Hydronidone induces apoptosis in activated hepatic stellate cells through endoplasmic reticulum stress-associated mitochondrial apoptotic pathway.

BACKGROUND AND AIM: Hydronidone (HDD) is a novel pirfenidone derivative developed initially to reduce hepatotoxicity. Our previous studies in animals and humans have demonstrated that HDD treatment effectively attenuates liver fibrosis, yet the underlying mechanism remains unclear. This study aimed to investigate whether HDD exerts its anti-fibrotic effect by inducing apoptosis in activated hepatic stellate cells (aHSCs) through the endoplasmic reticulum stress (ERS)-associated mitochondrial apoptotic pathway. METHODS: The carbon tetrachloride (CCl4)- and 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-induced liver fibrosis models were used for in vivo studies. In vitro studies were conducted using the human hepatic stellate cell line LX-2. The apoptotic effect of HDD on aHSCs was examined using TUNEL and flow cytometry assays. The small interfering RNA (siRNA) technique was employed to downregulate the expression of interest genes. RESULTS: HDD treatment significantly promoted apoptosis in aHSCs in both the CCl4- and DDC-induced liver fibrosis in mice and LX-2 cells. Mechanistic studies revealed that HDD triggered ERS and subsequently activated the IRE1α-ASK1-JNK pathway. Furthermore, the influx of cytochrome c from the mitochondria into the cytoplasm was increased, leading to mitochondrial dysfunction and ultimately triggering apoptosis in aHSCs. Notably, inhibition of IRE1α or ASK1 by siRNA partially abrogated the pro-apoptotic effect of HDD in aHSCs. CONCLUSIONS: The findings of both in vivo and in vitro studies suggest that HDD induces apoptosis in aHSCs via the ERS-associated mitochondrial apoptotic pathway, potentially contributing to the amelioration of liver fibrosis.

Establishment of Indirect Competitive Enzyme-linked Immunosorbent Assay (ic-ELISA) for Copper ion (Cu2+) in Raw Meat Products.

Adding an appropriate amount of copper to feed can promote the growth and development of livestock; however, a large amount of heavy metal copper can accumulate in livestock through the enrichment effect, which poses a serious threat to human health. Traditional Cu2+ detection relies heavily on complex and expensive instruments, such as inductively coupled plasma-optical emission spectrometry (ICP-OES) and inductively coupled plasma-mass spectrometry (ICP-MS); thus, convenient and simple rapid detection technologies are urgently needed. In this paper, synthesized copper antigens were used to immunize mice and highly specific anticopper monoclonal antibodies were obtained, which were verified to exhibit high affinity and specificity. Based on the above antibodies, an indirect competitive enzyme-linked immunosorbent assay (ic-ELISA) was established for the rapid detection of copper content in pork. The standard inhibition curve of the method was obtained by antigen-antibody working concentration screening, in which the half inhibitory concentration (IC50) was 11.888 ng/mL, the limit of detection (LOD) was 0.841 ng/mL and the correlation coefficient R2 of the curve was 0.998. In the additive recovery experiment, the recovery rate ranged from 90% to 110%, and the coefficient of variation (CV) was less than 10%, indicating that the method achieved high accuracy and precision. Finally, the results of ic-ELISA combined with Bland-Altman analysis showed a high correlation with ICP-MS, and the correlation coefficient (R2) reached 0.990 when the copper concentration was less than 200 ng/mL. Thus, the ic-ELISA method exhibits high reliability.

Identification of tumor heterogeneity associated with KRAS/TP53 co-mutation status in lung adenocarcinoma based on single-cell RNA sequencing.

Lung cancer stands as the predominant cause of cancer-related mortality globally. Lung adenocarcinoma (LUAD), being the most prevalent subtype, garners extensive attention due to its notable heterogeneity, which significantly influences tumor development and treatment approaches. This research leverages single-cell RNA sequencing (scRNA-seq) datasets to delve into the impact of KRAS/TP53 co-mutation status on LUAD. Moreover, utilizing the TCGA-LUAD dataset, we formulated a novel predictive risk model, comprising seven prognostic genes, through LASSO regression, and subjected it to both internal and external validation sets. The study underscores the profound impact of KRAS/TP53 co-mutational status on the tumor microenvironment (TME) of LUAD. Crucially, KRAS/TP53 co-mutation markedly influences the extent of B cell infiltration and various immune-related pathways within the TME. The newly developed predictive risk model exhibited robust performance across both internal and external validation sets, establishing itself as a viable independent prognostic factor. Additionally, in vitro experiments indicate that MELTF and PLEK2 can modulate the invasion and proliferation of human non-small cell lung cancer cells. In conclusion, we elucidated that KRAS/TP53 co-mutations may modulate TME and patient prognosis by orchestrating B cells and affiliated pathways. Furthermore, we spotlight that MELTF and PLEK2 not only function as prognostic indicators for LUAD, but also lay the foundation for the exploration of innovative therapeutic approaches.

