Endoplasmic Reticulum Stress in the Pathogenesis of Hyperglycemia Induced by Thiamine-Responsive Megaloblastic Anemia.

BACKGROUND: Thiamine responsive megaloblastic anemia (TRMA) is a genetic disease caused by SLC19A2 gene mutation. This study aimed to preliminarily explore the relationship between endoplasmic reticulum stress (ERS)-PERK signaling pathway and the pathogenesis of hyperglycemia induced by TRMA. METHODS: Islet ß (INS.1 and ß-TC-6) and HEK293T cell line models with stable overexpression of SLC19A2 and SLC19A2 (c.1409insT) were established. The cells were divided into empty virus group (control), wild-type group (overexpressed SLC19A2), and mutation group (overexpressed SLC19A2 (c.1409insT)). Quantitative reverse transcription-polymerase chain reaction (RT-qPCR) and western blotting were used to detect the expression levels of ERS-PERK signaling pathway-related proteins, including glucose-regulated protein 78 (GRP78), protein kinase R-like ER kinase (PERK), and eukaryotic initiation factor 2 (eIF2α), activating transcription factor 4 (ATF4), and C/EBP homologous protein (CHOP) in islet ß cells. Protein localization was assessed by immunofluorescence staining. RESULTS: Compared with the control group, the mRNA expression levels of SLC19A2 in wild-type and mutant islet ß cells (INS.1 and ß-TC-6) and HEK293T cells were significantly upregulated (all p < 0.05). Compared with the control group and the wild-type group, the mRNA expression levels of GRP78, PERK, eIF2α, ATF4, and CHOP were increased (all p < 0.05) in the mutant islet ß cells; the protein expression levels of PERK, GRP78, and eIF2α were elevated (all p < 0.05). In addition, the results of immunofluorescence staining showed that SLC19A2 (c.1409insT) mutation changed the localization of the proteins in the cells. Thus, they were not located on the cell surface, but in the cytoplasm and nuclei, and protein aggregation occurred in the cytoplasm. CONCLUSIONS: 1. Islet ß and HEK293Tcell lines, stably overexpressing SLC19A2 and SLC19A2 (c.1409insT) mutations, were successfully constructed. 2. SLC19A2 (c.1409insT) mutation could raise the expression levels of ERS-PERK signaling pathway-related proteins (GRP78, PERK, eIF2α, ATF4, and CHOP), and activate apoptosis pathway. 3. SLC19A2 (c.1409insT) mutation could change the localization of proteins and produce protein aggregation in cells. It could lead to protein misfolding and ERS, which would participate in the pathological mechanism of hyperglycemia induced by TRMA.

Initiating antiretroviral therapy within 2 weeks of anti-Pneumocystis treatment does not increase mortality or AIDS-defining events in patients with HIV-associated moderate to severe Pneumocystis pneumonia: results of a prospective observational multicenter study.

BACKGROUND: The mortality rate remains high among patients with coinfection with Pneumocystis pneumonia (PCP) and HIV. The timing for initiation of antiretroviral therapy (ART) after a diagnosis of moderate to severe PCP remains controversial, however. We therefore designed the present study to determine the optimal timing for ART initiation in AIDS-associated PCP (AIDS/PCP) patients. METHODS: This was a multicenter, observational, prospective clinical trial. Eligible participants were recruited from 14 hospitals in mainland China, and assigned to an Early ART arm (initiation of ART ≤ 14 days after PCP diagnosis) and a Deferred ART arm (initiation of ART > 14 days after PCP diagnosis). The primary outcomes were death and the incidence of AIDS-defining events at week 48. The secondary outcomes were the changes in CD4+ T-cell counts from baseline values at weeks 12, 24, and 48, the virological suppression rate at week 24 and week 48, the rate of development of PCP-associated immune reconstitution inflammatory syndrome (PCP/IRIS), and the rate of adverse events over 48 weeks. RESULTS: The present study was performed using the data of 363 participants, with 169 participants in the Early ART arm, and 194 participants in the Deferred ART arm. Immunological and virological outcomes were found to be similar in both treatment arms. At week 48, there were no significant differences for the incidence of mortality (20 vs. 26, p = 0.860), and AIDS-defining events (17 vs. 26, p = 0.412). Over 48 weeks, the rates of PCP/IRIS (2 vs. 3, p = 1.000), adverse events (70 vs. 72, p = 0.465), and grade 3 or 4 adverse events (28 vs. 34, p = 0.919) did not reach statistical significance. A significant difference observed between two study arms was that 11 participants (55.0%) in the Early ART arm compared to 23 participants (88.5%) in the Deferred ART arm (p = 0.026) succumbed before ART had ever been started. CONCLUSIONS: Early ART initiation results in no increase in mortality, AIDS-defining events, IRIS, adverse events, and immunological or virological outcomes. These results support the early initiation of ART in patients with moderate to severe AIDS/PCP. Clinical trial registration The present trial was registered at Chinese Clinical Trial Registry (ChiCTR1900021195). Registered 1 February 2019, http://www.chictr.org.cn/showproj.aspx?proj=35362 .

