Enantiospecific Analysis of Carboxylic Acids Using Cinchona Alkaloid Dimers as Chiral Solvating Agents.

Cinchona alkaloid derivatives as Brønsted base catalysts have attracted considerable attention in the field of asymmetric catalysis. However, their potential application as chiral solvating agents has not been described. In this research, we investigated the use of the Cinchona alkaloid dimer, namely, (DHQ)2PHAL, as a chiral solvating agent for discerning various mandelic acid derivatives through 1H NMR spectroscopy. The addition of catalytic amounts of DMAP facilitated this process. Our experimental results demonstrate that dimeric (DHQ)2PHAL exhibits remarkable chiral discrimination properties regarding the diagnostic split protons of 1H NMR signals (including 24 examples, up to 0.321 ppm). Furthermore, it serves as an excellent chiral discriminating agent and provides good resolution for racemic chiral phosphoric acid as determined by 31P NMR spectroscopy. The quality of enantiodifferentiation has also been evaluated by means of the parameter "resolution (Rs)". Significantly, this class of CSAs based on (alkaloid)2linker systems with an azaaromatic linker can be directly employed, which is commercially available in an enantiopure form at very low cost and exhibits promising potential in determining the enantiopurity of α-hydroxy acids by chemoselective and biocatalytic reactions.

Clinical characteristics of acute non-varicose upper gastrointestinal bleeding and the effect of endoscopic hemostasis.

BACKGROUND: Acute non-variceal upper gastrointestinal bleeding (ANVUGIB) constitutes a prevalent emergency within Gastroenterology, encompassing 80%-90% of all gastrointestinal hemorrhage incidents. This condition is distinguished by its abrupt onset, swift progression, and notably elevated mortality rate. AIM: To gather clinical data from patients with ANVUGIB at our hospital in order to elucidate the clinical characteristics specific to our institution and analyze the therapeutic effectiveness of endoscopic hemostasis. METHODS: We retrospectively retrieved the records of 532 patients diagnosed with ANVUGIB by endoscopy at our hospital between March 2021 and March 2023, utilizing our medical record system. Data pertaining to general patient information, etiological factors, disease outcomes, and other relevant variables were meticulously collected and analyzed. RESULTS: Among the 532 patients diagnosed with ANVUGIB, the male-to-female ratio was 2.91:1, with a higher prevalence among males. Notably, 43.6% of patients presented with black stool as their primary complaint, while 27.4% had hematemesis as their initial symptom. Upon admission, 17% of patients exhibited both hematemesis and black stool, while most ANVUGIB patients primarily complained of overt gastrointestinal bleeding. Urgent routine blood examinations at admission revealed that 75.8% of patients had anemia, with 63.4% experiencing moderate to severe anemia, and 1.5% having extremely severe anemia (hemoglobin < 30 g/L). With regard to etiology, 53.2% of patients experienced bleeding without a definitive trigger, 24.2% had a history of using gastric mucosa-irritating medications, 24.2% developed bleeding after alcohol consumption, 2.8% attributed it to improper diet, 1.7% to emotional excitement, and 2.3% to fatigue preceding the bleeding episode. Drug-induced ANVUGIB was more prevalent in the elderly than middle-aged and young individuals, while bleeding due to alcohol consumption showed the opposite trend. Additionally, diet-related bleeding was more common among the young age group compared to the middle-aged group. Gastrointestinal endoscopy identified peptic ulcers as the most frequent cause of ANVUGIB (73.3%), followed by gastrointestinal malignancies (10.9%), acute gastric mucous lesions (9.8%), and androgenic upper gastrointestinal bleeding (1.5%) among inpatients with ANVUGIB. Of the 532 patients with gastrointestinal bleeding, 68 underwent endoscopic hemostasis, resulting in an endoscopic treatment rate of 12.8%, with a high immediate hemostasis success rate of 94.1%. CONCLUSION: ANVUGIB patients exhibit diverse characteristics across different age groups, and endoscopic hemostatic treatments have demonstrated remarkable efficacy.

Structure-Based Rational and General Strategy for Stabilizing Single-Chain T-Cell Receptors to Enhance Affinity.

The T-cell receptor (TCR) is a crucial molecule in cellular immunity. The single-chain T-cell receptor (scTCR) is a potential format in TCR therapeutics because it eliminates the possibility of αß-TCR mispairing. However, its poor stability and solubility impede the in vitro study and manufacturing of therapeutic applications. In this study, some conserved structural motifs are identified in variable domains regardless of germlines and species. Theoretical analysis helps to identify those unfavored factors and leads to a general strategy for stabilizing scTCRs by substituting residues at exact IMGT positions with beneficial propensities on the consensus sequence of germlines. Several representative scTCRs are displayed to achieve stability optimization and retain comparable binding affinities with the corresponding αß-TCRs in the range of µM to pM. These results demonstrate that our strategies for scTCR engineering are capable of providing the affinity-enhanced and specificity-retained format, which are of great value in facilitating the development of TCR-related therapeutics.