Enhanced OER catalytic activity of single metal atoms supported by the pentagonal NiN2 monolayer: insight from density functional theory calculations.

Two-dimensional material-supported single metal atom catalysts have been extensively studied and proved effective in electrocatalytic reactions in recent years. In this work, we systematically investigate the OER catalytic properties of single metal atoms supported by the NiN2 monolayer. Several typical transition metals with high single atom catalytic activity, such as Fe, Co, Ru, Rh, Pd, Ir, and Pt, were selected as catalytic active sites. The energy calculations show that transition metal atoms (Fe, Co, Ru, Rh, Pd, Ir, and Pt) are easily embedded in the NiN2 monolayer with Ni vacancies due to the negative binding energy. The calculated OER overpotentials of Fe, Co, Ru, Rh, Pd, Ir and Pt embedded NiN2 monolayers are 0.92 V, 0.47 V, 1.13 V, 0.66 V, 1.25 V, 0.28 V, and 0.94 V, respectively. Compared to the 0.57 V OER overpotential of typical OER noble metal catalysts IrO2, Co@NiN2 and Ir@NiN2 exhibit high OER catalytic activity due to lower overpotential, especially for Ir@NiN2. The high catalytic activity of the Ir embedded NiN2 monolayer can be explained well by the d-band center model. It is found that the adsorption strength of the embedded TM atoms with intermediates follows a linear relationship with their d-band centers. Besides, the overpotential of the Ir embedded NiN2 monolayer can be further reduced to 0.24 V under -2% biaxial strain. Such findings are expected to be employed in more two-dimensional material-supported single metal atom catalyzed reactions.

Enhanced optical absorption in two-dimensional Ruddlesden-Popper (C6H5CH2NH3)2PbI4 perovskites via biaxial strain and surface doping.

Two-dimensional Ruddlesden-Popper (2D RP) perovskites can form layered protective materials using long organic cations as "barrier" caps, which is expected to solve the problem of instability of perovskites in the working environment. In this work, we systematically studied the 2D Ruddlesden-Popper (C6H5CH2NH3)2PbI4 hybrid perovskites using density functional theory. The results reveal that the 2D (C6H5CH2NH3)2PbI4 perovskites are semiconductors with band gaps of 2.22 eV. The optical absorption peak of the 2D (C6H5CH2NH3)2PbI4 perovskite structure is located at 532 nm in the visible region. Interestingly, the optical absorption spectrum of the 2D (C6H5CH2NH3)2PbI4 perovskite structure enhanced under suitable strains. The highest optical absorption peak appears in 2D (C6H5CH2NH3)2PbI4 under a -2% strain, and its theoretical photoelectric conversion efficiency is 28.5%. More interestingly, the replacement of surface I atoms with Br is another ways to enhance the optical absorption spectrum of the 2D (C6H5CH2NH3)2PbI4 perovskite structure. The optical absorption peak blue-shifts to the high energy region, which has higher solar energy flux density than the low energy region. The good stability, tuneable band gap and excellent theoretical photoelectric conversion efficiency of the 2D (C6H5CH2NH3)2PbI4 perovskite structure make it a promising candidate for novel 2D hybrid perovskite based photoelectronic devices and solar cells.

Reduced Serum Levels of Klotho are Associated with Mild Cognitive Impairment in Patients with Type 2 Diabetes Mellitus.

