A novel synthetic compound, deferiprone-resveratrol hybrid (DFP-RVT), promotes hepatoprotective effects and ameliorates iron-induced oxidative stress in iron-overloaded ß-thalassemic mice.

A high amount of iron in ß-thalassemia patients can lead to oxidative stress and organ dysfunction, especially liver, the main iron accumulated organ. Iron catabolism causes the generation of reactive oxygen species (ROS), triggering liver inflammation, fibrosis, and cirrhosis. Deferiprone-resveratrol hybrid (DFP-RVT) is chemically synthesized by combining deferiprone (DFP) and resveratrol (RVT) which shows an iron-chelating property along with antioxidant activity. This study explored the hepatoprotective effect of DFP-RVT in iron overloaded ß-knockout (BKO) thalassemic mice. The results revealed that DFP-RVT treatment improved liver function in iron-overloaded BKO mice by reducing liver enzymes and increasing hepcidin levels compared to iron overload control mice. Both DFP alone and DFP-RVT treatment groups demonstrated iron chelation effects by decreasing liver iron content (LIC), iron profiles, and iron deposition in the liver. Moreover, DFP-RVT powerfully showed antioxidant properties by decreasing liver and plasma thiobarbituric acid reactive substances (TBARs) and increasing reduced glutathione (GSH) and superoxide dismutase (SOD). Interestingly, transforming growth factor ß1 (TGFß1), which can contribute to chronic liver disease through liver injury, inflammation, fibrosis, and cirrhosis, is highly expressed in iron-overloaded mice. However, both DFP and DFP-RVT treatment significantly reduced TGFß1 levels compared to the iron-overloaded group. Therefore, DFP-RVT could be a potent hepatoprotective compound through the mobilization of iron, reduction of ROS, improvement of liver enzymes, and alleviation of liver damage, potentially relieving liver dysfunction in iron-overloaded BKO mice.

Study of the Energy Crossing Between Excited States Affected by the Electronegativity of Substituents for Three 4-Azido-1,8-naphthalimide Derivatives.

Rapid detection of H2S is crucial for human physiological health and natural ecosystems. In this study, the fluorescent sensing mechanisms of three 4-azido-1,8-naphthalimide-based fluorescent probes to monitor H2S were theoretically investigated by density functional theory and time-dependent density functional theory. The potential energy curve of the charge transfer (CT) state has a crossover with that of the locally excited (LE) state proved by the constructed linear interpolating internal coordinate pathway. Thus, the transform takes place from the LE state to the CT state causing the fluorescence quenching of the probes from a nonradiative transition process of the CT state. The distance between the Franck-Condon point and the minimal energy conical intersection becomes larger with the increase of the electronegativity of substituents on the 1,8-naphthalimide fluorophore. In addition, the degree of charge separation is closely related to the energy difference between the CT and the LE states which are also essentially affected by the electronegativity of the substituents. Since the electronegativity of the substituents has proved important for the probes, our work lays a certain theoretical foundation for the design and synthesis of more sensitive 4-azido-1,8-naphthalimide-based fluorescent probes.

Comparison of Nucleotide MALDI-TOF MS with Xpert MTB/RIF for Rifampicin Susceptibility Identification and Associated Risk Factors of Rifampicin Resistance Among Drug Resistant Mycobacterium tuberculosis.