Associations of muscle mass and strength with new-onset diabetes among middle-aged and older adults: evidence from the China health and retirement longitudinal study (CHARLS).

BACKGROUND: The associations of muscle mass and strength with new-onset Type 2 diabetes mellitus (T2DM) remain controversial. We aimed to longitudinally evaluate muscle mass and strength in predicting T2DM among Chinese middle-aged and older adults. METHODS: We enrolled 6033 participants aged ≥ 45 years from the China Health and Retirement Longitudinal Study (CHARLS), a cohort survey, between 2011 and 2012. The appendicular skeletal muscle mass (normalized by weight, ASM/BW%), relative hand grip strength (normalized by weight, HGS/BW), and five-repetition chair stand test (5CST). were all categorized into tertiles (lowest, middle, and highest groups) at baseline, respectively. Individuals were followed up until the occurrence of diabetes or the end of CHARLS 2018, whichever happened first. Cox proportional hazards models to calculate hazard ratios with 95% confidence intervals (CI) and mediation analysis were used. RESULTS: During follow-up, 815 (13.5%) participants developed T2DM. After adjusting for covariates, lower ASW/BW% was not associated with a higher risk of diabetes. Compared with individuals in the highest tertile of HGS/BW, those in the lowest tertile had 1.296 (95%CI 1.073-1.567) higher risk of diabetes. Compared with individuals in the lowest tertile of 5CST, those in the highest tertile had 1.329 times (95%CI 1.106-1.596) higher risk of diabetes. By subgroup, both the lowest HGS/BW and highest 5CST were risk factors for diabetes among obesity. The mediation analysis revealed that the effect of HGS/BW on the risk of diabetes is mainly mediated by insulin resistance. CONCLUSIONS: Lower muscle strength is associated with an increased risk of diabetes, especially in obese populations.

Digital health literacy and associated factors among internet users from China: a cross-sectional study.

BACKGROUND: As the internet develops and 5G technology becomes increasingly prominent, the internet has become a major source of health-related information. Increasingly, people use the internet to find health-related information, and digital health literacy is now a set of essential capabilities to improve their health in the digital era. However, little is known about the factors that influencing digital health literacy. This study aimed to assess digital health literacy scores and identify its influencing factors among internet users in China. Additionally, this study explored the participant's actual skills using an additional set of performance-based items from the Digital Health Literacy Instrument (DHLI). METHODS: An online cross-sectional study was conducted in August 2022. Participants aged ≥18 years were recruited to complete the survey. Data were collected using the Chinese revised version of the DHLI, the self-reported internet use questionnaire, and the sociodemographic questionnaire. We conducted multivariate linear regression analyses to explore the relationships among the sociodemographic variables, behavior of internet use, and the digital health literacy scores. RESULTS: In total, 702 participants completed the survey. The mean DHLI score was 2.69 ± 0.61. Multivariate linear regression analyses showed that the age groups 35-49 (ß = - 0.08, P = 0.033), 50-64 (ß = - 0.161, P < 0.001), and ≥ 65 (ß = - 0.138, P < 0.001) were negatively associated with DHL scores. However, education level, including bachelor's or associate degree (ß = 0.255, P = 0.002) and master's degree and above (ß = 0.256, P < 0.001), frequency of health-related Internet usage (ß = 0.192, P < 0.001), the number of digital devices used (ß = 0.129, P = 0.001), and OHISB (ß = 0.103, P = 0.006) showed a positive relationship with DHL scores. CONCLUSIONS: The study findings demonstrate that age, educational levels, number of technological devices used, and greater use of the web for health information were independently associated with DHL scores. Healthcare providers should consider providing training programs tailored to specific sociodemographic factors to improve the ability that find and use accurate information online to meet digital health services, which contributes to enhance their self-management and reduce health disparities.

Achieving Accuracy and Economy for Calculating Vertical Detachment Energies of Molecular Anions: A Model Chemistry Composite Methods.

