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Neuroinflammation, the result of microglial activation, is associated with the pathogenesis of a wide range of psychiatric and neurological disorders. Recently, chlorpromazine (CPZ), a dopaminergic D2 receptor antagonist and schizophrenia therapy, was proposed to exert antiinflammatory effects in the central nervous system. Here, we report that the expression of Kv1.3 channel, which is abundant in T cells, is upregulated in microglia upon infection, and that CPZ specifically inhibits these channels to reduce neuroinflammation. In the mouse medial prefrontal cortex, we show that CPZ lessens Kv1.3 channel activity and reduces proinflammatory cytokine production. In mice treated with LPS, we found that CPZ was capable of alleviating both neuroinflammation and depression-like behavior. Our findings suggest that CPZ acts as a microglial Kv1.3 channel inhibitor and neuroinflammation modulator, thereby exerting therapeutic effects in neuroinflammatory psychiatric/neurological disorders., (© 2024 The Author(s). GLIA published by Wiley Periodicals LLC.)

Purpose: Posterior elongation of the physiological terminal sulcus (TS) due to lateral femoral condyle impaction fracture (LFC-IF) after an anterior cruciate ligament (ACL) tear could potentially decrease the weight-bearing area of the tibiofemoral joint, decrease the tension on lateral meniscus and cause flattening of the LFC which would influence rotational knee motion and cause anisometry of the lateral and anterolateral stabilizers. Therefore, the purpose of the study was to assess if the LFC-IF elongates the physiological TS posteriorly., Methods: One hundred patients magnetic resonance images (MRIs) (75 males, 25 females, mean age 32.2 years, SD = 8.2) were included with a 1:1 ratio between the full-thickness ACL tear group and the control group (patients with knee MRI performed due to other reasons, with no tear of ACL on MRI and negative clinical tests). Two independent raters evaluated the sagittal T1-weighted preselected MRI scans. The principal measurement of interest was the distance from the intersection of the Blumensaat line with subchondral bone to the posterior border of the TS/LFC-IF., Results: The median distance from the Blumensaat line to the posterior border of the TS/LFC-IF was significantly higher in the ACL tear group: 14.3 mm, interquartile range (IQR) = 11.6-16.4 mm versus control group: 12.8 mm, IQR = 9.0-15.0 mm, p = 0.038. Intrarater and inter-rater reliabilities were >0.90., Conclusion: LFC-IF after full-thickness ACL tear significantly elongates the physiological TS in the posterior direction., Level of Evidence: Level III., (© 2024 European Society of Sports Traumatology, Knee Surgery and Arthroscopy.)

Background: The average glycated hemoglobin (HbA1c) may not accurately reflect glycemic control status during the mid-term after acute myocardial infarction (AMI). We aimed to evaluate changes in HbA1c and their effect on mid-term clinical outcomes in patients with diabetes and AMI., Methods: We enrolled patients with diabetes ( n  = 967) who underwent HbA1c measurement in the Korean nationwide registry. These patients were categorized into three groups based on changes in HbA1c from index admission to the 1-year follow-up visit: a decrease in HbA1c > 1%, changes in HbA1c within 1%, and an increase in HbA1c > 1%. Clinical outcomes at 24 months were examined., Results: The baseline HbA1c levels were 8.55 ± 0.85, 7.00 ± 0.98 and 7.07 ± 1.05 ( P  = 0.001) and HbA1c levels after 1 year were 6.62 ± 0.73, 7.05 ± 0.98 and 9.26 ± 1.59 ( P  = 0.001) for patients with 3 groups, respectively. Patients with a 1% decrease in HbA1c had significantly lower incidence of major adverse cardiovascular events (MACE), cardiac death, and rehospitalization after 24 months than those with a 1% increase in HbA1c. However, in the Cox regression analysis, a >1% decrease in HbA1c change was not an independent factor for MACE, cardiac death, and rehospitalization., Conclusions: Our analysis indicates that an HbA1c decrease of >1% within the first 12 months was not an independent prognostic factor until the 24-month mark. Therefore, standard diabetic control is recommended for patients with diabetes and AMI for up to 2 years., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Modern radiotherapeutic techniques, such as intensity-modulated radiation therapy or stereotactic body radiotherapy, require high-dose delivery precision. However, the precise localization of tumors during patient respiration remains a challenge. Therefore, it is essential to investigate effective methods for monitoring respiration to minimize potential complications. Despite several systems currently in clinical use, there are drawbacks, including the complexity of the setup, the discomfort to the patient, and the high cost., Purpose: This study investigated the feasibility of using a novel pressure sensor array (PSA) as a tool to monitor respiration during radiotherapy treatments. The PSA was positioned between the treatment couch and the back of the patient lying on it and was intended to overcome some limitations of current methods. The main objectives included assessing the PSA's capability in monitoring respiratory behavior and to investigate prospective applications that extend beyond respiratory monitoring., Methods: A PSA with 31 pressure-sensing elements was used in 12 volunteers. The participants were instructed to breathe naturally while lying on a couch without any audio or visual guidance. The performance of the PSA was compared to that of a camera-based respiratory monitoring system (RPM, Varian, USA), which served as a reference. Several metrics, including pressure distribution, weight sensitivity, and correlations between PSA and RPM signals, were analyzed. The PSA's capacity to provide information on potential applications related to patient stability was also investigated., Results: The linear relationship between the weight applied to the PSA and its output was demonstrated in this study, confirming its sensitivity to pressure changes. A comparison of PSA and RPM curves revealed a high correlation coefficient of 0.9391 on average, indicating consistent respiratory cycles. The PSA also effectively measured the weight distribution at the volunteer's back in real-time, which allows for monitoring the patient's movements during the radiotherapy., Conclusion: PSA is a promising candidate for effective respiratory monitoring during radiotherapy treatments. Its performance is comparable to the established RPM system, and its additional capabilities suggest its multifaceted utility. This paper shows the potential use of PSA for patient monitoring in radiotherapy and suggests possibilities for further research, including performance comparisons with other existing systems and real-patient applications with respiratory training., (© 2024 The Author(s). Medical Physics published by Wiley Periodicals LLC on behalf of American Association of Physicists in Medicine.)

Background and Objectives: Accumulating evidence shows that sodium-glucose cotransporter 2 inhibitors (SGLT2is) reduce adverse cardiovascular outcomes. However, whether SGLT2i, compared with other antidiabetic drugs, reduce the new development of atrial fibrillation (AF) is unclear. In this study, we compared SGLT2i with dipeptidyl peptidase-4 inhibitors (DPP-4is) in terms of reduction in the risk of AF in individuals with type 2 diabetes., Methods: We included 42,786 propensity score-matched pairs of SGLT2i and DPP-4i users without previous AF diagnosis using the Korean National Health Insurance Service database between May 1, 2016, and December 31, 2018., Results: During a median follow-up of 1.3 years, SGLT2i users had a lower incidence of AF than DPP-4i users (1.95 vs. 2.65 per 1,000 person-years; hazard ratio [HR], 0.73; 95% confidence interval [CI], 0.55-0.97; p=0.028]). In individuals without heart failure, SGLT2i users was associated with a decreased risk of AF incidence (HR, 0.70; 95% CI, 0.52-0.94; p=0.019) compared to DPP-4i users. However, individuals with heart failure, SGLT2i users was not significantly associated with a change in risk (HR, 1.04; 95% CI, 0.44-2.44; p=0.936)., Conclusions: In this nationwide cohort study of individuals with type 2 diabetes, treatment with SGLT2i was associated with a lower risk of AF compared with treatment with DPP-4i., Competing Interests: The authors have no financial conflicts of interest., (Copyright © 2024. The Korean Society of Cardiology.)

