Aryl hydrocarbon receptor-targeted therapy for CD4+ T cell-mediated idiopathic pneumonia syndrome in mice.

We previously demonstrated that interferon γ (IFN-γ) derived from donor T cells co-opts the indoleamine 2,3-dioxygenase 1 (IDO1) → aryl hydrocarbon receptor (AHR) axis to suppress idiopathic pneumonia syndrome (IPS). Here we report that the dysregulated expression of AP-1 family genes in Ahr-/- lung epithelial cells exacerbated IPS in allogeneic bone marrow transplantation settings. AHR repressed transcription of Jund by preventing STAT1 from binding to its promoter. As a consequence, decreased interleukin-6 impaired the differentiation of CD4+ T cells toward Th17 cells. IFN-γ- and IDO1-independent induction of Ahr expression indicated that the AHR agonist might be a better therapeutic target for IPS than the IDO1 activator. We developed a novel synthetic AHR agonist (referred to here as PB502) that potently inhibits Jund expression. PB502 was highly effective at inducing AHR activation and ameliorating IPS. Notably, PB502 was by far superior to the endogenous AHR ligand, L-kynurenine, in promoting the differentiation of both mouse and human FoxP3+ regulatory CD4+ T cells. Our results suggest that the IDO1-AHR axis in lung epithelial cells is associated with IPS repression. A specific AHR agonist may exhibit therapeutic activity against inflammatory and autoimmune diseases by promoting regulatory T-cell differentiation.

Exogenous S1P via S1P receptor 2 induces CTGF expression through Src-RhoA-ROCK-YAP pathway in hepatic stellate cells.

BACKGROUND: Hepatic fibrosis, a prevalent chronic liver condition, involves excessive extracellular matrix production associated with aberrant wound healing. Hepatic stellate cells (HSCs) play a pivotal role in liver fibrosis, activated by inflammatory factors such as sphingosine 1-phosphate (S1P). Despite S1P's involvement in fibrosis, its specific role and downstream pathway in HSCs remain controversial. METHODS: In this study, we investigated the regulatory role of S1P/S1P receptor (S1PR) in Hippo-YAP activation in both LX-2 cell lines and primary HSCs. Real-time PCR, western blot, pharmacological inhibitors, siRNAs, and Rho activity assays were adopted to address the molecular mechanisms of S1P mediated YAP activation. RESULTS: Serum and exogenous S1P significantly increased the expression of YAP target genes in HSCs. Pharmacologic inhibitors and siRNA-mediated knockdowns of S1P receptors showed S1P receptor 2 (S1PR2) as the primary mediator for S1P-induced CTGF expression in HSCs. Results using siRNA-mediated knockdown, Verteporfin, and Phospho-Tag immunoblots showed that S1P-S1PR2 signaling effectively suppressed the Hippo kinases cascade, thereby activating YAP. Furthermore, S1P increased RhoA activities in cells and ROCK inhibitors effectively blocked CTGF induction. Cytoskeletal-perturbing reagents were shown to greatly modulate CTGF induction, suggesting the important role of actin cytoskeleton in S1P-induced YAP activation. Exogeneous S1P treatment was enough to increase the expression of COL1A1 and α-SMA, that were blocked by YAP specific inhibitor. CONCLUSIONS: Our data demonstrate that S1P/S1PR2-Src-RhoA-ROCK axis leads to Hippo-YAP activation, resulting in the up-regulation of CTGF, COL1A1 and α-SMA expression in HSCs. Therefore, S1PR2 may represent a potential therapeutic target for hepatic fibrosis.

Ubiquitin-specific proteases UBP12 and UBP13 promote shade avoidance response by enhancing PIF7 stability.