The vertical detachment energy (VDE) is a vital factor for predicting the stability of anions that have important applications in the atom, molecule and cluster science. Due to the synthetic or characterization difficulty of anions, accurate and efficient predictions of VDE independent of laboratory data have always been an appealing task to remedy the experimental deficiencies. Unfortunately, the generally adopted CCSD(T) and electron propagator theory (EPT) methods have respectively been proven to be reliable but very cost-expensive, and cost-effective but sometimes problematic when Koopman's theorem is invalid. Here, we for the first time introduced and benchmarked a series of model chemistry composite methods (e. g., CBS-QB3, G4 and W1BD) on calculating VDE for 57 molecular anions. Notably, CBS-QB3 exceeds the accuracy of CCSD(T) while approaching the economy of EPT. Therefore, we highly recommend the composite method CBS-QB3 to compute VDEs for molecular anions in the attractive "killing two birds with one stone" manner.

Platanosides from Platanus × acerifolia: New molecules, SAR, and target validation of a strong lead for drug-resistant bacterial infections and the associated sepsis.

Three undescribed (1-3) and nine known (4-12) platanosides were isolated and characterized from a bioactive extract of the May leaves of Platanus × acerifolia that initially showed inhibition against Staphylococcus aureus. Targeted compound mining was guided by an LC-MS/MS-based molecular ion networking (MoIN) strategy combined with conventional isolation procedures from a unique geographic location. The novel structures were mainly determined by 2D NMR and computational (NMR/ECD calculations) methods. Compound 1 is a rare acylated kaempferol rhamnoside possessing a truxinate unit. 6 (Z,E-platanoside) and 7 (E,E-platanoside) were confirmed to have remarkable inhibitory effects against both methicillin-resistant S. aureus (MIC: ≤ 16 µg/mL) and glycopeptide-resistant Enterococcus faecium (MIC: ≤ 1 µg/mL). These platanosides were subjected to docking analyses against FabI (enoyl-ACP reductase) and PBP1/2 (penicillin binding protein), both of which are pivotal enzymes governing bacterial growth but not found in the human host. The results showed that 6 and 7 displayed superior binding affinities towards FabI and PBP2. Moreover, surface plasmon resonance studies on the interaction of 1/7 and FabI revealed that 7 has a higher affinity (KD = 1.72 µM), which further supports the above in vitro data and is thus expected to be a novel anti-antibacterial drug lead.

Associations of sarcopenia with peak expiratory flow among community-dwelling elderly population: based on the China Health and Retirement Longitudinal Study (CHARLS).

PURPOSE: To cross-sectionally and longitudinally investigate the correlations of sarcopenia and its components with peak expiratory flow (PEF) among Chinese community-dwelling elderly people. METHODS: The data were extracted from the China Health and Retirement Longitudinal Study (CHARLS). A total of 4053 participants aged ≥ 60 years were enrolled from CHARLS 2011, and 2810 were followed up until 2015. Participants were classified into no-sarcopenia, non-severe sarcopenia, and severe sarcopenia groups based on skeletal muscle mass index (SMI), hand grip strength (HGS), and physical performance [gait speed, five-repetition chair stand test (5CST) and short physical performance battery (SPPB)]. Multivariate linear and logistic regression analyses were used to evaluate the associations of sarcopenia and its components with PEF cross-sectionally and longitudinally. RESULTS: In the cross-sectional analysis, the prevalence of non-severe sarcopenia was 14.6% and severe sarcopenia was 4.9%. The results of linear regression analysis revealed that sarcopenia and its components were all correlated with PEF and PEF%pred. In the longitudinal analysis, compared with non-sarcopenia, subjects with severe sarcopenia were associated with a higher risk of PEF (OR = 2.05, 95%CI = 1.30-3.26) and PEF%pred (OR = 1.83, 95%CI = 1.17-2.86) decline. The changes in physical performance were correlated with changes in PEF and PEF%pred. No associations were observed between changes in SMI and PEF as well as PEF%pred. CONCLUSIONS: We demonstrated the associations of baseline sarcopenia status with PEF and longitudinal PEF decline. Also, the changes in physical performance were associated with changes in PEF during a 4-year follow-up. It indicates that improving sarcopenia, especially physical performance may increase PEF.

Peroxidase activity of a Cu-Fe bimetallic hydrogel and applications for colorimetric detection of ascorbic acid.

A Cu-Fe bimetallic hydrogel (2-QF-CuFe-G) was constructed through a simple method. The 2-QF-CuFe-G metallohydrogel possesses excellent peroxidase-like activity to catalyze the oxidation of 3,3',5,5'-tetramethylbenzidine (TMB) in the presence of H2O2. The catalytic mechanism was confirmed by the addition of •OH radical scavenger isopropyl alcohol (IPA), tert-butyl alcohol (TBA) and ˙OH trapping agent terephthalic acid (TA). Remarkably, the resultant blue ox-TMB system can be used to selectively and sensitively detect ascorbic acid (AA) with an LOD of 0.93 µM in the range of 4-36 µM through the colorimetric method. Moreover, the assay based on the 2-QF-CuFe-G metallohydrogel can be successfully applied to detect AA in fresh fruits.