Purpose: Nucleotide-based matrix-assisted laser desorption ionization time-of-flight mass spectrometry (nucleotide MALDI-TOF MS) is an emerging molecular technology used for the diagnosis of tuberculosis (TB) caused by Mycobacterium tuberculosis (MTB)and its drug resistance. This study aimed to compare the ability of nucleotide MALDI-TOF MS to detect rifampicin (RIF) resistance in drug-resistant TB (DR-TB) patients with Xpert MTB/RIF and to analyze the disparate results individually. Additionally, potential factors associated with rifampicin resistance among DR-TB patients in Qingdao were investigated. Patients and Methods: A retrospective study was conducted at Qingdao Chest Hospital, and patients with DR-TB were enrolled. Corresponding frozen isolates were recovered and subjected to nucleotide MALDI-TOF MS, Xpert MTB/RIF, and phenotypic drug susceptibility testing (pDST). Sanger sequencing was performed for the discordant results of nucleotide MALDI-TOF MS and Xpert MTB/RIF. Univariate and multivariate logistic regression analyses were used to identify potential factors associated with rifampicin resistance among patients with DR-TB. Results: A total of 125 patients with DR-TB (18.8%, 125/668) were enrolled in this study from May 1 to July 31, 2023. Rifampicin-resistant (DR-TB/RR, 29) and rifampicin-sensitive (DR-TB/RS, 96) groups were divided according to the pDST results. Nucleotide MALDI-TOF MS performed better than Xpert MTB/RIF in terms of sensitivity, specificity, accuracy, and agreement with pDST. Only six cases had inconsistent results, and the sequencing results of five cases were identical to nucleotide MALDI-TOF MS. Furthermore, chest pain (aOR=12.84, 95% CI, 2.29-91.97, p=0.005), isoniazid sensitivity (aOR=0.14, 0.02-0.59, p=0.013), and ethambutol sensitivity (aOR=0.02, 0.00-0.10, p=0.000) were potential factors associated with rifampicin resistance among DR-TB patients in Qingdao. Conclusion: The overall concordance between nucleotide MALDI-TOF MS and Xpert MTB/RIF was 95.2%, with the former performing better in determining rifampicin susceptibility among DR-TB cases in Qingdao. Chest pain, isoniazid, and ethambutol resistance might be factors associated with RIF resistance among patients with DR-TB in Qingdao.

Theoretical Investigations on the Sensing Mechanism of Dicyanoisophorone Fluorescent Probe for the Detection of Hydrogen Sulfide.

As one of the biomolecules, hydrogen sulfide (H2S) has received a lot of attention. Recent studies have shown that endogenous hydrogen sulfide plays different roles in different organs in biological systems. Fluorescent probe technology has been widely adopted due to its many advantages such as low cost, simple operation, and high sensitivity. Among many probes, dicyanoisophorone fluorophore is often used in probe design for real-time detection of endogenous H2S due to the large Stokes shift and long fluorescence emission wavelength. In this paper, the fluorescence sensing mechanism of dicyanoisophorone-like probe L and its product 3 with near-infrared fluorescence emission has been theoretically investigated by using theory methods. The analysis of infrared (IR) vibration spectra and reduced density gradient (RDG) showed that the hydrogen bond of the enolic structure of product 3 was significantly enhanced in the S1 state. The spectroscopic information revealed that the emission of NIR fluorescence originated from the keto structure of the product. Finally, potential energy curves and frontier molecular orbitals diagrams showed that the fluorescence quenching phenomenon of the probe L was attributed to the photoinduced electron transfer (PET) process, whereas the product 3 generated after the detection of H2S undergoes the excited state intramolecular proton transfer (ESIPT) process.

Knowledge, attitudes, and practice toward tuberculosis in high school students in Qingdao, China.

INTRODUCTION: The purpose of this study is to assess the levels of knowledge, attitude, and practice (KAP) related to TB, and to analyze the differences among various demographic groups. METHODOLOGY: A total of 621 students enrolled in Qingdao High School, coming from high TB burden settings. The cross-sectional study was conducted from May to July of 2022. Participants completed an online questionnaire. Differences in knowledge and practice based on participant characteristics were analyzed using the Wilcoxon rank test and Kruskal-Wallis rank test. Group differences were assessed using a rank-based analysis of variance. RESULTS: The mean percentage of correct answers for TB knowledge and practice was 82.09% and 83.25%, respectively. Grade Three students showed higher knowledge and practice scores than Grade One or Grade Two students (t = -3.9935, p = 0.0002, t = 3.4537, p = 0.0018. 8.58 vs 7.94, 8.58 vs 8.23. t = 3.4562, p = 0.0018, t = -2.8688, p = 0.0128. 1.78 vs 1.61, 1.78 vs 1.64). A significant majority (78.42%) of students expressed fear of being affected by TB. 49.28% of the students would support and help TB patients. 88.08% of participants had heard of TB, with 72.94% learning about it at school, mainly through visual aids like posters. Information was predominantly obtained from online sources (websites, microblogs, WeChat, etc.). CONCLUSIONS: It is recommended to develop a TB curriculum for lower-grade students to enhance awareness of TB prevention through various means, including the internet and social media.