Objective: The study objective was to investigate the serum levels of Klotho in patients with type 2 diabetes mellitus (T2DM) who had moderate cognitive impairment (MCI) and those without MCI and to determine its prediction of MCI in older patients with T2DM. Methods: Patients with diabetes were examined for MCI in 292 cases (using the Montreal Cognitive Assessment: MoCA score). Biomarkers and biochemical parameter data were accumulated. Results: Comparing T2DM patients with MCI (91 patients) and without MCI (101 patients), patients with MCI considerably reduced serum Klotho levels were observed. In all 292 hospitalized patients, serum Klotho levels were negatively correlated with age (r=-0.184, P=0.002), body mass index (BMI) (r=-0.151, P=0.010), glycosylated hemoglobin (HbA1c) (r=-0.197, P=0.001), creatinine (r=-0.178, P=0.002), and C-reactive protein (CRP) (r=-0.319, P<0.001). On the other hand, it is positively correlated with education (r=0.319, P<0.001) and high-density lipoprotein cholesterol (HDL-C) (r=0.272, P<0.001). Considering the findings of the multivariate logistic regression models, patients with type 2 diabetes who had reduced levels of serum Klotho (OR=0.987, 95% CI=0.980-0.994; P<0.001), lower HDL-C, increased levels of HbA1c, creatinine, and CRP, and limited years of formal education and a longer duration of T2DM, increase the risk of developing MCI. Conclusion: The results showed that diabetic patients with MCI have lower serum Klotho levels than diabetic patients without MCI. It might be possible to do a more extensive population-based prospective investigation to confirm the correlation between serum Klotho levels and cognitive impairment or dementia.

[A comparative study of tongue appliance combined with chin-cup and facemask in the treatment of anterior crossbite].

PURPOSE: To compare the efficacy of tongue appliance combined with chin-cup and facemask in the treatment of anterior crossbite, as well as the effects on the position of hyoid bone and airway, so as to provide reference for clinic. METHODS: Sixty cases with anterior crossbite were selected after treatment, using tongue appliance combined with chin-cup (n=30) and facemask (n=30). Cephalometric radiographs were taken before and after treatment, skeletal, dental, hyoid, and airway space measurements were analyzed with Winceph 9.0 and AutoCAD 2016. SPSS 21.0 software package was used for statistical analysis. RESULTS: Both appliances had a good effect on anterior crossbite. After treatment, SNA, ANS-PNS significantly increased(P<0.05), and SN-MP significantly increased(P<0.05). The upper anterior teeth showed a buccal inclination(P<0.01), the lower anterior teeth had a lingual inclination, and the overjet became normal(P<0.01). UL-E increased in both groups(P<0.05), PLA significantly increased in tongue appliance combined with chin-cup group(P<0.05). H-C3 decreased in both groups(P<0.05), while H-S, H-Ar increased(P<0.01), suggesting that the hyoid bone moved backward and downward. PNS-UPW increased in both groups(P<0.01), and U-MPW increased in facemask group(P<0.01). CONCLUSIONS: Facemask and tongue appliance combined with chin-cup can both promote the development of the maxilla, cause a clockwise rotation of the mandible, and effectively correct the anterior crossbite. Both methods can cause a backward and downward displacement of hyoid bone. Facemask can enlarge the width of nasopharynx and palatopharynx airway, while only the width of nasopharynx can be increased by tongue appliance combined with chin-cup.

China experts' consensus on preventive and interceptive orthodontic treatments of malocclusions of children.

Malocclusion is one of the three most common oral diseases reported by World Health Organization(WHO). In China, its incidence rate is rising. Malocclusion seriously affects the dental and maxillofacial function, facial appearance and growth development of nearly 260 million children in China, and what is more, it affects their physical and mental health development. Malocclusion occurrence is related to genetic and environmental factors. Early treatment of malocclusion can create a good dental and maxillofacial development environment, correct abnormal growth and control the adverse effects of abnormal genetic factors. It can effectively reduce the prevalence of children's malocclusion and enhance their physical and mental health. This is an urgent need from the economic perspective of our society, so it has great practical and social significance. Experts from the project group "standard diagnose and treatment protocols for early orthodontic intervention of malocclusions of children" which initiated by China National Health Institute of Hospital Administration wrote the "China Experts' Consensus on Preventive and Interceptive Orthodontic Treatments of Malocclusions of Children", which aims to guide and popularize the clinical practice, improve the clinical theory and practice level, and accelerate the disciplinary development of early treatment of children's malocclusion in China. The consensus elaborates the harmfulness of malocclusion and the necessity of early treatment, and brings up the principles and fundamental contents. Based on the law of dental and maxillofacial development, this paper puts forward the guiding suggestions of preventive and interceptive treatments in different stages of dental development ranging from fetus to early permanent dentition. It is a systematic project to promote and standardize the early treatment of malocclusion. Through scientific and comprehensive stratified clinical practice and professional training, the clinical system of early treatment of malocclusion in China will eventually be perfected, so as to comprehensively care for children's dental and maxillofacial health, and improve their oral and physical health in China.