Bile duct ligation causes opposite impacts on the expression and function of BCRP and P-gp in rat brain partly via affecting membrane expression of ezrin/radixin/moesin proteins.

Breast cancer resistance protein (BCRP) and P-glycoprotein (P-gp) are co-located at blood-brain barrier (BBB) cells, preventing their substrates from entering brain. Accumulating evidence demonstrates that liver failure impairs P-gp and BCRP expression and function in the brain. In the current study, we investigated how liver failure influenced the expression and function of brain BCRP and P-gp in rats subjected to bile duct ligation (BDL). The function of BCRP, P-gp and BBB integrity was assessed using distribution of prazosin, rhodamine 123 and fluorescein, respectively. We showed that BDL significantly decreased BCRP function, but increased P-gp function without affecting BBB integrity. Furthermore, we found that BDL significantly downregulated the expression of membrane BCRP and upregulated the expression of membrane P-gp protein in the cortex and hippocampus. In human cerebral microvascular endothelial cells, NH4Cl plus unconjugated bilirubin significantly decreased BCRP function and expression of membrane BCRP protein, but upregulated P-gp function and expression of membrane P-gp protein. The decreased expression of membrane BCRP protein was linked to the decreased expression of membrane radixin protein, while the increased expression of membrane P-gp protein was related to the increased location of membrane ezrin protein. Silencing ezrin impaired membrane location of P-gp, whereas silencing radixin impaired membrane location of BCRP protein. BDL rats showed the increased expression of membrane ezrin protein and decreased expression of membrane radixin protein in the brain. We conclude that BDL causes opposite effects on the expression and function of brain BCRP and P-gp, attributing to the altered expression of membrane radixin and ezrin protein, respectively, due to hyperbilirubinemia and hyperammonemia.

Bile duct ligation enhances AZT CNS toxicity partly by impairing the expression and function of BCRP in rat brain.

Breast cancer resistance protein (BCRP) is one of ATP-binding cassette (ABC) transporters in brain microvessel endothelial cells that transport their substrates from brain to blood, thus limiting substrates to crossing into brain through blood-brain barrier. Our previous works show that bile duct ligation (BDL) impairs expression and function of brain BCRP in rats. Since zidovudine (AZT) is BCRP substrate, we investigated whether impaired expression and function of BCRP increased brain distribution and toxicity of AZT in BDL-D7 rats. After administration of AZT (10 mg/kg, i.v.), BDL markedly increased brain AZT concentrations, compared with sham-operated (SO) rats. The ratio of AZT brain-to-plasma area under concentration curve (AUC) in BDL rats was increased to 1.6-folds of SO rats. After treatment with AZT (100 mg/kg every day, i.v.) for 7 days, BDL significantly impaired cognitive functions compared with SO rats, evidenced by the significantly decreased percentage of alternation in Y-maze test and prolonged escaped latency in two-way passive avoidance trial. Furthermore, AZT treatment caused significant decrease in copies of mitochondrial DNA and mitochondrial membrane potential in hippocampus of BDL rats. Moreover, AZT treatment caused a significant decrease of cortex microtubule-associated protein 2 and hippocampus synaptophysin levels in BDL rats. AZT-induced CNS adverse alterations in BDL rats were not observed in SO rats treated with AZT. In conclusion, BDL decreases the function and expression of brain BCRP in rats, leading to increased brain distribution of AZT, which in turn enhances AZT CNS toxicity, leading to mitochondrial dysfunction, neuronal damage, and ultimately cognitive dysfunction.

