Effectiveness of influenza vaccine among the population in Chongqing, China, 2018-2022: A test negative design-based evaluation.

Influenza vaccination is the most cost-effective strategy for influenza prevention. Influenza vaccines have been found to be effective against symptomatic and medically attended outpatient influenza illnesses. However, there is currently a lack of data regarding the effectiveness of inactivated influenza vaccines in Chongqing, China. We conducted a prospective observational test-negative design study. Outpatient and emergency cases presenting with influenza-like illnesses (ILI) and available influenza reverse transcription polymerase chain reaction (RT-PCR) were selected and classified as cases (positive influenza RT-PCR) or controls (negative influenza RT-PCR). A total of 7,307 cases of influenza and 7,905 control subjects were included in this study. The overall adjusted influenza vaccine effectiveness (IVE) was 44.4% (95% confidence interval (CI): 32.5-54.2%). In the age groups of less than 6 years old, 6-18 years old, and 19-59 years old, the adjusted IVE were 32.2% (95% CI: 10.0-48.9%), 48.2% (95% CI: 30.6-61.4%), and 72.0% (95% CI: 43.6-86.1%). The adjusted IVE for H1N1, H3N2 and B (Victoria) were 71.1% (95% CI: 55.4-81.3%), 36.1% (95% CI: 14.6-52.2%) and 33.7% (95% CI: 14.6-48.5%). Influenza vaccination was effective in Chongqing from 2018 to 2022. Evaluating IVE in this area is feasible and should be conducted annually in the future.

MOTAI: A Novel Method for the Study of O-GalNAcylation and Complex O-Glycosylation in Cancer.

The Tn antigen, an immature truncated O-glycosylation, is a promising biomarker for cancer detection and diagnosis. However, reliable methods for analyzing O-GalNAcylation and complex O-glycosylation are lacking. Here, we develop a novel method, MOTAI, for the sequential analysis of O-glycosylation using different O-glycoproteases. MOTAI conjugates glycopeptides on a solid support and releases different types of O-glycosylation through sequential enzymatic digestion by O-glycoproteases, including OpeRATOR and IMPa. Because OpeRATOR has less activity on O-GalNAcylation, MOTAI enriches O-GalNAcylation for subsequent analysis. We demonstrate the effectiveness of MOTAI by analyzing fetuin O-glycosylation and Jurkat cell lines. We then apply MOTAI to analyze colorectal cancer and benign colorectal polyps. We identify 32 Tn/sTn-glycoproteins and 43 T/sT-glycoproteins that are significantly increased in tumor tissues. Gene Ontology analysis reveals that most of these proteins are ECM proteins involved in the adhesion process of the intercellular matrix. Additionally, the protein disulfide isomerase CRELD2 has a significant difference in Tn expression, and the abnormally glycosylated T345 and S349 O-glycosylation sites in cancer group samples may promote the secretion of CRELD2 and ultimately tumorigenesis through ECM reshaping. In summary, MOTAI provides a powerful new tool for the in-depth analysis of O-GalNAcylation and complex O-glycosylation. It also reveals the upregulation of Tn/sTn-glycoproteins in colorectal cancer, which may provide new insights into cancer biology and biomarker discovery.

A smartphone-assisted portable on-site detection system for organophosphorus pesticides in vegetables and fruits based on all-in-one paper-based sensors: 2,2-Dichlorovinyl dimethyl phosphate as a model.

The improper use of organophosphate pesticides (OPs) can lead to residue posing a serious threat to human health and environment. Therefore, the development of a simple, portable, and sensitive detection method is crucial. Herein, a bioenzyme-nanozyme-chromogen all-in-one paper-based sensor was synthesized. Initially, the Ce/Zr-MOF with peroxidase-like activity was grown on filter paper (FP) using in-situ solvent thermal method, resulting in Ce/Zr-MOF@FP. Subsequently, the AChE-ChO-TMB system was immobilized onto Ce/Zr-MOF@FP using biocompatible gelatin, which enhanced cascade catalysis efficiency through the proximity effect. Based on the inhibition principle of OPs on AChE, we integrated this sensor with Python-based image recognition algorithm to achieve detection of OPs. Using 2,2-dichlorovinyl dimethyl phosphate (DDVP) as a model of OPs, it has good detection performance with a detection limit of 0.32 ng mL-1 and a recovery rate range of 95-107%. The potential for on-site detection of DDVP residues in vegetables and fruit samples is highly promising.

