Transcriptome analysis of the aged SAMP8 mouse model of Alzheimer's disease reveals novel molecular targets of formononetin protection.

Background: Senescence-accelerated mouse prone 8 (SAMP8) and age-matched SAMR1 mice are used to study the pathogenesis and therapeutics of Alzheimer's disease (AD); however, the molecular mechanisms are not completely understood. Objective: This study aimed to examine the effects of the 5-month administration of formononetin in SAMP8 mice and used RNA-seq to explore the molecular targets. Methods: SAMP8 mice were orally administered formononetin (0, 8, and 16 mg/kg) from 4 months of age, and age-matched SAMR1 mice were used as controls. Behavioral tests were performed in 9-month-old mice, followed by histopathologic analysis. Total RNA from the hippocampus was isolated and subjected to RNA-seq, RT-qPCR, and bioinformatics analysis. Results: The 9-month-old SAMP8 mice exhibited cognition deficits, evidenced by novel object recognition, open-field test, elevated plus maze, and passive avoidance. Nissl bodies in the cortex and hippocampus were decreased. Formononetin treatments ameliorated behavioral deficits and improved morphological changes, which were evidenced by Nissl and H&E staining. RNA-seq revealed distinct gene expression patterns between SAMP8 and SAMR1 mice. Differentially expressed genes in SAMP8 mice were attenuated or normalized by formononetin. Ingenuity pathway analysis (IPA) of canonical pathway and upstream regulators revealed increases in proinflammatory factors and immune dysfunction and decreases in NRF2 and SIRT-1 signaling pathways, leading to neuroinflammation. Formononetin treatment attenuated or reversed these molecular changes. The transcriptome of SAMP8 mice was correlated with transcriptomic profiles of other AD mouse models in the GEO database. Conclusion: Neuroinflammation and decreased antioxidant and SIRT-1 signaling contributed to cognitive deficits in aged SAMP8 mice, which are potential therapeutic targets of formononetin in combination with other therapies.

Multiple Comprehensive Analyses Identify Lysine Demethylase KDM as a Potential Therapeutic Target for Pancreatic Cancer.

Pancreatic cancer (PC) is a challenging and heterogeneous disease with a high mortality rate. Despite advancements in treatment, the prognosis for PC patients remains poor, with a high chance of disease recurrence. Biomarkers are crucial for diagnosing cancer, predicting patient prognosis and selecting treatments. However, the current lack of effective biomarkers for PC could contribute to the insufficiency of existing treatments. These findings underscore the urgent need to develop novel strategies to fight this disease. This study utilized multiple comprehensive bioinformatic analyses to identify potential therapeutic target genes in PC, focusing on histone lysine demethylases (KDMs). We found that high expression levels of KDM family genes, particularly KDM1A, KDM5A and KDM5B, were associated with improved overall survival in the cohort. Furthermore, the infiltration of various immune cells, including B cells, neutrophils, CD8+ T cells, dendritic cells, and macrophages, was positively correlated with KDM1A, KDM5A, and KDM5B expression. Moreover, MetaCore pathway analysis revealed interesting connections between KDM1A and the cell cycle and proliferation, between KDM5A and DNA damage and double-strand break repair through homologous recombination, and between KDM5B and WNT/ß-catenin signaling. These findings suggest that KDM1A, KDM5A and KDM5B may serve as promising biomarkers and therapeutic targets for PC, a disease of high importance due to its aggressive nature and urgent need for novel biomarkers to improve diagnosis and treatment.

Increased GluK1 Subunit Receptors in Corticostriatal Projection from the Anterior Cingulate Cortex Contributed to Seizure-Like Activities.

The corticostriatal connection plays a crucial role in cognitive, emotional, and motor control. However, the specific roles and synaptic transmissions of corticostriatal connection are less studied, especially the corticostriatal transmission from the anterior cingulate cortex (ACC). Here, a direct glutamatergic excitatory synaptic transmission in the corticostriatal projection from the ACC is found. Kainate receptors (KAR)-mediated synaptic transmission is increased in this corticostriatal connection both in vitro and in vivo seizure-like activities. GluK1 containing KARs and downstream calcium-stimulated adenylyl cyclase subtype 1 (AC1) are involved in the upregulation of KARs following seizure-like activities. Inhibiting the activities of ACC or its corticostriatal connection significantly attenuated pentylenetetrazole (PTZ)-induced seizure. Additionally, injection of GluK1 receptor antagonist UBP310 or the AC1 inhibitor NB001 both show antiepileptic effects. The studies provide direct evidence that KARs are involved in seizure activity in the corticostriatal connection and the KAR-AC1 signaling pathway is a potential novel antiepileptic strategy.