Mean platelet volume/platelet count ratio in colorectal cancer: a retrospective clinical study.

BACKGROUND: Mean platelet volume (MPV) is a marker of platelet activation. MPV and platelet count (PC) are negatively correlated, and their ratio (MPV/PC) is informative for the diagnosis of malignant tumors. However, the relationship between MPV/PC and colorectal cancer is unclear. This retrospective clinical study aimed to evaluate the diagnostic value of MPV/PC in colorectal cancer. METHODS: Hematological examinations were performed at initial diagnosis in patients with colorectal cancer (n = 186) or adenomatous polyp (n = 132) and healthy controls (n = 108). Hematological parameters evaluated included white blood cells, red blood cells, hemoglobin, neutrophils, lymphocytes, monocytes, PC, and MPV. Statistical analyses included Student's t-test, one-way ANOVA or Kruskal-Wallis H test, chi-square tests, Spearman's correlation test and receiver operating characteristic (ROC). ROC curve was used to evaluate the diagnostic values of MPV and MPV/PC in colorectal cancer. RESULTS: Among these groups, MPV was significantly lower in colorectal cancer than in adenomatous polyp (p = 0.002) and healthy controls (p < 0.001) but did not significantly differ between adenomatous polyp and healthy controls (p = 0.210). MPV/PC was lower in colorectal cancer compared with adenomatous polyp and healthy controls (p < 0.001) and in adenomatous polyp compared with healthy controls (p = 0.010). MPV did not significantly differ among colorectal cancer subgroups, while MPV/PC significantly differed between TNM stages and the presence/absence of lymph node metastasis. MPV/PC was negatively correlated with the neutrophil to lymphocyte ratio(NLR) (p = 0.002) and platelet to lymphocyte ratio(PLR) concentration (p < 0.001). In the differential diagnosis between colorectal cancer and adenomatous polyp, MPV/PC produced a larger ROC curve than MPV, NLR or PLR alone. Using MPV/PC to distinguish between colorectal cancer and controls produced a larger AUC than using MPV or NLR alone. CONCLUSIONS: MPV/PC may be useful for the diagnosis of colorectal cancer. However, further studies are warranted to include additional regions and more data, to assess the utility of MPV/PC as a novel diagnostic screening tool for colorectal cancer.

Diagnostic value of derived neutrophil-to-lymphocyte ratio in patients with ovarian cancer.

BACKGROUND: Inflammation plays an important role in the occurrence and development of cancer. Numerous studies have used the derived neutrophil-to-lymphocyte ratio (dNLR) to evaluate prognosis in many types of cancer. However, the relationship between dNLR and ovarian cancer and its value in the differential diagnosis of benign and malignant ovarian tumors remain unknown. METHODS: A total of 262 patients with ovarian cancer, 258 with benign ovarian disease, and 232 healthy controls were included in this study. dNLR was calculated using whole blood cell parameters. Receiver operating characteristic curves were generated to obtain sensitivity, specificity, and area under the ROC curve (AUC) to evaluate the diagnostic values of dNLR. RESULTS: dNLR was significantly different among the ovarian cancer, benign ovarian disease, and healthy control groups (all P < 0.001). Moreover, there were significant differences in dNLR between patients with early-stage (I and II) and advanced-stage (III and IV) disease (P < 0.001). dNLR was positively correlated with stage and carbohydrate antigen-125 in ovarian cancer. A cutoff value of dNLR ≤2.11 was diagnostic in distinguishing ovarian cancer from benign ovarian disease with AUC of 0.729 (95% confidence interval [CI], 0.689-0.767; P = 0.0001). A cutoff value of dNLR ≤1.9 was diagnostic in distinguishing ovarian cancer from healthy controls with an AUC of 0.821 (95% CI, 0.784-0.854; P = 0.0001). CONCLUSION: dNLR may be a useful indicator for distinguishing between ovarian cancer and benign ovarian disease and for identifying early and advanced ovarian cancer.