Polyarylisocyanides Derived from an Alkyne-Pd(II) Catalyst as Robust Alignment Media with Excellent Enantiodiscimination.

The development of chiral alignment media for measuring anisotropic NMR parameters provides an opportunity to determine the absolute configuration of chiral molecules without the need for derivatization. However, chiral alignment media with a high and robust enantiodiscriminating property for a wide range of chiral molecules are still scarce. In this study, we synthesized cholesterol-end-functionalized helical polyisocyanides from a chiral monomer using a cholesterol-based alkyne-Pd(II) initiator. These stereoregular polyisocyanides form stable and weak anisotropic lyotropic liquid crystals (LLCs) in dichloromethane systems, exhibiting highly optical activities in both single left- and right-handed helices. The preparation process of the media was straightforward, and the aligning property of the LLCs could be controlled by adjusting the concentration and temperature. Using the chiral polyisocyanides, we extracted the residual dipolar coupling for an enantiomeric pair of isopinocampheol (IPC), as well as a number of pharmaceutical molecules, demonstrating excellent enantiodiscriminating properties for a broad range of chiral compounds.

[Huangdi Anxiao Capsules-containing serum protects cell model from cognitive dysfunction in diabetes via inhibiting NLRP3-mediated pyroptosis].

This study aims to investigate the effects and the molecular mechanism of Huangdi Anxiao Capsules(HDAX)-containing serum in protecting the rat adrenal pheochromocytoma(PC12) cells from diabetes-associated cognitive dysfunction induced by high glucose and whether the mechanism is related to the regulation of NOD-like receptor thermal protein domain associated protein 3(NLRP3)-mediated pyroptosis. The PC12 cell model of diabetes-associated cognitive dysfunction induced by high glucose was established and mcc950 was used to inhibit NLRP3. PC12 cells were randomized into control, model, HDAX-containing serum, mcc950, and HDAX-containing serum+mcc950 groups. Methyl thiazolyl tetrazolium(MTT) assay was employed to determine the viability, and Hoechst 33258/PI staining to detect pyroptosis of PC12 cells. Enzyme-linked immunosorbent assay(ELISA) was employed to measure the levels of interleukin-1 beta(IL-1ß) and IL-18. Western blot was employed to determine the protein levels of postsynaptic density protein 95(PSD-95), NLRP3, apoptosis-associated speck-like protein containing a CARD(ASC), gasdermin D(GSDMD), GSDMD-N, and cleaved cysteinyl aspartate specific proteinase-1(caspase-1), and RT-PCR to determine the mRNA levels of NLRP3, ASC, GSDMD, and caspase-1. The immunofluorescence assay was adopted to measure the levels and distribution of NLRP3 and GSDMD-N in PC12 cells. Compared with the control group, the model group showed decreased cell proliferation, increased PI positive rate, down-regulated protein level of PSD-95, up-regulated protein levels of NLRP3, ASC, GSDMD-N, GSDMD, and cleaved caspase-1, up-regulated mRNA levels of NLRP3, ASC, GSDMD, and caspase-1, and elevated levels of IL-1ß and IL-18. Compared with the model group, HDAX-containing serum, mcc950, and the combination of them improved cell survival rate and morphology, decreased the PI positive rate, down-regulated the protein levels of NLRP3, ASC, GSDMD-N, GSDMD, and cleaved caspase-1 and the mRNA levels of NLRP3, ASC, GSDMD, and caspase-1, and promoted the secretion of IL-1ß and IL-18. The findings demonstrated that HDAX-containing serum can inhibit the pyroptosis-mediated by NLRP3 and protect PC12 cells from the cognitive dysfunction induced by high glucose.

Size-Regulated Hole and Triplet Energy Transfer from CdSe Quantum Dots to Organic Acceptors for Enhancing Singlet Oxygen Generation.

