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Aims: This study aimed to develop a population pharmacokinetic (PopPK) model of ilaprazole in healthy subjects and patients with duodenal ulcer in Chinese and investigate the effect of potential covariates on pharmacokinetic (PK) parameters.Methods: Pharmacokinetic data from 4 phase I clinical trials and 1 phase IIa clinical trial of ilaprazole were included in PopPK analysis. Phoenix NLME 8.3 was used to establish a PopPK model and quantify the effects of covariate, such as demographic data, biochemical indicators and disease state on the PK parameters of ilaprazole. The final model was evaluated by goodness-of-fit plots, bootstrap analysis, and visual predictive check.Results: A two-compartment model with first-order elimination successfully described the pharmacokinetic properties of ilaprazole. In the final PopPK model, body weight and sex were identified as statistically significant covariates for volume of peripheral compartment (Vp) and clearance of central compartment (CL), respectively, and disease status was also screened as a significant covariate affecting both CL and Vp. The validation results demonstrated the good predictability of the model, which was accurate and reliable.Conclusion: This is the first population pharmacokinetics study of ilaprazole in the Chinese, and the PopPK model developed in this study is expected to be helpful in providing relevant PK parameters and covariates information for further studies of ilaprazole.

Objectives: Aficamten is a selective, small-molecule allosteric inhibitor of cardiac sarcomere being developed as a chronic oral treatment for patients with symptomatic obstructive hypertrophic cardiomyopathy. This was the first-in-Chinese study aiming to investigate the safety, tolerability, pharmacokinetics, and pharmacodynamics of aficamten in healthy adults.Methods: This double-blind, randomized, placebo-controlled, phase 1 study was conducted in 28 healthy male and female Chinese participants after single ascending dose (SAD) and multi-dose (MD) administrations of aficamten. In the SAD cohort, 16 participants were randomized to receive a single oral dose of aficamten: 10 mg, 20 mg, or placebo. In the MD cohort, 12 participants were randomized to receive multiple doses of aficamten: 5 mg or placebo once daily for 14 days. Safety was monitored throughout the study with electrocardiograms, echocardiograms, clinical laboratory tests, and reporting of adverse events (AEs). Pharmacokinetic profiles of aficamten and metabolites, as well as CYP2D6 genetic impact, were evaluated.Results: A total of 35 treatment-emergent AEs were reported by 14 (50%) participants with mild severity. There were no serious AEs or adverse decreases in left ventricular ejection fraction below 50% during the study. Aficamten was dose-proportional over the dose range of 5–20 mg and accumulated in the MD cohort.Conclusion: Aficamten was safe and well-tolerated in the healthy Chinese adult participants. The pharmacokinetics of aficamten in the Chinese population was comparable to those previously found in Western participants. These phase 1 data support the progression of aficamten into future clinical studies in Chinese patients.Clinical Trial registration:https://clinicaltrials.gov, identifier: NCT04783766.

Background: Currently, the optimal therapy plan for idiopathic membranous nephropathy (IMN) remains controversial as there has been no comprehensive and systematic comparison of therapy plans for IMN. Therefore, in this study, a Bayesian meta-analysis was used to systematically evaluate the clinical efficacy and safety of various intervention plans involving traditional Chinese medicine TWM in the treatment of IMN.Methods: An electronic search in 7 databases was conducted from their inception to August 2022 for all published randomized controlled trials (RCTs) of various intervention plans for IMN. Network meta-analysis (NMA) was performed by using software R, and the surface under the cumulative ranking area (SUCRA) probability curve was plotted for each outcome indicator to rank the efficacy and safety of different intervention plans.Results: A total of 30 RCTs were included, involving 13 interventions. The results showed that (1) in terms of total remission (TR), ① GC + CNI + TWM was the best effective among all plans, and the addition and subtraction plan of CNI + TWM was the best effective for IMN; ② All plans involving TWM were more effective than GG; ③ Among monotherapy plans for IMN, TWM was more effective distinctly than GC, while TWM and CNI were similarly effective; ④ Among multidrug therapy plans for IMN, the addition of TWM to previously established therapy plans made the original plans more effective; ⑤The efficacy of combining TWM with other plans was superior to that of TWM alone. (2) In terms of lowering 24 h-UTP, GC + TWM was the best effective and more effective than TWM. (3) In terms of safety, there was no statistically significant difference between all groups. However, CNI + TWM was the safest. No serious adverse events (AEs) occurred in all the included studies.Conclusion: The addition of TWM may be beneficial to patients with IMN. It may enhance the efficacy of previously established treatment protocols without leading to additional safety risks. In particular, GC + CNI + TWM, GC + TWM, and CNI + TWM with better efficacy and higher safety can be preferred in clinical decision-making as the therapy plans for IMN.