Changes in light quality caused by the presence of neighbor proximity regulate many growth and development processes of plants. PHYTOCHROME INTERACTING FACTOR 7 (PIF7), whose subcellular localization, DNA-binding properties, and protein abundance are regulated in a photoreversible manner, plays a central role in linking shade light perception and growth responses. How PIF7 activity is regulated during shade avoidance responses has been well studied, and many factors involved in this process have been identified. However, the detailed molecular mechanism by which shade light regulates the PIF7 protein level is still largely unknown. Here, we show that the PIF7 protein level regulation is important for shade-induced growth. Two ubiquitin-specific proteases, UBP12 and UBP13, were identified as positive regulators in shade avoidance responses by increasing the PIF7 protein level. The ubp12-2w/13-3 double mutant displayed significantly impaired sensitivity to shade-induced cell elongation and reproduction acceleration. Our genetic and biochemical analysis showed that UBP12 and UBP13 act downstream of phyB and directly interact with PIF7 to maintain PIF7 stability and abundance through deubiquitination.

A Systematic Review of Nurses' Perceptions of Electronic Health Record Usability Based on the Human Factor Goals of Satisfaction, Performance, and Safety.

The poor usability of electronic health records contributes to increased nurses' workload, workarounds, and potential threats to patient safety. Understanding nurses' perceptions of electronic health record usability and incorporating human factors engineering principles are essential for improving electronic health records and aligning them with nursing workflows. This review aimed to synthesize studies focused on nurses' perceived electronic health record usability and categorize the findings in alignment with three human factor goals: satisfaction, performance, and safety. This systematic review was guided by the Preferred Reporting Items for Systematic Reviews and Meta-Analysis. Five hundred forty-nine studies were identified from January 2009 to June 2023. Twenty-one studies were included in this review. The majority of the studies utilized reliable and validated questionnaires (n = 15) to capture the viewpoints of hospital-based nurses (n = 20). When categorizing usability-related findings according to the goals of good human factor design, namely, improving satisfaction, performance, and safety, studies used performance-related measures most. Only four studies measured safety-related aspects of electronic health record usability. Electronic health record redesign is necessary to improve nurses' perceptions of electronic health record usability, but future efforts should systematically address all three goals of good human factor design.

Inositol polyphosphates-regulated polyubiquitination of PHR1 by NLA E3 ligase during phosphate starvation response in Arabidopsis.

Phosphate (Pi) availability is a major factor limiting plant growth and development. The key transcription factor controlling Pi-starvation response (PSR) is PHOSPHATE STARVATION RESPONSE 1 (PHR1) whose transcript levels do not change with changes in Pi levels. However, how PHR1 stability is regulated at the post-translational level is relatively unexplored in Arabidopsis thaliana. Inositol polyphosphates (InsPn) are important signal molecules that promote the association of stand-alone SPX domain proteins with PHR1 to regulate PSR. Here, we show that NITROGEN LIMITATION ADAPTATION (NLA) E3 ligase can associate with PHR1 through its conserved SPX domain and polyubiquitinate PHR1 in vitro. The association with PHR1 and its ubiquitination is enhanced by InsP6 but not by InsP5. Analysis of InsPn-related mutants and an overexpression plant shows PHR1 levels are more stable in itpk4-1 and vih2-4/VIH1amiRNA but less stable in ITPK4 overexpression plants. Under Pi-deficient conditions, nla seedlings contain high PHR1 levels, display long root hair and accumulate anthocyanin in shoots phenocopying PHR1 overexpression plants. By contrast, NLA overexpression plants phenocopy phr1 whose phenotypes are opposite to those of nla. Our results suggest NLA functions as a negative regulator of Pi response by modulating PHR1 stability and the NLA/PHR1 association depends on InsPn levels.

Influence of endoscopists' expertise level on clinical outcomes after bridge-to-surgery stenting in obstructive colorectal cancer.

