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Fang-Hong Shi,1,&ast; Bin-Bin Yu,2,&ast; Long Shen,3,&ast; Li Xu,3 Yi-Hong Jiang,4 Zhi-Chun Gu,1 Hou-Wen Lin,1 Hao Li5 1Department of Pharmacy, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 2Department of Pharmacy, Huangyan Hospital of Wenzhou Medical University, Taizhou First People’s Hospital, Zhejiang, People’s Republic of China; 3Department of Cardiology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 4Department of Endocrinology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 5Clinical Research Ward, Clinical Research Center, Shanghai Children’s Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zhi-Chun Gu, Department of Pharmacy, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China, Email guzhichun213@163.com Hao Li, Clinical Research Ward, Clinical Research Center, Shanghai Children’s Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, People’s Republic of China, Email lihao19880810@hotmail.comPurpose: The aim of this study was to evaluate whether intervention by clinical pharmacists can improve blood glucose and lipid levels in diabetic patients with complex medical conditions.Methods: The retrospective database included 138 patients with diabetes who had presented with acute myocardial infarction (AMI) between January 2019 and October 2021. Blood glucose and lipid levels were measured within 12 weeks and 78 weeks of follow-up. Propensity score matching (PSM) was used to balance the confounding effects of patients’ characteristics.Results: A total of 138 eligible patients were assigned to either the intervention group (n = 47) or the usual care group (n = 91). After the intervention, there were significant improvements in blood glucose (glycosylated hemoglobin-HbA1C % from 9.0 to 8.3; fasting blood glucose-FBG mmol/L from 11.3 to 7.1; postprandial blood glucose-PBG mmol/L from 17.0 to 12.1; p < 0.001) and lipid levels (total cholesterol-TC from 4.9 to 3.5, low-density lipoprotein cholesterol-LDL-C from 3.0 to 1.8, p < 0.001, mmol/L) in both follow-up periods. The blood glucose effects were most pronounced in the PBG control rate (76.9% vs 54.0%) before PSM, while HbA1C% and PBG control rate after PSM were significantly higher in the intervention group (HbA1C% rate: 65.6% vs 38.5%; PBG rate: 79.2% vs 45.8%; p < 0.05, intervention vs non-intervention). Subgroup analysis further confirmed the improvement of blood glucose and lipid mainly in patients with higher baseline FBG (≧10mmol/L) and moderate follow-up duration (4– 12 weeks).Conclusion: The intervention of clinical pharmacists in multidisciplinary team can significantly improve blood glucose and lipid levels in complex type 2 diabetic patients, especially those with high baseline FBG and moderate follow-up durations.Keywords: blood glucose, blood lipid, clinical pharmacist’s intervention, propensity score matching, complex diabetes

Hanh TH Nguyen,1,2 Khanh Linh Duong,2 Son T Nguyen,2 Quy Trinh,2 Hao TL Hoang,3 Toan Q Phung,4 Hsiang-Wen Lin,1,5 Huong TL Nguyen2 1School of Pharmacy and Graduate Institute, China Medical University, Taichung, Taiwan; 2Department of Clinical Pharmacy, Hanoi University of Pharmacy, Hanoi, Vietnam; 3Pharmacy Department, Hanoi Oncology Hospital, Hanoi, Vietnam; 4Pharmacy Department, Vietnam National Cancer Hospital, Hanoi, Vietnam; 5Department of Pharmacy, China Medical University Hospital, Taichung, TaiwanCorrespondence: Huong TL Nguyen, Hanoi University of Pharmacy, 13-15 Le Thanh Tong, Hoan Kiem, Hanoi, Vietnam, Tel +84 904 308 406, Fax +84 243 826 4464, Email huongntl@hup.edu.vnPurpose: This study aimed to evaluate the health-related quality of life (HRQOL) of cancer patients receiving chemotherapy and identify associated factors affecting the HRQOL after the third wave of the COVID-19 pandemic in Vietnam.Patients and Methods: Patients with solid cancers receiving chemotherapy at two oncology hospitals in Vietnam during April and May 2021 were included. The European Organisation for Research and Treatment of Cancer Core Quality of Life Questionnaire version 3 was used to measure the HRQOL. Three questions were asked to explore patients’ concern levels about contracting COVID-19, delaying chemotherapy, or not controlling cancer well. One question was used to explore whether patients were concerned about cancer progression or COVID-19 infection more, or equally, or had no concern about both. Multiple regression models were conducted to examine factors associated with the global health status (GHS) score.Results: Of 270 included patients, mean (Standard deviation [SD]) GHS was 56.7 (20.8). Among the functional statuses, social functioning (SF) had the lowest score of 63.6 (29.2). The symptoms with the highest means were insomnia and fatigue, obtaining the score of 38.5 (31.7) and 37.3 (29.2), respectively. The mean of financial difficulties was 54.1 (32.2). In univariate analysis, high concerns about contracting COVID-19, delaying chemotherapy, not controlling cancer well, or more concern about either cancer or COVID-19 over the other were associated with worse GHS, physical functioning, emotional functioning, and SF. In multivariate analysis, those concerns and no income were significantly related to lower GHS scores besides the non-modifiable factors, such as female gender and some cancer types.Conclusion: Patients at the high concern levels, or with more concern about either cancer or COVID-19 over the other had poorer HRQOL. Interventions to address the concerns are required to improve their HRQOL, particularly for women, those without income, or with some specific cancers.Keywords: chemotherapy, COVID-19, EORTC QLQ-C30, quality of life, low economic status

This meta-analysis investigated therapeautic effects of laser therapies in patients with Bell's palsy (BP). The authors performed the literature search in the PubMed, Embase, and Cochrane Library databases using the following search terms: (facial paralysis OR Bell's palsy OR facial palsy OR idiopathic facial paralysis) AND (laser OR low-level laser OR photobiomodulation OR phototherapy). Relevant studies published before October 29th 2024 were identified. Randomized trials comparing the outcomes of laser therapies with other interventions, including electrical stimulation and control or usual care in patients with BP were included. The mean difference (MD) was determined as the effect size for continuous outcomes, and outcome accuracy was determined using 95% confidence intervals (CIs). Twelve studies were included, with a total of 597 patients. Nine studies were further included in the quantitative analysis. Our meta-analysis revealed that laser therapy significantly improved disease severity (House-Brackmann facial paralysis scale) (MD = -1.51, 95% CI = -2.43 to -0.59), facial asymmetry (Sunnybrook facial grading system) (MD = 20.63, 95% CI = 10.33 to 30.94), and facial function and disability (Facial disability index) (MD = 17.91, 95% CI = 5.60 to 30.22) when compared with control care in adult patients. Moreover, laser therapy significantly improved facial severity (MD = 21.05, 95% CI = 16.77 to 25.33) when compared with electrical stimulation. In addition, no adverse effects of laser therapy were reported. Laser therapy has favorable effects on disease severity, facial asymmetry, and facial function and disability for patients with BP., Competing Interests: Declarations Ethical approval Not applicable. Conflict of interest The authors declare no financial or other conflicts of interest., (© 2024. The Author(s), under exclusive licence to Springer-Verlag London Ltd., part of Springer Nature.)