Up-regulation of cofilin-1 in cell senescence associates with morphological change and p27kip1 -mediated growth delay.

Morphological change is an explicit characteristic of cell senescence, but the underlying mechanisms remains to be addressed. Here, we demonstrated, after a survey of various actin-binding proteins, that the post-translational up-regulation of cofilin-1 was essential for the reduced rate of actin depolymerization morphological enlargement in senescent cells. Additionally, up-regulated cofilin-1 mainly existed in the serine-3 phosphorylated form, according to the 2D gel immunoblotting assay. The up-regulation of cofilin-1 was also detected in aged mammalian tissues. The over-expression of wild-type cofilin-1 and constitutively phosphorylated cofilin-1 promoted cell senescence with an increased cell size. Additionally, senescent phenotypes were also reduced by knockdown of total cofilin-1, which led to a decrease in phosphorylated cofilin-1. The senescence induced by the over-expression of cofilin-1 was dependent on p27Kip1 , but not on the p53 and p16INK4 expressions. The knockdown of p27Kip1 alleviated cell senescence induced by oxidative stress or replicative stress. We also found that the over-expression of cofilin-1 induced the expression of p27Kip1 through transcriptional suppression of the transcriptional enhancer factors domain 1 (TEAD1) transcription factor. The TEAD1 transcription factor played a transrepressive role in the p27Kip1  gene promoter, as determined by the promoter deletion reporter gene assay. Interestingly, the down-regulation of TEAD1 was accompanied by the up-regulation of cofilin-1 in senescence. The knockdown and restoration of TEAD1 in young cells and old cells could induce and inhibit p27Kip1 and senescent phenotypes, respectively. Taken together, the current data suggest that cofilin-1/TEAD1/p27Kip1 signaling is involved in senescence-related morphological change and growth arrest.

Inhibition of the INa/K and the activation of peak INa contribute to the arrhythmogenic effects of aconitine and mesaconitine in guinea pigs.

Aconitine (ACO), a main active ingredient of Aconitum, is well-known for its cardiotoxicity. However, the mechanisms of toxic action of ACO remain unclear. In the current study, we investigated the cardiac effects of ACO and mesaconitine (MACO), a structurally related analog of ACO identified in Aconitum with undocumented cardiotoxicity in guinea pigs. We showed that intravenous administration of ACO or MACO (25 µg/kg) to guinea pigs caused various types of arrhythmias in electrocardiogram (ECG) recording, including ventricular premature beats (VPB), atrioventricular blockade (AVB), ventricular tachycardia (VT), and ventricular fibrillation (VF). MACO displayed more potent arrhythmogenic effect than ACO. We conducted whole-cell patch-clamp recording in isolated guinea pig ventricular myocytes, and observed that treatment with ACO (0.3, 3 µM) or MACO (0.1, 0.3 µM) depolarized the resting membrane potential (RMP) and reduced the action potential amplitude (APA) and durations (APDs) in a concentration-dependent manner. The ACO- and MACO-induced AP remodeling was largely abolished by an INa blocker tetrodotoxin (2 µM) and partly abolished by a specific Na+/K+ pump (NKP) blocker ouabain (0.1 µM). Furthermore, we observed that treatment with ACO or MACO attenuated NKP current (INa/K) and increased peak INa by accelerating the sodium channel activation with the EC50 of 8.36 ± 1.89 and 1.33 ± 0.16 µM, respectively. Incubation of ventricular myocytes with ACO or MACO concentration-dependently increased intracellular Na+ and Ca2+ concentrations. In conclusion, the current study demonstrates strong arrhythmogenic effects of ACO and MACO resulted from increasing the peak INa via accelerating sodium channel activation and inhibiting the INa/K. These results may help to improve our understanding of cardiotoxic mechanisms of ACO and MACO, and identify potential novel therapeutic targets for Aconitum poisoning.

