Exploring the clinical significance of miR-148 expression variations in distinct subtypes of irritable bowel syndrome.

Irritable bowel syndrome (IBS) belongs to chronic functional gastrointestinal diseases featured by abdominal pain and changes in bowel habits. This study aimed to investigate the clinical significance of serum miR-148 expression in different subtypes of IBS. We enrolled 86 IBS patients and 55 healthy controls. miR-148 expression levels were assessed in IBS patients classified into IBS-constipation (IBS-C), IBS-diarrhea (IBS-D), and IBS-mixed stool pattern (IBS-M) subtypes. Receiver-operating characteristic (ROC) curves were employed to evaluate the diagnostic potential of miR-148 in distinguishing among IBS subtypes. Additionally, we analyzed the correlation between miR-148 expression and clinical characteristics, including IBS symptom severity. miR-148 expression was highest in IBS-D (diarrhea) group, followed by IBS-M and IBS-C. With the exception of the IBS-C group, miR-148 expression was elevated in IBS patients compared to controls. ROC curve analysis demonstrated that serum miR-148 exhibited higher diagnostic accuracy for discriminating IBS-C and IBS-D than IBS-M. Correlation analysis revealed a positive relationship between serum miR-148 relative expression and IBS symptom severity system scores. Univariate logistic analysis indicated a positive association between miR-148 expression and IBS-D and a negative correlation with IBS-C. miR-148 expression exhibits differential patterns among IBS subtypes and holds a potential to distinguish IBS-C and IBS-D. Furthermore, miR-148 expression correlates with the severity of IBS symptoms.

Maternal trans-general analysis of the human mitochondrial DNA pattern.

There is an intimate connection between mitochondrial DNA (mtDNA) methylation and some diseases, such as cancer. MtDNA is almost strictly maternally inherited. However, whether the aberrant mtDNA methylation involved in breast cancer progression and whether mtDNA methylation can be transmitted through maternal line are poorly understood. Here we applied bisulfite sequencing to global mitochondrial DNA and whole genomic DNA methylation array from fifteen members of five three-female-generation families with one breast cancer patient in each family. We found that mtDNA methylation was maternally inherited in D-loop region and eight aberrant mtDNA methylation sites were correlated with breast cancer. Furthermore, conjoint analysis showed that mtDNA methylation sites could be potential biomarkers combined with nuclear DNA methylation sites for breast cancer risk prediction.

Histone H4 Lys 20 methyltransferase SET8 promotes androgen receptor-mediated transcription activation in prostate cancer.

Histone methylation status in different lysine residues has an important role in transcription regulation. The effect of H4K20 monomethylation (H4K20me1) on androgen receptor (AR)-mediated gene transcription remains unclear. Here we show that AR agonist stimulates the enrichment of H4K20me1 and SET8 at the promoter of AR target gene PSA in an AR dependent manner. Furthermore, SET8 is crucial for the transcription activation of PSA. Co-immunoprecipitation analyses demonstrate that SET8 interacts with AR. Therefore, we conclude that SET8 is involved in AR-mediated transcription activation, possibly through its interaction with AR and H4K20me1 modification.

Dimer monomer transition and dimer re-formation play important role for ATM cellular function during DNA repair.

The ATM protein kinase, is a serine/threonine protein kinase that is recruited and activated by DNA double-strand breaks, mediates responses to ionizing radiation in mammalian cells. Here we show that ATM is held inactive in unirradiated cells as a dimer and phosphorylates the opposite strand of the dimer in response to DNA damage. Cellular irradiation induces rapid intermolecular autophosphorylation of serine 1981 that causes dimer dissociation and initiates cellular ATM kinase activity. ATM cannot phosphorylate the substrates when it could not undergo dimer monomer transition. After DNA repair, the active monomer will undergo dephosphorylation to form dimer again and dephosphorylation is critical for dimer re-formation. Our work reveals novel function of ATM dimer monomer transition and explains why ATM dimer monomer transition plays such important role for ATM cellular activity during DNA repair.

Risk factors for postpartum posttraumatic stress disorder after emergency admission.