This study is intended for exploring the effects of the physical activity combined with extra ciliary-muscle training with different frequencies on children's kinetic visual acuity and uncorrected distance visual acuity, and eventually figuring out the optimal frequency of ciliary-muscle training for each physical education class. To do the present research, A total of 160 students aged 10–11 from a school in Suzhou (a major city located in southeastern Jiangsu Province, East China) were randomly selected and divided into control group (n = 33), 15-frequency group (n = 44), 30-frequency group (n = 40) and 60-frequency group (n = 43), and the latter three experimental groups participated in a specially designed physical activity plan based on the training principles of ciliary muscle, while the control group participated in normal physical activity as usual. The experimental intervention period was 16 weeks, and all students' kinetic visual acuity and uncorrected distance visual acuity were measured before and after the experiment. The result showed that the kinetic visual acuity of the students in the 30 and 60-frequency groups got improved significantly after the experiment (p < 0.05), with the highest improvement occurring in the 30-frequency group, while there was no significant change in the 15-frequency group and the control group; The uncorrected distance visual acuity of the students in the 30 and 60-frequency groups was significantly improved after the experiment (p < 0.05), and the improvement range in these two groups was similar. In contrast, there was no significant change in the 15-frequency group, while the control group showed a significant decrease (p < 0.05). Physical activity combined with extra ciliary-muscle training has a positive effect on improving children's vision; at the same time, ciliary-muscle training with different frequencies bring out different outcomes on children's vision improvement, among which ciliary-muscle training with frequency of 30 in each physical education class is the best choice to enhance children's kinetic visual acuity and uncorrected distance visual acuity.

This study aimed to build a nasal semi-physiologically based pharmacokinetic (PBPK) model to predict the intranasal pharmacokinetic (PK) of the OC-01(varenicline) nasal spray and accelerate the development of this drug. Based on the physiology of the human upper respiratory system, the semi-PBPK model was established and validated using systemic plasma PK data of varenicline previously observed in Americans and Chinese. Drug concentrations, both in respiratory tissue and plasma circulation system, were well simulated, and it was indicated that local concentration at the target site (nasal cavity) was significantly higher than that of plasma when OC-01 nasal spray was administered. The nasal semi-PBPK model successfully depicted the absorption and distribution of intranasal varenicline in the respiratory tissues and provided an alternative to clinical PK study of OC-01 nasal spray in Chinese. Meanwhile the current study presented a viable framework for predicting respiratory concentrations for other novel nasal spray drugs by semi-PBPK modeling.

To compare the gut microbiota of healthy infants based on specific interactions of delivery modes and feeding types, we recruited 62 healthy babies who were followed up for 2 years from our previous cohort study of 91 infants (the rest were lost to follow-up). They were exclusively fed breast milk or specific formulas for more than 4 months after birth. The fecal bacterial composition was tested at 40 days, 3 months, and 6 months of age. Solid foods were introduced from 4 to 6 months of age and thus did not affect the microbiota before 4 months of age. According to the different delivery modes (i.e., vaginal delivery, VD, or cesarean section delivery, CS) and feeding types (i.e., breast-fed, br, or formula-fed, fo), the infants were assigned to four different groups, namely, the VD-br, VD-fo, CS-br, and CS-fo groups. We found that at 40 days of age, the α diversity (reported as the Shannon index) was lower in the br infants than in the fo infants. At 3 months of age, the α diversity was significantly lower in the CS-br group, although significant differences were not observed after solid food introduction. Bifidobacterium represented the most predominant genus in all groups at all time points, followed by Enterobacteriaceae. At 40 days of age, the abundance of Bifidobacterium was much higher in the CS-br group than in the CS-fo group but did not differ between the VD-br and VD-fo groups. The differences in Bifidobacterium disappeared at 3 and 6 months of age among the different groups. At 40 days of age, the abundance of Streptococcus and Enterococcus was much lower in the br infants than in the CS-fo group. At 3 months of age, Enterococcus was significantly lower in the CS-br group than in the fo infants, although for infants delivered by VD, the difference between feeding types was not significant. The specific interaction of delivery modes and feeding types has a large impact on the infants' gut microbiota. Breastfeeding and VD may decrease the potential adverse effects of formula feeding or CS delivery on gut microbiota, thus leading to a more stable and beneficial gut environment for infants.