Pharmacokinetics and Safety of Oliceridine Fumarate Injection in Chinese Patients with Chronic Non-Cancer Pain: A Phase I, Single-Ascending-Dose, Open-Label Clinical Trial.

Background: Oliceridine is a novel G protein-biased ligand µ-opioid receptor agonist. This study aimed to assess the pharmacokinetics and safety profile of single-ascending doses of oliceridine fumarate injection in Chinese patients with chronic non-cancer pain. Methods: Conducted as a single-center, open-label trial, this study administered single doses of 0.75, 1.5, and 3.0 mg to 32 adult participants. The trial was conducted in two parts. First, we conducted a preliminary test comprising the administration of a single dose of 0.75mg to 2 participants. Then, we conducted the main trial involving intravenous administration of escalating doses of oliceridine fumarate (0.75 to 3 mg) to 30 participants. Pharmacokinetic (PK) parameters were derived using non-compartmental analysis. Additionally, the safety evaluation encompassed the monitoring of adverse events (AEs). Results: 32 participants were included in the PK and safety analyses. Following a 2-min intravenous infusion of oliceridine fumarate injection (0.75, 1.5, or 3 mg), Cmax and Tmax ranged from 51.293 to 81.914 ng/mL and 0.034 to 0.083 h, respectively. AUC0-t and half-life (t1/2) increased more than proportionally with dosage (1.85-2.084 h). Treatment emergent adverse events (TEAEs) were found to be consistent with the commonly reported adverse effects of opioids, both post-administration and as documented in the original trials conducted in the United States. Critically, no serious adverse events were observed. Conclusion: Oliceridine demonstrated comparable PK parameters and a consistent PK profile in the Chinese population, in line with the PK results observed in the original trials conducted in the United States. Oliceridine was safe and well tolerated in Chinese patients with chronic non-cancer pain at doses ranging from 0.75 mg to 3.0 mg. Trial Registration: The trial is registered at chictr.org.cn (ChiCTR2100047180).

Insecticidal activity and underlying molecular mechanisms of a phytochemical plumbagin against Spodoptera frugiperda.

Introduction: Plumbagin is an important phytochemical and has been reported to exhibit potent larvicidal activity against several insect pests, However, the insecticidal mechanism of plumbagin against pests is still poorly understood. This study aimed to investigate the insecticidal activities of plumbagin and the underlying molecular mechanisms against a devastating agricultural pest, the fall armyworm Spodoptera frugiperda. Methods: The effects of plumbagin on S. frugiperda larval development and the activities of two detoxification enzymes were initially examined. Next, transcriptomic changes in S. frugiperda after plumbagin treatment were investigated. Furthermore, RNA-seq results were validated by qPCR. Results: Plumbagin exhibited a high larvicidal activity against the second and third instar larvae of S. frugiperda with 72 h LC50 of 0.573 and 2.676 mg/g, respectively. The activities of the two detoxification enzymes carboxylesterase and P450 were significantly increased after 1.5 mg/g plumbagin treatment. Furthermore, RNA-seq analysis provided a comprehensive overview of complex transcriptomic changes in S. frugiperda larvae in response to 1.5 mg/g plumbagin exposure, and revealed that plumbagin treatment led to aberrant expression of a large number of genes related to nutrient and energy metabolism, humoral immune response, insect cuticle protein, chitin-binding proteins, chitin synthesis and degradation, insect hormone, and xenobiotic detoxification. The qPCR results further validated the reproducibility and reliability of the transcriptomic data. Discussion: Our findings provide a valuable insight into understanding the insecticidal mechanism of the phytochemical plumbagin.