Cerebral amyloid angiopathy (CAA) is characterized by the deposition of amyloid-beta peptides within cerebral blood vessels, leading to neurovascular complications. Ischemic strokes result from acute disruptions in cerebral blood flow, triggering metabolic disturbances and neurodegeneration. Both conditions often co-occur and are associated with respiratory dysfunctions. The retrotrapezoid nucleus (RTN), which is crucial for CO 2 sensing and breathing regulation in the brainstem, may play a key role in breathing disorders seen in these conditions. This study aims to investigate the role of Transforming Growth Factor Beta (TGF-β) signaling in the RTN on respiratory and cognitive functions in CAA, both with and without concurrent ischemic stroke. Adult male Tg-SwDI (CAA model) mice and C57BL/6 wild-type controls underwent stereotaxic injections of lentivirus targeting TGF-βR2 in the RTN. Stroke was induced by middle cerebral artery occlusion using a monofilament. Respiratory functions were assessed using whole-body plethysmography, while cognitive functions were evaluated through the Barnes Maze and Novel Object Recognition Test (NORT). Immunohistochemical analysis was conducted to measure TGF-βR2 and GFAP expressions in the RTN. CAA mice exhibited significant respiratory dysfunctions, including reduced respiratory rates and increased apnea frequency, as well as impaired cognitive performance. TGF-βR2 silencing in the RTN improved respiratory functions and cognitive outcomes in CAA mice. In CAA mice with concurrent stroke, TGF-βR2 silencing similarly enhanced respiratory and cognitive functions. Immunohistochemistry confirmed reduced TGF-βR2 and GFAP expressions in the RTN following silencing. Our findings demonstrate that increased TGF-β signaling and gliosis in the RTN contribute to respiratory and cognitive dysfunctions in CAA and CAA with stroke. Targeting TGF-βR2 signaling in the RTN offers a promising therapeutic strategy to mitigate these impairments. This study is the first to report a causal link between brainstem gliosis and both respiratory and cognitive dysfunctions in CAA and stroke models., Competing Interests: Declarations Competing Interests The authors declare no competing interests. Disclosures The authors declare no potential conflicts of interest with respect to research, authorship, and/or publication of this article., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Stroke is one of the leading causes of death and permanent adult disability worldwide. Despite the improvements in reducing the rate and mortality, the societal burden and costs of treatment associated with stroke management are increasing. Most of the therapeutic approaches directly targeting ischemic injury have failed to reduce short- and long-term morbidity and mortality and more effective therapeutic strategies are still needed to promote post-stroke functional recovery. Decades of stroke research have been focused on hyperexcitability and glutamate-induced excitotoxicity in the acute phase of ischemia and their relation to motor deficits. Recent advances in understanding the pathophysiology of stroke have been made with several lines of evidence suggesting that changes in the neurotransmission of the major inhibitory system via γ-Aminobutyric acid (GABA) play a particularly important role in functional recovery and deserve further attention. The present review provides an overview of how GABAergic neurotransmission changes correlate with stroke recovery and outlines GABAergic system modulators with special emphasis on neurosteroids that have been shown to affect stroke pathogenesis or plasticity or to protect against cognitive decline. Supporting evidence from both animal and human clinical studies is presented and the potential for GABA signaling-targeted therapies for stroke is discussed to translate this concept to human neural repair therapies. Age and sex are considered crucial parameters related to the pathophysiology of stroke and important factors in the development of therapeutic pharmacological strategies. Future work is needed to deepen our knowledge of the neurochemical changes after stroke, extend the conceptual framework, and allow for the development of more effective interventions that include the modulation of the inhibitory system., (Copyright © 2024. Published by Elsevier Inc.)

Purpose: Hydrochlorothiazide (HCTZ) exposure has been linked to increased skin cancer in Caucasian (white) populations, especially squamous cell carcinoma (SCC), but not basal cell carcinoma (BCC). This study aimed to evaluate and compare skin cancer risks associated with HCTZ- and other antihypertensives use., Methods: This retrospective cohort study utilized Taiwan's National Health Insurance Research Database. We identified patients aged 20 years and older, newly receiving antihypertensive medications between 2004 and 2015. We calculated the medication possession ratio (MPR) for the first 2 years of treatment to determine patient eligibility and treatment classification, whereby only patients with MPR above 80% were included. These were subsequently categorized by the type of antihypertensives they received, namely HCTZ, other thiazide diuretics, non-thiazide diuretics or non-diuretic antihypertensives. Cox proportional hazards model was used to evaluate skin cancer risks, and these were then classified as SCC or BCC., Results: Our study included 41 086, 27 402, 19 613, and 856 782 patients receiving HCTZ, other thiazide diuretics, non-thiazide diuretics, and non-diuretic antihypertensives, respectively. We found BCC risks were similar when comparing HCTZ with other thiazides (adjusted hazard ratio: 0.84; 95% CI: 0.54-1.33), non-thiazide diuretics (0.93; 0.51-1.67), and non-diuretic antihypertensives (0.91; 0.66-1.26). We observed a higher SCC risk in the HCTZ group, compared to other thiazides (1.24; 0.74-2.08), non-thiazide diuretics (1.32; 0.70-2.51), and non-diuretic antihypertensives (1.23; 0.87-1.73), although the confidence intervals (CIs) were wide and crossed the null., Conclusions: We concluded that skin cancer need not be of major concern to physicians when prescribing antihypertensives for an Asian population., (© 2024 John Wiley & Sons Ltd.)

Objectives: Behavioral and psychological symptoms of dementia (BPSD) are common in people with dementia. Aromatherapy may reduce the frequency and severity of BPSD. We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) to evaluate the efficacy of aromatherapy in relieving BPSD and improving functional ability in people with dementia., Design: Systematic review and meta-analysis., Setting and Participants: Patients with dementia receiving aromatherapy., Methods: A literature search was conducted using PubMed, Embase, and Cochrane Library for RCTs published before March 2024 comparing aromatherapy with control treatments in patients with dementia., Results: There were 15 trials involving 821 patients. Overall, significant reduction in BPSD was observed after 1 month of aromatherapy treatment. Among 15 trials, 9 reported the Cohen-Mansfield Agitation Inventory (CMAI) score, and 7 evaluated the Neuropsychiatric Inventory (NPI) score. The meta-analysis showed significant improvement in CMAI score [weighted mean difference (WMD) -6.31, 95% CI -9.52 to -3.11] and NPI score (WMD -8.07, 95% CI -13.53 to -2.61) in patients receiving 3 to 4 weeks of aromatherapy compared with the control group. Four of the 15 trials reported improvement in depressive mood and 3 trials reported no significant improvement in functional ability., Conclusions and Implications: In conclusion, aromatherapy is a safe and viable nonpharmacologic treatment to improve BPSD in people with dementia and its combination with massage showed higher efficacy., Competing Interests: Disclosure The authors declare no conflicts of interest., (Copyright © 2024 Post-Acute and Long-Term Care Medical Association. Published by Elsevier Inc. All rights reserved.)

Noble-metal-free CO 2 reduction systems based on cobalt phthalocyanine ( CoPc ) and its derivatives have demonstrated remarkable photocatalytic performances; however, their structure-activity relationship with electronic tuning remains unexplored. Herein, we now provide a systematic study to investigate the electron effects of substituents on the CoPc family in photocatalytic CO 2 reduction, where a Cu(I) heteroleptic photosensitizer is utilized. The highest performance can be achieved using cobalt tetracarboxylphthalocyanine in light-driven CO 2 -to-CO reduction, with a maximum turnover number of 2950 at 450 nm and an outstanding apparent quantum yield of 63.5% at 425 nm, over ten times the activity with the tetra-dimethylamino-substituted CoPc derivative. The favorable electron-withdrawing effects have been further verified by DFT calculations and cyclic voltammetry, which reduces the overpotential required for CO 2 reduction and decreases the Gibbs free energy of the catalyst active intermediates, particularly the CO-desorption energetics.

Objectives: Obstructive sleep apnea is associated with alterations in slow-wave activity during sleep, potentially increasing the risk of Alzheimer's disease. This study investigated the associations between obstructive sleep apnea manifestations such as respiratory events, hypoxia, arousal, slow-wave patterns, and neurochemical biomarker levels., Methods: Individuals with suspected obstructive sleep apnea underwent polysomnography. Sleep disorder indices, oxygen metrics, and slow-wave activity data were obtained from the polysomnography, and blood samples were taken the following morning to determine the plasma levels of total tau (T-Tau) and amyloid beta-peptide 42 (Aβ 42 ) by using an ultrasensitive immunomagnetic reduction assay. Subsequently, the participants were categorized into groups with low and high Alzheimer's disease risk on the basis of their computed product Aβ 42 × T-Tau. Intergroup differences and the associations and mediation effects between sleep-related parameters and neurochemical biomarkers were analyzed., Results: Forty-two participants were enrolled, with 21 assigned to each of the low- and high-risk groups. High-risk individuals had a higher apnea-hypopnea index, oxygen desaturation index (≥3%, ODI-3%), fraction of total sleep time with oxygen desaturation (SpO 2- 90% TST ), and arousal index and greater peak-to-peak amplitude and slope in slow-wave activity, with a correspondingly shorter duration, than did low-risk individuals. Furthermore, indices such as the apnea-hypopnea index, ODI-3% and SpO 2- 90% TST were found to indirectly affect slow-wave activity, thereby raising the Aβ 42 × T-Tau level., Conclusions: Obstructive sleep apnea manifestations, such as respiratory events and hypoxia, may influence slow-wave sleep activity (functioning as intermediaries) and may be linked to elevated neurochemical biomarker levels. However, a longitudinal study is necessary to determine causal relationships among these factors., Statement of Significance: This research aims to bridge gaps in understanding how obstructive sleep apnea is associated with an elevated risk of Alzheimer's disease, providing valuable knowledge for sleep and cognitive health., Competing Interests: Declaration of conflicts of interest The authors declare that they have no competing interests., (Copyright © 2024 National Sleep Foundation. Published by Elsevier Inc. All rights reserved.)