Deferiprone-resveratrol hybrid attenuates iron accumulation, oxidative stress, and antioxidant defenses in iron-loaded human Huh7 hepatic cells.

Chronic liver diseases are complications of thalassemia with iron overload. Iron chelators are required to remove excessive iron, and antioxidants are supplemented to diminish harmful reactive oxygen species (ROS), purposing to ameliorate oxidative liver damage and dysfunctions. The deferiprone-resveratrol hybrid (DFP-RVT) is a synthetic iron chelator possessing anti-ß-amyloid peptide aggregation, anti-malarial activity, and hepatoprotection in plasmodium-infected mice. The study focuses on investigating the antioxidant, cytotoxicity, iron-chelating, anti-lipid peroxidation, and antioxidant defense properties of DFP-RVT in iron-loaded human hepatocellular carcinoma (Huh7) cells. In the findings, DFP-RVT dose dependently bound Fe(II) and Fe(III) and exerted stronger ABTS•- and DPPH•-scavenging (IC50 = 8.0 and 164 µM, respectively) and anti-RBC hemolytic activities (IC50 = 640 µM) than DFP but weaker than RVT (p < 0.01). DFP-RVT was neither toxic to Huh7 cells nor PBMCs. In addition, DFP-RVT diminished the level of redox-active iron (p < 0.01) and decreased the non-heme iron content (p < 0.01) in iron-loaded Huh7 cells effectively when compared without treatment in the order of DFP-RVT > RVT ∼ DFP treatments (50 µM each). Moreover, the compound decreased levels of hepatic ROS in a dose-dependent manner and the level of malondialdehyde, which was stronger than DFP but weaker than RVT. Furthermore, DFP-RVT restored the decrease in the GSH content and GPX and SOD activities (p < 0.01) in iron-loaded Huh7 cells in the dose-dependent manner, consistently in the order of RVT > DFP-RVT > DFP. Thus, the DFP-RVT hybrid possesses potent iron chelation, antioxidation, anti-lipid peroxidation, and antioxidant defense against oxidative liver damage under iron overload.

Insecure Parental Attachment and Anxiety in Vocational College Students: The Mediating Role of Subjective Well-Being and the Moderating Role of Self-Esteem.

Purpose: Although insecure parental attachment (IPA) has been shown to play an important role in anxiety, little is known about the mediating and moderating mechanisms underlying this relationship. Patients and Methods: In the present study, we examined the mediating role of subjective well-being (SWB) in the association between IPA and anxiety and the moderating role of self-esteem. 947 Chinese vocational college students completed the measures of IPA, anxiety, SWB, and self-esteem. Results: The results indicated that IPA was significantly and positively associated with anxiety, and SWB partially mediated this relationship. Moreover, the results indicated that self-esteem moderated the relationship between IPA and anxiety. The higher the level of self-esteem, the weaker the effect of insecure attachment on the anxiety of vocational college students. Conclusion: This study highlights the significance of identifying the mechanisms of mediating and moderating paths between IPA and anxiety in vocational college students.

Metabolite characterisation of the peptide-drug conjugate LN005 in liver S9s by UHPLC-Orbitrap-HRMS.

LN005 is a peptide-drug conjugate (PDC) targeting glucose-regulated protein 78 (GRP78) to treat several types of cancer, such as breast, colon, and prostate cancer.As a new drug modality, understanding its metabolism and elimination pathways will help us to have a whole picture of it. Currently, there are no metabolic studies on LN005; therefore, this study aimed to investigate the metabolism of LN005, clarify its metabolic profile in the liver S9s of different species, and identify the major metabolic pathways and differences between species.The incubation samples were measured by ultra-high performance liquid chromatography combined with orbitrap tandem mass spectrometry (UHPLC-Orbitrap-HRMS).The results showed that LN005 was metabolised by liver S9s, and four metabolites were identified. The main metabolic pathway of LN005 in liver S9s was oxidative deamination to ketone or hydrolysis. Similar metabolic profiles were observed in mouse, rat, dog, monkey, and human liver S9s, indicating no differences between these four animal species and humans.This study provides information for the structural modification and optimisation of LN005 and affords a reference for subsequent animal experiments and human metabolism of other PDCs.