Background: Midcheek lift has been performed for cosmetic or reconstructive surgery of the lower eyelid. For midcheek lift through the subciliary incision, preperiosteal and subperiosteal dissections are the most often implemented, with good clinical outcomes. However, a comparative assessment of the effects of these 2 methods had not been conducted., Objectives: In this study we compared the effects of midcheek lift according to preperiosteal or subperiosteal plane and range of midfacial dissection., Methods: Forty hemifaces of 20 fresh cadavers were dissected. One side of the hemiface underwent preperiosteal dissection, and the other side underwent subperiosteal dissection. After dissections of 5, 10, 15, 20, and 30 mm and all of the midcheek area from the inferior orbital rim, the length of the elevated lid-cheek junction was measured by placing upward traction on the lateral portion of the lower lid., Results: In both methods, the length of the midcheek lift increased as the dissection progressed, and the length of the lift on the lateral side was greater than that on the medial side. The length of the pulled skin in the preperiosteal group was the greatest in most cases. However, in the full dissection cases, the midcheek lift length was not statistically different between the 2 surgical methods, especially on the lateral side., Conclusions: Flap elevation in lower blepharoplasty surgery can be predicted based on the surgical method and dissection range. Implementing a surgical plan that takes this into account can enhance both reconstruction and aesthetic surgery outcomes in the midcheek area., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Aesthetic Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Age-dependent accumulation of amyloid plaques in patients with sporadic Alzheimer's disease (AD) is associated with reduced amyloid clearance. Older microglia have a reduced ability to phagocytose amyloid, so phagocytosis of amyloid plaques by microglia could be regulated to prevent amyloid accumulation. Furthermore, considering the aging-related disruption of cell cycle machinery in old microglia, we hypothesize that regulating their cell cycle could rejuvenate them and enhance their ability to promote more efficient amyloid clearance. First, we used gene ontology analysis of microglia from young and old mice to identify differential expression of cyclin-dependent kinase inhibitor 2A (p16 ink4a ), a cell cycle factor related to aging. We found that p16 ink4a expression was increased in microglia near amyloid plaques in brain tissue from patients with AD and 5XFAD mice, a model of AD. In BV2 microglia, small interfering RNA (siRNA)-mediated p16ink4a downregulation transformed microglia with enhanced amyloid phagocytic capacity through regulated the cell cycle and increased cell proliferation. To regulate microglial phagocytosis by gene transduction, we used poly (D,L-lactic-co-glycolic acid) (PLGA) nanoparticles, which predominantly target microglia, to deliver the siRNA and to control microglial reactivity. Nanoparticle-based delivery of p16 ink4a siRNA reduced amyloid plaque formation and the number of aged microglia surrounding the plaque and reversed learning deterioration and spatial memory deficits. We propose that downregulation of p16 ink4a in microglia is a promising strategy for the treatment of Alzheimer's disease., (© 2024. The Author(s).)

Leucine-rich repeat kinase 2 (LRRK2) mutations are the most common cause of Parkinson's disease (PD). Interestingly, recent studies have reported an increased risk of stroke in patients with PD harboring LRRK2 mutations, but there is no evidence showing the functional involvement of LRRK2 in stroke. Here, we found that LRRK2 kinase activity was significantly induced in the Rose-Bengal (RB) photothrombosis-induced stroke mouse model. Interestingly, stroke infarct volumes were significantly reduced, and neurological deficits were diminished by pharmacological inhibition of LRRK2 kinase activity using MLi-2, a brain-penetrant LRRK2 kinase inhibitor. Immunohistochemical analysis showed p-LRRK2 level in stroke lesions, co-localizing with mitophagy-related proteins (PINK, Parkin, LC3B, cytochrome c), suggesting their involvement in stroke progression. Overlapping p-LRRK2 with cytochrome c/TUNEL/JC-1 (an indicator of mitochondrial membrane potential) puncta in RB photothrombosis indicated LRRK2-induced mitochondrial apoptosis, which was blocked by MLi-2. These results suggest that pharmacological inhibition of LRRK2 kinase activity could attenuate mitochondrial apoptosis, ultimately leading to neuroprotective potential in stroke progression. In conclusion, LRRK2 kinase activity might be neuro-pathogenic due to impaired mitophagy in stroke progression, and pharmacological inhibition of LRRK2 kinase activity could be beneficial in reducing the risk of stroke in patients with LRRK2 mutations.

Purpose: External snapping hip syndrome (ESHS) was historically attributed to isolated iliotibial band (ITB) contracture. However, the gluteus maximus complex (GMC) may also be involved. This study aimed to intraoperatively identify the ESHS origin and assess the outcomes of endoscopic treatment based on the identified aetiological type., Methods: From 2008-2014, 30 consecutive patients (34 hips) with symptomatic ESHS cases refractory to conservative treatment underwent endoscopic stepwise "fan-like" release, gradually addressing all known reasons of ESHS: from the isolated ITB, through the fascial part of the GMC until a partial release of gluteus maximus femoral attachment occurred. Snapping was assessed intra-operatively after each surgical step and prospectively recorded. Functional outcomes were assessed via the MAHORN Hip Outcome Tool (MHOT-14)., Results: Twenty seven patients (31 hips) were available to follow-up at 24-56 months. In all cases, complete snapping resolution was achieved intra-operatively: in seven cases (22.6%) after isolated ITB release, in 22 cases (70.9%), after release of ITB + fascial part of the GMC, and in two cases (6.5%) after ITB + fascial GMC release + partial release of GM femoral insertion. At follow-up, there were no snapping recurrences and MHOT-14 score significantly increased from a pre-operative average of 46 to 93(p<0.001)., Conclusion: Intraoperative identification and gradual addressing of all known causes of ESHS allows for maximum preservation of surrounding tissue during surgery while precisely targeting the directly involved structures. Endoscopic stepwise "fan-like" release of the ITB and GMC is an effective, tailor-made treatment option for ESHS regardless of the snapping origin in the patients with possibility to manually reproduce the snapping., (© 2023. The Author(s).)

Aims: Heavy alcohol consumption is an established risk factor for atrial fibrillation (AF). However, the association between habitual changes in heavy habitual drinkers and incident AF remains unclear. The aim of this study was to evaluate whether absolute abstinence or reduced drinking decreases incident AF in heavy habitual drinkers., Methods and Results: Atrial fibrillation-free participants with heavy alcohol consumption registered in the Korean National Health Insurance Service database between 2005 and 2008 were enrolled. Habitual changes in alcohol consumption between 2009 and 2012 were classified as sustained heavy drinking, reduced drinking, and absolute abstinence. The primary outcome measure was new-onset AF during the follow-up. To minimize the effect of confounding variables on outcome events, inverse probability of treatment weighting (IPTW) analysis was performed. Overall, 19 425 participants were evaluated. The absolute abstinence group showed a 63% lower incidence of AF (IPTW hazard ratio: 0.379, 95% confidence interval: 0.169-0.853) than did the sustained heavy drinking group. Subgroup analysis identified that abstinence significantly reduced incident AF in participants with normal body mass index and without hypertension, diabetes, dyslipidaemia, heart failure, stroke, chronic kidney disease, or coronary artery disease (all P-value <0.05). There was no statistical difference in incident AF in participants with reduced drinking compared with sustained heavy alcohol group., Conclusion: Absolute abstinence could reduce the incidence of AF in heavy alcohol drinkers. Comprehensive clinical measures and public health policies are warranted to motivate alcohol abstinence in heavy drinkers., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Astrocytes are highly activated following brain injuries, and their activation influences neuronal survival. Additionally, SOX9 expression is known to increase in reactive astrocytes. However, the role of SOX9 in activated astrocytes following ischemic brain damage has not been clearly elucidated yet. Therefore, in the present study, we investigated the role of SOX9 in reactive astrocytes using a poly-lactic- co -glycolic acid (PLGA) nanoparticle plasmid delivery system in a photothrombotic stroke animal model. We designed PLGA nanoparticles to exclusively enhance SOX9 gene expression in glial fibrillary acidic protein (GFAP)-immunoreactive astrocytes. Our observations indicate that PLGA nanoparticles encapsulated with GFAP:SOX9:tdTOM reduce ischemia-induced neurological deficits and infarct volume through the prostaglandin D2 pathway. Thus, the astrocyte-targeting PLGA nanoparticle plasmid delivery system provides a potential opportunity for stroke treatment. Since the only effective treatment currently available is reinstating the blood supply, cell-specific gene therapy using PLGA nanoparticles will open a new therapeutic paradigm for brain injury patients in the future.