BACKGROUND AND AIM: This study aimed to investigate the effect of stenting-related factors, including endoscopists' expertise, on clinical outcomes after bridge-to-surgery (BTS) stenting for obstructive colorectal cancer (CRC). METHODS: We analyzed BTS stenting-related factors, including stenting expertise and the interval between stenting and surgery, in 233 patients (63 [13] years, 137 male) who underwent BTS stenting for obstructive CRC. We evaluated the influence of these factors on post-BTS stenting clinical outcomes such as stent-related complications and cancer recurrence. RESULTS: The interval between stenting and surgery was ≤ 7 days in 79 patients (33.9%) and > 7 days in 154 patients (66.1%). BTS stenting was performed by endoscopists with ≤ 50, 51-100, and > 100 prior stenting experiences in 94, 43, and, 96 patients, respectively. The clinical success rate of BTS stenting was 93.1%. Stent-related and postoperative complications developed in 19 (8.2%) and 20 (8.6%) patients, respectively. Cancer recurrence occurred in 76 patients (32.6%). Short BTS interval of ≤ 7 days increased the risk of postoperative complications (odds ratio [OR], 2.61 [1.03-6.75]; P = 0.043). Endoscopists' stenting experience > 100 showed greater clinical success of stenting (OR, 5.50 [1.45-28.39]; P = 0.021) and fewer stent-related complications (OR, 0.26 [0.07-0.80]; P = 0.028) compared with stenting experience ≤ 50. BTS stenting-related factors did not affect long-term oncological outcomes. CONCLUSION: Greater expertise of endoscopists was associated with better short-term outcomes, including high stenting success rate and low rate of stent-related complications after BTS stenting for obstructive CRC. An interval of > 7 days between BTS stenting and surgery was required to decrease postoperative complications.

Defect Detection in Printed Circuit Boards Using Semi-Supervised Learning.

Defect inspection is essential in the semiconductor industry to fabricate printed circuit boards (PCBs) with minimum defect rates. However, conventional inspection systems are labor-intensive and time-consuming. In this study, a semi-supervised learning (SSL)-based model called PCB_SS was developed. It was trained using labeled and unlabeled images under two different augmentations. Training and test PCB images were acquired using automatic final vision inspection systems. The PCB_SS model outperformed a completely supervised model trained using only labeled images (PCB_FS). The performance of the PCB_SS model was more robust than that of the PCB_FS model when the number of labeled data is limited or comprises incorrectly labeled data. In an error-resilience test, the proposed PCB_SS model maintained stable accuracy (error increment of less than 0.5%, compared with 4% for PCB_FS) for noisy training data (with as much as 9.0% of the data labeled incorrectly). The proposed model also showed superior performance when comparing machine-learning and deep-learning classifiers. The unlabeled data utilized in the PCB_SS model helped with the generalization of the deep-learning model and improved its performance for PCB defect detection. Thus, the proposed method alleviates the burden of the manual labeling process and provides a rapid and accurate automatic classifier for PCB inspections.

Detection of Muscle Activation during Resistance Training Using Infrared Thermal Imaging.

Infrared thermal imaging has been widely used to show the correlation between thermal characteristics of the body and muscle activation. This study aims to investigate a method using thermal imaging to visualize and differentiate target muscles during resistance training. Thermal images were acquired to monitor three target muscles (i.e., biceps brachii, triceps brachii, and deltoid muscle) in the brachium while varying the training weight, duration, and order of training. The acquired thermal images were segmented and converted to heat maps. By generating difference heat maps from pairs of heat maps during training, the target muscles were clearly visualized, with an average temperature difference of 0.86 °C. It was observed that training order had no significant effect on skin surface temperature. The difference heat maps were also used to train a convolutional neural network (CNN) to show the feasibility of target muscle classification, with an accuracy of 92.3%. This study demonstrated that infrared thermal imaging could be effectively utilized to locate and differentiate target muscle activation during resistance training.

In Vivo Quantitative Vasculature Segmentation and Assessment for Photodynamic Therapy Process Monitoring Using Photoacoustic Microscopy.

Vascular damage is one of the therapeutic mechanisms of photodynamic therapy (PDT). In particular, short-term PDT treatments can effectively destroy malignant lesions while minimizing damage to nonmalignant tissue. In this study, we investigate the feasibility of label-free quantitative photoacoustic microscopy (PAM) for monitoring the vasculature changes under the effect of PDT in mouse ear melanoma tumors. In particular, quantitative vasculature evaluation was conducted based on Hessian filter segmentation. Three-dimensional morphological PAM and depth-resolved images before and after PDT treatment were acquired. In addition, five quantitative vasculature parameters, including the PA signal, vessel diameter, vessel density, perfused vessel density, and vessel complexity, were analyzed to evaluate the influence of PDT on four different areas: Two melanoma tumors, and control and normal vessel areas. The quantitative and qualitative results successfully demonstrated the potential of the proposed PAM-based quantitative approach to evaluate the effectiveness of the PDT method.

