Development of an in vitro screening method for idiosyncratic hepatotoxic components in traditional Chinese medicine: a case study with Epimedii Folium and Psoraleae Fructus / 药学学报

Idiosyncratic drug-induced liver injury (IDILI) has long posed a challenging and pivotal concern in pharmaceutical research. The complex composition of traditional Chinese medicine (TCM) has introduced a bottleneck in current research, hindering the elucidation of the component basis associated with IDILI in TCM. Using Epimedii Folium (EF) and Psoraleae Fructus (PF) as illustrative examples, this study endeavors to establish an in vitro evaluation model, providing a high-throughput and preliminary assessment method for screening components related to TCM-induced IDILI. A TNF-α-mediated HepG2 susceptible model was first established in this study, with the focus on the index components present in EF and PF. The release of lactate dehydrogenase (LDH) in the cell supernatant served as the detection index. A concentration-toxicity response curve was constructed, and the hepatotoxic components of EF and PF were identified utilizing the synergistic toxicity index. The LDH results unveiled the hepatotoxic effects of bavachin, backuchiol, isobavachin, neobavaisoflavone, psoralidin, isobavachalcone, icarisid I, and icarisid II on both normal and susceptible cells, categorizing these 8 components as both direct hepatotoxicity components and idiosyncratic hepatotoxicity components. Bavachin and neobavaisoflavone exhibited no hepatotoxicity on normal cells but demonstrated significant effects on susceptible cells, designating them as potential idiosyncratic susceptible hepatotoxicity components. The study further delineated that 10 EF components and 3 PF components were direct immune-promoting hepatotoxicity components. Additionally, 14 idiosyncratic immune-promoting hepatotoxicity components were identified, encompassing 10 EF components and 4 PF components, with neobavaisoflavone, bavachinin, and isobavachin being potential idiosyncratic susceptible immune-promoting hepatotoxicity components. Synergistic toxicity index results indicated that 13 idiosyncratic immune-promoting hepatotoxicity components (except anhydroicaritin) combined with bavachin demonstrated synergistic hepatotoxicity on susceptible cells. Notably, 3 idiosyncratic susceptible immune-promoting hepatotoxicity components combined with bavachin exhibited synergistic hepatotoxicity, with neobavaisoflavone displaying the highest synergistic toxicity index and bavachinin the lowest. In summary, this methodology successfully screens hepatotoxic and immune-promoting hepatotoxic components in EF and PF, distinguishing the types of components inducing hepatotoxicity, evaluating the hepatotoxicity degree of each component, and elucidating the synergistic relationships among them. Importantly, these findings align with the characteristics of IDILI. The method provides an effective model tool for the fundamental research of TCM-related IDILI components.

Effects of HMGB1 on phenotypes, phagocytosis and ERK/JNK/P38 MAPK signaling pathway in dendritic cells / 中国药理学通报

Aim To explore the impacts of high mobility group box 1 (HMGB1) on the phenotypes, endocy-tosis and extracellular signal-regulated kinase (ERK)/ Jun N-terminal protein kinase (JNK)/P38 mitogen-ac-tivated protein kinase (MAPK) signaling pathway in indoxyl sulfate (IS) -induced dendritic cells (DCs). Methods After treatment with 30, 300 and 600 (xmol · L

Influence of quercetin on aging of bone marrow mesenchymal stem cells induced by microgravity / 中国药理学通报

Aim To investigate the effect of quercetin on the aging model of bone marrow mesenchymal stem cells established under microgravity. Methods Using 3D gyroscope, a aging model of bone marrow mesenchymal stem cells was constructed, and after receiving quercetin and microgravity treatment, the anti-aging effect of the quercetin was evaluated by detecting related proteins and oxidation indexes. Results Compared to the control group, the expressions of age-related proteins p21, pi6, p53 and RB in the microgravity group significantly increased, while the expressions of cyclin D1 and lamin B1 significantly decreased, with statistical significance (P<0.05). In the microgravity group, mitochondrial membrane potential significantly decreased (P<0.05), ROS accumulation significantly increased (P <0.05), SOD content significantly decreased and MDA content significantly increased (P<0.05). Compared to the microgravity group, the expressions of age-related proteins p21, pi6, p53 and RB in the quercetin group significantly decreased, while the expressions of cyclin D1 and lamin B1 significantly increased, with statistical significance (P<0.05). In the quercetin group, mitochondrial membrane potential significantly increased (P<0.05), ROS accumulation significantly decreased (P<0.05), SOD content significantly increased and MDA content significantly decreased (P<0.05). Conclusions Quercetin can resist oxidation, protect mitochondrial function and normal cell cycle, thus delaying the aging of bone marrow mesenchymal stem cells induced by microgravity.