Meta-analysis of the Efficacy and Safety of Pembrolizumab in the Treatment of Advanced Gastric Cancer and Gastroesophageal Junction Cancer.

●Introduction: Pembrolizumab have been approved for the first-line treatment of patients with advanced gastric cancer (GC) and gastroesophageal junction (GEJ) cancer. However, the results of several clinical trials are not entirely consistent, and the dominant population of first-line immunotherapy for advanced GC/GEJ still needs to be precisely determined. ●Purpose: The aim of this meta-analysis was to assess the efficacy and safety of pembrolizumab in the treatment of advanced GC/GEJ. ●Methods: We conducted computerized searches across multiple databases, including PubMed, Cochrane Library, Web of Science, and Embase. We established the inclusion criteria to comprise randomized clinical trials examining the efficacy of pembrolizumab in late-stage GC/GCJ cancer. We conducted a meta-analysis of outcome measures using STATA 14.0 software. ●Results: A total of six studies involving 1,448 cases were included in this analysis. The results of the meta-analysis indicate that, when compared to chemotherapy, patients in the pembrolizumab group experienced a significant reduction in the risk of mortality in terms of overall survival (OS) (HR=0.72, 95% CI: 0.65-0.79, p<0.01). In terms of progression-free survival (PFS), pembrolizumab was associated with a similar PFS as compared to chemotherapy (HR=0.88, 95% CI: 0.73-1.07, p=0.206). Subgroup analyses based on PD-L1 expression levels indicated a significantly longer PFS with pembrolizumab in subgroups of patients with PD-L1 CPS≥10, but not in these with PD-L1 CPS≥1 and PD-L1 CPS≥5. Subgroup analyses based on distinct geographical regions revealed a comparable effect of PFS in patients residing in Asia or the USA. Subgroup analysis based on tumor sites consistently demonstrated a similar effect of PFS in patients with EC/GEJ tumors and GC patients. ●Conclusion: Our findings demonstrated that pembrolizumab led to a significant extension in OS and ORR, along with a favorable tolerability profile compared to chemotherapy. Furthermore, the observed survival benefits were particularly pronounced in subgroup patients with a CPS of ≥10. Given the potential limitations inherent in our study, it is imperative to underscore the necessity for further large-scale RCTs to corroborate our results. ●Keywords: gastro-esophageal junction cancer, meta-analysis, chemotherapy, pembrolizumab.

Fluorinated chlorin chromophores for red-light-driven CO2 reduction.

The utilization of low-energy photons in light-driven reactions is an effective strategy for improving the efficiency of solar energy conversion. In nature, photosynthetic organisms use chlorophylls to harvest the red portion of sunlight, which ultimately drives the reduction of CO2. However, a molecular system that mimics such function is extremely rare in non-noble-metal catalysis. Here we report a series of synthetic fluorinated chlorins as biomimetic chromophores for CO2 reduction, which catalytically produces CO under both 630 nm and 730 nm light irradiation, with turnover numbers of 1790 and 510, respectively. Under appropriate conditions, the system lasts over 240 h and stays active under 1% concentration of CO2. Mechanistic studies reveal that chlorin and chlorinphlorin are two key intermediates in red-light-driven CO2 reduction, while corresponding porphyrin and bacteriochlorin are much less active forms of chromophores.

Regio- and Stereoselective Transfer Hydrogenation of Aryloxy Group-Substituted Unsymmetrical 1,2-Diketones: Synthetic Applications and Mechanistic Studies.

Developing a general method that leads to the formation of different classes of chiral bioactive compounds and their stereoisomers is an attractive but challenging research topic in organic synthesis. Furthermore, despite the great value of asymmetric transfer hydrogenation (ATH) in both organic synthesis and the pharmaceutical industry, the monohydrogenation of unsymmetrical 1,2-diketones remains underdeveloped. Here, we report the aryloxy group-assisted highly regio-, diastereo-, and enantioselective ATH of racemic 1,2-diketones. The work produces a myriad of enantioenriched dihydroxy ketones, and further transformations furnish all eight stereoisomers of diaryl triols, polyphenol, emblirol, and glycerol-type natural products. Mechanistic studies and calculations reveal two working modes of the aryloxy group in switching the regioselectivity from a more reactive carbonyl to a less reactive one, and the potential of ATH on 1,2-diketones in solving challenging synthetic issues has been clearly demonstrated.