Geometric Phase Effects in the H + H2+ Reaction on the Lowest Triplet Ground State.

To our knowledge, this is the first time geometric phase (GP) effects in the H + H2+ reaction on its lowest triplet ground state with collision energies lower than 1.85 eV have been studied using the quantum wave packet method and vector potential approach. We obtained the total reaction probabilities including and not including GP (NGP) effects for J ≤ 4. Visible GP effects could be seen at the lower energy regime but are tiny at the higher one. Moreover, they are more obvious in the product rovibrational state-resolved reaction probabilities, and the relative resonance magnitudes between GP and NGP results change with product rotational state values alternatively. The main reasons are the interferences between the one- and two-transition-state (1-TS and 2-TS) reaction paths, in that at the lower energy regime, the reaction probabilities from the 2-TS pathway show peaks of comparable probabilities compared with that of the 1-TS pathway. In addition, the "out-of-phase" trend observed in the H + H2 reaction does not exist rigorously in this system. Importantly, the visible GP effects exist in this H3+ system, which makes it a very useful candidate reaction for nonadiabatic investigations in both theory and experiment.

A new class of potent liver injury protective compounds: Structural elucidation, total synthesis and bioactivity study.

A new class of potent liver injury protective compounds, phychetins A-D (1-4) featuring an unique 6/6/5/6/5 pentacyclic framework, were isolated and structurally characterized from a Chinese medicinal plant Phyllanthus franchetianus. Compounds 2-4 are three pairs of enantiomers that were initially obtained in a racemic manner, and were further separated by chiral HPLC preparation. Compounds 1-4 were proposed to be originated biosynthetically from a coexisting lignan via an intramolecular Friedel-Crafts reaction as the key step. A bioinspired total synthesis strategy was thus designated, and allowed the effective syntheses of compounds 2-4 in high yields. Some of compounds exhibited significant anti-inflammatory activities in vitro via suppressing the production of pro-inflammatory cytokine IL-1ß. Notably, compound 4, the most active enantiomeric pair in vitro, displayed prominent potent protecting activity against liver injury at a low dose of 3 mg/kg in mice, which could serve as a promising lead for the development of acute liver injury therapeutic agent.

Luteolin Protects Pancreatic ß Cells against Apoptosis through Regulation of Autophagy and ROS Clearance.

Diabetes, which is mainly characterized by increased apoptosis and dysfunction of beta (ß) cells, is a metabolic disease caused by impairment of pancreatic islet function. Previous studies have demonstrated that death-associated protein kinase-related apoptosis-inducing kinase-2 (Drak2) is involved in regulating ß cell survival. Since natural products have multiple targets and often are multifunctional, making them promising compounds for the treatment of diabetes, we identified Drak2 inhibitors from a natural product library. Among the identified products, luteolin, a flavonoid, was found to be the most effective compound. In vitro, luteolin effectively alleviated palmitate (PA)-induced apoptosis of ß cells and PA-induced impairment of primary islet function. In vivo, luteolin showed a tendency to lower blood glucose levels. It also alleviated STZ-induced apoptosis of ß cells and metabolic disruption in mice. This function of luteolin partially relied on Drak2 inhibition. Furthermore, luteolin was also found to effectively relieve oxidative stress and promote autophagy in ß cells, possibly improving ß cell function and slowing the progression of diabetes. In conclusion, our findings show the promising effect of Drak2 inhibitors in relieving diabetes and offer a potential therapeutic target for the protection of ß cells. We also reveal some of the underlying mechanisms of luteolin's cytoprotective function.

Control of the fluorescence molecule 2-(2'-hydroxyphenyl) benzothiazole derivatives by introducing electron-donating and withdrawing substituents groups.