Aim: Amitriptyline (AMI) has been used to treat neuropathic pain. However, the clinical outcomes remain unsatisfactory, presumably due to a limited understanding of the underlying molecular mechanisms. Here, we investigated a drug repositioning strategy using a low-dose of AMI encapsulated in poly (D, L lactic-co-glycolic acid) (PLGA) nanoparticles (AMI NPs) for neuropathic pain, since PLGA nanoparticles are known to enhance delivery to microglia. Methods: We evaluated the anti-allodynic effects of AMI and AMI NPs on neuropathic pain by assessing behaviors and inflammatory responses in a rat model of spinal nerve ligation (SNL). While the anti-allodynic effect of AMI (30 μg) drug injection on SNL-induced neuropathic pain persisted for 12 h, AMI NPs significantly alleviated mechanical allodynia for 3 days. Results: Histological and cytokine analyses showed AMI NPs facilitated the reduction of microglial activation and pro-inflammatory mediators in the spinal dorsal horn. This study suggests that AMI NPs can provide a sustained anti-allodynic effect by enhancing the targeting of microglia and regulating the release of pro-inflammatory cytokines from activated microglia. Conclusion: Our findings suggest that the use of microglial-targeted NPs continuously releasing AMI (2 μg) as a drug repositioning strategy offers long-term anti-allodynic effects.

Neuropathic pain is caused by injury or disease of the somatosensory system, and its course is usually chronic. Several studies have been dedicated to investigating neuropathic pain-related targets; however, little attention has been paid to the persistent alterations that these targets, some of which may be crucial to the pathophysiology of neuropathic pain. The present study aimed to identify potential targets that may play a crucial role in neuropathic pain and validate their long-term impact. Through bioinformatics analysis of RNA sequencing results, we identified Slc9a1 and validated the reduced expression of sodium-hydrogen exchanger 1 (NHE1), the protein that Slc9a1 encodes, in the spinal nerve ligation (SNL) model. Colocalization analysis revealed that NHE1 is primarily co-localized with vesicular glutamate transporter 2-positive neurons. In vitro experiments confirmed that poly(lactic-co-glycolic acid) nanoparticles loaded with siRNA successfully inhibited NHE1 in SH-SY5Y cells, lowered intracellular pH, and increased intracellular calcium concentrations. In vivo experiments showed that sustained suppression of spinal NHE1 expression by siRNA-loaded nanoparticles resulted in delayed hyperalgesia in naïve and SNL model rats, whereas amiloride-induced transient suppression of NHE1 expression yielded no significant changes in pain sensitivity. We identified Slc9a1, which encodes NHE1, as a key gene in neuropathic pain. Utilizing the sustained release properties of nanoparticles enabled us to elucidate the chronic role of decreased NHE1 expression, establishing its significance in the mechanisms of neuropathic pain., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Previous studies demonstrated a J-shaped relationship between low diastolic blood pressure (DBP) and adverse clinical outcomes in patients with acute myocardial infarction (AMI) that was sensitive to revascularization. Hypothesized herein, was that this relationship differs between patients with multivessel disease (MVD) and those with single-vessel disease due to differing degrees of myocardial ischemic burden., Methods: Among 9,983 AMI patients from the Korea Acute Myocardial Infarction Registry database who underwent percutaneous coronary intervention and were followed up for a median duration of 3.2 years, average on-treatment DBP was calculated at admission, discharge, and every scheduled visit and divided into these parameters: < 70 mmHg, 70-74 mmHg, 75-79 mmHg, and ≥ 80 mmHg. The relationship between average on-treatment DBP and clinical outcomes including all-cause death, cardiovascular (CV) death, non-CV death, and hospitalization for heart failure was analyzed using the Cox regression models adjusted for clinical covariates., Results: In patients with MVD, all-cause death (hazard ratio [HR]: 1.47; 95% confidence interval [CI]: 1.06-2.04, p = 0.012) and CV death (HR: 1.59; 95% CI: 1.02-2.46, p = 0.027) were significantly increased in patients with a DBP < 70 mmHg, showing a J-shaped relationship. However, these findings were not significant for single-vessel disease. On a sensitivity analysis excluding subjects with a baseline SBP < 120 mmHg, an increased risk of a low DBP < 70 mmHg remained in MVD., Conclusions: The J-shaped relationship between low DBP and adverse clinical outcomes in AMI patients who underwent revascularization persisted in MVD, which has a high ischemic burden. These high-risk patients require cautious treatment.

58-year-old male presented with knee extension contracture (25°) with iatrogenic fixed anterior tibial subluxation. Consecutive arthroscopic arthrolysis, manipulation under anesthesia, and quadriceps-Z-plasty during one surgery failed to restore flexion. Therefore, shortened posterior cruciate ligament was released, which eliminated subluxation and allowed 115° flexion. Despite physiotherapy, flexion progressively decreased to 70° postoperatively. Revision quadricepsplasty by transverse incisions restored 120° of flexion maintained at 31-months follow-up. International Knee Documentation Committee increased 4/87- > 50/87, Knee injury and Osteoarthritis Outcome 7/100- > 68/100 at follow-up. Posterior cruciate ligament release and repeated quadricepsplasty could be a viable salvage option in severe extension contracture with fixed anterior tibial subluxation., (© 2023. The Author(s).)

Knee extension contracture is a common postinjury and postsurgical complication, which decreases knee joint flexion. Many techniques have been described in the literature to restore knee flexion, with the most common one being an arthroscopic lysis of adhesions. However, in severe cases, additional intra- and extra-articular procedures are needed to restore full knee flexion. Manipulation under anesthesia (MUA) is one of them. Unfortunately, it may lead to devastating complications, such as iatrogenic rupture of the patellar tendon or fractures of the patella or tibial tuberosity. Therefore, the purpose of this report is to present a safer modification of MUA for knee extension contracture in cases in which excessive force is demanded to achieve flexion. The key aim of the "patellar base support" technique (PBS technique) is to stretch the contracted quadriceps muscle with controlled and decreased tension on the patella, patellar tendon, and tibial tuberosity., (© 2023 The Authors.)

Arthroscopic visualization and access of the posterior knee are limited when using standard anterior and posterior portals. The creation of a trans-septal portal allows for complete access to the posterior compartment as arthroscopic instruments are able to be passed back and forth between the posteromedial and posterolateral compartments. Due to the close proximity of the popliteal artery and its branches, precise portal placement and safe orientation of arthroscopic instruments are critical to avoid iatrogenic injury. The conventional technique of trans-septal portal creation, involving a posterolateral portal, can be difficult in some cases. To overcome these obstacles, a posteromedial technique of trans-septal portal creation is presented. By using the medial parapatellar portal as the viewing portal, our technique allows for direct visualization of the posterior septum on each step of creation of the trans-septal portal, eliminating the need for "blind" maneuvers. What is more, no posterolateral portal is needed, decreasing the risk of potential complications. Using the posterior cruciate ligament fibers as a main landmark for trans-septal portal placement, preservation of the posterior part of the septum is achieved. This ensures optimal safe-margin distance away from the popliteal neurovascular bundle and making the technique safe and reproducible., (© 2023 The Authors.)