Prevalence and factors associated with flares following COVID-19 mRNA vaccination in patients with rheumatoid arthritis, psoriatic arthritis and spondyloarthritis: a national cohort study

Abstract Objective To determine prevalence and factors associated with flares post Coronavirus disease 2019 (COVID-19) mRNA vaccination in patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA) and spondyloarthritis (SpA). Methods A retrospective multi-centre study was conducted (January 2021 to February 2022). Data were collected during index visit, defined as first post-vaccine visit in which the patient had a physician-defined flare, or if at least 3 months had elapsed since first vaccine dose, whichever came first. Factors associated with flares were identified using mixed effects Cox regression and expressed as hazard ratio (HR) and 95% confidence interval (CI). Results Total of 2377 patients were included (1563 RA, 415 PsA and 399 SpA). Among patients with RA, PsA and SpA, 21.3%, 24.1% and 21.8% experienced a flare respectively. Of those who experienced a flare, only 10.2%, 11.0% and 14.9% were severe in patients with RA, PsA and SpA respectively. Patients with low or moderate/high disease were more likely to flare compared to those in remission in patients with RA only (HR: 1.68, 95% CI 1.22-2.31; HR: 2.28, 95% CI 1.50-3.48, respectively). Receiving the Moderna vaccine was associated with a higher HR of flare compared to the Pfizer vaccine in patients with PsA only (HR: 2.21, 95% CI 1.20-4.08). Patients who had two vaccine doses were found to be less likely to flare (HR: 0.08, 95% CI 0.06-0.10). HRs of flares were not significantly different among RA, PsA and SpA. Conclusion About one-fifth of patients experienced a disease flare post COVID-19 mRNA vaccination, but most flares were non-severe. Patients with active disease prior to vaccination should be monitored closely for disease flares, especially in patients with RA.

Advances on toxicity and metabolism of alkaloids from the "toxic" traditional Chinese medicines / 药学学报

The "toxicity" and safety of traditional Chinese medicines have been seriously concerned. Alkaloids are the main pharmacodynamic components of many kinds of traditional Chinese medicines, which show strong biological activity at low concentration. It will also cause toxic side effects but if used improperly. Some alkaloids are both active and toxic, and the safety of related traditional Chinese medicines is particularly noteworthy. The efficacy or toxicity of alkaloids may be the result of the combined action of parent compounds and metabolites, which is not only related to the structural types of compounds, but also has obvious species differences between humans and animals. This review focused on the alkaloids contained in the "toxic" traditional Chinese medicines that are officially recorded in Chinese Pharmacopoeia and the metabolism patterns of alkaloids with different structures as well as the enzymes involved were summarized and discussed by referencing the publications in recent two decades. The present study will be beneficial to the rational use of these traditional Chinese medicines in clinic.

Effect of Dickkopf-1 regulated Wnt pathway on transdifferentiation of hypoxia-induced lens epithelial cells / 国际眼科杂志(Guoji Yanke Zazhi)

AIM: To scrutinize the role of the Wnt/β-catenin signaling pathway in the epithelial-mesenchymal transition(EMT)of lens epithelial cells under hypoxic conditions, and to further analyze the effect of Dickkopf-1(DKK-1)expression on EMT of lens epithelial cells.METHODS: Human lens epithelial cells(HLEB3 cells)were propagated in vitro and then separated into two groups: one exposed to standard oxygen levels, added DMEM culture solution containing 10% FBS(normoxic group)and another subjected to low oxygen levels(hypoxic group). The hypoxic condition was emulated by applying a concentration of 100 μmol/L cobalt chloride(CoCl2)for 6, 12, 24, and 48h. The utilization of immunofluorescence staining enabled the detection of Wnt3a and DKK-1 expressions, along with the expression and localization of β-catenin protein in these groups. The expression of DKK-1 mRNA was discerned by quantitative real-time polymerase chain reaction(qRT-PCR).RESULTS: Immunofluorescence assays indicated an escalating trend in the Wnt3a and DKK-1 protein expression, which corresponded with the increasing duration of hypoxia. Likewise, an intensified nuclear accumulation of β-catenin protein was observed to be directly proportional to the length of hypoxia treatment. The qRT-PCR demonstrated that the difference in DKK-1 mRNA expression between the normoxic group and the group exposed to hypoxia for 6h was not statistically significant(P&#x003E;0.05), whereas the DKK-1 mRNA expression of the 12, 24, and 48h hypoxia groups were significantly increased(P&#x003C;0.001).CONCLUSION: Hypoxia can activate Wnt/β-catenin pathway in lens epithelial cells and induce the expression of DKK-1, thus regulating the Wnt/β-catenin pathway and affecting the EMT process.