Ubiquitination is reported to be a critical biological event on ACTH secretion in corticotroph adenomas. However, the effect of ubiquitylation on ACTH secretion in silent corticotroph adenomas (SCAs) remains unclear. The aim of our study was to explore the mechanism of decreased secretion of ACTH in SCAs with ubiquitinomics. The differently expressed ubiquitinated proteins between SCAs and functioning corticotroph adenomas (FCAs) were identified by 4D label-free mass spectrometer, followed by bioinformatics analysis. The function of the candidate ubiquitinated protein ATP7A (K333) was validated in AtT20 cells. A total of 111 ubiquitinated sites corresponding to 94 ubiquitinated proteins were typically different between SCAs and FCAs. Among all the ubiquitinated sites, 102 showed decreased ubiquitination in SCAs, which mapped to 85 ubiquitinated proteins. Pathway enrichment analysis revealed that ubiquitinated proteins were mainly enriched in vesicle pathway and protein secretion pathway. ATP7A (K333) was one of the proteins enriched in vesicle pathway and protein secretion pathway with decreased ubiquitination level in SCAs. In vitro assay indicated that both ATP7A siRNA and omeprazole (ATP7A protein inhibitor) increased the secretion of ACTH in AtT20 cell supernatant compared to control groups (p

Ischemic heart disease is one of the biggest threats to human life in the world. Reperfusion therapy is an effective strategy to reduce infarct size and ischemic injury. However, reperfusion process may cause secondary myocardial injury which is defined as ischemia-reperfusion injury (IRI). Exploring potential therapeutic strategy to attenuate IRI is extremely important. Danlou tablet (Dan), a Chinese herbal compound consisting of ten herbs, has been identified to be protective for the heart. However, the mechanism of Dan-induced cardioprotection after acute reperfusion was unelucidated. In this study, to investigate the role and mechanism of Dan in myocardial IRI, we performed acute IRI modeling in mice and oxygen-glucose deprivation–reperfusion (OGD/R)-induced apoptosis in primary neonatal rat cardiomyocytes (NRCMs). We found that Dan had protective effect against acute IRI in mice, as evidenced by reduced infarct size, TUNEL-positive cardiomyocytes (CMs), and Bax/Bcl2 ratio and cleaved-caspase 3/caspase 3 ratio in vivo. Meanwhile, Dan inhibited OGD/R-induced apoptosis of NRCMs in vitro. Mechanistically, Dan could activate proliferator-activated receptor gamma (PPARγ) in both IRI hearts and OGD/R-stressed NRCMs, while inhibition of PPARγ attenuated the protective effect of Dan against IRI in vivo and OGD/R-induced CM apoptosis in vitro. These data reveal that Dan attenuates acute myocardial IRI and CM apoptosis through activating PPARγ. Our findings may extend the knowledge of Chinese medicine and provide potential strategy for the precise treatment of ischemic heart diseases.