Purpose: To assess if incomplete meniscal healing during second-look arthroscopy at six to eight weeks after all-inside suture hook meniscus repair results in longer-term failure of repair in patients with restored knee stability., Methods: From 2008 to 2013, 41 patients with post-traumatic, longitudinal, vertical, complete meniscal tears with concomitant ACL injury were treated via a two-stage surgical procedure and prospectively evaluated. In the first stage, all-inside meniscus repair was performed using suture hook passers and non-absorbable sutures. In total, there were 26 medial and 16 lateral meniscus tears. A second-stage ACL reconstruction, performed six to eight weeks later, served as an early second-look arthroscopic evaluation of meniscal healing. Clinical follow-up was performed at a minimum of 24 months., Results: Second-look arthroscopy revealed 31 cases (75.6%) of complete and ten cases (24.4%) of incomplete meniscal healing. Two patients were lost prior to follow-up, and three were excluded due to recurrent instability. Therefore, 36 patients were assessed at the final follow-up. All patients with complete meniscal healing during second-look arthroscopy achieved clinical success at follow-up. Six out of nine (66.7%) of patients with incomplete meniscal healing during second-look arthroscopy achieved clinical success at follow-up (p = 0.012). One saphenous neuropathy occurred (2.4%)., Conclusion: Incomplete meniscal healing during early second-look arthroscopy after all-inside meniscal repair using suture hook passers and non-absorbable sutures did not necessarily result in longer-term failure in patients with restored knee stability. The described method of meniscal repair was associated with a low rate of symptomatic re-tears and complications., (© 2023. The Author(s).)

PTEN-induced kinase 1 (PINK1) is a well-known critical marker in the pathway for mitophagy regulation as well as mitochondrial dysfunction. Evidence suggests that mitochondrial dynamics and mitophagy flux play an important role in the development of brain damage from stroke pathogenesis. In this study, we propose a treatment strategy using nanoparticles that can control PINK1. We used a murine photothrombotic ischemic stroke (PTS) model in which clogging of blood vessels is induced with Rose Bengal (RB) to cause brain damage. We targeted PINK1 with poly(lactic-co-glycolic acid) (PLGA)-based nanoparticles loaded with PINK1 siRNA (PINK1 NPs). After characterizing siRNA loading in the nanoparticles, we assessed the efficacy of PINK1 NPs in mice with PTS using immunohistochemistry, 1% 2,3,5-triphenyltetrazolium chloride staining, measurement of motor dysfunction, and Western blot. PINK1 was highly expressed in microglia 24 h after PTS induction. PINK1 siRNA treatment increased phagocytic activity, migration, and expression of an anti-inflammatory state in microglia. In addition, the PLGA nanoparticles were selectively taken up by microglia and specifically regulated PINK1 expression in those cells. Treatment with PINK1 NPs prior to stroke induction reduced expression of mitophagy-inducing factors, infarct volume, and motor dysfunction in mice with photothrombotic ischemia. Experiments with PINK1-knockout mice and microglia depletion with PLX3397 confirmed a decrease in stroke-induced infarct volume and behavioral dysfunction. Application of nanoparticles for PINK1 inhibition attenuates RB-induced photothrombotic ischemic injury by inhibiting microglia responses, suggesting that a nanomedical approach targeting the PINK1 pathway may provide a therapeutic avenue for stroke treatment., (© 2023 Wiley Periodicals LLC.)

Background: Capsular contracture is a critical complication of silicone implantation caused by fibrotic tissue formation from excessive foreign body responses. Various approaches have been applied, but targeting the mechanisms of capsule formation has not been completely solved. Myofibroblast differentiation through the transforming growth factor beta (TGF-β)/p-SMADs signaling is one of the key factors for capsular contracture development. In addition, biofilm formation on implants may result chronic inflammation promoting capsular fibrosis formation with subsequent contraction. To date, there have been no approaches targeting multi-facted mechanisms of capsular contracture development., Methods: In this study, we developed a multi-targeting nitric oxide (NO) releasing bionanomatrix coating to reduce capsular contracture formation by targeting myofibroblast differentiation, inflammatory responses, and infections. First, we characterized the bionanomatrix coating on silicon implants by conducting rheology test, scanning electron microcsopy analysis, nanoindentation analysis, and NO release kinetics evaluation. In addition, differentiated monocyte adhesion and S. epidermidis biofilm formation on bionanomatrix coated silicone implants were evaluated in vitro. Bionanomatrix coated silicone and uncoated silicone groups were subcutaneously implanted into a mouse model for evaluation of capsular contracture development for a month. Fibrosis formation, capsule thickness, TGF-β/SMAD 2/3 signaling cascade, NO production, and inflammatory cytokine production were evaluated using histology, immunofluorescent imaging analysis, and gene and protein expression assays., Results: The bionanomatrix coating maintained a uniform and smooth surface on the silicone even after mechanical stress conditions. In addition, the bionanomatrix coating showed sustained NO release for at least one month and reduction of differentiated monocyte adhesion and S. epidermidis biofilm formation on the silicone implants in vitro. In in vivo implantation studies, the bionanomatrix coated groups demonstrated significant reduction of capsule thickness surrounding the implants. This result was due to a decrease of myofibroblast differentiation and fibrous extracellular matrix production through inhibition of the TGF-β/p-SMADs signaling. Also, the bionanomatrix coated groups reduced gene expression of M1 macrophage markers and promoted M2 macrophage markers which indicated the bionanomatrix could reduce inflammation but promote healing process., Conclusions: In conclusion, the bionanomatrix coating significantly reduced capsular contracture formation and promoted healing process on silicone implants by reducing myfibroblast differentiation, fibrotic tissue formation, and inflammation. A multi-targeting nitric oxide releasing bionanomatrix coating for silicone implant can reduce capsular contracture and improve healing process. The bionanomatrix coating reduces capsule thickness, α-smooth muscle actin and collagen synthesis, and myofibroblast differentiation through inhibition of TGF-β/SMADs signaling cascades in the subcutaneous mouse models for a month., (© 2023. The Author(s).)

Mitochondrial oxidative phosphorylation (OXPHOS) system dysfunction in cancer cells has been exploited as a target for anti-cancer therapeutic intervention. The downregulation of CR6-interacting factor 1 (CRIF1), an essential mito-ribosomal factor, can impair mitochondrial function in various cell types. In this study, we investigated whether CRIF1 deficiency induced by siRNA and siRNA nanoparticles could suppress MCF-7 breast cancer growth and tumor development, respectively. Our results showed that CRIF1 silencing decreased the assembly of mitochondrial OXPHOS complexes I and II, which induced mitochondrial dysfunction, mitochondrial reactive oxygen species (ROS) production, mitochondrial membrane potential depolarization, and excessive mitochondrial fission. CRIF1 inhibition reduced p53-induced glycolysis and apoptosis regulator (TIGAR) expression, as well as NADPH synthesis, leading to additional increases in ROS production. The downregulation of CRIF1 suppressed cell proliferation and inhibited cell migration through the induction of G0/G1 phase cell cycle arrest in MCF-7 breast cancer cells. Similarly, the intratumoral injection of CRIF1 siRNA-encapsulated PLGA nanoparticles inhibited tumor growth, downregulated the assembly of mitochondrial OXPHOS complexes I and II, and induced the expression of cell cycle protein markers (p53, p21, and p16) in MCF-7 xenograft mice. Thus, the inhibition of mitochondrial OXPHOS protein synthesis through CRIF1 deletion destroyed mitochondrial function, leading to elevated ROS levels and inducing antitumor effects in MCF-7 cells.

Background/aim: This study aimed to compare the dosimetric consequences of respiratory movement in volumetric-modulated arc therapy (VMAT) and three-dimensional conformal radiation therapy (3D-CRT) during postmastectomy radiation therapy, including internal mammary nodes (IMNs)., Materials and Methods: Respiratory motion was implemented to a phantom using a dynamic device. The plans were delivered during cranial-caudal and ventral-dorsal movement in 5-mm (R05) and 10-mm (R10) amplitudes., Results: At the IMN, the dose errors were -2.8% (R05) and -6.2% (R10) for 3D-CRT and -4.9% (R05) and -8.5% (R10) for VMAT. The dose errors in chest wall were -.5% (R05) and -6.0% (R10) for 3D-CRT and -1.9% (R05) and -5.3% (R10) for VMAT. The left anterior descending doses showed significantly small absolute values. The gamma pass rates of VMAT were higher than those of 3D-CRT., Conclusions: The benefit of VMAT technique in dose distribution was maintained, except in occasional instances of large breathing motion., (© 2022 John Wiley & Sons Australia, Ltd.)