Information flow and nursing care during the early phase of the COVID-19 pandemic.

AIMS: This study aimed to understand the dissemination of information relating to coronavirus disease 2019 (COVID-19) and its impact on nursing care in the early phase of transmission. BACKGROUND: COVID-19 has spread globally, causing an unprecedentedly large number of casualties. Nurses face challenges in dealing with patients with COVID-19 with limited information about the pathogen. DESIGN: This qualitative study followed the COREQ guidelines. METHODS: Fifteen nurses were recruited from two university hospitals in South Korea using a snowballing technique for in-depth interviews in May 2020. All interviews were recorded and transcribed verbatim. Content analysis was performed on the interview data. RESULTS: Two themes emerged: access to COVID-19 information and the impact of information on nursing care. The categories of access to COVID-19 information were lack of nursing-specific information, limited information cascading from top management and confusion due to varying points of view. The categories of the impact of information on nursing care were unprepared management that aggravates exhaustion, lack of personal protective equipment that creates anxiety and being a nurse leader to overcome the pandemic. CONCLUSION: During a pandemic of emerging infectious diseases, nurses should have access to up-to-date information tailored to their working environment. Human resources, material resources and systematic support are needed for nurses who provide care for patients with an infectious disease. RELEVANCE TO CLINICAL PRACTICE: A collaborative interprofessional education system for emerging infectious diseases is needed for effective communication and consistent care during a pandemic. Nurse leaders should be prepared to deliver profession-specific information for standardised care and respond to nursing management needs by using resources and tailoring the workforce.

OsCRP1, a Ribonucleoprotein Gene, Regulates Chloroplast mRNA Stability That Confers Drought and Cold Tolerance.

Chloroplast ribonucleoproteins (cpRNPs) are nuclear-encoded and highly abundant proteins that are proposed to function in chloroplast RNA metabolism. However, the molecular mechanisms underlying the regulation of chloroplast RNAs involved in stress tolerance are poorly understood. Here, we demonstrate that CHLOROPLAST RNA-BINDING PROTEIN 1 (OsCRP1), a rice (Oryza sativa) cpRNP gene, is essential for stabilization of RNAs from the NAD(P)H dehydrogenase (NDH) complex, which in turn enhances drought and cold stress tolerance. An RNA-immunoprecipitation assay revealed that OsCRP1 is associated with a set of chloroplast RNAs. Transcript profiling indicated that the mRNA levels of genes from the NDH complex significantly increased in the OsCRP1 overexpressing compared to non-transgenic plants, whereas the pattern in OsCRP1 RNAi plants were opposite. Importantly, the OsCRP1 overexpressing plants showed a higher cyclic electron transport (CET) activity, which is essential for elevated levels of ATP for photosynthesis. Additionally, overexpression of OsCRP1 resulted in significantly enhanced drought and cold stress tolerance with higher ATP levels compared to wild type. Thus, our findings suggest that overexpression of OsCRP1 stabilizes a set of mRNAs from genes of the NDH complex involved in increasing CET activity and production of ATP, which consequently confers enhanced drought and cold tolerance.

Clinical benefits of ridge preservation for implant placement compared to natural healing in maxillary teeth: A retrospective study.