While luminescent stimuli-responsive materials (LSRMs) have become one of the most sought-after materials owing to their potential in optoelectronic applications, the use of earth-scarce lanthanides remains a crucial problem to be solved for further development. In this work, two manganese-based LSRMs, ( R )-(+)-1-phenylethylammonium manganese bromide, (R-PEA) 2 MnBr 4 , and ( S )-(-)-1-phenylethylammonium manganese bromide, (S-PEA) 2 MnBr 4 , are successfully demonstrated. Both (R-PEA) 2 MnBr 4 and (S-PEA) 2 MnBr 4 show a kinetically stable red-emissive amorphous state and a thermodynamically stable green-emissive crystalline state at room temperature, where the fully reversible transition can be done through melt-quenching and annealing processes. Based on this property, a reusable manganese-halide-based time-temperature indicator is demonstrated for the first time. Furthermore, an X-ray scintillator with a low limit of detection (18.1 nGy/s) and a high spatial resolution limit (30.0 lp/mm) are achieved by exploiting the high transparency of amorphous states. These results uncover the multifunctionality of manganese halides and pave the way for upcoming research.

Atomic Ag cluster bonding is employed to reinforce the interface between PF3T nano-cluster and TiO 2 nanoparticle. With an optimized Ag loading (Ag/TiO 2  = 0.5 wt%), the Ag atoms will uniformly disperse on TiO 2 thus generating a high density of intermediate states in the band gap to form the electron channel between the terthiophene group of PF3T and the TiO 2 in the hybrid composite (denoted as T@Ag05-P). The former expands the photon absorption band width and the latter facilitates the core-hole splitting by injecting the photon excited electron (from the excitons in PF3T) into the conduction band (CB) of TiO 2 . These characteristics enable the high efficiency of H 2 production to 16 580 µmol h -1  g -1 and photocatalysis stability without degradation under visible light exposure for 96 h. Compared to that of hybrid material without Ag bonding (TiO 2 @PF3T), the H 2 production yield and stability are improved by 4.1 and 18.2-fold which shows the best performance among existing materials in similar component combination and interfacial reinforcement. The unique bonding method offers a new prospect to accelerate the development of photocatalytic hydrogen production technologies., (© 2024 Wiley‐VCH GmbH.)

Purpose: Acute erythroleukemia (AEL) is a rare and highly aggressive subtype of acute myeloid leukemia (AML) with an extremely poor prognosis when treated with available drugs. Therefore, new investigational agents capable of inducing remission are urgently required., Methods: Bioinformatics analysis, western blot and qRT-PCR were used to reveal the potential biological mechanism of bryostatin 4 (B4), an antineoplastic macrolide derived from the marine bryozoan Bugula neritina. Then, in vivo experiments were conducted to evaluate the role of transforming growth factor (TGF)-β signaling in the progression of AEL., Results: Our results revealed that the proliferation of K562 cells and TF-1 cells was significantly inhibited by B4 at IC 50 values of 37 nM and 52 nM, respectively. B4 inhibited TGF-β signaling and its downstream pathway targets, particularly the phosphorylation of Smad2, Smad3, Ras, C-RAF, ERK1/2, and MEK. B4 also played an important role in cell invasion and migration in K562 cells and TF-1 cells by reducing the protein levels of the mesenchymal cell marker vimentin. Moreover, Flow cytometry and western blot analyses demonstrated that B4 induced apoptosis and initiated G0/G1 phase arrest by modulating mitochondrial dysfunction and cyclin-dependent kinase (CDK) expression., Conclusion: These findings indicated that B4 could inhibit the proliferation, migration, invasion, and TGF-β signaling pathways of AEL cells, thus suggesting that B4 possesses therapeutic potential as a treatment for AEL., (© 2024. Springer Nature Switzerland AG.)

Achieving a narrow emission bandwidth is long pursued for display applications. Among all primary colors, obtaining pure red emission with high visual perception is the most challenging. In this work, CsPbI 3 halide perovskite nanoplatelets (NPLs) with rigorously controlled 2D  [PbI 6 ] 4- octahedron layer number (n) are demonstrated. A perovskite core-PbSO 4 shell structure is designed to prevent aggregation and fusion between NPLs, enabling consistent thickness and quantum confinement strength for each NPL. Consequently, exact n = 4 CsPbI 3  NPLs are demonstrated, exhibiting emission peaks around 630 nm, with very narrow spectral bandwidths of <24 nm and high absolute photoluminescence quantum yields up to 85%. The emission of n = 4 NPLs falls exactly within the pure-red region, closely aligning with the International Telecommunication Union Recommendation BT.2020  standard. Measurements suggest predominant stability and color homogeneity compared to traditional red-emitting CsPbI x Br 3- x nanocrystals. Finally, proof-of-concept pure-red emissive light-emitting diodes (LEDs) are demonstrated by integrating n = 4 CsPbI 3 NPLs films with a blue LED chip, showing an excellent external quantum efficiency of 18.3% and high brightness exceeding 3 × 10 6 nits. Stringent requirements for future display technologies, are satisfied based on the high color purity, stability, and brightness of CsPbI 3 NPLs., (© 2024 Wiley‐VCH GmbH.)

Age-related macular degeneration (AMD), a leading cause of blindness, is characterized by mitochondrial dysfunction of retinal pigment epithelium (RPE) cells. EUK-134 is a mimetic of SOD2 and catalase, widely used for its antioxidant properties in models of light-induced damage or oxidative stress. However, its effects on the retina are not yet clear. Here, we investigated the capability of EUK-134 in averting AMD using sodium iodate (NaIO 3 )-induced Balb/c mouse and ARPE-19 cells (adult RPE cell line). In vivo, EUK-134 effectively antagonized NaIO 3 -induced retinal deformation and prevented outer and inner nuclear layer thinning. In addition, it was found that the EUK-134-treated group significantly down-regulated the expression of cleaved caspase-3 compared with the group treated with NaIO 3 alone. Our results found that EUK-134 notably improved cell viability by preventing mitochondrial ROS accumulation-induced membrane potential depolarization-mediated apoptosis in NaIO 3 -inducted ARPE-19 cells. Furthermore, we found that EUK-134 could inhibit p-ERK, p-p38, p-JNK, p-p53, Bax, cleaved caspase-9, cleaved caspase-3, and cleaved PARP by increasing Bcl-2 protein expression. Additionally, we employed MAPK pathway inhibitors by SB203580 (a p38 inhibitor), U0126 (an ERK inhibitor), and SP600125 (a JNK inhibitor) to corroborate the aforementioned observation. The results support that EUK-134 may effectively prevent mitochondrial oxidative stress-mediated retinal apoptosis in NaIO 3 -induced retinopathy., (© 2024 Wiley Periodicals LLC.)