Vascular insults can create an inflammatory cascade involving endothelial cell, smooth muscle cell, and macrophage activation which can eventually lead to vascular disease such as atherosclerosis. Several studies have identified microRNA 146a's (miR-146a) anti-inflammatory potential based on its role in regulating the nuclear factor kappa beta (NF-κβ) pathway. Therefore, in this study, we introduced exogenous miR-146a encapsulated by liposomes to lipopolysaccharide (LPS) stimulated vascular cells and macrophages to reduce inflammatory responses. First, the miR-146a encapsulated liposomes showed uniform size (radius 96.4 ± 4.22 nm) and round shape, long term stability (at least two months), high encapsulation efficiency (69.73 ± 0.07%), and were well transfected to human aortic endothelial cells (HAECs), human aortic smooth muscle cells (SMCs), and human differentiated monocytes (U937 cells). In addition, we demonstrated that miR-146a encapsulated liposomes reduced vascular inflammation responses in HAECs and SMCs through inhibition of ICAM-1 expression and decreased monocyte adhesion. In macrophages, miR-146a liposome treatment demonstrated decreased production of proinflammatory cytokines, tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β), as well as reduced oxidized low-density lipoprotein (ox-LDL) uptake and foam cell formation. Thus, based on these results, miR-146a encapsulated liposomes may be promising for reducing vascular inflammation by targeting its multiple associated mediators.

Background: The relationship between autophagy and diabetic peripheral neuropathy (DPN) has been highlighted in few reports. Using an animal model, the authors investigated the relationship between autophagy and DPN, focused particularly on changes in autophagy in Schwann cells., Methods: The ultrastructural features of DPN mice were evaluated in vivo using transmission electron microscopy. Dysfunction of autophagy in DPN was evaluated using immunofluorescence microscopy and Western blot analysis of proteins related to autophagy, including Beclin1, LC3, and p62. Reactive oxygen species levels were measured in vitro in glucose-treated Schwann cells. Dysfunction of autophagy in glucose-treated Schwann cells was examined by immunofluorescence microscopy and Western blot analysis., Results: Reduced myelin thickness and axonal shrinkage were observed in the sciatic nerves of DPN mice. Reactive oxygen species levels were increased in Schwann cells treated with high glucose ( P < 0.05). The expression of Beclin1 was increased in DPN mice and Schwann cells treated with high glucose ( P < 0.05), whereas the expression of LC3-II/LC3-I ratio and p62 were decreased in DPN mice and Schwann cells treated with high glucose ( P < 0.05)., Conclusions: These results suggest that increased levels of reactive oxygen species induced by high glucose may contribute to autophagy dysfunction in Schwann cells. Autophagy dysfunction especially in Schwann cells may be an underlying cause of DPN., Clinical Relevance Statement: This study presents the pathological mechanism of diabetic peripheral neuropathy., (Copyright © 2022 by the American Society of Plastic Surgeons.)

Purpose: Accurate knowledge of greater palatine foramen (GPF) and greater palatine canal (GPC) anatomy is necessary to avoid injury to the greater palatine artery (GPA) when performing a variety of anesthesiologic, dental or surgical procedures. The aim of this paper was to perform a systematic review and meta-analysis of literature on the anatomy and localization of bony structures associated with the GPA, namely the GPF and GPC., Methods: A systematic literature search was performed using PubMed, Embase, ScienceDirect, and Web of Science databases. Seventy-five studies were included in the meta-analysis (n = 22,202 subjects)., Results: The meta-analysis showed that the GPF is positioned 17.21 mm (95% CI = 16.34-18.09 mm) from the posterior nasal spine, 2.56 mm (95% CI = 1.90-3.22 mm) from the posterior border of the hard palate, 46.24 mm (95% CI = 44.30-48.18 mm) from the anterior nasal spine, 15.22 mm (95% CI = 15.00-15.43 mm) from the midline maxillary suture, 37.32 mm (95% CI = 36.19-38.45 mm) from the incisive foramen, and opposite the third maxillary molar (M3) in 64.9% (58.7-70.7%) of the total population., Conclusion: An up-to-date, comprehensive analysis of GPF and GPC clinical anatomy is presented. The results from this evidence-based anatomical study provides a unified set of data to aid clinicians in their practice., (© 2023. The Author(s).)

Oxygenated water (OW) contains more oxygen than normal drinking water. It may induce oxygen enrichment in the blood and reduce oxidative stress. Hypoxia and oxidative stress could be involved in epilepsy. We aimed to examine the effects of OW-treated vs. control on four rodent models of epilepsy: (1) prenatal betamethasone priming with postnatal N-methyl-D-aspartate (NMDA)-triggered spasm, (2) no prenatal betamethasone, (3) repetitive kainate injection, and (4) intraperitoneal pilocarpine. We evaluated, in (1) and (2), the latency to onset and the total number of spasms; (3) the number of kainate injections required to induce epileptic seizures; (4) spontaneous recurrent seizures (SRS) (numbers and duration). In model (1), the OW-treated group showed significantly increased latency to onset and a decreased total number of spasms; in (2), OW completely inhibited spasms; in (3), the OW-treated group showed a significantly decreased number of injections required to induce epileptic seizures; and in (4), in the OW-treated group, the duration of a single SRS was significantly reduced. In summary, OW may increase the seizure threshold. Although the underlying mechanism remains unclear, OW may provide an adjunctive alternative for patients with refractory epilepsy.

A type of ultrathin films has been developed for suppressing capsule formation induced by medical silicone implants and hence reducing the inflammation response to such formation and the differentiation to myofibroblasts. The films were each fabricated from hyaluronic acid (HA) and modified β-cyclodextrin (Mod-β-CyD) polymer which was synthesized with a cyclodextrin with partially substituted quaternary amine. Ultrathin films comprising HA and Mod-β-CyD or poly(allylamine hydrochloride) (PAH) were fabricated by using a layer-by-layer dipping method. The electrostatic interactions produced from the functional groups of Mod-β-CyD and HA influenced the surface morphology, wettability, and bio-functional activity of the film. Notably, medical silicone implants coated with PAH/HA and Mod-β-CyD multilayers under a low pH condition exhibited excellent biocompatibility and antibiofilm and anti-inflammation properties. Implantation of these nanoscale film-coated silicones showed a reduced capsular thickness as well as reduced TGFβ-SMAD signaling, myofibroblast differentiation, biofilm formation, and inflammatory response levels. We expect our novel coating system to be considered a strong candidate for use in various medical implant applications in order to decrease implant-induced capsule formation.