Promotion of stem cell-like phenotype of lung adenocarcinoma by FAM83A via stabilization of ErbB2.

Lung cancer stands as the leading cause of mortality among all types of tumors, with over 40% of cases being lung adenocarcinoma (LUAD). Family with sequence similarity 83 member A (FAM83A) emerges as a notable focus due to its frequent overexpression in LUAD. Despite this, the precise role of FAM83A remains elusive. This study addresses this gap by unveiling the crucial involvement of FAM83A in maintaining the cancer stem cell-like (CSC-like) phenotype of LUAD. Through a global proteomics analysis, the study identifies human epidermal growth factor receptor 2 (HER2 or ErbB2) as a crucial target of FAM83A. Mechanistically, FAM83A facilitated ErbB2 expression at the posttranslational modification level via the E3 ubiquitin ligase STUB1 (STIP1-homologous U-Box containing protein 1). More importantly, the interaction between FAM83A and ErbB2 at Arg241 promotes calcineurin (CALN)-mediated dephosphorylation of ErbB2, followed by inhibition of STUB1-mediated ubiquitin-proteasomal ErbB2 degradation. The maintenance of the CSC-like phenotype by FAM83A, achieved through the posttranslational regulation of ErbB2, offers valuable insights for identifying potential therapeutic targets for LUAD.

Enhanced long-term potentiation in the anterior cingulate cortex of tree shrew.

Synaptic plasticity is a key cellular model for learning, memory and chronic pain. Most previous studies were carried out in rats and mice, and less is known about synaptic plasticity in non-human primates. In the present study, we used integrative experimental approaches to study long-term potentiation (LTP) in the anterior cingulate cortex (ACC) of adult tree shrews. We found that glutamate is the major excitatory transmitter and α-amino-3-hydroxy-5-methyl-4-isoxazole-propionicacid (AMPA) receptors mediate postsynaptic responses. LTP in tree shrews was greater than that in adult mice and lasted for at least 5 h. N-methyl-d-aspartic acid (NMDA) receptors, Ca2+ influx and adenylyl cyclase 1 (AC1) contributed to tree shrew LTP. Our results suggest that LTP is a major form of synaptic plasticity in the ACC of primate-like animals. This article is part of a discussion meeting issue 'Long-term potentiation: 50 years on'.

Safety, tolerability, pharmacokinetics, and pharmacodynamics of TG103 injection in participants who are overweight or obese: a randomized, double-blind, placebo-controlled, multiple-dose phase 1b study.

BACKGROUND: TG103, a glucagon-like peptide-1 analog, is being investigated as an option for weight management. We aimed to determine the safety, tolerability, pharmacokinetics, and pharmacodynamics of TG103 injection in participants who are overweight or obese without diabetes. METHODS: In this randomized, double-blind, placebo-controlled, multiple-dose phase 1b study, participants aged 18-75 years with a body-mass index (BMI) ≥ 26.0 kg/m2 and body weight ≥ 60 kg were enrolled from three centers in China. The study included three cohorts, and in each cohort, eligible participants were randomly assigned (3:1) to one of three once-weekly subcutaneous TG103 groups (15.0, 22.5 and 30.0 mg) or matched placebo, without lifestyle interventions. In each cohort, the doses of TG103 were escalated in 1-week intervals to the desired dose over 1 to 4 weeks. Then participants were treated at the target dose until week 12 and then followed up for 2 weeks. The primary endpoint was safety and tolerability assessed by the incidence and severity of adverse events (AEs) from baseline to the end of the follow-up period. Secondary endpoints included pharmacokinetic and pharmacodynamic profiles of TG103 and the occurrence of anti-drug antibodies to TG103. RESULTS: A total of 147 participants were screened, and 48 participants were randomly assigned to TG103 (15.0, 22.5 and 30.0 mg groups, n = 12 per group) or placebo (n = 12). The mean (standard deviation, SD) age of the participants was 33.9 (10.0) years; the mean bodyweight was 81.65 (10.50) kg, and the mean BMI was 29.8 (2.5) kg/m2. A total of 466 AEs occurred in 45 of the 48 participants, with 35 (97.2%) in the TG103 group and 10 (83.3%) in the pooled placebo group. Most AEs were grade 1 or 2 in severity, and there were no serious adverse events (SAEs), AEs leading to death, or AEs leading to discontinuation of treatment. The steady-state exposure of TG103 increased with increasing dose and was proportional to Cmax,ss, AUCss, AUC0-t and AUC0-inf. The mean values of Cmax,ss ranged from 951 to 1690 ng/mL, AUC0-t ranged from 150 to 321 µg*h/mL, and AUC0-inf ranged from 159 to 340 µg*h/mL. TG103 had a half-life of 110-116 h, with a median Tmax of 36-48 h. After treatment for 12 weeks, the mean (SD) values of weight loss from baseline in the TG103 15.0 mg, 22.5 mg and 30.0 mg groups were 5.65 (3.30) kg, 5.35 (3.39) kg and 5.13 (2.56) kg, respectively, and that in the placebo group was 1.37 (2.13) kg. The least square mean percent weight loss from baseline to D85 in all the TG103 groups was more than 5% with p < 0.05 for all comparisons with placebo. CONCLUSIONS: In this trial, all three doses of once-weekly TG103 were well tolerated with an acceptable safety profile. TG103 demonstrated preliminary 12-week body weight loss without lifestyle interventions, thus showing great potential for the treatment of overweight and obesity. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04855292. Registered on April 22, 2021.