Triplet energy transfer (TET) from semiconductor quantum dots (QDs) is an emerging strategy for sensitizing molecular triplets that have great potential in many applications. Here, CdSe QDs with varying sizes and 1-pyrenecarboxylic acid (PCA) are selected as the triplet donor and acceptor, respectively, to study the TET and charge transfer dynamics as well as enhanced singlet oxygen (1O2) generation properties. The results from static and transient spectroscopy measurements demonstrate that both the TET and hole transfer occur at the QDs-PCA interface. The observed significant drop in TET efficiency from 52 to 8% with increasing QD size results from the reduced TET driving force between the QDs and PCA, which is further confirmed by the more efficient sensitization of the anthracene derivative with a large TET driving force. In contrast, the hole transfer efficiency displays a small decrease with an increasing QD size due to a slight change in the hole driving force. The sensitized PCA triplets show a good ability of 1O2 generation, and the 1O2 formation rate increases 10-fold as the QD size decreases from 3.3 to 2.4 nm. These findings provide a profound understanding of the TET and hole transfer mechanism from QDs to molecules and are significant in designing efficient 1O2 generation systems based on semiconductor QDs and triplet molecules.

The subacute toxicity and underlying mechanisms of biomimetic mesoporous polydopamine nanoparticles.

Recently, mesoporous nanomaterials with widespread applications have attracted great interest in the field of drug delivery due to their unique structure and good physiochemical properties. As a biomimetic nanomaterial, mesoporous polydopamine (MPDA) possesses both a superior nature and good compatibility, endowing it with good clinical transformation prospects compared with other inorganic mesoporous nanocarriers. However, the subacute toxicity and underlying mechanisms of biomimetic mesoporous polydopamine nanoparticles remain uncertain. Herein, we prepared MPDAs by a soft template method and evaluated their primary physiochemical properties and metabolite toxicity, as well as potential mechanisms. The results demonstrated that MPDA injection at low (3.61 mg/kg) and medium doses (10.87 mg/kg) did not significantly change the body weight, organ index or routine blood parameters. In contrast, high-dose MPDA injection (78.57 mg/kg) is associated with disturbances in the gut microbiota, activation of inflammatory pathways through the abnormal metabolism of bile acids and unsaturated fatty acids, and potential oxidative stress injury. In sum, the MPDA dose applied should be controlled during the treatment. This study first provides a systematic evaluation of metabolite toxicity and related mechanisms for MPDA-based nanoparticles, filling the gap between their research and clinical transformation as a drug delivery nanoplatform.

hMSCs treatment attenuates murine herpesvirus-68 (MHV-68) pneumonia through altering innate immune response via ROS/NLRP3 signaling pathway.

Immunocompromised individuals are particularly vulnerable to viral infections and reactivation, especially endogenous herpes viruses such as Epstein-Barr virus (EBV), a member of oncogenic gamma-herpesviruses, which are commonly linked to pneumonia and consequently significant morbidity and mortality. In the study of human and animal oncogenic gammaherpesviruses, the murine gamma-herpesviruses-68 (MHV-68) model has been applied, as it can induce pneumonia in immunocompromised mice. Mesenchymal stem cell (MSC) treatment has demonstrated therapeutic potential for pneumonia, as well as other forms of acute lung injury, in preclinical models. In this study, we aim to investigate the therapeutic efficacy and underlying mechanisms of human bone marrow-derived MSC (hMSC) on MHV-68-induced pneumonia. We found that intravenous administration of hMSCs significantly reduced lung damages, diminished inflammatory mediators and somehow inhibited MHV-68 replication. Furthermore, hMSCs treatment can regulate innate immune response and induce macrophage polarization from M1 to M2 phenotype, could significantly alter leukocyte infiltration and reduce pulmonary fibrosis. Our findings with co-culture system indicated that hMSCs effectively reduced the secretion of of inflammation-related factors and induced a shift in macrophage polarization, consistent with in vivo results. Further investigations revealed that hMSCs treatment suppressed the activation of macrophage ROS/NLRP3 signaling pathway in vivo and in vitro. Moreover, administration of MCC950, a selective NLRP3 inhibitor has been shown to effectively reduce ROS production and subsequently alleviate inflammation induced by MHV-68. Taken together, our work has shown that hMSCs can effectively protect mice from lethal MHV-68 pneumonia, which may throw new light on strategy for combating human EBV-associated pneumonia.

Regioselective synthesis of 3-nitroindoles under non-acidic and non-metallic conditions.

An electrophilic substitution reaction, without acid and metal, of indole with ammonium tetramethylnitrate for accessing 3-nitroindole has been developed. In this protocol, trifluoroacetyl nitrate (CF3COONO2) was produced by metathesis of ammonium tetramethyl nitrate and trifluoroacetic anhydride at sub-room temperature. Trifluoroacetyl nitrate (CF3COONO2) is an electrophilic nitrating agent for a variety of indoles, aromatic and heterocyclic aromaticity. Meanwhile, this strategy could be applied to construct the skeleton structure of many kinds of bioactive molecules. Interestingly, 3-nitroindole can be further derivatived as a pyrrolo[2,3-b]indole.