BACKGROUND: Postpartum posttraumatic stress disorder (PTSD) can occur in women who give birth after emergency admission. The identification of risk factors for this condition is crucial for developing effective preventive measures. This retrospective study aimed to explore the incidence and risk factors for postpartum PTSD in women who give birth after emergency admission. METHODS: Medical records of women who gave birth after emergency admission were collected between March 2021 and April 2023. The patients' general conditions and perinatal clinical indicators were recorded. The puerperae were divided into PTSD group and control group based on symptom occurrence at six weeks postpartum. Multivariate logistic regression analysis was performed to identify risk factors. RESULTS: A total of 276 puerperae were included, with a PTSD incidence of 20.3% at six weeks postpartum. Multivariate logistic regression analysis identified emergency cesarean section (odds ratio [OR]=2.102; 95% confidence interval [CI]: 1.114-3.966, P=0.022), admission to the emergency department after midnight (12:00 AM) (OR=2.245; 95%CI: 1.170-4.305, P<0.001), and cervical dilation (OR=3.203; 95%CI: 1.670-6.141, P=0.039) as independent risk factors for postpartum PTSD. Analgesia pump use (OR= 0.500; 95%CI: 0.259-0.966, P=0.015) was found to be a protective factor against postpartum PTSD. CONCLUSION: Emergency cesarean section, admission to the emergency department after midnight, and cervical dilation were identified as independent risk factors for postpartum PTSD, while analgesic pump use was a protective factor. These findings provide insights for developing more effective preventive measures for women who give birth after emergency admission.

Hepatobiliary surgery based on intelligent image segmentation technology.

Liver disease is an important disease that seriously threatens human health. It accounts for the highest proportion in various malignant tumors, and its incidence rate and mortality are on the rise, seriously affecting human health. Modern imaging has developed rapidly, but the application of image segmentation in liver tumor surgery is still rare. The application of image processing technology represented by artificial intelligence (AI) in surgery can greatly improve the efficiency of surgery, reduce surgical complications, and reduce the cost of surgery. Hepatocellular carcinoma is the most common malignant tumor in the world, and its mortality is second only to lung cancer. The resection rate of liver cancer surgery is high, and it is a multidisciplinary surgery, so it is necessary to explore the possibility of effective switching between different disciplines. Resection of hepatobiliary and pancreatic tumors is one of the most challenging and lethal surgical procedures. The operation requires a high level of doctors' experience and understanding of anatomical structures. The surgical segmentation is slow and there may be obvious complications. Therefore, the surgical system needs to make full use of the relevant functions of AI technology and computer vision analysis software, and combine the processing strategy based on image processing algorithm and computer vision analysis model. Intelligent optimization algorithm, also known as modern heuristic algorithm, is an algorithm with global optimization performance, strong universality, and suitable for parallel processing. This algorithm generally has a strict theoretical basis, rather than relying solely on expert experience. In theory, the optimal solution or approximate optimal solution can be found in a certain time. This work studies the hepatobiliary surgery through intelligent image segmentation technology, and analyzes them through intelligent optimization algorithm. The research results showed that when other conditions were the same, there were three patients who had adverse reactions in hepatobiliary surgery through intelligent image segmentation technology, accounting for 10%. The number of patients with adverse reactions in hepatobiliary surgery by conventional methods was nine, accounting for 30%, which was significantly higher than the former, indicating a positive relationship between intelligent image segmentation technology and hepatobiliary surgery.

Multi-omics integrated circulating cell-free DNA genomic signatures enhanced the diagnostic performance of early-stage lung cancer and postoperative minimal residual disease.

BACKGROUND: Liquid biopsy is a promising non-invasive alternative for cancer screening and minimal residual disease (MRD) detection, although there are some concerns regarding its clinical applications. We aimed to develop an accurate detection platform based on liquid biopsy for both cancer screening and MRD detection in patients with lung cancer (LC), which is also applicable to clinical use. METHODS: We applied a modified whole-genome sequencing (WGS) -based High-performance Infrastructure For MultIomics (HIFI) method for LC screening and postoperative MRD detection by combining the hyper-co-methylated read approach and the circulating single-molecule amplification and resequencing technology (cSMART2.0). FINDINGS: For early screening of LC, the LC score model was constructed using the support vector machine, which showed sensitivity (51.8%) at high specificity (96.3%) and achieved an AUC of 0.912 in the validation set prospectively enrolled from multiple centers. The screening model achieved detection efficiency with an AUC of 0.906 in patients with lung adenocarcinoma and outperformed other clinical models in solid nodule cohort. When applied the HIFI model to real social population, a negative predictive value (NPV) of 99.92% was achieved in Chinese population. Additionally, the MRD detection rate improved significantly by combining results from WGS and cSMART2.0, with sensitivity of 73.7% at specificity of 97.3%. INTERPRETATION: In conclusion, the HIFI method is promising for diagnosis and postoperative monitoring of LC. FUNDING: This study was supported by CAMS Innovation Fund for Medical Sciences, Chinese Academy of Medical Sciences, National Natural Science Foundation of China, Beijing Natural Science Foundation and Peking University People's Hospital.