Inhibition of CXCR4: A perspective on miracle fruit seed for Alzheimer's disease treatment.

Alzheimer's disease (AD) is the most prevalent type of dementia, and its causes are currently diverse and not fully understood. In a previous study, we discovered that short-term treatment with miracle fruit seed (MFS) had a therapeutic effect on AD model mice, however, the precise mechanism behind the effect remains unclear. In this research, we aimed to establish the efficacy and safety of long-term use of MFS in AD model mice. A variety of cytokines and chemokines have been implicated in the development of AD. Previous studies have validated a correlation between the expression levels of C-X-C chemokine receptor type 4 (CXCR4) and disease severity in AD. In this research, we observed an upregulation of CXCR4 expression in hippocampal tissues in the AD model group, which was then reversed after MFS treatment. Moreover, CXCR4 knockout led to improving cognitive function in AD model mice, and MFS showed the ability to regulate CXCR4 expression. Finally, our findings indicate that CXCR4 knockout and long-term MFS treatment produce comparable effects in treating AD model mice. In conclusion, this research demonstrates that therapeutic efficacy and safety of long-term use of MFS in AD model mice. MFS treatment and the subsequent reduction of CXCR4 expression exhibit a neuroprotective role in the brain, highlighting their potential as therapeutic targets for AD.

Impact of prior SARS-CoV-2 infection on college students' hesitancy to receive additional COVID-19 vaccine booster doses: A study from Taizhou, China.

Purpose: This study aimed to examine the impact of a history of SARS-CoV-2 infection on the hesitancy of college students to receive additional COVID-19 vaccine booster doses. Methods: A population-based self-administered online survey was conducted in July 2024 in Taizhou, China. A total of 792 respondents were included in this study. Logistic regression was conducted to identify factors associated with college students' hesitation to receive booster doses of the COVID-19 vaccine. Results: Of 792 respondents, 32.2 % hesitated to receive additional doses of the COVID-19 vaccine booster. Furthermore, 23.5 % of the respondents reported an increase in hesitancy to receiving additional COVID-19 vaccine booster doses compared to before they were infected with SARS-CoV-2. In the regression analyses, college students who had a secondary infection were more hesitant to receive additional COVID-19 vaccine booster doses (OR = 0.481, 95 % CI: (0.299-0.774), P = 0.003). Moreover, students with secondary infections who were male (OR = 0.417, 95 % CI: 0.221-0.784, P = 0.007), with lower than a bachelor's degree (OR = 0.471, 95 % CI: 0.272-0.815, P = 0.007), in non-medical majors (OR = 0.460, 95 % CI: 0.248-0.856, P = 0.014), and sophomores or below (OR = 0.483, 95 % CI: 0.286-0.817, P = 0.007) were more hesitant to receive additional COVID-19 vaccine booster doses. Conclusion: A history of SARS-CoV-2 infection affects college students' hesitation to receive additional COVID-19 vaccine booster doses, which was higher in those who experienced secondary infections.

The effects of food provisioning on the gut microbiota community and antibiotic resistance genes of Yunnan snub-nosed monkey.