Objective: Studies have shown that electroacupuncture (EA) can alleviate cognitive impairments from Alzheimer's disease (AD) by regulating the expression of adenosine monophosphate-activated protein kinase (AMPK), but the specific mechanism involved remains to be elucidated. Therefore, this study explores the potential mechanism by which EA improves cognitive function from the perspective of mitochondrial dynamics., Methods: The four-month-old transgenic mice with amyloid precursor protein (APP)/presenilin 1 (PS1) and AMPKα1-subunit conditional knockout (AMPKα1-cKO) were used for experiments. To evaluate the effects of EA treatment on cognitive function, the T-maze and Morris water maze were used. In addition, chemical exchange saturation transfer, thioflavin staining, transmission electron microscopy, mitochondrial membrane potential, and Western blotting were used to examine the potential mechanisms underlying the effects of EA on APP/PS1 mice., Results: Both APP/PS1 mice and AMPKα1-cKO mice exhibited dysfunction in mitochondrial dynamics accompanied by learning and memory impairment. Inactivation of the AMPK/peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) pathway increased pathological amyloid-β (Aβ) deposition and aggravated the dysfunction in mitochondrial dynamics. In addition, EA rescued learning and memory deficits in APP/PS1 mice by activating the AMPK/PGC-1α pathway, specifically by reducing pathological Aβ deposition, normalizing energy metabolism, protecting the structure and function of mitochondria, increasing the levels of mitochondrial fusion proteins, and downregulating the expression of fission proteins. However, the therapeutic effect of EA on cognition in APP/PS1 mice was hindered by AMPKα1 knockout., Conclusion: The regulation of hippocampal mitochondrial dynamics and reduction in Aβ deposition via the AMPK/PGC-1α pathway are critical for the ability of EA to ameliorate cognitive impairment in APP/PS1 mice. Please cite this article as: Jia WW, Lin HW, Yang MG, Dai YL, Ding YY, Xu WS, Wang SN, Cao YJ, Liang SX, Wang ZF, Chen C, Liu WL. Electroacupuncture activates AMPKα1 to improve learning and memory in the APP/PS1 mouse model of early Alzheimer's disease by regulating hippocampal mitochondrial dynamics. J Integr Med. 2024; 22(5): 588-599., (Copyright © 2024 Shanghai Yueyang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine. Published by Elsevier B.V. All rights reserved.)

Background: Venous thromboembolism (VTE) significantly affects the prognosis of surgical patients with inguinal hernia. The complex Caprini score, commonly used for postoperative VTE risk assessment, poses practical challenges for surgeons in clinical settings., Methods: The CHAT-3 trial, a prospective, multicenter, randomized controlled trial, compared a simple three-factor model to assess VTE risk against routine practices in postinguinal hernia surgery (IHS) patients. The patients were randomly assigned (1:1) to the intervention or control arm. The intervention group used the three-factor model to identify patients at moderate or high risk of VTE for subsequent prophylaxis according to clinical guidelines. Both groups were followed for 4 weeks, with randomization implemented using computer-generated sequences. The primary outcome measured was the rate of VTE prophylaxis. Secondary outcomes included time spent on VTE risk assessment (surgeon self-reported), postoperative D-dimer trends, perioperative VTE occurrence, bleeding events, and the net clinical benefit., Results: Of the 1109 participants, 508 in the experimental group and 601 in the control group completed follow-up. The three-factor model showed higher VTE prophylaxis rates in all patients (pharmacologic prophylaxis: 26.2 vs. 6.00%, P <0.001) and particularly in those at high risk (pharmacologic prophylaxis: 57.3 vs. 9.50%, P <0.001). The experimental group significantly reduced VTE risk assessment time compared to the Caprini score (1.39±0.55 min vs. 5.73±1.35 min, P <0.001). The experimental group had lower D-dimer levels (0.26±0.73 mg/l vs. 0.35±0.55 mg/l, P =0.028). In the experimental group, the patients did not experience an increased risk of VTE (0 vs. 1.66%, P =0.268) and bleeding (1.18 vs. 0.67%, P =0.558) compared to the controls. There was no significant difference in net clinical benefit, which combined VTE and bleeding events, between the experimental and control groups (1.18 vs. 0.83%, P =0.559)., Conclusion: Applying the simple three-factor model in perioperative VTE management could quickly identify the patient with a high risk of VTE and improve the prophylaxis rate of perioperative VTE., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: The global prevalence of autoimmune hepatitis (AIH) is increasing due in part to the lack of effective pharmacotherapies. Growing evidence suggests that fibroblast growth factor 4 (FGF4) is crucial for diverse aspects of liver pathophysiology. However, its role in AIH remains unknown. Therefore, we investigated whether FGF4 can regulate M1 macrophage and thereby help treat liver inflammation in AIH., Methods: We obtained transcriptome-sequencing and clinical data for patients with AIH. Mice were injected with concanavalin A to induce experimental autoimmune hepatitis (EAH). The mechanism of action of FGF4 was examined using macrophage cell lines and bone marrow-derived macrophages., Results: We observed higher expression of markers associated with M1 and M2 macrophages in patients with AIH than that in individuals without AIH. EAH mice showed greater M1-macrophage polarization than control mice. The expression of M1-macrophage markers correlated positively with FGF4 expression. The loss of hepatic Fgf4 aggravated hepatic inflammation by increasing the abundance of M1 macrophages. In contrast, the pharmacological administration of FGF4 mitigated hepatic inflammation by reducing M1-macrophage levels. The efficacy of FGF4 treatment was compromised following the in vivo clearance of macrophage populations. Mechanistically, FGF4 treatment activated the phosphatidylinositol 3-kinase (PI3K)-protein kinase B (AKT)-signal pathway in macrophages, which led to reduced M1 macrophages and hepatic inflammation., Conclusion: We identified FGF4 as a novel M1/M2 macrophage-phenotype regulator that acts through the PI3K-AKT-signaling pathway, suggesting that FGF4 may represent a novel target for treating inflammation in patients with AIH., (© 2024. The Author(s).)

Background: A fixed 10-year lead-time in composite time-trade-off (C-TTO) tasks might compromise the precision of utility values below - 1. This study explored how alternative lead-times (ALTs) influence EQ-5D-5L value sets and their implications in economic evaluations., Methods: Leveraging data from Taiwan's EQ-5D-5L valuation and capitalizing on its exploratory willingness-to-accept question, we explored participants' quantification of "worse-than-dead (WTD)" health states with ALTs up to 50 years. We then derived alternative value sets incorporating these ALTs through interval regression and compared them against those from conventional models. To evaluate their impact on health change valuation, we simulated utility differences for all possible EQ-5D-5L health-state-pairs using each value set., Results: With a salient floor effect observed in the C-TTO values, the model with ALT led to a wider range of predicted utilities ( - 2.3897 ~ 1), compared with those of conventional models (generalized least squares (GLS):  - 0.7773 ~ 1; Tobit-GLS:  - 0.9583 ~ 1). Compared to the Tobit-GLS model, the model with ALT increased the numerical distance in 80% of health-state-pairs, with 11% decreasing and 9% altering direction (e.g., positive to negative) in utility differences., Conclusions: While ALTs offer insights into patient preferences, their integration into economic evaluations might require rescaling. Future research should prioritize advanced rescaling methods or enhanced elicitation strategies for populations with substantial censoring. This is pivotal for improving the elicitation of extreme WTD states and accurately discerning the relative distances between health states. Countries developing EQ-5D-5L value sets should consider pilot studies and incorporating region-specific questions on social determinants, especially where pronounced floor effects are suspected., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: Several guidelines do not recommend beta-blocker as the first-line treatment for hypertension because of its inferior efficacy in stroke prevention. Combination therapy with beta-blocker is commonly used for blood pressure control. We compared the clinical outcomes in patients treated with amlodipine plus bisoprolol (A + B), a ß1-selective beta-blocker and amlodipine plus valsartan (A + V)., Methods: A population-based cohort study was performed using data from the Taiwan National Health Insurance Research Database. From 2012 to 2019, newly diagnosed adult hypertensive patients who received initial amlodipine monotherapy and then switched to A + V or A + B were included. The efficacy outcomes included all-cause death, atherosclerotic cardiovascular disease (ASCVD) event (cardiovascular death, myocardial infarction, ischemic stroke, and coronary revascularization), hemorrhagic stroke, and heart failure. Multivariable Cox proportional hazards model was used to evaluate the relationship between outcomes and different treatments., Results: Overall, 4311 patients in A + B group and 10980 patients in A + V group were included. After a mean follow-up of 4.34 ± 1.79 years, the efficacy outcomes were similar between the A + V and A + B groups regarding all-cause death (adjusted hazard ratio [aHR] 0.99, 95% confidence interval [CI] 0.83-1.18), ASCVD event (aHR 0.97, 95% CI 0.84-1.12), and heart failure (aHR 1.06, 95% CI 0.87-1.30). The risk of hemorrhagic stroke was lower in A + B group (aHR 0.70, 95% CI 0.52-0.94). The result was similar when taking death into consideration in competing risk analysis. The safety outcomes were similar between the 2 groups., Conclusions: There was no difference of all-cause death, ASCVD event, and heart failure in A + B vs. A + V users. But A + B users had a lower risk of hemorrhagic stroke.