Effect of SARS-CoV-2 Breakthrough Infection on HIV Reservoirs and T-Cell Immune Recovery in 3-Dose Vaccinated People Living with HIV.

People living with human immunodeficiency virus (PLWH) are a vulnerable population with a higher risk of severe coronavirus disease 2019 (COVID-19); therefore, vaccination is recommended as a priority. Data on viral reservoirs and immunologic outcomes for PLWH breakthrough infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are currently limited. In this study, we investigated the effects of SARS-CoV-2 breakthrough infection on hematological parameters, human immunodeficiency virus (HIV) reservoir size, and T-cell recovery in PLWH receiving antiretroviral therapy (ART) after SARS-CoV-2 booster vaccination. The results indicated that during breakthrough infection, booster vaccination with homologous and heterologous vaccines was safe in PLWH after receiving two doses of inactivated vaccination. The absolute CD4 counts decreased in the heterologous group, whereas the CD8 counts decreased in the homologous booster group after breakthrough infection in PLWH. Breakthrough infection increased HIV reservoirs and was associated with increased T-cell activation in PLWH who received virally suppressed ART and a 3-dose vaccination. According to our data, the breakthrough infection of SARS-CoV-2 may put PLWH at a greater risk for increased HIV reservoirs, even if these individuals were virally suppressed with ART after 3-dose SARS-CoV-2 vaccination.

Protein disulfide-isomerase A3 knockdown attenuates oxidized low-density lipoprotein-induced oxidative stress, inflammation and endothelial dysfunction in human umbilical vein endothelial cells by downregulating activating transcription factor 2.

Atherosclerosis is a chronic inflammatory disease implicated in oxidative stress and endothelial dysfunction. Protein disulfide-isomerase A3 (PDIA3) has been reported to regulate oxidative stress and suppress inflammation. This study aimed to explore the function of PDIA3 in atherosclerosis and the underlying mechanisms. PDIA3 expression in oxidized low-density lipoprotein (ox-LDL)-induced human umbilical vein endothelial cells (HUVECs) was detected using RT-qPCR and Western blotting. Following PDIA3 knockdown through transfection with small interfering RNA targeting PDIA3, cell viability, oxidative stress and inflammation in ox-LDL-induced HUVECs was examined using a Cell Counting Kit-8, corresponding kits and ELISA, respectively. The levels of CD31, α-smooth muscle, iNOS, p-eNOS, eNOS and NO were assessed using RT-qPCR, Western blotting and an NO kit to reflect endothelial dysfunction in ox-LDL-induced HUVECs. The relationship between PDIA3 and the activating transcription factor 2 (ATF2) was confirmed using co-immunoprecipitation. In addition, ATF2 expression was examined following PDIA3 silencing. The results indicated that PDIA3 was highly expressed in ox-LDL-induced HUVECs. PDIA3 silencing increased cell viability, and reduced oxidative stress and inflammation, as evidenced by the decreased levels of reactive oxygen species, malondialdehyde, TNF-α, IL-1ß and IL-6, and increased superoxide dismutase and glutathione peroxidase activity. In addition, PDIA3 deletion improved endothelial dysfunction. PDIA3 interacted with ATF2, and PDIA3 deletion downregulated ATF2 expression. Furthermore, ATF2 overexpression reversed the effects of PDIA3 knockdown on ox-LDL-induced damage of HUVECs. Collectively, PDIA3 knockdown was found to attenuate ox-LDL-induced oxidative stress, inflammation and endothelial dysfunction in HUVECs by downregulating ATF2 expression, showing promise for the future treatment of atherosclerosis.

Study on the Risk Factors of Pulmonary Infection after Laparoscopic Surgery and Analysis of the Detection Results of Drug-Resistant Bacteria.