Lifestyle improvement and the reduced risk of cardiovascular disease: the China-PAR project / 老年心脏病学杂志（英文版）

BACKGROUND@#The benefits of healthy lifestyles are well recognized. However, the extent to which improving unhealthy lifestyles reduces cardiovascular disease (CVD) risk needs to be discussed. We evaluated the impact of lifestyle improvement on CVD incidence using data from the China-PAR project (Prediction for Atherosclerotic Cardiovascular Disease Risk in China).@*METHODS@#A total of 12,588 participants free of CVD were followed up for three visits after the baseline examination. Changes in four lifestyle factors (LFs) (smoking, diet, physical activity, and alcohol consumption) were assessed through questionnaires from the baseline to the first follow-up visit. Cox proportional hazard models were used to estimate hazard ratios (HRs) and corresponding 95% confidence intervals (CIs). The risk advancement periods (RAPs: the age difference between exposed and unexposed participants reaching the same incident CVD risk) and population-attributable risk percentage (PAR%) were also calculated.@*RESULTS@#A total of 909 incident CVD cases occurred over a median follow-up of 11.14 years. Compared with maintaining 0-1 healthy LFs, maintaining 3-4 healthy LFs was associated with a 40% risk reduction of incident CVD (HR = 0.60, 95% CI: 0.45-0.79) and delayed CVD risk by 6.31 years (RAP: -6.31 [-9.92, -2.70] years). The PAR% of maintaining 3-4 unhealthy LFs was 22.0% compared to maintaining 0-1 unhealthy LFs. Besides, compared with maintaining two healthy LFs, improving healthy LFs from 2 to 3-4 was associated with a 23% lower risk of CVD (HR = 0.77, 95% CI: 0.60-0.98).@*CONCLUSIONS@#Long-term sustenance of healthy lifestyles or improving unhealthy lifestyles can reduce and delay CVD risk.

Application and mechanism of nanomedicine and nanomaterials in antibacterial infection therapy / 药学学报

Antibacterial therapy is a global health issue. The antibiotic resistance is becoming an increasingly serious threat, which caused by misuse and overuse of antibacterial agents combined with the emergence of new resistance mechanism. The resulting infection treatment risk and incidence of the spread of disease, severe cases and deaths are increased in different degrees. With the extensive application of biomaterials and nanotechnology to biomedicine, extensive research has been conducted on antibacterial infection. With the specific physicochemical properties like optical, electric and magnetic and high penetration, inorganic nanomaterials can produce natural antibacterial effect. Nanomedicine can be designed to allow controlled drug release and targeting effect, thus demonstrated better antibacterial efficiency. In this review, the mechanism of antibacterial resistance is described, and the antibacterial infection research on inorganic nanomaterials, as well as nano-drug delivery system including liposomes, nanoparticles, dendrimers and biomimetic nanocarriers are summarized. Nanomaterials and nanotechnology offer promising strategies for the development of new agents that can improve efficacy on antibacterial infections and overcome antibiotic resistance potentially.

UPLC-Q-TOF-MS metabolomic study on improvement of acute myocardial ischemia in rats by Dalbergia cochinchinensis heartwood / 中国中药杂志