Yunnan snub-nosed monkeys (Rhinopithecus bieti) are the highest elevation lived non-human primate, and their survival has been threatened for decades. To promote their population growth, a reserve provides a typical monkey population with supplemental food. However, the influences of this food provisioning on their gut microbiota and antibiotic resistance genes (ARGs) were unknown. Therefore, we investigated the gut microbiota and ARGs of the food-provisioned monkey population compared with another wild foraging population. We found that food provisioning significantly increased the gut microbiota diversity and changed the community composition, particularly increased both the Firmicutes abundance and Firmicutes/Bacteroidetes ratio. Meanwhile, the food provisioning decreased the complex and stable gut microbiota network. KEGG functions were also influenced by food provisioning, with wild foraging monkeys showing higher functions of metabolism and genetic information processing, especially the carbohydrate metabolism, while food-provisioned monkeys exhibited increased environmental information processing, cellular processes, and organismal systems, including valine, leucine, and isoleucine degradation. In addition, food provisioning increased the abundance of ARGs in the gut microbiota, with most increasing the abundance of bacA gene and changing the correlations between specific ARGs and bacterial phyla in each population. Our study highlights that even food provisioning could promote wildlife nutrient intake, and it is necessary to pay attention to the increased ARGs and potential effects on gut microbiota stability and functions for this human conservation measure.

Positive and negative factors of parents vaccinating their children against COVID-19: An umbrella review.

Purpose: This umbrella review summarized the factors influencing parents' hesitancy to vaccinate their children against COVID-19 and the evidence to reduce it. Methods: The analysis included PubMed, Embase, Cochrane Library, Web of Science, and Scopus articles published before March 22, 2024. It considered all meta-analyses that investigated parental COVID-19 vaccine hesitancy. Results: Eight studies were included. Hesitancy rate of parents from five continents to vaccinate their children against COVID-19 was between 0.69 % and 95.0 %. The comprehensive synthesis in this review shows that the influencing factors originate from four aspects: Parents' attitudes, including their trust in the scientific community, concerns about COVID-19 complications, perceptions of children's susceptibility, and support from the social environment, including government incentives, low vaccination costs, and specific sociodemographic characteristics, were positive factors that reduced parental vaccine hesitancy in children. Conversely, negative aspects, including vaccine distrust, the spread of misinformation, poor economic status, and concern about unprecedentedly short development time, were associated with increased hesitancy. Conclusion: Our study identified positive and negative factors for parental COVID-19 vaccine hesitancy in children and highlighted that parental attitude was the most important determinant.

Insect cells of Spodoptera frugiperda support WSSV gene replication but not progeny virion assembly.

The lacking of stable and susceptible cell lines has hampered research on pathogenic mechanism of crustacean white spot syndrome virus (WSSV). To look for the suitable cell line which can sustain WSSV infection, we performed the studies on WSSV infection in the Spodoptera frugiperda (Sf9) insect cells. In consistent with our previous study in vitro in crayfish hematopoietic tissue cells, the WSSV envelope was detached from nucleocapsid around 2 hpi in Sf9 cells, which was accompanied with the cytoplasmic transport of nucleocapsid toward the cell nucleus within 3 hpi. Furthermore, the expression profile of both gene and protein of WSSV was determined in Sf9 cells after viral infection, in which a viral immediate early gene IE1 and an envelope protein VP28 exhibited gradually increased presence from 3 to 24 hpi. Similarly, the significant increase of WSSV genome replication was found at 3-48 hpi in Sf9 cells after infection with WSSV, indicating that Sf9 cells supported WSSV genome replication. Unfortunately, no assembled progeny virion was observed at 24 and 48 hpi in Sf9 cell nuclei as determined by transmission electron microscope, suggesting that WSSV progeny could not be assembled in Sf9 cell line as the viral structural proteins could not be transported into cell nuclei. Collectively, these findings provide a cell model for comparative analysis of WSSV infection mechanism with crustacean cells.

Icariin ameliorates glycolytic dysfunction in Alzheimer's disease models by activating the Wnt/ß-catenin signaling pathway.