This study aimed to investigate and analyze the risk of pulmonary infection after laparoscopic surgery and the detection results of drug-resistant bacteria. With the laparoscopic technology developing rapidly in recent years and people's minimally invasive concept improving continuously, laparoscopic radical surgery has been widely used in the treatment of a variety of diseases. Laparoscopic surgery has the probability of causing complications. In order to avoid this, the risk factors after surgery were analyzed, and the drug-resistant bacteria were analyzed for accurate prevention and treatment. A total of 600 patients who underwent elective laparoscopic surgery in our hospital from January 2017 to September 2021 were included in the study. The risk factors and pathogen distribution of pulmonary infection were analyzed. The risk factors of pulmonary infection after laparoscopic surgery were hypoproteinemia, diabetes mellitus, pulmonary disease history, and perioperative blood transfusion. The main pathogens were Klebsiella pneumoniae, Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli, and Streptococcus pneumoniae. In clinical work, relevant nursing intervention measures can be developed for the above factors, so as to reduce the incidence of pulmonary infection. This study finds the risk factors for pulmonary infection after surgery, and the common drug-resistant bacteria has an indicative and guiding effect on the formulation of nursing management measures.

Novel insights into the inhibitory mechanism of (+)-catechin against trimethylamine-N-oxide demethylase.

Trimethylamine-N-oxide demethylase (TMAOase) is a key enzyme for the decomposition of trimethylamine oxide into formaldehyde. The study investigated the inhibitory effects of (+)-catechin on TMAOase and involved mechanism to minimize the formaldehyde (FA) content of seafood during storage. TMAOase was purified by DEAE-52 cellulose and Sephacryl S-300 chromatography and the inhibitory mechanism of TMAOase was studied by Lineweaver-Burk plots, fluorescence spectroscopy, and circular dichroism. Specific activity of 37 ± 0.7 U/mg was obtained with 205 -fold purification and 15% yield, and molecular mass was 25 kDa. (+)-Catechin was a reversible inhibitor of TMAOase and its induced mechanism was the non-competitive inhibition type. (+)-Catechin binding to TMAOase formed a complex with the binding constant (Ksv) of 0.72 × 103 at 298 K. The formation of complex induced the static fluorescence quenching and changes in the conformation of TMAOase, leading to a reduction in the rate of catalysis.

Knockdown of TANK-Binding Kinase 1 Enhances the Sensitivity of Hepatocellular Carcinoma Cells to Molecular-Targeted Drugs.

The protein kinase, TANK-binding kinase 1 (TBK1), not only regulates various biological processes but also functions as an important regulator of human oncogenesis. However, the detailed function and molecular mechanisms of TBK1 in hepatocellular carcinoma (HCC), especially the resistance of HCC cells to molecular-targeted drugs, are almost unknown. In the present work, the role of TBK1 in regulating the sensitivity of HCC cells to molecular-targeted drugs was measured by multiple assays. The high expression of TBK1 was identified in HCC clinical specimens compared with paired non-tumor tissues. The high level of TBK1 in advanced HCC was associated with a poor prognosis in patients with advanced HCC who received the molecular-targeted drug, sorafenib, compared to patients with advanced HCC patients and a low level of TBK1. Overexpression of TBK1 in HCC cells induced their resistance to molecular-targeted drugs, whereas knockdown of TBK1 enhanced the cells' sensitivity to molecular-targeted dugs. Regarding the mechanism, although overexpression of TBK1 enhanced expression levels of drug-resistance and pro-survival-/anti-apoptosis-related factors, knockdown of TBK1 repressed the expression of these factors in HCC cells. Therefore, TBK1 is a promising therapeutic target for HCC treatment and knockdown of TBK1 enhanced sensitivity of HCC cells to molecular-targeted drugs.

Comparison of CT findings and histopathological characteristics of pulmonary cryptococcosis in immunocompetent and immunocompromised patients.