Despite similar brachial blood pressure, central hemodynamics could be different. The objective of the present study was to investigate the factors, which could influence the discrepancy between central BP (cBP) and brachial blood pressure. Six hundred forty-seven patients (364 males, 48 ± 12 years old) were enrolled. Using applanation tonometry, cBP was noninvasively derived. The median difference between brachial systolic BP (bSBP) and central systolic BP (cSBP) was 8 mm Hg. We defined the discrepancy between bSBP and cSBP as differences >8 mm Hg. For adjustment of cBP, population was divided into 3 groups according to the cBP: group 1, <140 mm Hg of cSBP; group 2, 140 > cSBP < 160 mm Hg; group 3, =160 mm Hg of cSBP. All the central hemodynamic parameters of the patients, including augmentation pressure, augmentation index (AI), heart rate (75 bpm) adjusted augmentation index (AI@HR75), and subendocardial viability ratio, were measured. Using multivariate logistic regression analysis, we evaluated the factors which could influence the discrepancy between bSBP and cSBP. Age, gender, augmentation pressure, AI, and AI@HR75 were correlated with the discrepancy between bSBP and cSBP. AI@HR75 was significantly correlated with the discrepancy between bSBP and cSBP (β-coefficient = -0.376, P < .001 in group 1; β-coefficient = -0.297, P < .001 in group 2; and β-coefficient = -0.545, P < .001 in group 3). In groups 1 and 2, male gender was significantly correlated with the discrepancy between bSBP and cSBP (β-coefficient = -0.857, P = .035 in group 1; β-coefficient = -1.422, P = .039 in group 2). In present study, arterial stiffness might affect the discrepancy between bSBP and cSBP. Also, male gender was closely related to the discrepancy between bSBP and cSBP especially with cSBP <160 mm Hg. Not only cSBP, the discrepancy between cSBP and bSBP should be considered for understanding the central hemodynamics., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Influenza vaccination reduces cardiovascular events in patients with cardiovascular disease (CVD). Identifying the factors that affect influenza vaccination uptake can help improve the prognosis in patients with CVD. This study aimed to evaluate the secular trends of influenza vaccination uptake and factors associated with lack of vaccination in individuals with CVD., Materials and Methods: We analyzed the annual trends and factors associated with influenza vaccination among 3,264 patients with CVD, included from the Korea National Health and Nutrition Examination Survey which reflect the health and nutritional status of the nationwide population of Korea conducted between 2007/2008 and 2018/2019. We used a stratified, multistage sampling method., Results: The influenza vaccination rate was greater in patients with CVD (53-74%) than in those without CVD (28-40%). Multivariable logistic regression analysis showed that age <50 years [odds ratio (OR), 16.22; 95% confidence interval (CI), 7.72-34.07], 50-64 years (OR, 6.71; 95% CI, 4.37-10.28), male sex (OR, 1.45; 95% CI, 1.14-1.65), and asthma (OR, 0.45; 95% CI, 0.22-0.92) were independently associated with a lack of influenza vaccination. Among patients aged <65 years, smoking (OR, 2.30; 95% CI, 1.31-4.04), college graduation status (OR, 1.81; 95% CI, 1.16-2.82), and hypertension (OR, 0.70; 95% CI, 0.51-0.95) were independently associated with influenza vaccination. For individuals aged 65years, there was no significant determinant of lack of vaccination., Conclusion: In patients with CVD, a continuous increase in the secular trend of influenza vaccination was demonstrated in Korea. Young age, male sex, and non-asthma status were independently associated with lack of influenza vaccination uptake., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Kim, Yang, Gu, Kim, Kim, Oh, Yoon, Bae, Lee, Kim, Choi, Bae, Hwang, Kim, Cho, Lee and Lee.)

Background: This article describes 2 cases of post-coronavirus disease 2019 (COVID-19) transient spontaneous osteonecrosis of the knee (PCT-SONK) observed in patients who had previously recovered from COVID-19 without corticosteroid administration., Objectives: The possible pathomechanisms by which a recent SARS-CoV-2 infection may contribute as a causative factor for osteonecrosis are reviewed, and the differential diagnosis and treatment are discussed., Material and Methods: Two patients (males, 45- and 47-year-old) presented with sudden onset knee pain with no trauma history. The pain persisted during rest and at night. On magnetic resonance imaging (MRI), no subchondral bone thickening was observed; bone edema was diffusely distributed in the whole femoral condyle, in contrast to the more focal edema that is typically concentrated mainly around the subchondral region in classic SONK. Both patients were treated nonoperatively with no weight bearing and pharmacological agents, and complete resolution of symptoms was achieved., Results: A follow-up MRI 10 weeks after presentation revealed a near-complete loss of signal in the medial femoral condyle in both patients., Conclusion: Orthopedic surgeons should be cautious when sudden knee pain without concurrent trauma or a history of injury occurs shortly after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, even with mild COVID-19 illness. While some studies report the development of post-COVID-19 osteonecrosis after lower doses of corticosteroids and sooner after their administration than in comparable non-COVID-19 cases, our study is the first to report 2 cases with no corticosteroid administration at all. Therefore, the authors believe it adds to the body of knowledge on the potential connections between COVID-19 and PCT-SONK. The transient nature of symptoms and radiological findings suggest that aggressive surgical treatment of non-injury local bone edema occurring shortly after SARS-CoV-2 infection should be avoided.

Targeting microglial activation is emerging as a clinically promising drug target for neuropathic pain treatment. Fexofenadine, a histamine receptor 1 antagonist, is a clinical drug for the management of allergic reactions as well as pain and inflammation. However, the effect of fexofenadine on microglial activation and pain behaviors remains elucidated. Here, we investigated nanomedicinal approach that targets more preferentially microglia and long-term analgesics. Fexofenadine significantly abolished histamine-induced microglial activation. The fexofenadine-encapsulated poly(lactic-co-glycolic acid) nanoparticles (Fexo NPs) injection reduced the pain sensitivity of spinal nerve ligation rats in a dose-dependent manner. This alleviation was sustained for 4 days, whereas the effective period by direct fexofenadine injection was 3 h. Moreover, Fexo NPs inhibited microglial activation, inflammatory signaling, cytokine release, and a macrophage phenotype shift towards the alternative activated state in the spinal cord. These results show that Fexo NPs exhibit drug repositioning promise as a long-term treatment modality for neuropathic pain., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2022. Published by Elsevier Inc.)

Purpose: Ischemic stroke is a leading cause of death and disability worldwide. Additionally, neonatal ischemia is a common cause of neonatal brain injury, resulting in cerebral palsy with subsequent learning disabilities and epilepsy. However, there is currently a lack of effective treatments available for patients with perinatal ischemic stroke. In this study, we investigated the effect of perampanel (PER)-loaded poly lactic-co-glycolic acid (PLGA) by targeting microglia in perinatal stroke., Methods: After formation of focal ischemic stroke by photothrombosis in P7 rats, PER-loaded PLGA was injected intrathecally. Proinflammatory markers (TNF-α, IL-1β, IL-6, COX2, and iNOS) and M2 polarization markers (Ym1 and Arg1) were evaluated. We investigated whether PER increased M2 microglial polarization in vitro., Results: PER-loaded PLGA nanoparticles decreased the pro-inflammatory cytokines compared to the control group. Furthermore, they increased M2 polarization., Conclusion: PER-loaded PLGA nanoparticles decreased the size of the infarct and increased motor function in a perinatal ischemic stroke rat model. Pro-inflammatory cytokines were also reduced compared to the control group. Finally, this development of a drug delivery system targeting microglia confirms the potential to develop new therapeutic agents for perinatal ischemic stroke., Competing Interests: The authors report no conflicts of interest in this work., (© 2022 Shin et al.)

This Korean population-based study aimed to describe the patterns of hypothyroidism after adjuvant radiation therapy (RT) in patients with breast cancer. The Korean Health Insurance Review and Assessment Service database was searched for patients with invasive breast carcinomas. We calculated the cumulative incidence and incidence rates per 1,000 person-years of subsequent hypothyroidism and compared them using the log-rank test and the Cox proportional hazards model. Between 2007 and 2018, 117,135 women diagnosed with breast cancer with a median follow-up time of 4.6 years were identified. The 8-year incidence of hypothyroidism was 9.3% in patients treated with radiation and 8.6% in those treated without radiation (p = 0.002). The incidence rates per 1,000 person-years in the corresponding treatment groups were 6.2 and 5.7 cases, respectively. The hazard ratio (HR) in patients receiving RT was 1.081 (95% confidence interval [CI], 1.013-1.134; p = 0.002). After mastectomy, RT showed a trend toward a higher risk of hypothyroidism (HR = 1.248; 95% CI, 0.977-1.595; p = 0.076). Our study provides one of the largest population-based data analyses regarding the risk of hypothyroidism among Korean patients with breast cancer. The adjusted risk for patients treated with RT exceeded that for patients with breast cancer treated without RT. The effect was evident immediately after treatment and lasted up to approximately 9 years., Competing Interests: The authors have declared that no competing interests exist.