Effect of Danhong Injection on platelet metabolites based on metabonomics technology / 中国中药杂志

The effect of Danhong Injection on the endogenous metabolites of rabbit platelets was analyzed by the liquid chromatography-mass spectrometry( LC-MS) based metabonomic approach. Anti-platelet aggregation was detected after Danhong Injection treatment and the changes of platelet metabolites were analyzed by metabonomics. Principal component analysis( PCA) and partial least squares discriminant analysis( PLS-DA) were performed to investigate the effect of Danhong Injection on endogenous metabolites of platelets,characterize the biomarkers,and explore the relevant pathways and the underlying mechanism. As demonstrated by the pharmacodynamic results,Danhong Injection of different doses and concentrations antagonized platelet aggregation in a dose-and concentration-dependent manner. In contrast to the control group,25 differential metabolites such as nicotinic acid,nicotinic acid riboside,and hypoxanthine were screened out after platelets were treated by Danhong Injection. These metabolites,serving as important biomarkers,were mainly enriched in the nicotinic acid-niacinamide metabolic pathway and purine metabolic pathway. This study explored the therapeutic mechanism of Danhong Injection from a microscopic perspective by metabonomics,which is expected to provide a new idea for the investigation of platelet-related mechanisms.

China experts' consensus on preventive and interceptive orthodontic treatments of malocclusions of children / 华西口腔医学杂志

Malocclusion is one of the three most common oral diseases reported by World Health Organization(WHO). In China, its incidence rate is rising. Malocclusion seriously affects the dental and maxillofacial function, facial appearance and growth development of nearly 260 million children in China, and what is more, it affects their physical and mental health development. Malocclusion occurrence is related to genetic and environmental factors. Early treatment of malocclusion can create a good dental and maxillofacial development environment, correct abnormal growth and control the adverse effects of abnormal genetic factors. It can effectively reduce the prevalence of children's malocclusion and enhance their physical and mental health. This is an urgent need from the economic perspective of our society, so it has great practical and social significance. Experts from the project group "standard diagnose and treatment protocols for early orthodontic intervention of malocclusions of children" which initiated by China National Health Institute of Hospital Administration wrote the "China Experts' Consensus on Preventive and Interceptive Orthodontic Treatments of Malocclusions of Children", which aims to guide and popularize the clinical practice, improve the clinical theory and practice level, and accelerate the disciplinary development of early treatment of children's malocclusion in China. The consensus elaborates the harmfulness of malocclusion and the necessity of early treatment, and brings up the principles and fundamental contents. Based on the law of dental and maxillofacial development, this paper puts forward the guiding suggestions of preventive and interceptive treatments in different stages of dental development ranging from fetus to early permanent dentition. It is a systematic project to promote and standardize the early treatment of malocclusion. Through scientific and comprehensive stratified clinical practice and professional training, the clinical system of early treatment of malocclusion in China will eventually be perfected, so as to comprehensively care for children's dental and maxillofacial health, and improve their oral and physical health in China.

Analysis and comparison of metabolic processes of salvianolic acid A and salvianolic acid B in rats based on UHPLC-LTQ-Orbitrap MS technology / 中国中药杂志

The metabolites of salvianolic acid A and salvianolic acid B in rats were analyzed and compared by ultra-high-perfor-mance liquid chromatography with linear ion trap-orbitrap mass spectrometry(UHPLC-LTQ-Orbitrap MS). After the rats were administrated by gavage, plasma at different time points and urine within 24 hours were collected to be treated by solid phase extraction(SPE), then they were gradient eluted by Acquity UPLC BEH C_(18) column(2.1 mm×100 mm, 1.7 μm) and 0.1% formic acid solution(A)-acetonitrile(B) mobile phase system, and finally all biological samples of rats were analyzed under negative ion scanning mode. By obtaining the accurate relative molecular mass and multi-level mass spectrometry information of metabolites, combined with the characteristic cleavage law of the reference standard and literature reports, a total of 30 metabolites, including salvianolic acid A and B, were identified. Among them, there were 24 metabolites derived from salvianolic acid A, with the main metabolic pathways including ester bond cleavage, dehydroxylation, decarboxylation, hydrogenation, methylation, hydroxylation, sulfonation, glucuronidation, and their multiple reactions. There were 15 metabolites of salvianolic acid B, and the main biotransformation pathways were five-membered ring cracking, ester bond cleavage, decarboxylation, dehydroxylation, hydrogenation, methylation, sulfonation, glucuronidation, and their compound reactions. In this study, the cross-metabolic profile of salvianolic acid A and B was elucidated completely, which would provide reference for further studies on the basis of pharmacodynamic substances and the exploration of pharmacological mechanism.