Pulmonary cryptococcosis (PC) is a common fungal infectious disease, and infection can occur in patients with any immune function. To better understand PC, we compared the CT findings and histopathological results in immunocompetent and immunocompromised patients. The clinical data of 68 patients with PC were collected retrospectively and divided into the immunocompetent group and immunocompromised group. The clinical characteristics, CT manifestations and histopathological characteristics of the two groups of patients were compared. Forty-two patients (61.8%) were immunocompetent, and 26 patients (38.2%) were immunocompromised. Compared with immunocompromised patients, 57.14% (24/42) of immunocompetent patients were asymptomatic (p = 0.002). Compared with immunocompetent patients, cough (14/26, 53.9%) and fever (13/26, 50.0%) were the main symptoms in immunocompromised patients (p = 0.044, p = 0.007). Nodular lesions (97.6%, 41/42) were the most common CT type in immunocompetent patients, and the CT characteristic was a single lesion (25/42, 59.5%); the main histopathological type was nodular fibrogranuloma (30/42, 71.4%), and the main histopathological characteristic was inflammatory granuloma (31/42, 73.81%) formed by macrophage phagocytosis of Cryptococcus. Consolidation (15/26, 57.7%) was more common in the CT type of immunocompromised patients. Multiple lesions (24/26, 92.31%), air bronchial signs (19/26, 73.081%) and cavities (9/26, 34.62%) were the main CT characteristics. The mucinous colloid type (19/26, 73.1%) was its main histopathological type, which was mainly characterized by a small amount of surrounding inflammatory cell infiltration (17/26, 65.4%). There were significant differences in the classification and characteristics of CT and pathology between the two groups (p < 0.05). Through the CT manifestations and histopathological characteristics of PC under different immune function states, it was found that immune function has a significant impact on the CT manifestations and histopathological characteristics of patients with PC.

Clinical and computed tomography features in patients with coronavirus disease 2019.

Coronavirus disease 2019 (COVID-19) has recently broken out in China. To describe the clinical and computed tomography (CT) characteristics in patients with COVID-19-induced pneumonia, the current study retrospectively analyzed the data of 152 patients with pneumonia between December 30, 2019 and February 29, 2020. Pharyngeal swabs for nucleic acid detection of respiratory secretions were used for all patients. A total of 65 cases were diagnosed as COVID-19, and 87 cases were non-COVID-19. When comparing the clinical and CT characteristics of the two groups of patients, only sex and history of exposure presented a statistically significant difference. The normal/low white blood cell count, low lymphocyte ratio and high C-reactive protein (CRP) exhibited a statistically significant difference between the two groups. A total of 62 patients in the COVID-19 group exhibited ground-glass opacity (GGO), which was higher than that in the non-COVID-19 group. In the COVID-19 group, 33 cases presented angiographic thickening in GGO, and 27 cases displayed a paving stone sign, which were higher than those in the non-COVID-19 group. Compared with the non-COVID-19 group, the lesions in the COVID-19 group were principally characterized by bilateral lungs, multifocal and subpleural distribution. The results of the present study revealed that when the male patients with contact history in the epidemic area exhibited fever and cough symptoms, the laboratory tests indicated normal/low white blood cell counts, low lymphocyte ratios and elevated CRP levels. CT scans were recommended for subsequent examination. GGO or GGO and consolidation with bilateral lungs were indicated to be primarily distributed in the multifocal subpleural area and were accompanied by angiographic thickening in GGO and paving stone sign. In conclusion, regardless of whether the viral nucleic acid test is positive, COVID-19 should be considered for medical treatment observation in isolation.

[Astragaloside II inhibits the proliferation of rat pulmonary artery smooth muscle cells induced by hypoxia via blocking NOX/ROS/AKT/mTOR signaling pathway].

Objective To investigate the inhibitory effect of astragaloside II (AS-II) on the proliferation of pulmonary artery smooth muscle cells (PASMCs) induced by hypoxia and its relevant mechanism. Methods Rat primary PASMCs were divided into normoxia group, hypoxia group, hypoxia combined with 20, 40, 80 µmol/L AS-II treated groups, hypoxia combined with nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) inhibitor VAS2870 treated group, and then cultured either in normoxic (210 mL/L O2) or hypoxic (20 mL/L O2) condition for 24 hours. The proliferation of PASMCs was detected by CCK-8 assay. The level of intracellular reactive oxygen species (ROS) was detected by DCFH-DA staining. Protein kinase B (AKT), phospho-AKT (p-AKT), mammalian target of rapamycin (mTOR), phospho-mTOR (p-mTOR), proliferating cell nuclear antigen (PCNA), NOX1 and NOX4 protein expression were assessed by Western blotting. Results In the hypoxia group, the proliferation of PASMCs, level of intracellular ROS, protein expression of PCNA, p-AKT, p-mTOR, NOX1 and NOX4 increased significantly compared with those in the normoxia group. However, AS-II treatment inhibited hypoxia-induced PASMCs proliferation, decreased the level of intracellular ROS, and suppressed protein expression of PCNA, p-AKT, p-mTOR, NOX1 and NOX4. Moreover, VAS2870 treatment lead to similar changes. Conclusion AS-II can inhibit the proliferation of PASMCs induced by hypoxia, which may be associated with the blocking of NOX/ROS/AKT/mTOR signaling pathway.