Abstract: The synthesis costs of macrolide musks are higher than those of other commercial musks. To make this process less expensive, eggshell waste was calcined at a low temperature to obtain a catalyst for the cyclopentadecanolide production via reactive distillation using a glycerol entrainer. X-ray diffraction, Fourier-transform infrared spectroscopy, scanning electron microscopy, transmission electron microscopy, and X-ray photoelectron spectroscopy analyses of the original and recovered catalysts revealed that the main catalytic ingredient was calcium glycerolate (CaG) and not calcium diglyceroxide (CaDG). The basic strengths of CaG and CaDG obtained by Hammett indicators were 7.2 < H_≤ 15.0 and 9.8 < H_≤15.0, while the corresponding base amounts were 1.9 and 7.3 mmol/ g, respectively. Because CaG was soluble in glycerine, the catalyst was efficiently reused. The reaction product containing over 95.0% cyclopentadecanolide with a yield of 49.8% was obtained at a temperature of 190°C and catalyst amount of 12 wt% after 7 h of reaction. Thus, eggshell waste may be directly placed into the reaction mixture after calcination at 600°C to synthesise a large amount of cyclopentadecanolide within a relatively short time. The results of this work indicate that eggshell waste can serve as a potential eco-friendly and affordable catalyst source for the production of macrolide musks.

Curative therapies for chronic hepatitis B virus (HBV) infection remain a distant goal, and the persistence of stable covalently closed circular DNA (cccDNA) during HBV replication is a key barrier that is hard to break through using the drugs currently approved for HBV treatment. Due to the accuracy, efficiency, and cost-effectiveness of genome editing, CRISPR/Cas technologies are being widely used for gene therapy and in antiviral strategies. Although CRISPR/Cas could possibly clear cccDNA, ensuring its safety is requirement for application. In our study, we analyzed the liver specificity of several promoters and constructed candidate promoters in the CRISPR/Staphylococcus aureus Cas9 (SaCas9) system combined with hepatotropic AAV8 (whereby AAV refers to adeno-associated virus) to verify the efficacy against HBV. The results revealed that the reconstructed CRISPR/SaCas9 system in which the original promoter replaced with a liver-specific promoter could still inhibit HBV replication both in vitro and in vivo. Three functional guide RNAs (gRNAs), T2, T3, and T6, which target the conserved regions of different HBV genotypes, demonstrated consistently better anti-HBV effects with different liver-specific promoters. Moreover, the three gRNAs inhibited the replication of HBV genotypes A, B, and C to varying degrees. Under the action of the EnhII-Pa1AT promoter and AAV8, the expression of SaCas9 was further decreased in other organs or tissues in comparison to liver. These results are helpful for clinical applications in liver by ensuring the effects of the CRISPR/Cas9 system remain restricted to liver and, thereby, reducing the probability of undesired and harmful effects through nonspecific targeting in other organs.

The outbreak of COVID-19 is a public health crisis that has had a profound impact on society. Stigma is a common phenomenon in the prevalence and spread of infectious diseases. In the crisis caused by the pandemic, widespread public stigma has influenced social groups. This study explores the negative emotions arousal effect from online public stigmatization during the COVID-19 pandemic and the impact on social cooperation. We constructed a model based on the literature and tested it on a sample of 313 participants from the group being stigmatized. The results demonstrate: (1) relevance and stigma perception promote negative emotions, including anxiety, anger, and grief; (2) the arousal of anger and grief leads to a rise in the altruistic tendency within the stigmatized group; and (3) stigmatization-induced negative emotions have a complete mediating effect between perceived relevance and altruistic tendency, as well as perceived stigma and altruistic tendency. For a country and nation, external stigma will promote the group becoming more united and mutual help. One wish to pass the buck but end up helping others unintentionally. We should not simply blame others, including countries, regions, and groups under the outbreak of COVID-19, and everyone should be cautious with the words and actions in the Internet public sphere.

The 14-3-3 protein family has attracted much attention in research into the pathogenesis of human tumors because of its involvement in tumorigenesis. In previous studies, we found that 14-3-3η was highly expressed in pituitary oncocytoma. However, the mechanism by which 14-3-3η regulates tumorigenesis in pituitary oncocytoma is unclear. 14-3-3η-binding proteins were investigated in pituitary oncocytoma by immunoprecipitation and proteomic analysis. A total of 443 proteins were identified as 14-3-3η binding proteins. The interactions of 14-3-3η and its binding partners were identified by a network analysis using the STRING database. The network included 433 nodes and 564 edges. PRAS40 (AKT1S1) was a binding protein of 14-3-3η and showed experimental interactions with 14-3-3η in the STRING database. The combined score was 0.407, which suggested a functional link. The 443 binding proteins of 14-3-3η showed enriched molecular signatures in GSEA and GO analysis. PRAS40 (AKT1S1) was enriched in the mTOR signaling pathway. Western blot analysis showed that the relative expression of p-PRAS40 (T246)/PRAS40 was significantly higher in pituitary oncocytoma than in normal pituitary tissues (p < 0.05). R18, a 14-3-3 protein inhibitor, inhibited MMQ cell proliferation after treatment with 8 μM R18 for 48 h compared to the control group (p < 0.01). These results suggest that 14-3-3η may be involved in promoting tumorigenesis in pituitary oncocytoma by interacting with PRAS40 (T246) via the mTOR signaling pathway.