Susceptibility-guided therapy for Helicobacter pylori-infected penicillin-allergic patients: A prospective clinical trial of first-line and rescue therapies.

BACKGROUND: Helicobacter pylori (H pylori) treatment remains a challenge for penicillin-allergic patients. AIM: To evaluate the efficacy and tolerability of susceptibility-guided first-line and rescue treatment in H pylori-infected penicillin-allergic patients. METHODS: Consecutive H pylori-infected patients with penicillin allergy received a 14-day triple or quadruple therapy based on susceptibility to clarithromycin, levofloxacin, and metronidazole. All received esomeprazole 20 mg twice a day. Metronidazole-susceptible infections received metronidazole plus clarithromycin or levofloxacin triple therapy if susceptible. Clarithromycin- and levofloxacin-resistant infections received metronidazole plus tetracycline triple therapy. Metronidazole-resistant infections received a bismuth-high-dose metronidazole plus clarithromycin or levofloxacin quadruple therapy. Triple-resistant infections received classical bismuth quadruple therapy with high-dose metronidazole. Antimicrobial susceptibility was assessed using the E test method. RESULTS: 112 patients were entered (34.8% men, average 47.1 years). Infections in 83.8% (31/37) of treatment-naive subjects and 12.0% (9/75) (P < .001) receiving rescue treatment were susceptible to at least one of the three tested antibiotics. Overall, susceptibility-guided therapy achieved eradication rates of 92.9% (104/112, 95% CI 88.1%-97.7%) by intent-to-treat analysis and 99% (100/101, 95% CI 97.1%-100%) by per-protocol analysis. All regimens achieved eradication rates greater than 90% (P = .327) in the PP populations. Adverse events were relatively frequent; however, compliance remained high. CONCLUSION: Susceptibility-guided therapy proved highly effective for penicillin-allergic patients. When available and proven locally effective, the alternative was empiric classical bismuth quadruple therapy. This trial is registered with ClinicalTrials.gov as NCT03708848.

In vivo infection of Bursaphelenchus xylophilus by the fungus Esteya vermicola.

BACKGROUND: As the causal agent of pine wilt disease, Bursaphelenchus xylophilus, is a serious pathogen of forest pine trees. Esteya vermicola is a nematophagous fungus of B. xylophilus and exhibits great potential as a biological control agent. However, the in vivo infection mechanism of E. vermicola on B. xylophilus is unclear. Experiments were conducted to study the colonization of host plant and infection of B. xylophilus by E. vermicola inside pine tree xylem. RESULTS: A green fluorescent protein (GFP)-tagged E. vermicola transformant was constructed as a biomarker to study the in vivo colonization and infection of B. xylophilus in pine trees. The in vitro infection of B. xylophilus by E. vermicola was observed through GFP expression. The bacilloid conidia produced by trophic hyphae in the body of the nematode are described. Additionally, the monitoring of in vivo colonization by GFP-tagged E. vermicola showed the germination and hyphal extension of this fungus after inoculation. Moreover, B. xylophilus infected by this biocontrol agent were extracted from healthy seedlings and observed in the xylem of trees that were wilting due to pine wilt disease. CONCLUSION: Evidence of fungal colonization and infection of B. xylophilus by E. vermicola is provided to improve our understanding of the in vivo infection mechanisms used by this nematophagous fungus against B. xylophilus. The infection of B. xylophilus by E. vermicola was inferred to begin with the implantation of propagules, and this inference will require future investigation. The colonization of Esteya vermicola in host pine tree xylem and the in vivo infection of pinewood nematode by E. vermicola were investigated using the green fluorescence protein transformant. © 2020 Society of Chemical Industry.

14-Day High-Dose Amoxicillin- and Metronidazole-Containing Triple Therapy With or Without Bismuth as First-Line Helicobacter pylori Treatment.