Pyrrolidinedithiocarbamic Acid Ammonium Salt Inhibits Apoptosis and Phenotypic Transformation of Co-Culture of Myeloma Cells and Renal Tubular Epithelial Cells by Reducing the Secretion of Light Chain Protein.

BACKGROUND: We investigate the effects of NFÏ°B inhibitor pyrrolidinedithiocarbamic acid ammonium salt (PDTC) on the viability, apoptosis and cell phenotype of HK-2 cells in the co-culture system of myeloma cells in renal tubular epithelial cells. METHODS: This study was performed in Qiqihar Medical University, Qiqihar, China from Jun 2018 to Jan 2019. RPMI-8226 cells and HK-2 cells were inoculated in the co-culture chamber and cultured to establish the co-culture system. An immunoturbidimetric assay was performed to detect Ï° light chain and λ light chain in RPMI-8226 cells. The effect of PDTC on the secretion of Ï° light chain and λ light chain of RPMI-8226 cells was detected by immunoturbidimetry and the ratio was calculated. RESULTS: PDTC significantly increased the viability of HK-2 cells. PDTC reduced the apoptosis of renal tubular epithelial cells. After PDTC treatment, the expression of cell surface marker E-cadherin decreased, and the expression of α-SMA increased, which induced the renal interstitial fibrosis. The secretion of Ï° light chain and λ light chain of RPMI-8226 cells was significantly decreased after the addition of PDTC, but the ratio was not changed. CONCLUSION: PDTC can inhibit the cell activity, promote apoptosis, and reduce the secretion of secretion of Ï° light chain and λ light chain through inhibiting the NF-Ï°B pathway activation of myeloma cell RPMI-8226.

Mechanism of Probiotic VSL#3 Inhibiting NF-κB and TNF-α on Colitis through TLR4-NF-κB Signal Pathway.

BACKGROUND: We aimed to investigate the effect of probiotic VSL#3 on NF-κB and TNF-α in rats with colitis and the correlation with TLR4-NF-κB signal pathway. METHODS: Sixty Sprague Dawley (SD) rats were divided into the control, model and therapy groups (n=20) according to the random number table. Rats in the model and therapy groups were modeled for colitis, and rats in the therapy group were intragastrically administered with probiotic VSL#3. The expression of TLR4 and NF-κB protein, and the levels of NF-κB, TLR4, and TNF-α mRNA in the colon tissue were detected. The concentration of TNF-α in the serum after modeling but before intragastric administration (T0), 3d (T1) and 7d after intragastric administration (T2) was detected. RESULTS: The expression of TLR4 and NF-κB p65 protein, and the levels of TLR4, NF-κB, and TNF-α mRAN in the therapy group decreased (P < 0.001). At T0, T1, and T2, the concentration of TNF-α in the model and control groups increased (P < 0.001). TLR4 and NF-κB in the therapy group were positively correlated with TNF-α mRAN (P < 0.050).Conclusion: In conclusion, probiotic VSL#3 inhibits the expression of NF-κB and TNF-α in rats with colitis through TLR4-NF-κB signal pathway, so it is expected to be a first choice drug for the treatment of colitis. CONCLUSION: In conclusion, probiotic VSL#3 inhibits the expression of NF-κB and TNF-α in rats with colitis through TLR4-NF-κB signal pathway, so it is expected to be a first choice drug for the treatment of colitis.

Jatrorrhizine suppresses the antimicrobial resistance of methicillin-resistant Staphylococcus aureus.