Establishing Virtual Bioequivalence and Clinically Relevant Specifications for Omeprazole Enteric-Coated Capsules by Incorporating Dissolution Data in PBPK Modeling.

Currently, Biopharmaceutics Classification System (BCS) classes I and III are the only biological exemptions of immediate-release solid oral dosage forms eligible for regulatory approval. However, through virtual bioequivalence (VBE) studies, BCS class II drugs may qualify for biological exemptions if reliable and validated modeling is used. Here, we sought to establish physiologically based pharmacokinetic (PBPK) models, in vitro-in vivo relationship (IVIVR), and VBE models for enteric-coated omeprazole capsules, to establish a clinically-relevant dissolution specification (CRDS) for screening BE and non-BE batches, and to ultimately develop evaluation criteria for generic omeprazole enteric-coated capsules. To establish omeprazole's IVIVR based on the PBPK model, we explored its in vitro dissolution conditions and then combined in vitro dissolution profile studies with in vivo clinical trials. The predicted omeprazole pharmacokinetics (PK) profiles and parameters closely matched the observed PK data. Based on the VBE results, the bioequivalence study of omeprazole enteric-coated capsules required at least 48 healthy Chinese subjects. Based on the CRDS, the capsules' in vitro dissolution should not be < 28%-54%, < 52%, or < 80% after two, three, and six hours, respectively. Failure to meet these dissolution criteria may result in non-bioequivalence. Here, PBPK modeling and IVIVR methods were used to bridge the in vitro dissolution of the drug with in vivo PK to establish the BE safety space of omeprazole enteric-coated capsules. The strategy used in this study can be applied in BE studies of other BCS II generics to obtain biological exemptions and accelerate drug development.

A crystal capping layer for formation of black-phase FAPbI3 perovskite in humid air.

Black-phase formamidinium lead iodide (α-FAPbI3) perovskites are the desired phase for photovoltaic applications, but water can trigger formation of photoinactive impurity phases such as δ-FAPbI3. We show that the classic solvent system for perovskite fabrication exacerbates this reproducibility challenge. The conventional coordinative solvent dimethyl sulfoxide (DMSO) promoted δ-FAPbI3 formation under high relative humidity (RH) conditions because of its hygroscopic nature. We introduced chlorine-containing organic molecules to form a capping layer that blocked moisture penetration while preserving DMSO-based complexes to regulate crystal growth. We report power conversion efficiencies of >24.5% for perovskite solar cells fabricated across an RH range of 20 to 60%, and 23.4% at 80% RH. The unencapsulated device retained 96% of its initial performance in air (with 40 to 60% RH) after 500-hour maximum power point operation.

Lead Bromide Complex in Tri-n-octylphosphine Oxide Matrix with Bright Photoluminance and Exceptional Thermoplasticity.

Metal halide materials have recently drawn increasing research interest for their excellent opto-electronic properties and structural diversity, but their resulting rigid structures render them brittle and poor formability during manufacturing. Here we demonstrate a thermoplastic luminant hybrid lead halide solid by integrating lead bromide complex into tri-n-octylphosphine oxide (TOPO) matrix. The construction of the hybrid materials can be achieved by a simple dissolution process, in which TOPO molecules act as the solvents and ligands to yield the monodispersed clusters. The combination of these functional units enables the near-room-temperature melt-processing of the materials into targeted geometry by simple molding or printing techniques, which offer possibilities for fluorescent writing inks with outstanding self-healing capacity to physical damage. The intermarriage between metal halide clusters with functional molecules expands the range of practical applications for hybrid metal halide materials.