Prevalence of hyperhomocysteinemia during routine physical examination in Guangxi Province, China and related risk factors.

BACKGROUND: Studies on homocysteine (Hcy) have mainly focused on the correlation between the homocysteine concentration and disease development. Few epidemiological investigations have been performed. This study was conducted to investigate the prevalence of hyperhomocysteinemia (HHcy) during routine physical examination in Guangxi Province, China and the correlation of serum Hcy with gender, age, serum uric acid (UA), total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and blood glucose (GLU) to provide evidence for preventing and treating HHcy. METHODS: Data of 8043 patients who underwent physical examinations at the First Affiliated Hospital of Guangxi Medical University, China from 2015 to 2016 were collected. These data included gender, age, and the serum Hcy, UA, GLU, TC, TG, HDL-C, and LDL-C concentrations. RESULTS: The overall prevalence of HHcy was 50.8% (52.3% in males, 48.1% in females). Age, UA, TC, TG, and LDL-C were significantly higher and HDL-C was significantly lower in patients with than without HHcy, regardless of gender (all P<.05). The Hcy level was positively correlated with UA, TC, TG, and LDL-C but negatively correlated with HDL-C. Gender, age, UA, TC, and TG were independent risk factors for HHcy. CONCLUSION: The prevalence of HHcy was very high during routine physical examination in Guangxi Province, China. HHcy was related to gender, age, high concentrations of UA, TC, TG, and LDL-C; and low concentrations of HDL-C. Strengthening early intervention of HHcy can reduce the risk of cardiovascular disease.

Rare LPL gene missense mutation in an infant with hypertriglyceridemia.

BACKGROUND: Severe hypertriglyceridemia usually results from a combination of genetic and environmental factors and is most often attributable to mutations in the lipoprotein lipase (LPL) gene. OBJECTIVES: The aim of this study was to identify rare mutations in the LPL gene causing severe hypertriglyceridemia. METHODS: A Chinese infant who presented classical features of severe hypertriglyceridemia recruited for DNA sequencing of the LPL gene. The pathogenicity grade of the variants was defined based on the prediction of pathogenicity using in silico prediction tools. Review some studies to understand the molecular mechanisms underlying the severe hypertriglyceridemia. RESULTS: We identified a rare mutation in the LPL gene causing severe hypertriglyceridemia: a nucleotide substitution (c.836T>G) resulting in a leucine to arginine substitution at position 279 of the protein (p.Leu279Arg).The pathogenicity of the variant was predicted by in silico analysis using PolyPhen2 and SIFT prediction programs, which indicated that mutation p.Leu279Arg is probably harmful. We have also reviewed published studies concerning the molecular mechanisms underlying severe hypertriglyceridemia. A missense mutation in the 6 exon of the LPL gene is reportedly associated with LPL deficiency. CONCLUSIONS: We have here identified a rare pathogenic mutation in the LPL gene in a Chinese infant with severe hypertriglyceridemia.

Reduced Nicotinamide Adenine Dinucleotide Phosphate, a Pentose Phosphate Pathway Product, Might Be a Novel Drug Candidate for Ischemic Stroke.

BACKGROUND AND PURPOSE: Our previous study has defined a role of TP53-induced glycolysis and apoptosis regulator in neuroprotection against ischemic injury through increasing the flow of pentose phosphate pathway. We hypothesized that the pentose phosphate pathway product nicotinamide adenine dinucleotide phosphate (NADPH) could be a novel drug for treatment of ischemic stroke. METHODS: The NADPH was given before, at the onset, or after stroke onset with single or repeated intravenous (mice and rats) or intraperitoneal injections (monkey). The short- and long-term therapeutic effects of NADPH were evaluated in male adult ICR mice (total=614) with transient middle cerebral artery occlusion, in male adult Sprague-Dawley rats (total=114) with permanent middle cerebral artery occlusion, and in male adult rhesus monkey (total=12) with thrombotic middle cerebral artery occlusion. RESULTS: Administration of NADPH led to a dramatic increase in the levels of ATP and reduced form of glutathione, whereas it decreased the levels of reactive oxygen species. NADPH significantly reduced infarct volume, improved poststroke survival, and recovery of neurological functions in mouse and rat models of stroke. Robust neuroprotection of a single dose of NADPH was seen when it was administered within 5 hours after reperfusion; however, repeat administration of NADPH twice a day for 7 days starting 24 hours after the onset of stroke also offered therapeutic effects. Pretreatment with NADPH also significantly improved the outcome of stroke insult. CONCLUSIONS: Administration of exogenous NADPH significantly protected neurons against ischemia/reperfusion-induced injury in 2 rodent stroke models. Thus, NADPH might be a promising drug candidate for treatment of ischemic stroke.