Bacterial resistance to antimicrobial agents, including multidrug resistance, is an increasing problem in the treatment of infectious diseases. The development of resistance-modifying agents represents a potential strategy to alleviate the spread of bacterial resistance to antibiotics. A checkerboard microdilution assay was used to determine the synergy of jatrorrhizine and the antibiotic, norfloxacin (NFX). A bacterial ethidium bromide efflux assay, reverse transcription semi-quantitative polymerase chain reaction analysis and molecular docking study were performed. The three-dimensional structure of NorA multidrug efflux pump (NorA) was generated using a multiple threading approach. A murine thigh infection model was used to evaluate the in vivo synergistic effect. As a natural product, jatrorrhizine exhibited little antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA) SA1199B with a minimum inhibitory concentration (MIC) of 64 mg/l. According to the investigations of the mechanism, jatrorrhizine significantly inhibited bacterial drug efflux and the expression of NorA in the mRNA level as it can bind to NorA by hydrogen-bonds, hydrophobic and electrostatic interactions. The in vivo synergistical bactericidal activity of jatrorrhizine and NFX against MRSA was confirmed in a murine thigh infection model. As a novel resistance-modifying agent, jatrorrhizine exhibited in vitro and in vivo synergistic activities against MRSA, and inhibited bacterial drug efflux. The effects were mediated by the suppression of NorA mRNA expression and/or interactions with NorA efflux pump. These data support the hypothesis that jatrorrhizine is a potential agent for therapeutic use in infections caused by MRSA.

Isoliquiritigenin Attenuates Monocrotaline-Induced Pulmonary Hypertension via Inhibition of the Inflammatory Response and PASMCs Proliferation.

Pulmonary hypertension (PH) is a progressive and serious disease, where exacerbated inflammatory response plays a critical role. Isoliquiritigenin (ISL), an important flavonoid isolated from Glycyrrhizae radix, exhibits a wide range of pharmacological actions including anti-inflammation. Previously we found ISL alleviated hypoxia-induced PH; in the present study, to extend this, we evaluated the effects of ISL on monocrotaline (MCT)-induced PH and the relevant mechanisms. Rats received a single intraperitoneal injection of MCT, followed by intragastric treatments with ISL (10 mg/kg/d or 30 mg/kg/d) once a day for 28 days. The MCT administration increased the right ventricular systolic pressure (RVSP) (p < 0.001), the median width of pulmonary arteries (p < 0.01), and the weight ratio of the right ventricular wall/left ventricular wall plus septum (Fulton index) (p < 0.01) in rats; however, these changes were inhibited by both doses of ISL (p < 0.05). In addition, treatment with ISL suppressed the upregulated production of serum interleukin-6 (p < 0.01) and tumor necrosis factor-α (p < 0.05) by MCT and reversed the increases in the numbers of proliferating cell nuclear antigen (PCNA)-positive cells (p < 0.01) in the medial wall of pulmonary arteries. In in vitro experiments, ISL (10 µM, 30 µM, and 100 µM) inhibited excessive proliferation of cultured primary pulmonary artery smooth muscle cells (PASMCs) (p < 0.05, p < 0.01, and p < 0.001) in a dose-dependent manner and prevented an increase in the expressions of PCNA (p < 0.01) and phospho-Akt (p < 0.05) in PASMCs induced by hypoxia. These results suggest that ISL can attenuate MCT-induced PH via its anti-inflammatory and antiproliferative actions.

Lower genomic stability of induced pluripotent stem cells reflects increased non-homologous end joining.

BACKGROUND: Induced pluripotent stem cells (iPSCs) and embryonic stem cells (ESCs) share many common features, including similar morphology, gene expression and in vitro differentiation profiles. However, genomic stability is much lower in iPSCs than in ESCs. In the current study, we examined whether changes in DNA damage repair in iPSCs are responsible for their greater tendency towards mutagenesis. METHODS: Mouse iPSCs, ESCs and embryonic fibroblasts were exposed to ionizing radiation (4 Gy) to introduce double-strand DNA breaks. At 4 h later, fidelity of DNA damage repair was assessed using whole-genome re-sequencing. We also analyzed genomic stability in mice derived from iPSCs versus ESCs. RESULTS: In comparison to ESCs and embryonic fibroblasts, iPSCs had lower DNA damage repair capacity, more somatic mutations and short indels after irradiation. iPSCs showed greater non-homologous end joining DNA repair and less homologous recombination DNA repair. Mice derived from iPSCs had lower DNA damage repair capacity than ESC-derived mice as well as C57 control mice. CONCLUSIONS: The relatively low genomic stability of iPSCs and their high rate of tumorigenesis in vivo appear to be due, at least in part, to low fidelity of DNA damage repair.