Rapid Construction of Polycyclic Skeletons via Brønsted-Base-Catalyzed Annulations of Ethylidene 1,3-Indenediones and Vinyl 1,2-Diketones.

Brønsted-base-catalyzed diversified annulations between ethylidene 1,3-indenediones and vinyl 1,2-diketones have been achieved, delivering three types of products containing oxabicyclo[3.2.1]octane, spiro[4.5]decane, and branched triquinane skeletons, respectively, which widely exist in natural products and bioactive substances. Two unprecedented reaction modes have been disclosed, and the reactions could be readily scaled up. The protocol shows the potential of 1,2-diketone-mediated reactions in the rapid construction of complicated polycyclic scaffolds.

Collaborative CRISPR-Cas System-Enabled Detection of Circulating Circular RNA for Reliable Monitoring of Acute Myocardial Infarction.

Acute myocardial infarction (AMI) is one of the major causes of death worldwide, posing significant global health challenges. Circular RNA (circRNA) has recently emerged as a potential diagnostic biomarker for AMI, providing valuable information for timely medical care. In this work, a new electrochemical method for circRNA detection by engineering a collaborative CRISPR-Cas system is developed. This system integrates the unique circRNA-targeting ability with cascade trans-cleavage activities of Cas effectors, using an isothermal primer exchange reaction as the bridge. Using cZNF292, a circulating circRNA biomarker for AMI is identified by this group; as a model, the collaborative CRISPR-Cas system-based method exhibits excellent accuracy and sensitivity with a low detection limit of 2.13 × 10-15 m. Moreover, the method demonstrates a good diagnostic performance for AMI when analyzing whole blood samples. Therefore, the method may provide new insight into the detection of circRNA biomarkers and is expected to have great potential in AMI diagnosis in the future.

Excess multi-cause mortality linked to influenza virus infection in China, 2012-2021: a population-based study.

Objectives: The aim of this study is to estimate the excess mortality burden of influenza virus infection in China from 2012 to 2021, with a concurrent analysis of its associated disease manifestations. Methods: Laboratory surveillance data on influenza, relevant population demographics, and mortality records, including cause of death data in China, spanning the years 2012 to 2021, were incorporated into a comprehensive analysis. A negative binomial regression model was utilized to calculate the excess mortality rate associated with influenza, taking into consideration factors such as year, subtype, and cause of death. Results: There was no evidence to indicate a correlation between malignant neoplasms and any subtype of influenza, despite the examination of the effect of influenza on the mortality burden of eight diseases. A total of 327,520 samples testing positive for influenza virus were isolated between 2012 and 2021, with a significant decrease in the positivity rate observed during the periods of 2012-2013 and 2019-2020. China experienced an average annual influenza-associated excess deaths of 201721.78 and an average annual excess mortality rate of 14.53 per 100,000 people during the research period. Among the causes of mortality that were examined, respiratory and circulatory diseases (R&C) accounted for the most significant proportion (58.50%). Fatalities attributed to respiratory and circulatory diseases exhibited discernible temporal patterns, whereas deaths attributable to other causes were dispersed over the course of the year. Conclusion: Theoretically, the contribution of these disease types to excess influenza-related fatalities can serve as a foundation for early warning and targeted influenza surveillance. Additionally, it is possible to assess the costs of prevention and control measures and the public health repercussions of epidemics with greater precision.

A Meta-analysis of the Efficacy of Different Surgical Methods in the Treatment of Uterine Prolapse.

