine the linear relationship between the training sessions and the effect on spasticity. Results: A total of 764 studies were identified. After screening, 12 selected studies were used for the qualitative synthesis, in which eight of them were quantitatively analyzed. Eight studies included ninety-nine subjects in total with SCI (male: female = 83:16). The time since injury was from less than 4 weeks to 17 years. The age ranged from 20 to 67 years. American Spinal Injury Association (ASIA) impairment level of the number of participants was 59 for ASIA A, 11 for ASIA B, 18 for ASIA C, and 11 for ASIA D. There were 43 subjects with tetraplegia and 56 subjects with paraplegia. Spasticity decreased significantly (95% CI = - 1.538 to - 0.182, p = 0.013) in favor of FES-cycling training. The walking ability and LEMS also improved significantly in favor of FES-cycling training. The subgroup analysis showed that spasticity decreased significantly only in more than 20 training sessions (95% CI = - 1.749 to - 0.149, p = 0.020). The meta-regression analysis showed training sessions and spasticity were not significantly associated (coefficient = - 0.0025, SE = 0.0129, p = 0.849, R 2 analog = 0.37). Conclusion: Functional electrical stimulation-cycling training can improve spasticity, walking ability, and the strength of the lower limbs in the individuals with SCI. The number of training sessions is not linearly related to the decrease of spasticity. Twenty sessions of FES-cycling training are required to obtain the efficacy to decrease spasticity.

Mulberry Leaf Polyphenol Extract and Rutin Induces Autophagy Regulated by p53 in Human Hepatoma HepG2 Cells.

The edible leaves of the mulberry (Morus alba L.) plant are used worldwide. They contain abundant polyphenolic compounds with strong anticancer properties. We previously revealed that apoptosis was mediated in p53-negative Hep3B cells, and mulberry leaf polyphenol extract (MLPE) induced autophagy in p53-transfected Hep3B cells. However, how this autophagy is induced by p53 in human hepatoma HepG2 (p53 wild type) cells remains unclear. In the current study, MLPE induced autophagy, as demonstrated by enhanced acidic vesicular organelle staining, by upregulating beclin-1, increasing LC3-II conversion, and phosphorylating AMPK. In HepG2 cells, these processes were associated with p53. Western blot also revealed phosphatidylinositol-3 kinase (PI3K), p-AKT, and fatty acid synthase (FASN) suppression in MLPE-treated cells. Moreover, treatment with the p53 inhibitor pifithrin-α (PFT-α) inhibited autophagy and increased apoptotic response in MLPE-treated HepG2 cells. PFT-α treatment also reversed MLPE-induced PI3K, p-AKT, and FASN suppression. Thus, co-treatment with MLPE and PFT-α significantly increased caspase-3, caspase-8, and cytochrome c release, indicating that p53 deficiency caused the apoptosis. In addition, rutin, a bioactive polyphenol in MLPE, may affect autophagy in HepG2 cells. This study demonstrates that MLPE is a potential anticancer agent targeting autophagy and apoptosis in cells with p53 status. Moreover, this work provides insight into the mechanism of p53 action in MLPE-induced cytotoxicity in hepatocellular carcinoma.

Therapeutic perspectives of extracellular vesicles and extracellular microRNAs in atherosclerosis.

Extracellular signaling molecules, such as growth factors, cytokines, and hormones, regulate cell behaviors and fate through endocrine, paracrine, and autocrine actions and play essential roles in maintaining tissue homeostasis. MicroRNAs, an important class of posttranscriptional modulators, could stably present in extracellular space and body fluids and participate in intercellular communication in health and diseases. Indeed, recent studies demonstrated that microRNAs could be secreted through vesicular and non-vesicular routes, transported in body fluids, and then transmitted to recipient cells to regulate target gene expression and signaling events. Over the past decade, a great deal of effort has been made to investigate the functional roles of extracellular vesicles and extracellular microRNAs in pathological conditions. Emerging evidence suggests that altered levels of extracellular vesicles and extracellular microRNAs in body fluids, as part of the cellular responses to atherogenic factors, are associated with the development of atherosclerosis. This review article provides a brief overview of extracellular vesicles and perspectives of their applications as therapeutic tools for cardiovascular pathologies. In addition, we highlight the role of extracellular microRNAs in atherogenesis and offer a summary of circulating microRNAs in liquid biopsies associated with atherosclerosis.

A Comparative Efficacy Study of Robotic Priming of Bilateral Approach in Stroke Rehabilitation.

Background: Stroke survivors can remain impaired in body functions, activity, and participation. A novel rehabilitation regimen is required to obtain scientific evidence and to help clinicians determine effective interventions for stroke. Mirror therapy (MT) and bilateral upper limb training (BULT) are based on the tenet of bilateral movement practice; however, the additional effect of bilateral robotic priming combined with these two therapies is unclear. Objectives: This study examined the effects of two hybrid therapies, robotic priming combined with MT and robotic priming combined with BULT, in stroke survivors. Methodology: The study randomized 31 participants to groups that received robotic priming combined with MT (n = 15) or robotic priming combined with BULT (n = 16). Outcome measures included the Fugl-Meyer Assessment (FMA), the revised Nottingham Sensory Assessment (rNSA), the Chedoke Arm and Hand Activity Inventory (CAHAI), and accelerometer data. Results: Both groups showed statistically significant within-group improvements in most outcome measures. Significant between-group differences and medium-to-large effect sizes were found in favor of the group that received robotic priming combined with MT based on the FMA distal part subscale scores, FMA total scores, and accelerometer data. Conclusion: Robotic priming combined with MT may have beneficial effects for patients in the improvements of overall and distal arm motor impairment as well as affected arm use in real life. Additional follow-up, a larger sample size, and consideration of the effect of lesion location or different levels of cognitive impairment are warranted to validate our findings in future studies. Clinical trial registration: www.ClinicalTrials.gov, identifier NCT03773653.