Using density functional theory (DFT) and time-dependent density functional theory (TDDFT), we investigate the fluorescence mechanism of (E)-4-(3-(benzo[d]thiazol-2-yl)-2-hydroxy-5-methylstyryl)-1-methylpyridin-1-ium (HBTMY) and the excited-state intramolecular proton transfer process (ESIPT) of hydroxyphenyl. Herein, we introduce two electron-donating (amino and methoxy) and two electron-withdrawing (hydrogen and cyano) groups into HBTMY to study their effects on the fluorescence and the ESIPT process. Structural parameters, infrared vibration frequency, vertical excitation and emission energies as well as frontier molecular orbitals show that the substituents have different impacts on intramolecular hydrogen bonding behavior. The result shows that the fluorescence wavelength of molecules with the amino group could reach the near-infrared area, which favors using this fluorescence in the living cell. As the ability of electron-absorbing groups increases, the forward energy barrier in the potential energy curves decreases sharply making the ESIPT process more familiar to take place. Thus, this work offers a guide for cell imaging and provides strategies to adjust and control fluorescence by introducing substituents.

Unmet needs and depression among spousal caregivers: the mediating role of marital satisfaction.

OBJECTIVES: Previous research has identified that unmet needs are associated with adverse mental health outcomes in older adults. However, the unmet needs of older adults' spousal caregivers are unknown. The present study examined the association between unmet needs and depression among spousal caregivers, and whether marital satisfaction mediated this association. METHODS: We included 1,856 participants who provided care to their spouses with difficulties in activities of daily living (ADL) and instrumental activities of daily living (IADL) from the 2018 China Health and Retirement Longitudinal Survey. Unmet needs of spousal caregivers were assessed as the total number of ADL/IADL tasks with which respondents had unmet needs. Path models were conducted to evaluate the associations between unmet needs, marital satisfaction, and depression. Subgroup analyses by sex were conducted to examine the sex differences regarding the associations. RESULTS: Spousal caregivers with more unmet ADL/IADL needs reported higher levels of depression (p < 0.001). Additionally, for wife caregivers, unmet ADL/IADL needs were associated with lower marital satisfaction, and lower marital satisfaction was associated with higher degrees of depression, indicating that marital satisfaction partially mediated the association between unmet needs and depression (p < 0.01). However, marital satisfaction did not mediate the association between unmet needs and depression among husband caregivers. CONCLUSIONS: The mediating effect of marital satisfaction on the association between unmet needs and depression only existed in wife caregivers. Social services should be provided to meet the needs of caregivers with ADL/IADL difficulties, and interventions should be implemented to promote the marital satisfaction of wife caregivers.

Transmission of tuberculosis in an incarcerated population during the subclinical period: A cross-sectional study in Qingdao, China.

Objectives: As a closed gathering place, prison is the cradle of tuberculosis (TB) outbreak. Therefore, the analysis of the prevalence rate and risk factors of latent tuberculosis infection (LTBI) in prison will be a necessary measure to intervene in the spread of tuberculosis. Methods: In this study, we consecutively recruited 506 adult prisoners in Qingdao to carry out this cross-sectional study. TB and LTBI were screened by IGRA, X-ray, X-pert, sputum smear and culture. Results: A total of 17 TB, 101 LTBI and 388 HC were identified, with an infection rate of 23.32% (118/506) and a TB incidence rate of 3282/100,000 population. Age, malnutrition and inmates living with TB prisoners were risk factors for LTBI. Additionally, most TB cases (70.59%, 12/17) were subclinical tuberculosis (STB), contributing significantly to TB transmission. Conclusion: Our results demonstrate that the transmission efficiency of asymptomatic patients is not essentially different from that of symptomatic patients, indicating that TB transmission occurs during the subclinical period. Our findings highlight the need to strengthen active case-finding strategies to increase TB case detection in this population.

Enantiomeric pairs of macrocyclic acylphloroglucinols from Syzygium szemaoense.