BACKGROUND: Amoxicillin, metronidazole, proton pump inhibitor, bismuth quadruple therapy had been shown to reliably achieve high eradication rates. The role of individual components remains undefined. AIM: To identify the additional benefit/role of bismuth in amoxicillin, metronidazole, proton pump inhibitor, bismuth quadruple therapy for Helicobacter pylori (H. pylori) treatment. METHODS: This was a non-inferiority factorial design trial. Treatment-naive H. pylori-infected subjects were randomly (1:1) assigned to receive 14-day amoxicillin- and metronidazole-containing triple therapy consisting of esomeprazole 20 mg twice a day, amoxicillin 1 g, and metronidazole 400 mg both thrice daily with or without 220 mg bismuth twice a day. Six weeks after treatment, H. pylori eradication was assessed by 13C-urea breath test. Antimicrobial susceptibility was assessed by the twofold agar dilution method. RESULTS: From July 2018 to June 2019, a total of two hundred and sixteen subjects were randomized. Both therapies achieved high eradication rates. Per-protocol with bismuth = 97.9% (94/96, 95% CI 95.1-100%) and without bismuth = 94.7% (90/95, 95% CI 90.3-99.1%) (P = 0.43). Intent-to-treat analysis = 90.7% (98/108, 95% CI 85.2-96.2%) versus 88.9% (96/108, 95% CI 82.8-95.0%) with and without bismuth (P = 0.65). The two regimens were not inferior by intent-to-treat or per-protocol analyses. Metronidazole resistance did not affect the efficacy of either therapy. CONCLUSION: Neither the presence nor absence of bismuth or metronidazole resistance reduced the effectiveness of triple therapy containing esomeprazole 20 mg twice a day, amoxicillin 1 g, and metronidazole 400 mg thrice daily in this population. The clinical trial was registered with ClinicalTrials.gov, NCT03557437.

Analysis of carnosic acid metabolites in rats by UHPLC-Q-Exactive MS / 中国中药杂志

A method of ultra-high performance liquid chromatography coupled with quadrupole/electrostatic field Obitrap high-resolution mass spectrometry(UHPLC-Q-Exactive MS) was established to comprehensively identify the metabolites of carnosic acid in rats. After oral gavage of carnosic acid CMC-Na suspension in rats, urine, plasma and feces samples were collected and pretreated by solid phase extraction(SPE). Acquity UPLC BEH C_(18 )column(2.1 mm×100 mm, 1.7 μm) was used with 0.1% formic acid solution(A)-acetonitrile(B) as the mobile phase for the gradient elution. Biological samples were analyzed by quadrupole/electrostatic field Obitrap high-resolution mass spectrometry in positive and negative ion mode. Based on the accurate molecular mass, fragment ion information, and related literature reports, a total of 28 compounds(including carnosic acid) were finally identified in rat samples. As a result, the main metabolic pathways of carnosic acid in rats are oxidation, hydroxylation, methylation, glucuronide conjugation, sulfate conjugation, S-cysteine conjugation, glutathione conjugation, demethylation, decarbonylation and their composite reactions. The study showed that the metabolism of carnosic acid in rats could be efficiently and comprehensively clarified by using UHPLC-Q-Exactive MS, providing a reference for clarifying the material basis and metabolic mechanism of carnosic acid.

Susceptibility-guided therapy for Helicobacter pylori infection treatment failures.

BACKGROUND: Empirical therapy of Helicobacter pylori frequently results in treatment failure due to unrecognized antimicrobial resistance. The aim of this study was to investigate the effectiveness of susceptibility-guided therapy for rescue treatment of H. pylori infection in China. METHODS: This was a prospective study of consecutive 200 patients infected with H. pylori with one or more treatment failures. The therapy chosen was susceptibility based using the most effective, best-tolerated regimens first and a locally proven, reliably effective regimen for multidrug-resistant infections. All patients received 14-day triple therapy, i.e. esomeprazole 20 mg and amoxicillin 1 g twice a day plus clarithromycin 500 mg twice a day, metronidazole 400 mg twice a day, or levofloxacin 500 mg daily, or, for multidrug-resistant infections, amoxicillin-containing bismuth quadruple therapy with esomeprazole 20 mg twice a day, bismuth 220 mg twice a day, amoxicillin 1 g three times a day, and metronidazole 400 mg four times a day. Antibiotic resistance was determined by agar dilution. RESULTS: The eradication rate of susceptibility-guided therapy overall was 94.5% (189/200, 95% confidence interval: 90.4-97.2%). Around 28% (56/200) of patients carried strains susceptible to one of the tested antibiotics and were prescribed the triple therapy. A total of 144 multidrug-resistant patients received bismuth quadruple therapy. The eradication rates were all greater than 90%, i.e. 91.7% (11/12), 92.3% (12/13), and 93.5% (29/31) in those who received clarithromycin, metronidazole, and levofloxacin-containing triple therapy and 95.1% (137/144) for the bismuth quadruple therapy. There were no differences in eradication rates between the subgroups. CONCLUSIONS: Although susceptibility-guided therapy proved high efficacious despite the high proportion of multidrug-resistant strains, the strategy suggested the best approach for this population would be empirical amoxicillin-containing bismuth quadruple therapy. ClinicalTrials.gov identifier: NCT03413020.