AIM: The purpose of this retrospective study was to determine clinical benefits of ridge preservation in terms of surgical invasiveness of implant placement compared to natural healing in the maxilla. MATERIALS & METHODS: This study included 178 patients with 206 implants placed at ridge-preserved sites and 493 patients with 656 implants placed at naturally healed sites in maxillary anterior and posterior regions. Patient- and implant-related data were collected from electronic dental records including additional augmentation procedures performed before or during implant placement and surgical complications. Cumulative survival rate was assessed using Kaplan-Meier method. The annual peri-implant marginal bone loss between the two groups was compared using the Mann-Whitney U test. RESULTS: The follow-up period was 24.4 ± 18.1 months (mean ± standard deviation) for ridge-preserved sites and 45.7 ± 29.6 months for naturally healed sites. Sinus augmentation was performed at similar frequencies in the two groups, but lateral approach was applied significantly more at naturally healed sites (37.2%) than ridge-preserved sites (8.3%, p ≤ .001). There was no intergroup difference in the cumulative survival rate or annual peri-implant marginal bone loss. CONCLUSION: Ridge preservation can be clinically beneficial for minimizing the invasiveness of implant surgery by simplifying the procedure when sinus augmentation is expected in the maxilla.

Application of Ultrasound Thermal Imaging for Monitoring Laser Ablation in Ex Vivo Cardiac Tissue.

BACKGROUND AND OBJECTIVE: Laser ablation can be used to treat atrial fibrillation by thermally isolating pulmonary veins. In this study, we evaluated the feasibility of high-resolution (<1 mm) ultrasound thermal imaging to monitor spatial temperature distribution during laser ablation on ex vivo cardiac tissue. STUDY DESIGN/MATERIALS AND METHODS: Laser ablation (808 nm) was performed on five porcine cardiac tissue samples. A thermocouple was used to measure the interstitial tissue temperature during the laser ablation process. Tissue-strain-based ultrasound thermal imaging was conducted to monitor the spatial distribution of the temperature in the cardiac tissue. The tissue temperature was estimated from the time shifts of ultrasound signals owing to the changes in the speed of sound and was compared with the measured temperature. The temperature estimation coefficient k of porcine cardiac tissue was calculated from the estimated thermal strain and the measured temperature. The degree of tissue coagulation (temperatures > 50°C) was derived from the estimated temperature and was compared with that of the tested cardiac tissue. RESULTS: The estimated tissue temperature using strain-based ultrasound thermal imaging at a depth of 1 mm agreed with thermocouple measurements. During the 30-second period of the laser ablation process, the estimated tissue temperature increased from 25 to 70°C at a depth of 0.1 mm, while the estimated temperature at a depth of 1 mm increased up to 46°C. Owing to the uncertainty of the coefficient k, the k value of the porcine cardiac tissue varied from 160 to 220°C with temperature changes of up to 20°C. The estimated coagulation region in the ultrasound thermal imaging was 20% wider (+0.6 mm) but 9% shallower (-0.1 mm) than the measured region of the ablated porcine cardiac tissue. CONCLUSIONS: The current study demonstrated the feasibility of temperature monitoring with the use of ultrasound thermal imaging during the laser ablation on ex vivo porcine cardiac tissue. The high-resolution ultrasound thermal imaging could map the spatial distribution of the tissue temperature. The proposed method can be used to monitor the temperature and thermal coagulation to achieve effective laser ablation for atrial fibrillation. Lasers Surg. Med. © 2019 Wiley Periodicals, Inc.

Multi-Angle Liquid Flow Measurement Using Ultrasonic Linear Array Transducer.

Most ultrasonic flowmeters utilize several wedge sensors for transmission and reception. Thus, the location and alignment of the sensors are critical factors that determine the performance of the ultrasonic flowmeter. In this study, we proposed an ultrasound liquid flowmeter utilizing a 128-element linear array transducer with a transmit delay control for varying the incidence angles of ultrasound wave transmission. The performance of the flowmeter was evaluated at flow rates of 0-50 L/min in a specially designed pipe system. Flow estimation was performed with the transit-time method using cross-correlation with phase zero-crossing for sub-sample estimation. While a single plane wave approach performed invasive electromagnetic measurements with only 74% accuracy as a reference, a multiple angular compensation method with 24 angles was proposed to increase the accuracy of measurements up to 93%. This study demonstrated the capability of the non-invasive single-sided ultrasonic flowmeter with a linear array transducer for liquid flow measurements in the metal pipe system.

Quantitative Monitoring of Tattoo Contrast Variations after 755-nm Laser Treatments in In Vivo Tattoo Models.