It was reported that the Wnt/ß-catenin pathway is involved in the regulation of aerobic glycolysis and that brain glycolytic dysfunction results in the development of Alzheimer's disease (AD). Icariin (ICA), an active component extracted from Epimedii Folium, has been reported to produce neuroprotective effects in multiple models of AD, but its underlying mechanism remains to be fully described. We aimed to investigate the protective effects of ICA on animal and cell models of AD and confirm whether the Wnt/ß-catenin pathway has functions in the neuroprotective function of ICA. The 3 × Tg-AD mice were treated with ICA. HT22 cells, the Aß25-35 peptide and Dickkopf-1 (DKK1) agent (a specific inhibitor of the Wnt/ß-catenin pathway) were used to further explore the underlying mechanism of ICA that produces anti-AD effects. Behavioral examination, western blotting assay, staining analysis, biochemical test, and lactate dehydrogenase (LDH) assays were applied. We first demonstrated that ICA significantly improved cognitive function and autonomous behavior, reduced neuronal damage, and reversed the protein levels and activities of glycolytic key enzymes, and expression of protein molecules of the canonical Wnt signaling pathway, in 3 × Tg-AD mice back to wild-type levels. Next, we further found that ICA increased cell viability and effectively improved the dysfunctional glycolysis in HT22 cells injured by Aß25-35. However, when canonical Wnt signaling was inhibited by DKK1, the above effects of ICA on glycolysis were abolished. In summary, ICA exerts neuroprotective effects in 3 × Tg-AD animals and AD cellular models by enhancing the function of glycolysis through activation of the Wnt/ß-catenin pathway.

The crustacean DNA virus tegument protein VP26 binds to SNAP29 to inhibit SNARE complex assembly and autophagic degradation.

Autophagy generally functions as a cellular surveillance mechanism to combat invading viruses, but viruses have evolved various strategies to block autophagic degradation and even subvert it to promote viral propagation. White spot syndrome virus (WSSV) is the most highly pathogenic crustacean virus, but little is currently known about whether crustacean viruses such as WSSV can subvert autophagic degradation for escape. Here, we show that even though WSSV proliferation triggers the accumulation of autophagosomes, autophagic degradation is blocked in the crustacean species red claw crayfish. Interestingly, the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex including CqSNAP29, CqVAMP7, and the novel autophagosome SNARE protein CqSyx12 is required for autophagic flux to restrict WSSV replication, as revealed by gene silencing experiments. Simultaneously, the expressed WSSV tegument protein VP26, which likely localizes on autophagic membrane mediated by its transmembrane region, binds the Qb-SNARE domain of CqSNAP29 to competitively inhibit the binding of CqSyx12-Qa-SNARE with CqSNAP29-Qb-SNARE; this in turn disrupts the assembly of the CqSyx12-SNAP29-VAMP7 SNARE complex, which is indispensable for the proposed fusion of autophagosomes and lysosomes. Consequently, the autophagic degradation of WSSV is likely suppressed by the expressed VP26 protein in vivo in crayfish, thus probably protecting WSSV components from degradation via the autophagosome-lysosome pathway, resulting in evasion by WSSV. Collectively, these findings highlight how a DNA virus can subvert autophagic degradation by impairing the assembly of the SNARE complex to achieve evasion, paving the way for understanding host-DNA virus interactions from an evolutionary point of view, from crustaceans to mammals.IMPORTANCEWhite spot syndrome virus (WSSV) is one of the largest animal DNA viruses in terms of its genome size and has caused huge economic losses in the farming of crustaceans such as shrimp and crayfish. Detailed knowledge of WSSV-host interactions is still lacking, particularly regarding viral escape from host immune clearance. Intriguingly, we found that the presence of WSSV-VP26 might inhibit the autophagic degradation of WSSV in vivo in the crustacean species red claw crayfish. Importantly, this study is the first to show that viral protein VP26 functions as a core factor to benefit WSSV escape by disrupting the assembly of the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex, which is necessary for the proposed fusion of autophagosomes with lysosomes for subsequent degradation. These findings highlight a novel mechanism of DNA virus evasion by blocking SNARE complex assembly and identify viral VP26 as a key candidate for anti-WSSV targeting.

PTPRH promotes the progression of non-small cell lung cancer via glycolysis mediated by the PI3K/AKT/mTOR signaling pathway.