This paper aimed to study the effect of Dalbergia cochinchinensis heartwood on plasma endogenous metabolites in rats with ligation of the left anterior descending coronary artery, and to analyze the mechanism of D. cochinchinensis heartwood in improving acute myocardial ischemic injury. The stability and consistency of the components in the D. cochinchinensis heartwood were verified by the establishment of fingerprint, and 30 male SD rats were randomly divided into a sham group, a model group, and a D. cochinchinensis heartwood(6 g·kg~(-1)) group, with 10 rats in each group. The sham group only opened the chest without ligation, while the other groups established the model of ligation. Ten days after administration, the hearts were taken for hematoxylin-eosin(HE) staining, and the content of heart injury indexes in the plasma creatine kinase isoenzyme(CK-MB) and lactate dehydrogenase(LDH), energy metabolism-related index glucose(Glu) content, and vascular endothelial function index nitric oxide(NO) was determined. The endogenous metabolites were detected by ultra-high-performance liquid chromatography-time-of-flight-mass spectrometry(UPLC-Q-TOF-MS). The results showed that the D. cochinchinensis heartwood reduced the content of CK-MB and LDH in the plasma of rats to relieve myocardial injury, reduced the content of Glu in the plasma, improved myocardial energy metabolism, increased the content of NO, cured the vascular endothelial injury, and promoted vasodilation. D. cochinchinensis heartwood improved the increase of intercellular space, myocardial inflammatory cell infiltration, and myofilament rupture caused by ligation of the left anterior descending coronary artery. The metabolomic study showed that the content of 26 metabolites in the plasma of rats in the model group increased significantly, while the content of 27 metabolites decreased significantly. Twenty metabolites were significantly adjusted after the administration of D. cochinchinensis heartwood. D. cochinchinensis heartwood can significantly adjust the metabolic abnormality in rats with ligation of the left anterior descending coronary artery, and its mechanism may be related to the regulation of cardiac energy metabolism, NO production, and inflammation. The results provide a corresponding basis for further explaining the effect of D. cochinchinensis on the acute myocardial injury.

Mechanism of Berberis atrocarpa anthocyanin against Alzheimer's disease based on network pharmacology and experimental verification / 中国中药杂志

This study aimed to explore the potential mechanism of Berberis atrocarpa Schneid. anthocyanin against Alzheimer's disease(AD) based on network pharmacology, molecular docking technology, and in vitro experiments. Databases were used to screen out the potential targets of the active components of B. atrocarpa and the targets related to AD. STRING database and Cytoscape 3.9.0 were adopted to construct a protein-protein interaction(PPI) network and carry out topological analysis of the common targets. Gene Ontology(GO) and Kyoto Encyclopedia of Genes and Genomes(KEGG) enrichment analyses were performed on the target using the DAVID 6.8 database. Molecular docking was conducted to the active components and targets related to the nuclear factor kappa B(NF-κB)/Toll-like receptor 4(TLR4) pathway. Finally, lipopolysaccharide(LPS) was used to induce BV2 cells to establish the model of AD neuroinflammation for in vitro experimental validation. In this study, 426 potential targets of active components of B. atrocarpa and 329 drug-disease common targets were obtained, and 14 key targets were screened out by PPI network. A total of 623 items and 112 items were obtained by GO functional enrichment analysis and KEGG pathway enrichment analysis, respectively. Molecular docking results showed that NF-κB, NF-κB inhibitor(IκB), TLR4, and myeloid differentiation primary response 88(MyD88) had good binding abilities to the active components, and malvidin-3-O-glucoside had the strongest binding ability. Compared with the model group, the concentration of nitric oxide(NO) decreased at different doses of malvidin-3-O-glucoside without affecting the cell survival rate. Meanwhile, malvidin-3-O-glucoside down-regulated the protein expressions of NF-κB, IκB, TLR4, and MyD88. This study uses network pharmacology and experimental verification to preliminarily reveal that B. atrocarpa anthocyanin can inhibit LPS-induced neuroinflammation by regulating the NF-κB/TLR4 signaling pathway, thereby achieving the effect against AD, which provides a theoretical basis for the study of its pharmacodynamic material basis and mechanism.

Dryness-alleviating effect of processed Aurantii Fructus from Lingnan based on correlation of fecal metabolomics and dryness / 中国中药杂志