Neonatal hypoxia-ischemia (HI) results in behavioral deficits, characterized by neuronal injury and retarded myelin formation. To date, limited treatment methods are available to prevent or alleviate neurologic sequelae of HI. Intermittent theta-burst stimulation (iTBS), a non-invasive therapeutic procedure, is considered a promising therapeutic tool for treating some neurocognitive disorders and neuropsychiatric diseases. Hence, this study aims to investigate whether iTBS can prevent the negative behavioral manifestations of HI and explore the mechanisms for associations. We exposed postnatal day 10 Sprague-Dawley male and female rats to 2 h of hypoxia (6% O 2 ) following right common carotid artery ligation, resulting in oligodendrocyte (OL) dysfunction, including reduced proliferation and differentiation of oligodendrocyte precursor cells (OPCs), decreased OL survival, and compromised myelin in the corpus callosum (CC) and hippocampal dentate gyrus (DG). These alterations were concomitant with cognitive dysfunction and depression-like behaviors. Crucially, early iTBS treatment (15 G, 190 s, seven days, initiated one day post-HI) significantly alleviated HI-caused myelin damage and mitigated the neurologic sequelae both in male and female rats. However, the late iTBS treatment (initiated 18 days after HI insult) could not significantly impact these behavioral deficits. In summary, our findings support that early iTBS treatment may be a promising strategy to improve HI-induced neurologic disability. The underlying mechanisms of iTBS treatment are associated with promoting the differentiation of OPCs and alleviating myelin damage., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Inc.)

Two new 9,11-secosterols, hipposponols A ( 1 ) and B ( 2 ), together with five known analogues, aplidiasterol B ( 3 ), (3 β ,5 α ,6 β )-3,5,6-triol-cholest-7-ene ( 4 ), (3 β ,5 α ,6 β ,22 E )-3,5,6-triol-ergosta-7,22-diene ( 5 ), and one pair of inseparable C-24 epimers of (3 β ,5 α ,6 β ,22E)-3,5,6-triol-stigmasta-7,22-diene ( 6 / 7 ), were isolated from the marine sponge Hippospongia lachne de Laubenfels. The structures of isolated compounds were extensively elucidated based on HRESIMS and NMR data. Compounds 2  -  5 showed cytotoxicity against PC9 cells with IC 50 values ranging from 34.1 ± 0.9 to 38.9 ± 1.0 µM and compound 4 displayed cytotoxicity against MCF-7 cells with IC 50 value of 39.0 ± 0.4 µM.

Diffuse large B-cell lymphoma (DLBCL) is a genetically heterogeneous non-Hodgkin lymphoma that is extremely aggressive and has an intermediate to high malignancy. Some patients still experience treatment failure, relapse, or resistance to rituximab, cyclophosphamide, adriamycin, vincristine, and prednisone (R-CHOP) therapy. Therefore, there is an urgent need for further research on new agents for the treatment of DLBCL. AP-48 is an aaptamine alkaloid analog with potent anti-tumor effects that originates from marine natural products. In this study, we found that AP-48 exhibits dose-dependent cytotoxicity in DLBCL cell lines. Flow cytometry showed that AP-48 induced cell cycle arrest in the G0/G1 phase in SU-DHL-4 and Farage cells and in the S phase in WSU-DLCL-2 cells. AP-48 also accelerated apoptosis via the caspase-3-mediated intrinsic apoptotic pathway. Further experiments demonstrated that AP-48 exerted its anti-DLBCL effects through the PI3K/AKT/mTOR pathway, and that the PI3K agonist YS49 partially alleviated the inhibition of cell proliferation and apoptosis induced by AP-48. Finally, in a tumor xenograft model, AP-48 inhibited tumor growth and promoted apoptosis in tumor tissues, indicating its therapeutic potential in DLBCL., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Even though much progress has been made to improve clinical outcomes, acute respiratory distress syndrome (ARDS) remains a significant cause of acute respiratory failure. Protective mechanical ventilation is the backbone of supportive care for these patients; however, there are still many unresolved issues in its setting. The primary goal of mechanical ventilation is to improve oxygenation and ventilation. The use of positive pressure, especially positive end-expiratory pressure (PEEP), is mandatory in this approach. However, PEEP is a double-edged sword. How to safely set positive end-inspiratory pressure has long been elusive to clinicians. We hereby propose a pressure-volume curve measurement-based method to assess whether injured lungs are recruitable in order to set an appropriate PEEP. For the most severe form of ARDS, extracorporeal membrane oxygenation (ECMO) is considered as the salvage therapy. However, the high level of medical resources required and associated complications make its use in patients with severe ARDS controversial. Our proposed protocol also attempts to propose how to improve patient outcomes by balancing the possible overuse of resources with minimizing patient harm due to dangerous ventilator settings. A recruitment-potential-oriented evaluation-based protocol can effectively stabilize hypoxemic conditions quickly and screen out truly serious patients.

Multidrug resistance is a substantial obstacle in treating non-small cell lung cancer (NSCLC) with therapies like cisplatin (DDP)-based adjuvant chemotherapy and EGFR-tyrosine kinase inhibitors (TKIs). Aaptamine-7 (AP-7), a benzonaphthyridine alkaloid extracted from Aaptos aaptos sponge, has been shown to exhibit a broad spectrum of anti-tumor activity. However, the anti-cancer activity of AP-7 in combination with DDP and its molecular mechanisms in multidrug-resistant NSCLC are not yet clear. Our research indicates that AP-7 bolsters the growth inhibition activity of DDP on multidrug-resistant NSCLC cells. AP-7 notably disrupts DDP-induced cell cycle arrest and amplifies DDP-induced DNA damage effects in these cells. Furthermore, the combination of AP-7 and DDP downregulates Chk1 activation, interrupts the DNA damage repair-dependent Chk1/CDK1 pathway, and helps to overcome drug resistance and boost apoptosis in multidrug-resistant NSCLC cells and a gefitinib-resistant xenograft mice model. In summary, AP-7 appears to enhance DDP-induced DNA damage by impeding the Chk1 signaling pathway in multidrug-resistant NSCLC, thereby augmenting growth inhibition, both in vitro and in vivo . These results indicate the potential use of AP-7 as a DDP sensitizer in the treatment of multidrug-resistant NSCLC., 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 © 2024 Guan, Liao, Cao, Liu, Xue, Zhu, Bian, Yang, Lin, Liao and Sun.)

Two new cytochalasans, marcytoglobosins A (1) and B (2) were isolated from the marine sponge associated fungus Chaetomium globosum 162105, along with six known compounds (3-8). The complete structures of two new compounds were determined based on 1D/2D NMR and HR-MS spectroscopic analyses coupled with ECD calculations. All eight isolates were evaluated for their antibacterial activity. Among them, compounds 3-8 displayed antibacterial effects against Staphylococcus epidermidis, Bacillus thuringiensis, Pseudomonas syringae pv. Actinidiae, Vibrio alginolyticus, and Edwardsiella piscicida with minimum inhibitory concentration (MIC) values ranging from 10 to 25 μg/mL., (© 2024 Wiley-VHCA AG, Zurich, Switzerland.)

Background: The CRC-VTE trial conducted in China revealed a significant occurrence of venous thromboembolism (VTE) in patients following colorectal cancer (CRC) surgery, raising concerns about implementing thromboprophylaxis measures. The present study aimed to identify and analyze inappropriate aspects of current thromboprophylaxis practices., Methods: This study performed an analysis of the CRC-VTE trial, a prospective multicenter study that enrolled 1836 patients who underwent CRC surgery. The primary objective was to identify independent risk factors for VTE after CRC surgery using multivariate logistic regression analysis. Furthermore, among the cases in which VTE occurred, the appropriateness of thromboprophylaxis was assessed based on several factors, including pharmacologic prophylaxis, time to initiate prophylaxis, drug selection, drug dosage, and duration of pharmacologic prophylaxis. Based on the analysis of the current state of thromboprophylaxis and relevant clinical guidelines, a modified Delphi method was used to develop a clinical pathway for VTE prophylaxis after CRC surgery., Results: In this analysis of 1836 patients, 205 (11.2%) were diagnosed with VTE during follow-up. The multifactorial analysis identified several independent risk factors for VTE, including age (≥70 years), female sex, varicose veins in the lower extremities, intraoperative blood transfusion, and the duration of immobilization exceeding 24 h. None of the patients diagnosed with VTE in the CRC trial received adequate thromboprophylaxis. The main reasons for this inappropriate practice were the omission of thromboprophylaxis, delayed initiation, and insufficient duration of thromboprophylaxis. We developed a specialized clinical pathway for thromboprophylaxis after CRC surgery to address these issues., Conclusions: This study offers a comprehensive nationwide evaluation of existing thromboprophylaxis practices in patients after CRC surgery in China. A specialized clinical pathway was developed to address the identified gaps and improve the quality of care. This clinical pathway incorporates explicit, tailored, detailed recommendations for thromboprophylaxis after CRC surgery., (© 2024 Pharmacotherapy Publications, Inc.)