BACKGROUND: The protein tyrosine phosphatase H receptor (PTPRH) is known to regulate the occurrence and development of pancreatic and colorectal cancer. However, its association with glycolysis in non-small cell lung cancer (NSCLC) is still unclear. In this study, we aimed to investigate the relationship between PTPRH expression and glucose metabolism and the underlying mechanism of action. METHODS: The expression of PTPRH in NSCLC cells was evaluated by IHC staining, qRT‒PCR and Western blotting. The effect of PTPRH on cell biological behavior was evaluated by colony assays, EdU experiments, Transwell assays, wound healing assays and flow cytometry. Changes in F-18-fluorodeoxyglucose (18F-FDG) uptake and glucose metabolite levels after altering PTPRH expression were detected via a gamma counter and lactic acid tests. The expression of glycolysis-related proteins in NSCLC cells was detected by Western blotting after altering PTPRH expression. RESULTS: The results showed that PTPRH was highly expressed in clinical patient tissue samples and closely related to tumor diameter and clinical stage. In addition, PTPRH expression was associated with glycometabolism indexes on 18F-FDG positron emission tomography/computed tomography (PET/CT) imaging, the expression level of Ki67 and the expression levels of glycolysis-related proteins. PTPRH altered cell behavior, inhibited apoptosis, and promoted 18F-FDG uptake, lactate production, and the expression of glycolysis-related proteins. In addition, PTPRH modulated the glycometabolism of NSCLC cells via the phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway, as assessed using LY294002 and 740Y-P (an inhibitor and agonist of PI3K, respectively). The same results were validated in vivo using a xenograft tumor model in nude mice. Protein expression levels of PTPRH, glycolysis-related proteins, p-PI3K/PI3K and p-AKT/AKT were measured by IHC staining using a subcutaneous xenograft model in nude mice. CONCLUSIONS: In summary, we report that PTPRH promotes glycolysis, proliferation, migration, and invasion via the PI3K/AKT/mTOR signaling pathway in NSCLC and ultimately promotes tumor progression, which can be regulated by LY294002 and 740Y-P. These results suggest that PTPRH is a potential therapeutic target for NSCLC.

Pharmacokinetics and Safety of the Tyrosine Kinase 2 Inhibitor Deucravacitinib in Healthy Chinese Subjects.

INTRODUCTION: Deucravacitinib, an oral, selective, allosteric tyrosine kinase 2 inhibitor, blocks cytokine signaling involved in psoriasis pathogenesis. This ethnic-bridging study evaluated deucravacitinib pharmacokinetics, tolerability, and safety in healthy Chinese subjects. METHODS: This phase I, double-blind, single-/multiple-dose study randomized healthy Chinese subjects 4:1 to a single dose of deucravacitinib 6 mg or placebo (group 1) or deucravacitinib 12 mg or placebo (group 2) on day 1; groups 1 and 2 received deucravacitinib 6 mg and 12 mg once daily, respectively, or placebo on days 5-19. Blood samples were collected on days 1-5 (0 predose-96 h postdose), day 5 (0-24 h postdose), days 9 and 12 (0 h), and day 19 (0-24 h postdose). Deucravacitinib and metabolite (BMT-153261, BMT-158170) concentrations were determined using liquid chromatography/mass spectrometry; pharmacokinetic parameters were calculated using noncompartmental analysis. Urine was collected on days 1-4 (4 h predose-96 h postdose). Safety was monitored throughout. RESULTS: Forty healthy Chinese subjects (groups 1 and 2: deucravacitinib, n = 32; placebo, n = 8) were enrolled. Deucravacitinib was rapidly absorbed after single-/multiple-dose administration, with median time to maximal plasma concentration of 1.5-2.3 h. Systemic exposure after single or multiple doses increased approximately twofold with twofold dose increase. Modest deucravacitinib accumulation was observed after multiple-dose administration (1.3- to 1.4-fold increase in area under the curve [AUC] under one dosing interval). Metabolite-to-parent ratios for maximal plasma concentration and AUC remained consistent in each dose group. Mean urinary percent recovery and renal clearance were similar between dose groups. Most adverse events (AEs) were mild/moderate, with no serious treatment-related AEs, deaths, or discontinuations due to AEs. CONCLUSION: Deucravacitinib was safe and well tolerated in healthy Chinese subjects. Deucravacitinib exhibited rapid absorption, dose-related increases in exposure, comparable half-life, and no evidence of time-dependent pharmacokinetics, suggesting minimal effect of Chinese ethnicity on deucravacitinib pharmacokinetics. CLINICAL TRIAL REGISTRATION: NCT03956953.