With the approach of untargeted metabolomics and correlation analysis, this study aimed to explore the mechanism of Aurantii Fructus from Lingnan region in alleviating dryness by analyzing the different effects of raw Aurantii Fructus(RAF) and processed Aurantii Fructus(PAF) on fecal endogenous metabolism in normal rats. Eighteen Sprague-Dawley(SD) rats were randomly divided into a control group(C), an RAF group(10 g·kg~(-1)), and a PAF group(10 g·kg~(-1)). After seven days of administration, the effects of RAF and PAF on dryness-related indexes were compared, including water intake, fecal water content, salivary secretion, the expression of AQP5, VIP, and 5-HT in the submandibular gland, as well as the expression of AQP3, VIP, and 5-HT in the colon. The fecal samples in each group were determined by LC-MS. Multivariate statistical analysis and Pearson correlation coefficient were used for screening the differential metabolites and metabolic pathways in alleviating dryness of RAF. The results indicated that both RAF and PAF showed certain dryness, and the dryness of RAF was more significant. Moreover, PAF could alleviate dryness of RAF to a certain extent by reducing the water intake, fecal water content, and the expression of AQP3, VIP, and 5-HT in the colon and increasing the salivary secretion and the levels of AQP5, VIP, and 5-HT in the submandibular gland. According to the analysis of fecal metabolomics, 99 and 58 metabolites related to dryness were found in RAF and PAF respectively, where 16 of them played an important role in alleviating dryness of RAF. Pathway analysis revealed that the mechanism of PAF in alleviating dryness of RAF was presumably related to the regulation of riboflavin metabolism, purine metabolism, arginine biosynthesis, pyrimidine metabolism, alanine metabolism, aspartate metabolism, glutamate metabolism, and retinol metabolism pathways. This study suggested that PAF might alleviate dryness of RAF by affecting the metabolic levels of the body, which provides a new basis for further clarifying the processing mechanism of PAF.

Effect of repetitive peripheral magnetic stimulation on upper limb motor function of stroke patients after contralateral seventh cervical nerve transfer / 中国康复理论与实践

ObjectiveTo explore the effect of repetitive peripheral magnetic stimulation on upper limb motor function rehabilitation of stroke patients after contralateral seventh cervical nerve transfer (CC7). MethodsFrom May, 2020, to May, 2022, 34 stroke patients with hemiplegia underwent CC7 in Jing'an District Centre Hospital of Shanghai were randomly divided into control group (n = 17) and observation group (n = 17). Both groups received conventional rehabilitation. The observation group accepted repetitive peripheral magnetic stimulation, and the control group received sham stimulation, for eight weeks. They were assessed with Fugl-Meyer Assessment-Upper Extremities (FMA-UE) and Hua-Shan Grading of Upper Extremity (H-S grading) before and after treatment. ResultsTwo cases dropped down in each group. There was difference in gender between two groups (χ2 = 6.136, P < 0.05). After treatment, the scores of FMA-UE and H-S grading significantly improved in both groups (t > 4.000, P < 0.01), and the improvement was better in the observation group than in the control group (t > 2.362, P < 0.05). ConclusionRepetitive peripheral magnetic stimulation could improve the motor function of upper limb and hand of stroke patients with hemiplegia after CC7.

Expert consensus on clinical practice in perioperative nursing for elderly patients with hip fracture (version 2023) / 中华创伤杂志

Hip fracture is considered as the most severe osteoporotic fracture characterized by high disability and mortality in the elderly. Improved surgical techniques and multidisciplinary team play an active role in alleviating prognosis, which places higher demands on perioperative nursing. Dysfunction, complications, and secondary impact of anaesthesia and surgery add more difficulties to clinical nursing. Besides, there still lack clinical practices in perioperative nursing for elderly patients with hip fracture in China. In this context, led by the Orthopedic Nursing Committee of Chinese Nursing Association, the Expert consensus on clinical practice in perioperative nursing for elderly patients with hip fracture ( version 2023) is developed based on the evidence-based medicine. This consensus provides 11 recommendations on elderly patients with hip fracture from aspects of perioperative health education, condition monitoring and inspection, complication risk assessment and prevention, and rehabilitation, in order to provide guiding advices for clinical practice, improve the quality of nursing and ameliorate the prognosis of elderly patients with hip fracture.

Analysis of influencing factors and therapeutic effects of hemodialysis combined with pulmonary infection in patients with diabetes nephropathy / 中国医师杂志