A TIGAR-regulated metabolic pathway is critical for protection of brain ischemia.

TP53-induced glycolysis and apoptosis regulator (TIGAR) inhibits glycolysis and increases the flow of pentose phosphate pathway (PPP), which generates NADPH and pentose. We hypothesized that TIGAR plays a neuroprotective role in brain ischemia as neurons do not rely on glycolysis but are vulnerable to oxidative stress. We found that TIGAR was highly expressed in brain neurons and was rapidly upregulated in response to ischemia/reperfusion insult in a TP53-independent manner. Overexpression of TIGAR in normal mice with lentivirus reduced ischemic neuronal injury, whereas lentivirus-mediated TIGAR knockdown aggravated it. In cultured primary neurons, increasing TIGAR expression reduced oxygen and glucose deprivation (OGD)/reoxygenation-induced injury, whereas decreasing its expression worsened the injury. The glucose 6-phosphate dehydrogenase was upregulated in mouse and cellular models of stroke, and its upregulation was further enhanced by overexpression of TIGAR. Supplementation of NADPH also reduced ischemia/reperfusion brain injury and alleviated TIGAR knockdown-induced aggravation of ischemic injury. In animal and cellular stroke models, ischemia/reperfusion increased mitochondrial localization of TIGAR. OGD/reoxygenation-induced elevation of ROS, reduction of GSH, dysfunction of mitochondria, and activation of caspase-3 were rescued by overexpression of TIGAR or supplementation of NADPH, while knockdown of TIGAR aggravated these changes. Together, our results show that TIGAR protects ischemic brain injury via enhancing PPP flux and preserving mitochondria function, and thus may be a valuable therapeutic target for ischemic brain injury.

The combined detection of hematological indicators is used for the differential diagnosis of colorectal cancer and benign-colorectal lesions.

OBJECTIVE: This article aims to investigate the clinical value of hemoglobin/red cell distribution width ratio (Hb/RDW), C-reactive protein/albumin ratio (CAR) and plateletcrit (PCT) combined with carcinoembryonic antigen (CEA) in colorectal cancer (CRC) auxiliary diagnosis. METHODS: We retrospectively analyzed in 718 subjects (212 with CRC, 209 with benign colorectal lesions (BCL), 111 with other cancers, and 186 healthy controls). RESULTS: The CAR, PCT, and CEA in the CRC group were higher than those in the BCL, other cancers, and the healthy control group. However, Hb/RDW in the CRC group was lower than the other three groups. Moreover, there were significant differences in Hb/RDW and CEA among different T-N-M stages (all P< 0.05). Multivariate logistic regression showed that low level of Hb/RDW and high level of CAR, CEA, PCT were risk factors for CRC, and are correlated with CRC stage. Additionally, the area under the receiver operating characteristic curve (AUC) of Hb/RDW+CEA (AUC: 0.735), CAR+CEA (AUC: 0.748), PCT+CEA (AUC: 0.807) was larger than that of Hb/RDW (AUC: 0.503), CAR (AUC: 0.614), or PCT (AUC: 0.713) alone (all P< 0.001) in distinguishing CRC from BCL. CONCLUSIONS: Hb/RDW, CAR, PCT, and CEA are independent risk factors for CRC. Hb/RDW, CAR, and PCT combined with CEA have significant value for auxiliary differential diagnosis of CRC and BCL.