[Effect of premolars scissor bite on the sagittal position of mandible].

PURPOSE: To study the effect of adolescent premolar scissor bite on the sagittal position of mandible and provide proper reference for correct orthodontic diagnosis and right time to treatment. METHODS： One hundred adolescents (54 females, 46 males) with scissor bite of premolars(70 were unilateral,30 were bilateral) were selected as experimental group between 2004 to 2017 from the Department of Orthodontics, Stomatological Hospital of China Medical University. Among them, 54 females served as female group, 46 males served as male group; 30 were bilateral and 70 were unilateral. Lateral cephalograms were recorded before treatment. 16 sagittal hard tissue variables on maxilla and mandible were measured cephalometrically by Winceph 9.0 software, and the cephalometric data were analyzed statistically by using SPSS 21.0 software package. RESULTS: Compared with normal occlusion, Beta angle, SNB, SND, ANB, AB-Plane angle, APDI, convexity angle, facial angle, Wits, Co-Po showed statistically significant difference in both unilateral group and bilateral group (P<0.05). In addition, Go-Pog showed statistically significant difference between normal occlusion and unilateral group(P<0.05). CONCLUSIONS: Adolescents with premolar scissor bite restricts the sagittal position of mandible and tend to have skeletal Ⅱ sagittal jaw relationship. Scissor bite affects the growth of mandible and makes mandibular body length and mandibular length less than normal. More attention should be paid to scissor bite as early as possible to decrease the harmful effects on growth of mandible and sagittal jaw relationship.

High-dose PPI-amoxicillin dual therapy with or without bismuth for first-line Helicobacter pylori therapy: A randomized trial.

BACKGROUND: A reliably highly effective high-dose proton-pump inhibitor plus amoxicillin (dual Helicobacter pylori therapy) has remained elusive. We compared whether the addition of bismuth to high-dose dual therapy would improve the efficacy of high-dose dual therapy as first-line treatment. METHODS: This was an open-label, randomized single-center study of 160 treatment-naive patients with H. pylori infection who were randomly assigned to 14-day therapy with esomeprazole 40 mg twice a day plus amoxicillin 1 g three times a day with or without bismuth potassium citrate 600 mg (elemental bismuth 220 mg) twice a day. Antibiotic resistance was determined by agar dilution method and eradication by 13 C-urea breath test. RESULTS: The per-protocol eradication rates were 96.1%; 95% CI = 88.9%-99.2% (73/76) without bismuth vs 93.3%; 95% CI = 85.1%-97.8% (70/75) with bismuth (P = 0.494). The intention-to-treat eradication rates were 92.5%; 95% CI = 84.4%-97.2% (74/80) without bismuth and 88.8%; 95% CI = 79.7%-94.7% (71/80) with bismuth (P = 0.416). Resistance to amoxicillin, clarithromycin, metronidazole, and levofloxacin was 0%, 31.7%, 81.4%, and 40.7%, respectively. Smoking reduced treatment effectiveness limited to those not receiving bismuth. The per-protocol eradication rates were 70% (7/10) vs 100% (66/66) in smokers vs non-smokers without bismuth (P = 0.002), and 100% (10/10) in smokers vs 92.3% (60/65) in non-smokers with bismuth (P = 1.0). The adverse event rates were 7.5% (6/80) without bismuth vs 11.3% (9/80) with bismuth (P = 0.416). CONCLUSIONS: Fourteen-day high-dose dual therapy was both effective and safe for first-line treatment in a region of high prevalence antibiotic resistance. Adding bismuth only improved treatment effectiveness among smokers.