Objective:To investigate and analyze the risk factors of pulmonary infection in hemodialysis patients with diabetes nephropathy (DN), and explore the effect of different antibiotic application methods on the efficacy of DN patients with pulmonary infection.Methods:337 inpatients with DN who were admitted to Lishui Central Hospital from August 2021 to April 2022 were selected as the study subjects, and the proportion of pathogenic bacteria in patients with pulmonary infection caused by hemodialysis was analyzed, and the influencing factors of pulmonary infection were analyzed by single factor and multiple factor logistic regression models. DN patients with pulmonary infection were treated with single or multiple antibiotics, and their curative effects were analyzed and compared.Results:Among 337 hospitalized patients with DN in this study, the rate of pulmonary infection caused by hemodialysis was 24.04%(81/337). 87 strains of pathogenic bacteria were cultivated, and the main pathogens of the infected individuals were Klebsiella pneumoniae (36.78%, 32/87), Staphylococcus aureus (17.24%, 15/87), and Acinetobacter baumannii (16.09%, 14/87). The results of univariate analysis showed that patient age, dialysis time, hospital stay, hemoglobin, postprandial blood glucose, malnutrition (blood albumin level<35 g/L), renal function, and volume load were the influencing factors for pulmonary infection in DN patients undergoing hemodialysis (all P<0.05). Multivariate logistic regression model analysis showed that dialysis time, hemoglobin, postprandial, blood glucose malnutrition, renal function, and volume load were risk factors for pulmonary infection caused by hemodialysis (all P<0.05). After treatment, the levels of white blood cells, neutrophils, and hypersensitive reactive protein in patients with pulmonary infection were significantly reduced compared to before treatment (all P<0.05). The effective rate of multi antibiotic therapy (97.44%, 38/39) was higher than that of single antibiotic therapy (80.95%, 34/42) (χ 2=5.563, P=0.018). Conclusions:There are many independent risk factors for pulmonary infection during hemodialysis in DN patients. The infection rate should be reduced through adequate dialysis, blood glucose control, nutrition supplementation, anemia correction and other measures, and the infected can be treated timely with antibiotics according to the situation.

The Deubiquitinating Enzyme USP14 Promotes the Proliferation and Migration Ability of Pancreatic Cancer Cells / 中国生物化学与分子生物学报

Pancreatic cancer remains one of the deadliest cancer types with few effective treatment options. While the overexpression of ubiquitin-specific protease 14 (USP14) has been observed in many tumor cells, including pancreatic cancer cells, its precise role in pancreatic cancer is not well defined. Here, we investigated the biological function of USP14 in pancreatic cancer and its molecular mechanisms. Our analysis of the Cancer Genome Atlas database revealed that USP14 was highly expressed in pancreatic cancer tissues,and further investigation revealed that its expression level was negatively correlated with the prognosis of patients. In SW1990 and MIAPaCa2 pancreatic cancer cells,we established stable USP14-knockdown cell lines using the shRNA-USP14 lentivirus and found that USP14 knockdown inhibited the proliferation and migration ability of pancreatic cancer cells by CCK8, colony formation assay, wound-healing and Transwell assays. Western blotting analysis showed that downregulation of USP14 expression resulted in a decrease in CyclinD3 protein levels, while overexpression of USP14 increased the protein levels in SW1990 and MIAPaCa2 pancreatic cancer cells. Furthermore, co-immunoprecipitation demonstrated that USP14 interacts with CyclinD3 and ubiquitination assays show that overexpression of USP14 reduces the ubiquitination level of CyclinD3. Moreover, CRISPR / Cas9-mediated USP14 knockout in SW1990 pancreatic cancer cells resulted in decreased CyclinD3 protein levels. These findings suggest that USP14 promotes the proliferation and migration ability of pancreatic cancer cells by interacting with CyclinD3, highlighting USP14 as a potential therapeutic target for pancreatic cancer.

Anthraquinone modifier KA-4c triggers endoplasmic reticulum stress and targets ATF6 against breast cancer cells / 中国药理学通报

Aim To explore the mechanism of the effect of anthraquinone modifier KA-4c on breast cancer cells, and determine its action target by drug affinity reaction target stability technique (DARTS). Methods The cell viability was detected by MTT method. The effect of KA-4c on the morphology of breast cancer cells was studied by HE staining, ER-Tracker Red and electron microscope. The apoptosis rate of breast cancer cells induced by KA-4c was detected by flow cytometry. The expression of apoptotic protein was detected by Western blotting. DARTS and CETSA were used to determine the target of KA-4c. Results KA-4c had the most significant inhibitory effect on the proliferation of triple negative breast cancer MDA-MB231 cells, and could cause endoplasmic reticulum and mitochondrial vacuolation to damage the cells. The apoptosis rate and the expression of apoptosis-related proteins CHOP and caspase-7 increased with the increase of KA-4c concentration. DARTS results showed that KA-4c could activate endoplasmic reticulum protein processing signaling pathway, in which KA-4c bound to ATF6 protein and was resistant to protease hydrolysis. The results of CETSA experiments showed that KA-4c could enhance the expression of ATF6 protein in a concentration-dependent manner. Conclusions KA-4 triggers endoplasmic reticulum stress to induce apoptosis in breast cancer cells. ATF6 may be one of the targets of KA-4c.