In vivo quantitative whole-brain diffusion tensor imaging analysis of APP/PS1 transgenic mice using voxel-based and atlas-based methods.

INTRODUCTION: Diffusion tensor imaging (DTI) has been applied to characterize the pathological features of Alzheimer's disease (AD) in a mouse model, although little is known about whether these features are structure specific. Voxel-based analysis (VBA) and atlas-based analysis (ABA) are good complementary tools for whole-brain DTI analysis. The purpose of this study was to identify the spatial localization of disease-related pathology in an AD mouse model. METHODS: VBA and ABA quantification were used for the whole-brain DTI analysis of nine APP/PS1 mice and wild-type (WT) controls. Multiple scalar measurements, including fractional anisotropy (FA), trace, axial diffusivity (DA), and radial diffusivity (DR), were investigated to capture the various types of pathology. The accuracy of the image transformation applied for VBA and ABA was evaluated by comparing manual and atlas-based structure delineation using kappa statistics. Following the MR examination, the brains of the animals were analyzed for microscopy. RESULTS: Extensive anatomical alterations were identified in APP/PS1 mice, in both the gray matter areas (neocortex, hippocampus, caudate putamen, thalamus, hypothalamus, claustrum, amygdala, and piriform cortex) and the white matter areas (corpus callosum/external capsule, cingulum, septum, internal capsule, fimbria, and optic tract), evidenced by an increase in FA or DA, or both, compared to WT mice (p < 0.05, corrected). The average kappa value between manual and atlas-based structure delineation was approximately 0.8, and there was no significant difference between APP/PS1 and WT mice (p > 0.05). The histopathological changes in the gray matter areas were confirmed by microscopy studies. DTI did, however, demonstrate significant changes in white matter areas, where the difference was not apparent by qualitative observation of a single-slice histological specimen. CONCLUSION: This study demonstrated the structure-specific nature of pathological changes in APP/PS1 mouse, and also showed the feasibility of applying whole-brain analysis methods to the investigation of an AD mouse model.

UPLC-Q-TOF/MS-Based Serum Metabolomics Reveals Potential Anti-tumor Mechanism of Banxia Xiexin Decoction in Colorectal Cancer Mice.

OBJECTIVE: To clarify the potential mechanism of Banxia Xiexin Decoction (BXD) on colorectal cancer (CRC) from the perspective of metabolomics. METHODS: Forty male C57BL/6 mice were randomly divided into normal control (NC), azoxymethane/dextran sulfate sodium (AOM/DSS) model, low-dose BXD (L-BXD), high-dose BXD (H-BXD) and mesalamine (MS) groups according to a random number table, 8 mice in each group. Colorectal cancer model was induced by AOM/DSS. BXD was administered daily at doses of 3.915 (L-BXD) and 15.66 g/kg (H-BXD) by gavage for consecutive 21 days, and 100 mg/kg MS was used as positive control. Following the entire modeling cycle, colon length of mice was measured and quantity of colorectal tumors were counted. The spleen and thymus index were determined by calculating the spleen/thymus weight to body weight. Inflammatory cytokine and changes of serum metabolites were analyzed by enzyme-linked immunosorbent assay kits and ultra performance liquid chromatography-quadrupole/time-of-flight mass spectrometry (UPLC-Q/TOF-MS), respectively. RESULTS: Notably, BXD supplementation protected against weight loss, mitigated tumor formation, and diminished histologic damage in mice treated with AOM/DSS (P<0.05 or P<0.01). Moreover, BXD suppressed expression of serum inflammatory enzymes, and improved the spleen and thymus index (P<0.05). Compared with the normal group, 102 kinds of differential metabolites were screened in the AOM/DSS group, including 48 potential biomarkers, involving 18 main metabolic pathways. Totally 18 potential biomarkers related to CRC were identified, and the anti-CRC mechanism of BXD was closely related to D-glutamine and D-glutamate metabolism, phenylalanine, tyrosine and tryptophan biosynthesis, arginine biosynthesis, nitrogen metabolism and so on. CONCLUSION: BXD exerts partial protective effects on AOM/DSS-induced CRC by reducing inflammation, protecting organism immunity ability, and regulating amino acid metabolism.