AIM: The management of uterine prolapse poses a significant clinical challenge, with surgical intervention often necessary for symptom relief and restoration of pelvic floor function. However, the optimal surgical approach for uterine prolapse remains uncertain, prompting a comprehensive meta-analysis to compare the efficacy of various surgical methods. This study aims to assess the effectiveness of different surgical methods for treating uterine prolapse. METHODS: We used computer search to retrieve relevant literature to compare the therapeutic effects of different surgical methods for treating uterine prolapse. The search was conducted in the Web of Science and PubMed databases, and articles published until October 2023 were obtained. We employed random effects and fixed effects models and performed a meta-analysis using the R software. RESULTS: This study included 40 standard papers covering 25,896 patients with uterine prolapse. We used random and fixed effects models to conduct a meta-analysis of hysterectomy and uterine fixation procedures. The findings indicated that different surgical approaches had no significant impact on surgical success rates (I2 = 69%, p < 0.01; risk ratio (RR) (95% confidence intervals (CI)): 1.00 [0.98; 1.03]) or postoperative adverse reactions (I2 = 54%, p < 0.01; RR (95% CI), 1.10 [0.83; 1.45]). However, the durations of the surgical procedure for hysterectomy (I2 = 91%, p < 0.01; standardized mean difference (SMD) (95% CI), 0.78 [0.49; 1.07]), surgical blood loss (I2 = 97%, p < 0.01, SMD (95% CI): 1.14 [0.21; 2.07]), and intraoperative adverse reactions (I2 = 0%, p = 0.61, RR (95% CI): 1.37 [1.10; 1.71]) were statistically significant between hysterectomy and uterine fixation procedures. Additionally, publication bias and sensitivity tests showed no publication bias in this meta-analysis and no literature causing significant sensitivity. CONCLUSIONS: In the treatment of uterine prolapse, both hysterectomy and uterine fixation are similar in terms of surgical success rates and postoperative adverse reactions. However, hysterectomy is associated with longer duration of the surgical procedure, increased blood loss and higher incidence of intraoperative adverse reactions compared to uterine fixation.

PCK1-mediated glycogenolysis facilitates ROS clearance and chemotherapy resistance in cervical cancer stem cells.

Cervical cancer, one of the most common gynecological cancers, is primarily caused by human papillomavirus (HPV) infection. The development of resistance to chemotherapy is a significant hurdle in treatment. In this study, we investigated the mechanisms underlying chemoresistance in cervical cancer by focusing on the roles of glycogen metabolism and the pentose phosphate pathway (PPP). We employed the cervical cancer cell lines HCC94 and CaSki by manipulating the expression of key enzymes PCK1, PYGL, and GYS1, which are involved in glycogen metabolism, through siRNA transfection. Our analysis included measuring glycogen levels, intermediates of PPP, NADPH/NADP+ ratio, and the ability of cells to clear reactive oxygen species (ROS) using biochemical assays and liquid chromatography-mass spectrometry (LC-MS). Furthermore, we assessed chemoresistance by evaluating cell viability and tumor growth in NSG mice. Our findings revealed that in drug-resistant tumor stem cells, the enzyme PCK1 enhances the phosphorylation of PYGL, leading to increased glycogen breakdown. This process shifts glucose metabolism towards PPP, generating NADPH. This, in turn, facilitates ROS clearance, promotes cell survival, and contributes to the development of chemoresistance. These insights suggest that targeting aberrant glycogen metabolism or PPP could be a promising strategy for overcoming chemoresistance in cervical cancer. Understanding these molecular mechanisms opens new avenues for the development of more effective treatments for this challenging malignancy.

Melatonin improves mouse oocyte quality from 2-ethylhexyl diphenyl phosphate-induced toxicity by enhancing mitochondrial function.

2-Ethylhexyl diphenyl phosphate (EHDPP) is a representative organophosphorus flame retardant (OPFR) that has garnered attention due to its widespread use and potential adverse effects. EHDPP exhibits cytotoxicity, genotoxicity, developmental toxicity, and endocrine disruption. However, the toxicity of EHDPP in mammalian oocytes and the underlying mechanisms remain poorly understood. Melatonin is a natural free radical scavenger that has demonstrated cytoprotective properties. In this study, we investigated the effect of EHDPP on mouse oocytes in vitro culture system and evaluated the rescue effect of melatonin on oocytes exposed to EHDPP. Our results indicated that EHDPP disrupted oocyte maturation, resulting in the majority of oocytes arrested at the metaphase I (MI) stage, accompanied by cytoskeletal damage and elevated levels of reactive oxygen species (ROS). Nevertheless, melatonin supplementation partially rescued EHDPP-induced mouse oocyte maturation impairment. Results of single-cell RNA sequencing (scRNA-seq) analysis elucidated potential mechanisms underlying these protective effects. According to the results of scRNA-seq, we conducted further tests and found that EHDPP primarily disrupts mitochondrial distribution and function, kinetochore-microtubule (K-MT) attachment, DNA damage, apoptosis, and histone modification, which were rescued upon the supplementation of melatonin. This study reveals the mechanisms of EHDPP on female reproduction and indicates the efficacy of melatonin as a therapeutic intervention for EHDPP-induced defects in mouse oocytes.