Laser lights have been used by dermatologists for tattoo removal through photothermal interactions. However, most clinical studies used a visual scoring method to evaluate the tattoo removal process less objectively, leading to unnecessary treatments. This study aimed to develop a simple and quantitative imaging method to monitor the degree of tattoo removal in in vivo skin models. Sprague Dawley rat models were tattooed with four different concentrations of black inks. Laser treatment was performed weekly on the tattoos using a wavelength of 755 nm over six weeks. Images of non-treated and treated samples were captured using the same method after each treatment. The intensities of the tattoos were measured to estimate the contrast for quantitative comparison. The results demonstrated that the proposed monitoring method quantified the variations in tattoo contrast after the laser treatment. Histological analysis validated the significant removal of tattoo inks, no thermal injury to adjacent tissue, and uniform remodeling of epidermal and dermal layers after multiple treatments. This study demonstrated the potential of the quantitative monitoring technique in assessing the degree of clearance level objectively during laser treatments in clinics.

Arabidopsis ubiquitin-specific proteases UBP12 and UBP13 shape ORE1 levels during leaf senescence induced by nitrogen deficiency.

Nitrogen deficiency (-N) in plants triggers leaf senescence which is regulated by the transcription factor ORE1. Little is known about post-translational regulation of ORE1 in this process. Here, we show that UBP12/UBP13 (ubiquitin-specific protease 12/13) antagonize the action of NLA (nitrogen limitation adaptation) E3 ligase to maintain ORE1 homeostasis. In vitro pull-down and in vivo co-immunoprecipitation assays demonstrated specific binding between UBP12/UBP13 and ORE1. We further analyzed in various genotypes total Chl content and expression levels of senescence-related genes under -N conditions. We found that UBP12/UBP13 can deubiquitinate polyubiquitinated ORE1 in vitro and increase the stability of ORE1 in vivo in MG132/cycloheximide-chase experiments. Plants overexpressing UBP12/UBP13 display accelerated leaf senescence which is reversed by the ore1 mutation. By contrast, the senescence phenotype of plants overexpressing ORE1 is exacerbated by UBP12/UBP13 overexpression. The expression of senescence-related genes tracks the senescence phenotype. ORE1 protein levels can be elevated by UBP12/UBP13 overexpression but decreased in ubp12-2w/13-3. In conclusion, UBP12/UBP13 deubiquitinate ORE1 to stabilize this transcription factor and promote its activity as a positive regulator for leaf senescence under -N conditions. Our study shows that UBP12/UBP13 counteracts the effect of NLA E3 ligase to accelerate leaf senescence under nitrogen starvation.

Development of temperature controller-integrated portable HIFU driver for thermal coagulation.

BACKGROUND: Temperature monitoring during high-intensity focused ultrasound (HIFU) therapy on tissue is essential to regulate the degree of thermal coagulation and to achieve the desired treatment outcomes eventually. The aim of the current study was to design and investigate the feasibility of a proportional-integral-derivative (PID) temperature controller-integrated portable HIFU driver for thermal coagulation. METHODS: A portable HIFU driver was designed and operated at a maximum output voltage of 50 V with pulse-width modulation signals at 2 MHz. The temperature of ex vivo bovine liver tissue was monitored using a K-type thermocouple during the 2-MHz HIFU exposure. RESULTS: The tissue temperature was maintained at 60 °C using a PID controller-integrated HIFU driver that modulated the output voltage during the 300-s HIFU exposure. The ex vivo testing demonstrated that the tissue temperature at the focal point approached the chosen temperature, i.e., 60 °C, within 70 s. The temperature was maintained with a deviation of less than 4 °C until the HIFU driver voltage was turned off at 300 s. CONCLUSIONS: The designed PID controller-integrated HIFU driver can be used as a small portable tool to regulate the tissue temperature in real time and achieve thermal coagulation via HIFU sonication.

Alveolar ridge preservation in the posterior maxilla reduces vertical dimensional change: A randomized controlled clinical trial.