In osteoarthritis (OA), chondrocytes in cartilage undergo phenotypic changes and senescence, restricting cartilage regeneration and favoring disease progression. Although senescence biomarker p16INK4a expression is known to induce aging by halting the cell cycle, therapeutic applications for p16INK4a targeting are limited. Here, we aimed to reduce cartilage damage and alleviate pain using p16INK4a nanoparticles in OA. The p16INK4a expression of human OA chondrocytes and synoviocytes from patients with knee OA was measured and the levels of p16INK4a, tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and matrix metalloproteinase (MMP) 13 were examined. p16INK4a siRNA was encapsulated into poly (lactic- co -glycolic acid) (PLGA) nanoparticles and characterized. The partial medial meniscectomy (pMMx) model was performed for the OA model which was investigated by molecular analysis and behavioral tests. The expression of p16INK4a was increased in the synovium and articular cartilage from OA patients. p16INK4a siRNA-loaded PLGA nanoparticles (p16 si&#95;NP) reduced the levels of TNF-α, IL-1β, and IL-6 especially in fibroblast-like synoviocytes (FLSs), and MMP13 in chondrocytes. Rhodamine-tagged NPs injected into the mouse knee joints were found mainly in the synovium. p16 si&#95;NP injection in the pMMx model alleviated pain-associated behavior, and reduced cartilage damage and p16INK4a in the synovium, and MMP13, collagen X, and NITEGE in cartilage. The preferential reduction of p16INK4a in FLSs by the application of RNAi nanomedicine could contribute to the recovery of osteoarthritic cartilage and relieve pain, suggesting that p16INK4a may be a viable future therapeutic candidate.

Background and Purpose: There is a scarcity of information regarding the role of prothrombin kringle-2 (pKr-2), which can be generated by active thrombin, in hippocampal neurodegeneration and Alzheimer's disease (AD)., Experimental Approach: To assess the role of pKr-2 in association with the neurotoxic symptoms of AD, we determined pKr-2 protein levels in post-mortem hippocampal tissues of patients with AD and the hippocampi of five familial AD (5XFAD) mice compared with those of age-matched controls and wild-type (WT) mice, respectively. In addition, we investigated whether the hippocampal neurodegeneration and object memory impairments shown in 5XFAD mice were mediated by changes to pKr-2 up-regulation., Key Results: Our results demonstrated that pKr-2 was up-regulated in the hippocampi of patients with AD and 5XFAD mice, but was not associated with amyloid-β aggregation in 5XFAD mice. The up-regulation of pKr-2 expression was inhibited by preservation of the blood-brain barrier (BBB) via addition of caffeine to their water supply or by treatment with rivaroxaban, an inhibitor of factor Xa that is associated with thrombin production. Moreover, the prevention of up-regulation of pKr-2 expression reduced neurotoxic symptoms, such as hippocampal neurodegeneration and object recognition decline due to neurotoxic inflammatory responses in 5XFAD mice., Conclusion and Implications: We identified a novel pathological mechanism of AD mediated by abnormal accumulation of pKr-2, which functions as an important pathogenic factor in the adult brain via blood brain barrier (BBB) breakdown. Thus, pKr-2 represents a novel target for AD therapeutic strategies and those for related conditions., (© 2021 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Social isolation is common in modern society and is a contributor to depressive disorders. People with depression are highly vulnerable to alcohol use, and abusive alcohol consumption is a well-known obstacle to treating depressive disorders. Using a mouse model involving isolation stress (IS) and/or ethanol intake, we investigated the mutual influence between IS-derived depressive and ethanol-seeking behaviors along with the underlying mechanisms. IS increased ethanol craving, which robustly exacerbated depressive-like behaviors. Ethanol intake activated the mesolimbic dopaminergic system, as evidenced by dopamine/tyrosine hydroxylase double-positive signals in the ventral tegmental area and c-Fos activity in the nucleus accumbens. IS-induced ethanol intake also reduced serotonergic activity, via microglial hyperactivation in raphe nuclei, that was notably attenuated by a microglial inhibitor (minocycline). Our study demonstrated that microglial activation is a key mediator in the vicious cycle between depression and alcohol consumption. We also propose that dopaminergic reward might be involved in this pathogenicity.

Reactive oxygen species (ROS) exacerbate stroke-induced cell damage. We found that ShcA, a protein that regulates ROS, is highly expressed in a Rose Bengal photothrombosis model. We investigated whether ShcA is essential for mitophagy in ROS-induced cellular damage and determined whether ROS exacerbate mitochondrial dysfunction via ShcA protein expression. Ischemic stroke was generated by Rose Bengal photothrombosis in mice. To silence ShcA protein expression in the mouse brain, ShcA-targeting siRNA-encapsulated nanoparticles were intrathecally injected into the cisterna magna. Upon staining with antibodies against ShcA counterpart caspase-3 or NeuN, we found that the ShcA protein expression was increased in apoptotic neurons. In addition, mitochondrial dysfunction and excessive mitophagy were evident in photothrombotic stroke tissue. Infarct volumes were significantly reduced, and neurological deficits were diminished in the ShcA siRNA nanoparticle-treated group, compared with the negative control siRNA nanoparticle-treated group. We confirmed that the reduction of ShcA expression by nanoparticle treatment rescued the expression of genes, associated with mitochondrial dynamics and mitophagy mediation in a stroke model. This study suggests that the regulation of ShcA protein expression can be a therapeutic target for reducing brain damage with mitochondrial dysfunction caused by thrombotic infarction., (© 2020. Springer Science+Business Media, LLC, part of Springer Nature.)

Duloxetine (DLX) is a selective serotonin and noradrenaline reuptake inhibitor (SNRI) used for the treatment of pain, but it has been reported to show side effects in 10-20% of patients. Its analgesic efficacy in central pain is putatively related to its influence on descending inhibitory neuronal pathways. However, DLX can also affect the activation of microglia. This study was performed to investigate whether PLGA nanoparticles (NPs), which are expected to enhance targeting to microglia, can improve the analgesic efficacy and limit the side effects of DLX. PLGA NPs encapsulating a low dose of DLX (DLX NPs) were synthesized and characterized and their localization was determined. The analgesic and anti-inflammatory effects of DLX NPs were evaluated in a spinal nerve ligation (SNL)-induced neuropathic pain model. The analgesic effect of DLX lasted for only a few hours and disappeared within 1 day. However, DLX NPs alleviated mechanical allodynia, and the effect was maintained for 1 week. DLX NPs were localized to the spinal microglia and suppressed microglial activation, phosphorylation of p38/NF-κB-mediated pathways and the production of inflammatory cytokines in the spinal dorsal horn of SNL rats. We demonstrated that DLX NPs can provide a prolonged analgesic effect by enhanced targeting of microglia. Our observations imply that DLX delivery through nanoparticle encapsulation allows drug repositioning with a prolonged analgesic effect, and reduces the potential side effects of abuse and overdose.

At the 2017 St. Gallen International Expert Consensus Conference on the Primary Therapy for Early Breast Cancer, the consensus panel recognized "partial breast irradiation as an option for women meeting the low-risk criteria put forward by the American Society for Radiation Oncology/European Society for Radiotherapy and Oncology (ASTRO/ESTRO) guideline," although acknowledging that there was less evidence for this approach. Partial breast irradiation is defined as irradiation localized to the surgical resection cavity only as opposed to the entire breast. Accelerated partial breast irradiation (APBI) involves intensive treatment in a short time period. The methods vary, and three available APBI options are brachytherapy, external beam and intra-operative irradiation. The long-term follow-up results from two large-scale, well-designed phase III randomized clinical trials have been released. However, further discussion of the optimal treatment candidates and delivery method is needed before the clinical application of APBI as a mainstream breast conservation treatment., (© 2020 John Wiley & Sons Australia, Ltd.)