2-Monoacylglycerol Mimetic Liposomes to Promote Intestinal Lymphatic Transport for Improving Oral Bioavailability of Dihydroartemisinin.

Purpose: Reducing the first-pass hepatic effect via intestinal lymphatic transport is an effective way to increase the oral absorption of drugs. 2-Monoacylglycerol (2-MAG) as a primary digestive product of dietary lipids triglyceride, can be assembled in chylomicrons and then transported from the intestine into the lymphatic system. Herein, we propose a biomimetic strategy and report a 2-MAG mimetic nanocarrier to target the intestinal lymphatic system via the lipid absorption pathway and improve oral bioavailability. Methods: The 2-MAG mimetic liposomes were designed by covalently bonding serinol (SER) on the surface of liposomes named SER-LPs to simulate the structure of 2-MAG. Dihydroartemisinin (DHA) was chosen as the model drug because of its disadvantages such as poor solubility and high first-pass effect. The endocytosis and exocytosis mechanisms were investigated in Caco-2 cells and Caco-2 cell monolayers. The capacity of intestinal lymphatic transport was evaluated by ex vivo biodistribution and in vivo pharmacokinetic experiments. Results: DHA loaded SER-LPs (SER-LPs-DHA) had a particle size of 70 nm and a desirable entrapment efficiency of 93%. SER-LPs showed sustained release for DHA in the simulated gastrointestinal environment. In vitro cell studies demonstrated that the cellular uptake of SER-LPs primarily relied on the caveolae- rather than clathrin-mediated endocytosis pathway and preferred to integrate into the chylomicron assembly process through the endoplasmic reticulum/Golgi apparatus route. After oral administration, SER-LPs efficiently promoted drug accumulation in mesenteric lymphatic nodes. The oral bioavailability of DHA from SER-LPs was 10.40-fold and 1.17-fold larger than that of free DHA and unmodified liposomes at the same dose, respectively. Conclusion: SER-LPs improved oral bioavailability through efficient intestinal lymphatic transport. These findings of the current study provide a good alternative strategy for oral delivery of drugs with high first-pass hepatic metabolism.

Catalytic Asymmetric Transfer Hydrogenation of Acylboronates: BMIDA as the Privileged Directing Group.

Developing a general, highly efficient, and enantioselective catalytic method for the synthesis of chiral alcohols is still a formidable challenge. We report in this article the asymmetric transfer hydrogenation (ATH) of N-methyliminodiacetyl (MIDA) acylboronates as a general substrate-independent entry to enantioenriched secondary alcohols. ATH of acyl-MIDA-boronates with (het)aryl, alkyl, alkynyl, alkenyl, and carbonyl substituents delivers a variety of enantioenriched α-boryl alcohols. The latter are used in a range of stereospecific transformations based on the boron moiety, enabling the synthesis of carbinols with two closely related α-substituents, which cannot be obtained with high enantioselectivities using direct asymmetric hydrogenation methods, such as the (R)-cloperastine intermediate. Computational studies illustrate that the BMIDA group is a privileged enantioselectivity-directing group in Noyori-Ikariya ATH compared to the conventionally used aryl and alkynyl groups due to the favorable CH-O attractive electrostatic interaction between the η6-arene-CH of the catalyst and the σ-bonded oxygen atoms in BMIDA. The work expands the domain of conventional ATH and shows its huge potential in addressing challenges in symmetric synthesis.