Alleviation of ischemic brain injury by exercise preconditioning is associated with modulation of autophagy and mitochondrial dynamics in cerebral cortex of female aged mice.

Evidence from clinical studies and preclinical studies supports that exercise preconditioning can not only reduce the risk of stroke but also improve brain tissue and functional outcome after stroke. It has been demonstrated that autophagy and mitochondrial dynamics are involved in ischemic stroke. However, it is still unclear whether exercise preconditioning-induced neuroprotection against stroke is associated with modulation of autophagy and mitochondrial dynamics. Although age and sex interactively affect ischemic stroke risk, incidence, and outcome, studies based on young male animals are most often used to explore the role of exercise preconditioning in the prevention of ischemic stroke. In the current study, we examined whether exercise preconditioning could modulate autophagy and mitochondrial dynamics in a brain ischemia and reperfusion (I/R) model of female aged mice. The results showed that exercise preconditioning reduced infarct volume and improved neurological deficits. Additionally, increased levels of autophagy-related proteins LC3-II/LC3-I, LC3-II, p62, Atg7, and mitophagy-related proteins Bnip3L and Parkin, as well as increased levels of mitochondrial fusion modulator Mfn2 and mitochondrial fission modulator Drp1 in the ischemic cortex of female aged mice at 12 h after I/R were present. Our results could contribute to a better understanding of exercise preconditioning-induced neuroprotection against ischemic stroke for the elderly.

A pan-cancer analysis of the MAPK family gene and their association with prognosis, tumor microenvironment, and therapeutic targets.

The mitogen-activated protein kinases family of genes plays a crucial role in a wide range of inflammatory responses in the human body. The MAPK family of genes includes ERK, ERK5, JNK, P-38 mitogen-activated protein kinases. However, the correlation between MAPK family gene expression and pan-cancer prognosis, as well as the tumor microenvironment, has not been extensively studied. This study integrated multiple bioinformatics analysis methods to assess the expression and prognostic value of MAPK family genes, as well as their relationship with tumor microenvironment in patients with pan-cancer. The results showed that ERK, JNK, and P-38 MAPK expression were found to be significantly upregulated in rectum adenocarcinoma (READ), colon adenocarcinoma/rectum adenocarcinoma esophageal carcinoma (COADREAD), and kidney renal clear cell carcinoma (KIRC), and significantly downregulated in acute myeloid leukemia. And the results revealed good prognostic results for ERK, JNK, and P-38 MAPK in READ, COADREAD, and KIRC. We observed significant positive correlation between MAPK family gene expression and immune scores especially dendritic cells in READ, COADREAD, and KIRC. And we observed that the expression levels of MAPK family genes were significantly correlated with the expression of immune-related genes, such as CXCL1, CXCL2, CXCL8, CXCR1, CXCR2, CTLA-4, CD80, CD86, and CD28, suggesting their important role in regulating immune infiltrates and tumor progression. Therefore, our study suggested that MAPK family gene plays an important role in regulating immune infiltrates and tumor progression.

Non-invasive Assessment of Axillary Lymph Node Metastasis Risk in Early Invasive Breast Cancer Adopting Automated Breast Volume Scanning-Based Radiomics Nomogram: A Multicenter Study.

OBJECTIVE: The aim of the work described here was to develop a non-invasive tool based on the radiomics and ultrasound features of automated breast volume scanning (ABVS), clinicopathological factors and serological indicators to evaluate axillary lymph node metastasis (ALNM) in patients with early invasive breast cancer (EIBC). METHODS: We retrospectively analyzed 179 ABVS images of patients with EIBC at a single center from January 2016 to April 2022 and divided the patients into training and validation sets (ratio 8:2). Additionally, 97 ABVS images of patients with EIBC from a second center were enrolled as the test set. The radiomics signature was established with the least absolute shrinkage and selection operator. Significant ALNM predictors were screened using univariate logistic regression analysis and further combined to construct a nomogram using the multivariate logistic regression model. The receiver operating characteristic curve assessed the nomogram's predictive performance. DISCUSSION: The constructed radiomics nomogram model, including ABVS radiomics signature, ultrasound assessment of axillary lymph node (ALN) status, convergence sign and erythrocyte distribution width (standard deviation), achieved moderate predictive performance for risk probability evaluation of ALNs in patients with EIBC. Compared with ultrasound, the nomogram model was able to provide a risk probability evaluation tool not only for the ALNs with positive ultrasound features but also for micrometastatic ALNs (generally without positive ultrasound features), which benefited from the radiomics analysis of multi-sourced data of patients with EIBC. CONCLUSION: This ABVS-based radiomics nomogram model is a pre-operative, non-invasive and visualized tool that can help clinicians choose rational diagnostic and therapeutic protocols for ALNM.