Effect of a novel phosphodiesterase type 5 inhibitor, CPD1, on carbon tetrachloride-induced liver fibrosis in mice / 中国药理学通报

Aim To investigate the effects of CPD1, a novel phosphodiesterase 5 inhibitor, on liver pathological phenotype and hepatic stellate cells (HSCs) activation in hepatic fibrosis model mice caused by carbon tetrachloride ( CCl

The Dual Role of Non-coding RNAs in the Development of Periodontitis / 生物医学与环境科学（英文）

This review aims to sum up how Non-coding RNAs (ncRNAs) regulate the development of periodontitis and provides a new perspective for understanding the pathogenesis of periodontitis. We explored the ncRNA's dual role in the development of periodontitis by summarizing evidence from previous in vivo and in vitro studies as well as clinical samples. In our review, the downregulation of 18 miRNAs, 22 lncRNAs and 10 circRNAs demonstrates protective roles in periodontitis. In contrast, the expression of other 11 miRNAs, 7 lncRNAs and 6 circRNAs are upregulated in periodontitis, which promote the progression of periodontitis. These dysregulated ncRNAs exert their protective or destructive roles by mainly influencing cell proliferation, differentiation and apoptosis via cross-talking with various molecules or signaling pathways. Our findings suggested which and how ncRNAs promote or delay the progression of periodontitis, which may greatly contribute to diagnose and therapy development of periodontitis based on ncRNAs in the future.

Dihydrofolate reductase-like protein inactivates hemiaminal pharmacophore for self-resistance in safracin biosynthesis

Dihydrofolate reductase (DHFR), a housekeeping enzyme in primary metabolism, has been extensively studied as a model of acid-base catalysis and a clinic drug target. Herein, we investigated the enzymology of a DHFR-like protein SacH in safracin (SAC) biosynthesis, which reductively inactivates hemiaminal pharmacophore-containing biosynthetic intermediates and antibiotics for self-resistance. Furthermore, based on the crystal structure of SacH-NADPH-SAC-A ternary complexes and mutagenesis, we proposed a catalytic mechanism that is distinct from the previously characterized short-chain dehydrogenases/reductases-mediated inactivation of hemiaminal pharmacophore. These findings expand the functions of DHFR family proteins, reveal that the common reaction can be catalyzed by distinct family of enzymes, and imply the possibility for the discovery of novel antibiotics with hemiaminal pharmacophore.

Clinical characteristics and risk factors for early-onset necrotizing enterocolitis in preterm infants with very/extremely low birth weight / 中国当代儿科杂志

OBJECTIVES@#To investigate the clinical characteristics and risk factors for early-onset necrotizing enterocolitis (NEC) in preterm infants with very/extremely low birth weight (VLBW/ELBW).@*METHODS@#A retrospective analysis was performed on the medical data of 194 VLBW/ELBW preterm infants with NEC who were admitted to Children's Hospital Affiliated to Zhengzhou University from January 2014 to December 2021. These infants were divided into early-onset group (onset in the first two weeks of life; n=62) and late-onset group (onset two weeks after birth; n=132) based on their onset time. The two groups were compared in terms of perinatal conditions, clinical characteristics, laboratory examination results, and clinical outcomes. Sixty-two non-NEC infants with similar gestational age and birth weight who were hospitalized at the same period as these NEC preterm infants were selected as the control group. The risk factors for the development of early-onset NEC were identified using multivariate logistic regression analysis.@*RESULTS@#Compared with the late-onset group, the early-onset group had significantly higher proportions of infants with 1-minute Apgar score ≤3, stage III NEC, surgical intervention, grade ≥3 intraventricular hemorrhage, apnea, and fever or hypothermia (P<0.05). The multivariate logistic regression analysis showed that feeding intolerance, blood culture-positive early-onset sepsis, severe anemia, and hemodynamically significant patent ductus arteriosus were independent risk factors for the development of early-onset NEC in VLBW/ELBW preterm infants (P<0.05).@*CONCLUSIONS@#VLBW/ELBW preterm infants with early-onset NEC have more severe conditions compared with those with late-onset NEC. Neonates with feeding intolerance, blood culture-positive early-onset sepsis, severe anemia, or hemodynamically significant patent ductus arteriosus have a higher risk of early-onset NEC.