Chronic obstructive pulmonary disease (COPD) is now considered among the top three contributors to mortality globally. There is limited understanding surrounding the contribution of magnesium to the progression of COPD. This survey aims to evaluate the connection between dietary magnesium intake and both lung function and COPD prevalence among the US population. The research comprised 4865 participants in the National Health and Nutrition Examination Survey (NHANES) program conducted from 2007 to 2012. To evaluate the association between dietary magnesium intake and lung function as well as COPD, the study conducted multiple regression analyses, stratified analyses, and smoothed curves. In this study, we explored the relationship between higher magnesium intake and higher FEV 1 [β = 0.21 (95% CI 0.12, 0.30)] and FVC [β = 0.25 (95% CI 0.14, 0.36)] after accounting for all potential confounding factors. We demonstrated a relationship between increased magnesium intake and reduced odds of developing COPD [OR = 0.9993 (95% CI 0.9987, 1.0000)]. The results of stratified analyses further indicated that the relationship between magnesium intake and the risk of COPD is more pronounced in the 40-60 age group and males. The study demonstrated positive associations between the intake of dietary magnesium and both FEV 1 and FVC. Additionally, an adverse relationship between magnesium intake and the prevalence of COPD was also observed, suggesting that supplementation with magnesium may be a practical approach to preventing and managing COPD., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Competing Interests: Declaration of interests We declare no competing interests.

The acute and long-term consequences of mild traumatic brain injury (mTBI) are far reaching. Though it may often be overlooked due to the now expansive field of research dedicated to understanding the consequences of mTBI on the brain, recent work has revealed that substantial changes in the vestibulo-auditory system can also occur due to mTBI. These changes, termed "labyrinthine" or "cochlear concussion," include hearing loss, vertigo, and tinnitus that develop after mTBI in the setting of an intact bony labyrinthine capsule (as detected on imaging). In the review that follows, we focus our discussion on the effects of mTBI on the peripheral structures and pathways of the auditory and vestibular systems. Although the effects of indirect trauma (e.g., noise and blast trauma) have been well-investigated, there exists a profound need to improve our understanding of the effects of direct head injury (such as mTBI) on the auditory and vestibular systems. Our aim is to summarize the current evidentiary foundation upon which labyrinthine and/or cochlear concussion are based to shed light on the ways in which clinicians can refine the existing modalities used to diagnose and treat patients experiencing mTBI as it relates to hearing and balance.

High-intensity statin (HIS) is recommended for high-risk patients in current guidelines. However, the risk of hemorrhagic stroke (HS) with HIS is a concern for Asians. Pitavastatin carries pharmacological differences compared with other statins. We compared the risk of HS in patients treated with pitavastatin-ezetimibe vs. HIS. We conducted a population-based, propensity score-matched cohort study using data from the Taiwan National Health Insurance Research Database. From January 2013 to December 2018, adults (≥ 18 years) who received pitavastatin 2-4 mg/day plus ezetimibe 10 mg/day (combination group, N = 3,767) and those who received atorvastatin 40 mg/day or rosuvastatin 20 mg/day (HIS group, N = 37,670) were enrolled. The primary endpoint was HS. We also assessed the difference of a composite safety endpoint of hepatitis or myopathy requiring hospitalization and new-onset diabetes mellitus. Multivariable Cox proportional hazards model was used to evaluate the relationship between study endpoints and different treatment. After a mean follow-up of 3.05 ± 1.66 years, less HS occurred in combination group (0.74%) than in HIS group (1.35%) [adjusted hazard ratio (aHR) 0.65, 95% confidence interval (CI) 0.44-0.95]. In subgroup analysis, the lower risk of HS in combination group was consistent among all pre-specified subgroups. There was no significant difference of the composite safety endpoint between the 2 groups (aHR 0.91, 95% CI 0.81-1.02). In conclusion, pitavastatin-ezetimibe combination treatment had less HS compared with high-intensity atorvastatin and rosuvastatin. Pitavastatin-ezetimibe may be a favorable choice for Asians who need strict lipid control but with concern of HS.

Structurally symmetric dyes using functionalized fluorenes and benzotriazole as the main building moieties have been synthesized and found to exhibit efficient dual-state emission (DSE) and interesting two-wavelength or dual amplified spontaneous emission (dual-ASE) behaviors in the solution phase, which may benefit the development of organic gain materials with dual-wavelength amplification.

Introduction: Myasthenia gravis (MG) is a chronic neuromuscular disease leading to significant disease burden. This study aimed to investigate the epidemiology of MG in Taiwan., Methods: A retrospective study was conducted using the Taiwan National Health Insurance Research Database. Prevalent patients with MG diagnosis (either ocular or generalized MG) from 2013 to 2019 were identified, and 2813 patients with initial MG diagnosis from 2014 to 2019 were further defined as the incident cohort. Patient characteristics, treatment patterns, and the occurrence of MG-related events were analyzed., Results: The number of prevalent patients with MG increased from 4476 in 2013 to 5752 in 2019, with the prevalence rate increasing from 19 to 24 per 100,000 population. The incidence rate also slightly increased from 1.9 to 2.3 per 100,000 population during the study period. Almost all incident patients (99%, n = 2791) received MG-related treatment during the follow-up period. Among 1876 patients who received monotherapy as their initial treatment in the outpatient setting, the mean time from the index date to initial treatment was 48.8 (standard deviation 164.3) days, and most patients received acetylcholinesterase inhibitors (88.5%, n = 1661) as their initial treatment. During the first year after the index date, 133 (4.7%) incident patients experienced their first myasthenic crisis, and 96.2% of these events occurred within 3 months., Conclusion: The prevalence of MG increased steadily in Taiwan, and the treatment of patients with MG was consistent with guidelines. Despite a high treatment rate, patients still experienced MG-related events, highlighting the limitation of current treatments and emphasizing the need for early intervention and novel treatment approaches., (© 2024. The Author(s).)

Alzheimer's disease (AD) is the leading cause of mortality, disability, and long-term care burden in the United States, with women comprising the majority of AD diagnoses. While AD-related dementia is associated with tau and amyloid beta accumulation, concurrent derangements in cerebral blood flow have been observed alongside these proteinopathies in humans and rodent models. The homeostatic production of nitric oxide synthases (NOS) becomes uncoupled in AD which leads to decreased NO-mediated vasodilation and oxidative stress via the production of peroxynitrite (ONOO-∙) superoxide species. Here, we investigate the role of the novel protein arginine methyltransferase 4 (PRMT4) enzyme function and its downstream product asymmetric dimethyl arginine (ADMA) as it relates to NOS dysregulation and cerebral blood flow in AD. ADMA (type-1 PRMT product) has been shown to bind NOS as a noncanonic ligand causing enzymatic dysfunction. Our results from RT-qPCR and protein analyses suggest that aged (9-12 months) female mice bearing tau- and amyloid beta-producing transgenic mutations (3xTg-AD) express higher levels of PRMT4 in the hippocampus when compared to age- and sex-matched C57BL6/J mice. In addition, we performed studies to quantify the expression and activity of different NOS isoforms. Furthermore, laser speckle contrast imaging analysis was indicative that 3xTg-AD mice have dysfunctional NOS activity, resulting in reduced production of NO metabolites, enhanced production of free-radical ONOO-, and decreased cerebral blood flow. Notably, the aforementioned phenomena can be reversed via pharmacologic PRMT4 inhibition. Together, these findings implicate the potential importance of PRMT4 signaling in the pathogenesis of Alzheimer's-related cerebrovascular derangement., (© 2022 The Authors. Journal of Cellular Physiology published by Wiley Periodicals LLC.)