OBJECTIVES: To test whether or not alveolar ridge preservation reduces vertical changes in the posterior maxilla compared to spontaneous healing following tooth extraction. MATERIALS AND METHODS: Forty subjects requiring extraction of maxillary posterior teeth with root apices protruding into the maxillary sinus floor were consecutively enrolled. Patients were randomly assigned to either one of two surgical interventions: an alveolar ridge preservation procedure using collagenated bovine bone mineral and a resorbable collagen membrane (test) or no grafting (control). Cone-beam computed tomographies were taken immediately and at 6 months after surgery, prior to dental implant placement. RESULTS: Based on radiographic data, the level of the sinus floor remained stable over time (baseline to 6 months) in the test group (-0.14 mm [-0.31, -0.02]). In the control group, the sinus floor level shifted more coronally (-1.16 mm [-1.73, -0.61]) than the test group (p < 0.05). The test group demonstrated a significantly larger residual bone height than the control group at 6 months (7.30 mm [6.36, 8.20] vs. 4.83 mm [3.94, 5.76], respectively, p < 0.05). Implant placement without any additional sinus augmentation procedure was performed in 42.9% of test group cases, whereas in all of the subjects in the control group an additional augmentation procedure was needed (100% of the cases). CONCLUSION: Alveolar ridge preservation in the posterior maxilla maintained the vertical bone height more efficiently and resulted in less need for sinus augmentation procedures at 6 months compared to spontaneous healing.

Eckol as a Potential Therapeutic against Neurodegenerative Diseases Targeting Dopamine D3/D4 Receptors.

The G protein-coupled receptor (GPCR) family of proteins comprises signaling proteins that mediate cellular responses to various hormones and neurotransmitters, and serves as a prime target for drug discovery. Towards our goal of discovering secondary metabolites from natural sources that can function as neuronal drugs, we evaluated the modulatory effect of eckol on various GPCRs via cell-based functional assays. In addition, we conducted in silico predictions to obtain molecular insights into the functional effects of eckol. Functional assays revealed that eckol had a concentration-dependent agonist effect on dopamine D3 and D4 receptors. The half maximal effective concentration (EC50) of eckol for the dopamine D3 and D4 receptors was 48.62 ± 3.21 and 42.55 ± 2.54 µM, respectively, while the EC50 values of dopamine as a reference agonist for these two receptors were 2.9 and 3.3 nM, respectively. In silico studies revealed that a low binding energy in addition to hydrophilic, hydrophobic, π⁻alkyl, and π⁻π T-shaped interactions are potential mechanisms by which eckol binds to the dopamine receptors to exert its agonist effects. Molecular dynamics (MD) simulation revealed that Phe346 of the dopamine receptors is important for binding of eckol, similar to eticlopride and dopamine. Our results collectively suggest that eckol is a potential D3/D4 agonist for the management of neurodegenerative diseases, such as Parkinson's disease.

Chronic effects of bisphenol S and bisphenol SIP on freshwater waterflea and ecological risk assessment.

Bisphenol S (BPS) and 4-hydroxyphenyl 4-isoprooxyphenylsulfone (BPSIP) have been used as substitutes for bisphenol A (BPA) owing to increased regulation of BPA in plastics. In this study, long-term toxicity tests of BPS and BPSIP were performed using Daphnia magna and Moina macrocopa. The predicted no-effect concentration (PNEC) of BPA, BPS, and BPSIP were derived by the assessment factor (AF) method and the species sensitivity distribution (SSD) method. An ecological risk assessment was performed based on the measured environmental concentrations of BPA in surface water worldwide and the derived PNECs. The chronic NOEC of D. magna was 2.5 mg/L for BPS and 0.5 mg/L for BPSIP, and that of M. macrocopa was 0.03 mg/L for BPS and 0.1 mg/L for BPSIP. The PNECAF was generally one order of magnitude less than the PNECSSD, and the PNEC of BPS was 10 times lower than that of BPA. The hazard quotients of BPA and BPS exceeded 1, indicating that concentrations in ambient water conditions could pose a potential risk to aquatic organisms. Since the use of alternative compounds is increasing, further monitoring data of the water environment and chronic toxicity in various aquatic organisms appears to be necessary.