Deucravacitinib, a new oral medication, blocks an enzyme called tyrosine kinase 2 (TYK2), which is activated in plaque psoriasis. This reduces thick, scaly patches of skin, itching, and other symptoms. How a drug is absorbed and its effects can vary between patients of different races and ethnicities. We studied the safety of deucravacitinib in healthy Chinese volunteers. We also studied how bigger or smaller doses of deucravacitinib change how much of it is absorbed into the blood. We found that most side effects of deucravacitinib were mild or moderate compared to volunteers taking placebo, a look-alike pill that contains no drug. The most common side effects were skin rashes and headaches. No serious side effects were related to deucravacitinib. Deucravacitinib was quickly absorbed into the blood. The time it took for deucravacitinib to reach its maximum amount in the blood was similar regardless of how large of a dose was initially taken. Increasing the amount of deucravacitinib taken also increased the total amount of deucravacitinib absorbed, both in terms of the total amount absorbed and the maximum amount in blood at one time. These results in healthy Chinese volunteers were similar to the results of other studies in a general population of many races and ethnicities. Deucravacitinib works the same in Chinese patients as in patients of other ethnicities. Chinese patients will not need to adjust their dose when taking deucravacitinib.

A first-in-human phase 1 study of simnotrelvir, a 3CL-like protease inhibitor for treatment of COVID-19, in healthy adult subjects.

Safe and efficacious antiviral therapeutics are in urgent need for the treatment of coronavirus disease 2019. Simnotrelvir is a selective 3C-like protease inhibitor that can effectively inhibit severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We evaluated the safety, tolerability, and pharmacokinetics of dose escalations of simnotrelvir alone or with ritonavir (simnotrelvir or simnotrelvir/ritonavir) in healthy subjects, as well as the food effect (ClinicalTrials.gov Identifier: NCT05339646). The overall incidence of adverse events (AEs) was 22.2% (17/72) and 6.3% (1/16) in intervention and placebo groups, respectively. The simnotrelvir apparent clearance was 135-369 L/h with simnotrelvir alone, and decreased significantly to 19.5-29.8 L/h with simnotrelvir/ritonavir. The simnotrelvir exposure increased in an approximately dose-proportional manner between 250 and 750 mg when co-administered with ritonavir. After consecutive twice daily dosing of simnotrelvir/ritonavir, simnotrelvir had a low accumulation index ranging from 1.39 to 1.51. The area under the curve of simnotrelvir increased 44.0 % and 47.3 % respectively, after high fat and normal diet compared with fasted status. In conclusion, simnotrelvir has adequate safety and tolerability. Its pharmacokinetics indicated a trough concentration above the level required for 90 % inhibition of SARS-CoV-2 in vitro at 750 mg/100 mg simnotrelvir/ritonavir twice daily under fasted condition, supporting further development using this dosage as the clinically recommended dose regimen.

Impact of household decision makers' hesitancy to vaccinate children against COVID-19 on other household members: A family-based study in Taizhou, China.

Background: Vaccination is the most effective means of preventing outbreaks of infectious diseases, and family ;decision makers play an important role in decision-making regarding family matters and may influence other family members to take an active role in vaccinating children against COVID-19. Purpose: This study examined the influence of family decision makers on the hesitation of other family members to vaccinate their children against COVID-19. Methods: A population-based, self-administered online questionnaire was administered in Taizhou, China, from September 1, 2021, to September 15, 2021. The questionnaire included demographic information, knowledge, attitudes, and perceptions about the COVID-19 vaccine as well as hesitation regarding the use of the COVID-19 vaccination in children. In total, 490 respondents were included in this study. Logistic regression was used to assess the factors associated with vaccine hesitancy. Results: In total, 490 respondents from 190 households were interviewed. Of the 190 family decision makers, 43.7% (83/190) were hesitant to vaccinate their children against COVID-19. When family decision makers were hesitant to vaccinate children against COVID-19, 65.1% (82/126) of the other family members expressed similar hesitancy regarding vaccination. When family decision makers were not hesitant to vaccinate children, only 21.3% (37/174) of other family members were hesitant to do so. In the regression analysis, family decision makers' hesitation to vaccinate their children was associated with other family members' hesitation (OR=6.264, 95% CI:3.132-12.526). In addition, decision makers' perceptions of the safety of the vaccine (OR=0.422, 95% CI:0.215-0.826) and hesitation to vaccinate themselves (OR=8.967, 95% CI:4.745-16.948) influenced their hesitation to vaccinate their children. Conclusion: The present study found that family decision makers' hesitation to vaccinate children against COVID-19 influenced other family members' hesitation to vaccinate children. In addition, family decision makers' perceptions of the safety of the vaccine and their hesitation to vaccinate themselves influenced other family members' hesitation to vaccinate their children.