Non-alcoholic fatty liver disease (NAFLD), including non-alcoholic steatohepatitis (NASH), affects 25% of the global population. Despite the prevalence of NAFLD worldwide, effective therapeutics are currently lacking. Amomum villosum var. xanthioides (Wall. ex Baker) T.L.Wu & S.J.Chen (AX) is a medicinal herb traditionally used for treating digestive tract disorders in countries across Asia. We aimed to examine the pharmacological effects of the ethyl acetate fraction of AX (AXEF) against tunicamycin (TM)-induced ER stress in a NASH mouse model using C57/BL6J male mice. Following TM injections (2 mg/kg), the mice were orally administrated AXEF (12.5, 25, or 50 mg/kg), silymarin (50 mg/kg), or distilled water daily for 5 days, and the outcomes for fatty liver, inflammation, and oxidative stress were measured in serum or liver tissue levels. AXEF drastically attenuated hepatic ER stress-induced NASH as indicated by decreases in lipid droplet accumulations, serum liver enzymes, hepatic inflammations, and cell death signals in the hepatic tissue and/or serum levels. Interestingly, AXEF showed potent antioxidant effects by quenching reactive oxidative stress and its final product lipid peroxide in the hepatic tissue, specifically an increase in metallothionein (MT). To confirm the underlying actions of AXEF, we observed that AXEF increases MT1 gene promoter activities in the physiological levels. Collectively, AXEF showed antioxidant properties on TM-induced ER stress in a NASH mice model through the improvement of MTs.

Polyamidoamine (PAMAM) dendrimers are biocompatible polymers utilized in multiple biomedical applications including tissue engineering, medical diagnosis, drug and gene delivery systems, and biosensors. Normally, high-generation PAMAM dendrimers are advantageous for use in gene therapy research because they have a relatively high transfection efficiency. A high-generation PAMAM dendrimer has a high charge density, which induces greater damage to the membranous organelles than that induced by a low-generation PAMAM dendrimer. In this study, we added NLS sequences derived from the human papillomavirus (HPV) type 11 E2 protein to the low-generation PAMAM generation 2 (PAMAM G2) dendrimer and simultaneously introduced histidine residues to reduce cytotoxicity. RKRARH-PAMAM G2 showed similar and high transfection efficiencies in Neuro-2A and NIH3T3 cell lines and relatively low cytotoxicities relative to that of polyethylenimine 25 kDa (PEI 25 kDa).

Activation of nuclear factor-kappa B (NF-κB) in microglia plays a decisive role in the progress of neuropathic pain, and the inhibitor of kappa B (IκB) is a protein that blocks the activation of NF-κB and is degraded by the inhibitor of NF-κB kinase subunit beta (IKBKB). The role of IKBKB is to break down IκB, which blocks the activity of NF-kB. Therefore, it prevents the activity of NK-kB. This study investigated whether neuropathic pain can be reduced in spinal nerve ligation (SNL) rats by reducing the activity of microglia by delivering IKBKB small interfering RNA (siRNA)-encapsulated poly (lactic- co -glycolic acid) (PLGA) nanoparticles. PLGA nanoparticles, as a carrier for the delivery of IKBKB genes silencer, were used because they have shown potential to enhance microglial targeting. SNL rats were injected with IKBKB siRNA-encapsulated PLGA nanoparticles intrathecally for behavioral tests on pain response. IKBKB siRNA was delivered for suppressing the expression of IKBKB . In rats injected with IKBKB siRNA-encapsulated PLGA nanoparticles, allodynia caused by mechanical stimulation was reduced, and the secretion of pro-inflammatory mediators due to NF-κB was reduced. Delivering IKBKB siRNA through PLGA nanoparticles can effectively control the inflammatory response and is worth studying as a treatment for neuropathic pain.

A synthetic zwitterionic dopamine derivative (ZW-DOPA) containing both catechol and amine groups was recently shown to exhibit excellent antifouling activity on marine surfaces. Here, we have extended these analyses to investigate the effects of ZW-DOPA coating on silicone implants. Successful formation of ZW-DOPA coatings on silicone implants was confirmed based on a combination of decreased static water contact angles on silicone implants, evidence of new peaks at 400.2 (N 1s), 232.2 (S 2s), and 168.0 (S 2p) eV, and increased quantitative atomic composition of C 1s with a concurrent decrease of Si 2p. Anti-biofilm formation assays revealed that ZW-DOPA coating prevented biofilm formation on silicone at a non-lethal concentration (0.5 mg mL-1). Capsule formation was also significantly inhibited by ZW-DOPA coating in vivo and the differentiation of fibroblasts into myofibroblasts was significantly suppressed. Together, these data suggest that silicone implants coated with ZW-DOPA may prevent capsular contracture after insertion when used in breast surgery.

Nuclear factor of activated T cells (NFAT5) is a well-known transcription factor that regulates the expression of genes involved in osmotic stress. However, the role of NFAT5 in inflammatory pain remains unknown. Here, we studied the function of NFAT5 in inflammatory pain using NFAT5-heterozygous (Het) mice. To study inflammatory pain, we injected 10 µL of 2% formalin into the right hind paws of mice and monitored pain behaviors, such as licking, lifting, and flinching, for 60 min. After the first 15 min (phase I), there were no significant differences in pain behaviors between wild-type (WT) and NFAT5-Het mice. However, from 15-60 min (phase II), NFAT5-Het mice displayed significantly fewer pain behaviors compared to WT mice. Further, the expression levels of inflammatory-pain-related factors, including c-Fos, phosphorylated extracellular signal-regulated kinase (p-ERK), and phosphorylated n -methyl-D-aspartate receptor subunit 2B (p-NR2B), were significantly elevated in the spinal dorsal neurons of formalin-treated WT mice but was not elevated in NFAT5-Het mice. Similarly, c-Fos, p-ERK, and p-NR2B levels were significantly higher in glutamate-treated PC12 neuronal cells but were not affected by Nfat5 silencing in glutamate-treated PC12 cells. Altogether, our findings suggest that NFAT5 deficiency may mitigate formalin-induced inflammatory pain by upregulating mammalian target of rapamycin (mTOR) expression and downregulating its downstream factors in spinal dorsal neurons. Therefore, NFAT5 is a potential therapeutic target for the treatment of inflammatory pain.

Background/aims: Coronary endothelial and microvascular function play important roles in cardiovascular disease. We aimed to evaluate the effect of ticagrelor on coronary artery function and tested the antiplatelet effect of low dose ticagrelor in East-Asian patients., Methods: Sixty-one consecutive patients with non-significant coronary disease were included in the study. Initially, patients were randomized in 1:1:1 ratio to receive drugs: ticagrelor 90 mg twice a day (bid; n = 22), ticagrelor 45 mg bid (n = 19) or clopidogrel 75 mg once a day (qd; n = 20) and then divided into two groups (ticagrelor vs clopidogrel) for evaluation of coronary artery function, and three groups for evaluation of antiplatelet function. Endothelial dysfunction was measured by coronary flow reserve (CFR), and changes in the levels of asymmetric dimethylarginine (ADMA), cluster of differentiation (CD) 40 ligand, and P-selectin. Microvascular function was evaluated as index of microvascular resistance (IMR). Platelet reactivity was assessed by VerifyNow P2Y12 assay., Results: The levels of CFR, ADMA, and CD 40 ligand were not different between the two groups. However, P-selectin was lower in the ticagrelor group compared with clopidogrel group. IMR was significantly lower in the ticagrelor group compared with clopidogrel group (median, 15.0 [interquartile range, 12.0 to 21.0] vs. 47.5 [23.0 to 67.5], p = 0.014). There was significant difference in platelet inhibition among the three groups (ticagrelor 90 mg bid vs. ticagrelor 45 mg bid vs. clopidogrel 75 mg qd; 85.57 ± 47.63 vs. 120.33 ± 51.09 vs. 256.42 ± 55.10, p < 0.001)., Conclusion: It is hypothesized that ticagrelor might ameliorate the coronary microvascular function. When compared with clopidogrel, low dose ticagrelor exhibited satisfactory antiplatelet effect in the present study.