Introduction: Cerebral amyloid angiopathy (CAA) is characterized by the deposition of amyloid-beta peptides within cerebral blood vessels, leading to neurovascular complications. Ischemic strokes result from acute disruptions in cerebral blood flow, triggering metabolic disturbances and neurodegeneration. Both conditions often co-occur and are associated with respiratory dysfunctions. The retrotrapezoid nucleus (RTN), which is crucial for CO 2 sensing and breathing regulation in the brainstem, may play a key role in breathing disorders seen in these conditions. This study aims to investigate the role of Transforming Growth Factor Beta (TGF-β) signaling in the RTN on respiratory and cognitive functions in CAA, both with and without concurrent ischemic stroke., Methods: Adult male Tg-SwDI (CAA model) mice and C57BL/6 wild-type controls underwent stereotaxic injections of lentivirus targeting TGF-β2R2 in the RTN. Stroke was induced by middle cerebral artery occlusion using a monofilament. Respiratory functions were assessed using whole-body plethysmography, while cognitive functions were evaluated through the Barnes Maze and Novel Object Recognition Test (NORT). Immunohistochemical analysis was conducted to measure TGF-βR2 and GFAP expressions in the RTN., Results: CAA mice exhibited significant respiratory dysfunctions, including reduced respiratory rates and increased apnea frequency, as well as impaired cognitive performance. TGF-βR2 knockdown in the RTN improved respiratory functions and cognitive outcomes in CAA mice. In CAA mice with concurrent stroke, TGF-βR2 knockdown similarly enhanced respiratory and cognitive functions. Immunohistochemistry confirmed reduced TGF-βR2 and GFAP expressions in the RTN following knockdown., Conclusions: Our findings demonstrate that increased TGF-β signaling and gliosis in the RTN contribute to respiratory and cognitive dysfunctions in CAA and CAA with stroke. Targeting TGF-βR2 signaling in the RTN offers a promising therapeutic strategy to mitigate these impairments. This study is the first to report a causal link between brainstem gliosis and both respiratory and cognitive dysfunctions in CAA and stroke models., Competing Interests: Disclosures The authors declare no potential conflicts of interest with respect to research, authorship, and/or publication of this article.

Highly emissive semiconductor nanocrystals, or so-called quantum dots (QDs) possess a variety of applications from displays and biology labeling, to quantum communication and modern security. Though ensembles of QDs have already shown very high photoluminescent quantum yields (PLQYs) and have been widely utilized in current optoelectronic products, QDs that exhibit high absorption cross-section, high emission intensity, and, most important, nonblinking behavior at single-dot level have long been desired and not yet realized at room temperature. In this work, infrared-emissive MAPbI 3 -based halide perovskite QDs is demonstrated. These QDs not only show a ≈100% PLQY at the ensemble level but also, surprisingly, at the single-dot level, display an extra-large absorption cross-section up to 1.80 × 10 -12 cm 2 and non-blinking single photon emission with a high single photon purity of 95.3%, a unique property that is extremely rare among all types of quantum emitters operated at room temperature. An in-depth analysis indicates that neither trion formation nor band-edge carrier trapping is observed in MAPbI 3 QDs, resulting in the suppression of intensity blinking and lifetime blinking. Fluence-dependent transient absorption measurements reveal that the coexistence of non-blinking behavior and high single photon purity in these perovskite QDs results from a significant repulsive exciton-exciton interaction, which suppresses the formation of biexciton, and thus greatly reduces photocharging. The robustness of these QDs is confirmed by their excellent stability under continuous 1 h electron irradiation in high-resolution transmission electron microscope inspection. It is believed that these results mark an important milestone in realizing nonblinking single photon emission in semiconductor QDs., (© 2023 Wiley‐VCH GmbH.)

Previous studies showed that NaIO 3 can induce oxidative stress-mediated retinal pigment epithelium (RPE) damage to simulate age-related macular degeneration (AMD). Lemon peel is rich in antioxidants and components that can penetrate the blood-retinal barrier, but their role in retinal oxidative damage remains unexplored. Here, we explore the protection of lemon peel ultrasonic-assisted water extract (LUWE), containing large amounts of flavonoids and polyphenols, against NaIO 3 -induced retinal degeneration. We initially demonstrated that LUWE, orally administered, prevented retinal distortion and thinning on the inner and outer nuclei layers, downregulating cleaved caspase-3 protein expression in RPE cells in NaIO 3 -induced mice. The effect of LUWE was achieved through the suppression of apoptosis and the associated proteins, such as cleaved PARP and cleaved caspase-3, as suggested by NaIO 3 -induced ARPE-19 cell models. This is because LUWE reduced reactive oxygen species-mediated mitochondrial fission via regulating p-Drp-1 and Fis1 expression. We further confirmed that LUWE suppresses the expression of p-MEK-1/2 and p-ERK-1/2 in NaIO 3 -induced ARPE-19 cells, thereby providing the protection described above, which was confirmed using PD98059 and U0126. These results indicated that LUWE prevents mitochondrial oxidative stress-mediated RPE damage via the MEK/ERK pathway. Elucidation of the molecular mechanism may provide a new protective strategy against retinal degeneration.

Unraveling the intricacies between oxygen dynamics and cellular processes in the tumor microenvironment (TME) hinges upon precise monitoring of intracellular and intratumoral oxygen levels, which holds paramount significance. The majority of these reported oxygen nanoprobes suffer compromised lifetime and quantum yield when exposed to the robust ROS activities prevalent in TME, limiting their prolonged in vitro usability. Herein, the ruthenium-embedded oxygen nano polymeric sensor (Ru-ONPS) is proposed for precise oxygen gradient monitoring within the cellular environment and TME. Ru-ONPS (≈64±7 nm) incorporates [Ru(dpp) 3 ]Cl 2 dye into F-127 and crosslinks it with urea and paraformaldehyde, ensuring a prolonged lifetime (5.4 µs), high quantum yield (66.65 ± 2.43% in N 2 and 49.80 ± 3.14% in O 2 ), superior photostability (>30 min), and excellent stability in diverse environmental conditions. Based on the Stern-Volmer plot, the Ru-ONPS shows complete linearity for a wide dynamic range (0-23 mg L -1 ), with a detection limit of 10 µg mL -1 . Confocal imaging reveals Ru-ONPS cellular uptake and intratumoral distribution. After 72 h, HCT-8 cells show 5.20±1.03% oxygen levels, while NIH3T3 cells have 7.07±1.90%. Co-culture spheroids display declining oxygen levels of 17.90±0.88%, 10.90±0.88%, and 5.10±1.18%, at 48, 120, and 216 h, respectively. Ru-ONPS advances cellular oxygen measurement and facilitates hypoxia-dependent metastatic research and therapeutic target identification., (© 2023 Wiley‐VCH GmbH.)

Marine sponges are well known as prolific producers of structurally diverse molecules with valuable pharmacological potential. As part of our ongoing program to discover bioactive compounds from marine sponges collected from the Xisha Islands in the South China Sea, a chemical study on the specimens of Hippospongia lachne was conducted. As a result, eight undescribed compounds, including four zwitterionic alkylpyridinium salts, hippospondines A-D (1-4), and four 3-alkylpyridine alkaloids, hippospondines E (5), F (6), and (±)-hippospondine G (7), were isolated from the marine sponge H. lachne, together with one known 3-alkylpyridine alkaloid (8). The undescribed structures were elucidated by HRESIMS, NMR, DP4+ and CP3 probability analysis, and the Snatzke's method. Hippospondines A-D (1-4) represent the rare example of inner salt type alkylpyridinium alkaloid with a farnesyl moiety. Compounds 1-3 and 8 were subjected to cytotoxic and lymphocyte proliferation assays. Compound 3 exhibited a weak promotion effect on the ConA-induced T lymphocyte proliferation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

This study presents a dataset of audio-visual soundscape recordings at 62 different locations in Singapore, initially made as full-length recordings over spans of 9-38 min. For consistency and reduction in listener fatigue in future subjective studies, one-minute excerpts were cropped from the full-length recordings. An automated method using pre-trained models for Pleasantness and Eventfulness (according to ISO 12913) in a modified partitioning around medoids algorithm was employed to generate the set of excerpts by balancing the need to encompass the perceptual space with uniformity in distribution. A validation study on the method confirmed its adherence to the intended design., (© 2024 Author(s). All article content, except where otherwise noted, is licensed under a Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).)