Six New Phenolic Glycosides from the Seeds of Moringa oleifera Lam. and Their α-Glucosidase Inhibitory Activity.

Plant-derived phytochemicals have recently drawn interest in the prevention and treatment of diabetes mellitus (DM). The seeds of Moringa oleifera Lam. are widely used in food and herbal medicine for their health-promoting properties against various diseases, including DM, but many of their effective constituents are still unknown. In this study, 6 new phenolic glycosides, moringaside B-G (1-6), together with 10 known phenolic glycosides (7-16) were isolated from M. oleifera seeds. The structures were elucidated by 1D and 2D NMR spectroscopy and high-resolution electrospray ionization mass spectrometry (HR-ESI-MS) data analysis. The absolute configurations of compounds 2 and 3 were determined by electronic circular dichroism (ECD) calculations. Compounds 2 and 3 especially are combined with a 1,3-dioxocyclopentane moiety at the rhamnose group, which are rarely reported in phenolic glycoside backbones. A biosynthetic pathway of 2 and 3 was assumed. Moreover, all the isolated compounds were evaluated for their inhibitory activities against α-glucosidase. Compounds 4 and 16 exhibited marked activities with IC50 values of 382.8 ± 1.42 and 301.4 ± 6.22 µM, and the acarbose was the positive control with an IC50 value of 324.1 ± 4.99 µM. Compound 16 revealed better activity than acarbose.

Suppression of hnRNP A1 binding to HK1 RNA leads to glycolytic dysfunction in Alzheimer's disease models.

Objective: To investigate the mechanism of RNA-binding protein hnRNP A1 in mouse hippocampal neurons (HT22) on glycolysis. Methods: RIP and CLIP-qPCR were performed by HT22 in vitro to observe the mechanism of hnRNP A1 regulating the expression of key proteins in glycolysis. The RNA binding domain of hnRNP A1 protein in HT22 was inhibited by VPC-80051, and the effect of hnRNP A1 on glycolysis of HT22 was observed. Lentivirus overexpression of hnRNP A1 was used to observe the effect of overexpression of hnRNP A1 on glycolysis of Aß25-35-injured HT22. The expression of hnRNP A1 in brain tissues of wild-type mice and triple-transgenic (APP/PS1/Tau) AD mice at different ages was studied by Western blot assay. Results: The results of RIP experiment showed that hnRNP A1 and HK1 mRNA were significantly bound. The results of CLIP-qPCR showed that hnRNP A1 directly bound to the 2605-2821 region of HK1 mRNA. hnRNP A1 inhibitor can down-regulate the expression of HK1 mRNA and HK1 protein in HT22 cells. Overexpression of hnRNP A1 can significantly reduce the toxic effect of Aß25-35 on neurons via the hnRNP A1/HK1/ pyruvate pathway. In addition, inhibition of hnRNP A1 binding to amyloid precursor protein (APP) RNA was found to increase Aß expression, while Aß25-35 also down-regulated hnRNP A1 expression by enhancing phosphorylation of p38 MAPK in HT22. They interact to form bidirectional regulation, further down-regulating the expression of hnRNP A1, and ultimately aggravating glycolytic dysfunction. Protein immunoblotting showed that hnRNP A1 decreased with age in mouse brain tissue, and the decrease was greater in AD mice, suggesting that the decrease of hnRNP A1 may be a predisposed factor in the pathogenesis of AD.

Discharge domains regulation and dynamic processes of direct-current triboelectric nanogenerator.

Direct-current triboelectric nanogenerators arising from electrostatic breakdown can eliminate the bottleneck problem of air breakdown in conventional triboelectric nanogenerators, offering critical benefits of constant-current output, resistance to electromagnetic interference, and high output power density. Previous understanding is that its output characteristics are described by a capacitor-breakdown model or dictated by one or two discharge domains in direct-current triboelectric nanogenerators. Here, we demonstrate that the former holds only for ideal conditions and the latter cannot fully explain the dynamic process and output performance. We systematically image, define, and regulate three discharge domains in direct-current triboelectric nanogenerators, then a "cask model" is developed to bridge the cascaded-capacitor-breakdown dynamic model in ideal conditions and real outputs. Under its guidance, the output power is increased by an order of magnitude within a wide range of resistive loads. These unexplored discharge domains and optimization methods revolutionize the output performance and potential applications of direct-current triboelectric nanogenerators.