HR7056 is a new benzodiazepine, showing more faster acting onset and recovery than currently available short-acting sedatives. To avoid inadequate anesthesia and predict return of cognition, allowing for immediate neurological evaluation, HR7056 pharmacokinetics and pharmacodynamics were characterized in Chinese healthy subjects. We report on modeling of the data and simulations of dosage regimens for future study. Up to 63 subjects were evaluated, using Bispectral Index (BIS) and Modified Observer's Assessment of Alertness/Sedation (MOAA/S) as pharmacodynamics endpoints. A three-compartment model best described HR7056 pharmacokinetics. Total clearance was 1.49 L min−1, central volume was 2.1 L, inter-compartmental clearances were 0.96 and 0.27 L min−1, respectively. The population mean pharmacodynamic parameters were as follows: BIS, E0: 95.3; IC50: 503 ng mL−1; γ: 1.5; ke0: 0.0855 min−1; Imax: 47.9 and MOAA/S, IC50: 436 ng mL−1; γ: 1.5; ke0: 0.05 min−1; Imax: 27.9. The model simulation will enable maintenance doses to be given more accurately for future study.Clinical Trial Registration: identifier: NCT01970072

Objective: This phase Ia study was designed to assess the pharmacokinetic (PK) characters of free vincristine (F-VCR, refer to as non-liposomal VCR and VCR released from liposome) and total vincristine (T-VCR, the sum of both liposomal VCR and F-VCR), urinary excretion and safety of intravenous administration of vincristine sulfate liposomes injection (VSLI) in Chinese patients with malignant lymphoma and compare the results with those for conventional vincristine sulfate injection (VSI).Methods: In the phase Ia, randomized, open-label, two sequence cross-over study, patients from one group were exposed to treatment 1 including cytoxan (cyclophosphamide power injection), hydroxyrubicin (adriamycin power injection), oncovin (VSI), and prednisone tablets (standard CHOP scheme) before crossed over to treatment 2 (modified CHOP scheme in which VSI was replaced with VSLI). Patients from another group received treatments in reverse order.Results: In this phase Ia study, a total of eight subjects participated. VCR elimination from the circulation after injection of VSLI was characterized by a significantly increased maximum concentration (Cmax, 86.6 ng/mL) and plasma area under the plasma concentration-time curve from zero to infinity (AUC0-Inf, 222.1 ng/mL h), markedly decreased distribution volume (Vz, 224.1 L) and plasma clearance (CL, 8.9 L/h) compared to lower Cmax (26.6 ng/mL) and AUC0-Inf (95.1 ng/mL h), larger Vz (688.8 L) and CL (22.1 L/h) for VSI. The small proportion of F-VCR following infusion of VSLI in circulation was reflected by very low Cmax (1.8 ng/mL) and AUC0-Inf (50.5 ng/mL h). Less than 3% of the administered dose of VSLI was excreted in urine and the extent was similar to that for VSI. The elimination percentage of 40–21–14% for VSI changed to 6.2–24–39% for VSLI at intervals of 0–5, 5–13 and 13–25 h, respectively. Significant difference of toxicity between VSLI and VSI was not observed.Conclusion: VSLI exhibits higher AUC0-Inf of T-VCR, lower CL and Vz compared with VSI. VSLI was well tolerated, maybe due to the markedly decreasing AUC0-Inf of F-VCR. The majority of VCR was enveloped in liposome and VCR was released gradually from liposome following injection of VSLI. Liposomal encapsulation of VCR does not alter the route and extent of VCR excretion in urine.