Background: Natural tetramates are a family of hybrid polyketides bearing tetramic acid (pyrrolidine-2,4-dione) moiety exhibiting a broad range of bioactivities. Biosynthesis of tetramates in microorganisms is normally directed by hybrid polyketide synthase (PKS) and nonribosomal peptide synthetase (NRPS) machineries, which form the tetramic acid ring by recruiting trans- or cis-acting thioesterase-like Dieckmann cyclase in bacteria. There are a group of tetramates with unique skeleton of 3-(2H-pyran-2-ylidene)pyrrolidine-2,4-dione, which remain to be investigated for their biosynthetic logics., Results: Herein, the tetramate type compounds bripiodionen (BPD) and its new analog, featuring the rare skeleton of 3-(2H-pyran-2-ylidene)pyrrolidine-2,4-dione, were discovered from the sponge symbiotic bacterial Streptomyces reniochalinae LHW50302. Gene deletion and mutant complementation revealed the production of BPDs being correlated with a PKS-NRPS biosynthetic gene cluster (BGC), in which a Dieckmann cyclase gene bpdE was identified by sit-directed mutations. According to bioinformatic analysis, the tetramic acid moiety of BPDs should be formed on an atypical NRPS module constituted by two discrete proteins, including the C (condensation)-A (adenylation)-T (thiolation) domains of BpdC and the A-T domains of BpdD. Further site-directed mutagenetic analysis confirmed the natural silence of the A domain in BpdC and the functional necessities of the two T domains, therefore suggesting that an unusual aminoacyl transthiolation should occur between the T domains of two NRPS subunits. Additionally, characterization of a LuxR type regulator gene led to seven- to eight-fold increasement of BPDs production. The study presents the first biosynthesis case of the natural molecule with 3-(2H-pyran-2-ylidene)pyrrolidine-2,4-dione skeleton. Genomic mining using BpdD as probe reveals that the aminoacyl transthiolation between separate NRPS subunits should occur in a certain population of NRPSs in nature., (© 2024. The Author(s).)

Background: Perioperative immunosuppressants, such as surgical stress and opioid use may downregulate anti-cancer immunocytes for patients undergoing pancreatectomy. Thoracic epidural analgesia (TEA) may attenuate these negative effects and provide better anti-cancer immunocyte profile change than intravenous analgesia using opioid., Methods: We randomly assigned 108 adult patients undergoing pancreatectomy to receive one of two 72-h postoperative analgesia protocols: one was TEA, and the other was intravenous patient-controlled analgesia (IV-PCA). The perioperative proportional changes of immunocytes relevant to anticancer immunity-namely natural killer (NK) cells, cytotoxic T cells, helper T cells, mature dendritic cells, and regulatory T (Treg) cells were determined at 1 day before surgery, at the end of surgery and on postoperative day 1,4 and 7 using flow cytometry. In addition, the progression-free survival and overall survival between the two groups were compared., Results: After surgery, the proportions of NK cells and cytotoxic T cells were significantly decreased; the proportion of B cells and mature dendritic cells and Treg cells were significantly increased. However, the proportions of helper T cells exhibited no significant change. These results were comparable between the two groups. Furthermore, there were no significant differences in progression-free survival (52.75 [39.96] and 57.48 [43.66] months for patients in the TEA and IV-PCA groups, respectively; p = 0.5600) and overall survival (62.71 [35.48] and 75.11 [33.10] months for patients in the TEA and IV-PCA groups, respectively; p = 0.0644)., Conclusions: TEA was neither associated with favorable anticancer immunity nor favorable oncological outcomes for patients undergoing pancreatectomy., Competing Interests: Declaration of competing interest None declared., (Copyright © 2024 Formosan Medical Association. Published by Elsevier B.V. All rights reserved.)

Cyanogramide (AC14), a novel alkaloid, isolated from the fermentation broth of the marine-derived Actinoalloteichus cyanogriseus. However, the exact role of AC14 in inflammatory bowel disease (IBD) is poorly understood. Our results demonstrated that AC14 exhibited significant inhibition of IL-6 release in THP-1 cells and a "Caco-2/THP-1" coculture system after stimulation with LPS for 24 h. However, no significant effect on TNF-α production was observed. Furthermore, in 2.5 % DSS-induced colitis mice, AC14 treatment led to improvement in body weight, colon length, and intestine mucosal barrier integrity. AC14 also suppressed serum IL-6 production and modulated dysregulated microbiota in the mice. Mechanistically, AC14 was found to inhibit the phosphorylation of Janus kinase (JAK) 2 and signal transducers and activators of transcription (STAT) 3, while simultaneously elevating the expression of suppressor of cytokine signaling (SOCS) 3, both in vivo and in vitro. These findings suggest that AC14 exerts its suppressive effects on IL-6 production in DSS-induced IBD mice through the JAK2-STAT3-SOCS3 signaling pathway. Our study highlights the potential of AC14 as a therapeutic agent for the treatment of IBD., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Lead (Pb) is nonbiodegradable and toxic to the lungs. To investigate the potential mechanisms of Pb-induced reactive oxygen species (ROS) accumulation and cell death in the lungs, human non-small lung carcinoma H460 cells were stimulated with Pb(NO 3 ) 2 in this study. The results showed that Pb(NO 3 ) 2 stimulation increased cell death by inducing cell apoptosis which showed a reduced Bcl-2 expression and an enhanced caspase 3 activation. Pb(NO 3 ) 2 also caused the production of H 2 O 2 in H460 cells that triggering the buildup of ROS and mitochondrial membrane potential loss. We found that Pb(NO 3 ) 2 modulates oxidoreductive activity through reduced the glutathione-disulfide reductase and glutathione levels in Pb(NO 3 ) 2 -exposed H460 cells. Furthermore, the superoxide dismutase (SOD) upstream molecule sirtuin 3 (SIRT3) was increased with Pb(NO 3 ) 2 dose. Collectively, these results demonstrate that Pb(NO 3 ) 2 promotes lung cell death through SIRT3/SOD-mediated ROS accumulation and mitochondrial dysfunction., (© 2023 Wiley Periodicals LLC.)

Six new sesquiterpene quinone/hydroquinone meroterpenoids, arenarialins A-F ( 1 - 6 ), were isolated from the marine sponge Dysidea arenaria collected from the South China Sea. Their chemical structures and absolute configurations were determined by HRMS and NMR data analyses coupled with DP4+ and ECD calculations. Arenarialin A ( 1 ) features an unprecedented tetracyclic 6/6/5/6 carbon skeleton, whereas arenarialins B-D ( 2 - 4 ) possess two rare secomeroterpene scaffolds. Arenarialins A-F showed inhibitory activity on the production of inflammatory cytokines TNF-α and IL-6 in LPS-induced RAW264.7 macrophages with arenarialin D regulating the NF-κB/MAPK signaling pathway.

We aim to clarify the relationship between low skeletal muscle mass and varying levels of adiposity and to identify the types of physical function impairments associated with sarcopenic obesity (SO). This study examined cross-sectional data from the National Health and Nutrition Examination Survey with whole-body dual-energy X-ray absorptiometry (DXA) scans. The data included age, gender, DXA-assessed body composition, and physical functional activity with performing daily tasks by questionnaire. We subdivided the data by body composition into a non-SO group and a SO group (ASMI 0-49.99% and FMI of 50-100%), after which the SO data were subdivided into three classes. A higher class indicated higher adiposity and lower muscle mass. The physical function impairment of the two groups was compared. Our study examined 7161 individuals, of which 4907 did not have SO and 2254 had SO, and their data were further divided into three classes (i.e., class I, 826 individuals; class II, 1300 individuals; and class III, 128 individuals). Significant differences in demographics and DXA parameters were identified between the non-SO and SO groups (P < 0.001); the individuals with SO were older, included more women, and exhibited high adiposity and less lean muscle mass. The individuals with class III SO exhibited greater differences and reported more difficulty in performing daily activities. The individuals with class III SO exhibited the most severe physical function impairment. Our study highlights the considerable difficulties encountered by individuals with SO in performing daily activities. Given this finding, customized rehabilitation strategies should be implemented to improve the quality of life of individuals with SO., (© 2024. The Author(s).)