Two enantiomeric pairs of macrocyclic acylphloroglucinols (1a/1b and 2a/2b) with an unprecedented carbon skeleton featuring a bicyclo[12.3.1]octadecane core, together with an undescribed biogenetically related long-chain acylphloroglucinol (3), were isolated from Syzygium szemaoense. Their structures were fully established by spectroscopic method, X-ray crystallographic analysis, and ECD calculation. Compounds 1b and 2a/2b exhibited inhibition against death-associated protein kinase-related apoptosis inducing protein kinase 2 (DRAK2) and ATP citrate lyase (ACLY), respectively.

Chemoselective N-acylation of indoles using thioesters as acyl source.

The selective acylation of indoles often requires sensitive and reactive acyl chloride derivatives. Here, we report a mild, efficient, functional group tolerant, and highly chemoselective N-acylation of indoles using thioesters as a stable acyl source. A series of indoleamides have been obtained with moderate to good yields. In addition, heterocycles, such as carbazole, can also be used as nucleophiles in this reaction.

The relation between self-stigma and loneliness in visually impaired college students: Self-acceptance as mediator.

BACKGROUND: Loneliness, a negative emotion that is common in college students, may cause psychological disorders and behavioral issues. Particularly vulnerable are visually impaired college students, who are at an increased risk of loneliness. OBJECTIVES: This study was aimed at explaining the current situation of loneliness among visually impaired college students as well as its influencing factors and exploring the intermediary role of self-acceptance between self-stigma and loneliness. METHOD: Seventy-eight college students with visual impairment completed a series of self-report questionnaires, including the Self-Stigma of Disabled Scale (SSDS), the Self-Acceptance Questionnaire (SAQ), and the University of California-Los Angeles (UCLA) Loneliness Scale. Mediation analyses were conducted using PROCESS in SPSS. RESULTS: Participants' mean loneliness score was 44.97 ± 9.35. Two survey factors were significantly associated with loneliness: visual impairment status and relationship with parents (p < 0.05). When controlling for extent of visual damage and relationship with parents, self-stigma showed a significant predictive effect on loneliness (B = 0.37, t = 4.1023, p < 0.01). CONCLUSIONS: In China, visually impaired students suffer from a high level of loneliness, and self-acceptance plays a central role in connecting their self-stigma and loneliness.

Systematic evaluation of potential pathogenicity of Salmonella Indiana.

Salmonella Indiana has emerged in recent years as an important zoonotic pathogen, but its pathogenicity has not been fully elucidated. In this study, using in vivo and in vitro animal and cellular experimental model systems, we evaluated the pathogenicity of Salmonella Indiana (S. Indiana) compared with three other serotypes of Salmonella, S. Enteritidis, S. Typhimurium and S. Thompson. The animal experiments included observations of clinical symptoms, pathological changes and determination of median lethal dose in mice. The adhesion and invasiveness and intracellular proliferative capacity of Salmonella in vitro were measured with the murine macrophage-like cell line RAW264.7 cells and the human colon adenocarcinoma cell line Caco-2 cells. The results of animal experiments showed that S. Indiana, S. Enteritidis, S. Typhimurium and S. Thompson caused histopathological changes in most organs to varying degrees, primarily in the liver and intestine of mice. The gross lesions included white necrotic foci on the liver surface with different levels. The histopathological changes of monocyte/macrophage infiltration and coagulative necrosis were observed in the liver. Intestinal villi became short and were sloughed off, and lymphocyte infiltration was found in the submucosa. Compared with the other serotypes, the pathological changes caused by S. Indiana were slighter and had a relatively high median lethal dose in mice. The results of adhesion and invasion tests showed that the intracellular growth trend of most Salmonella strains was positively correlated with the number of pathogens adhering to and invading cells. Compared with the strains of the other three serotypes, most S. Indiana strains exhibited significantly lower adhesion and invasiveness to RAW264.7 and Caco-2 cells within 30 min. Most S. Indiana strains displayed twice to four times lower intracellular proliferation within 24 h in RAW264.7 cells. In conclusion, S. Indiana was pathogenic, but its pathogenicity was lower than that of S. Typhimurium and S. Enteritidis, and was similar to that of S. Thompson.