The Effects of Different Doses of Alfentanil and Dexmedetomidine on Prevention of Emergence Agitation in Pediatric Tonsillectomy and Adenoidectomy Surgery.

Background: Emergence agitation (EA) is a common problem often observed in children after sevoflurane anesthesia, which can be prevented by dexmedetomidine and alfentanil. This study aims to compare the effectiveness of dexmedetomidine alone and with different doses of alfentanil in preventing EA in children under sevoflurane anesthesia. Materials and Methods: In a double-blind trial, 80 children (ASA I or II, 3-7 years old) undergoing tonsillectomy alone and adenotonsillectomy with sevoflurane anesthesia were randomly assigned into four groups: the control group, dexmedetomidine (DEX) group, dexmedetomidine plus 10 µg/kg alfentanil group (DEX + Alf1), and dexmedetomidine plus 20 µg/kg alfentanil group (DEX + ALf2). The incidence of EA was assessed with the Aono's scale, and the severity of EA was evaluated with the Pediatric Anesthesia Emergence Delirium (PAED) scale. The time of tracheal extubation and time of wake were recorded. Postoperative pain and complications such as nausea and vomiting, cough, laryngospasm, and bradycardia were recorded. Results: The incidence of EA was 50% in the control group, 25% in the DEX group, and 5% in the DEX + Alf1 group, and it never happened in the DEX + Alf2 group. The Aono's scale, the PAED scale, and the FLACC scale in the control group and the DEX group were significantly more than those in the DEX + Alf1 group and the DEX + Alf2 group after the tracheal extubation (p < 0.05). The time of tracheal extubation of the control group and the DEX group were significantly shorter than those in the DEX + Alf1 group and the DEX + Alf2 group (p < 0.05). The awakening time of the DEX + Alf2 group is significantly longer than those in other groups (p < 0.05). The case of postoperative nausea and vomiting in the DEX + Alf1 group was fewer than those in the other groups (p < 0.05). And, the cases of cough and laryngospasm and bronchospasm in the DEX + Alf1 group and the DEX + Alf2 group were significantly less than those in the control group and the DEX group after the tracheal extubation (p < 0.05). Conclusion: The combined administration of alfentanil and dexmedetomidine can reduce EA in children undergoing tonsillectomy alone and adenotonsillectomy with sevoflurane anesthesia. Dexmedetomidine plus 10 µg/kg alfentanil seems to be more appropriate than other dose combinations as it reduced EA and postoperative nausea and vomiting but did not prolong the time to awake.

Targeted pharmacokinetics and bioinformatics screening strategy reveals JAK2 as the main target for Xin-Ji-Er-Kang in treatment of MIR injury.

BACKGROUND AND PURPOSE: Xin-Ji-Er-Kang (XJEK) is traditional Chinese formula presented excellent protective effects on several heart diseases, but the potential components and targets are still unclear. The aim of this study is to elucidate the effective components of XJEK and reveal its potential mechanism of cardioprotective effect in myocardial ischemia-reperfusion (MIR) injury. EXPERIMENTAL APPROACH: Firstly, the key compounds in XJEK, plasma and heart tissue were analyzed by high resolution mass spectrometry. Bioinformatics studies were also involved to disclose the potential targets and the binding sites for the key compounds. Secondly, to study the protective effect of XJEK on MIR injury and related mechanism, mice subjected to MIR surgery and gavage administered with XJEK for 6 weeks. Cardiac function parameters and apoptosis level of cardiac tissue were assessed. The potential mechanism was further verified by knock down of target protein in vitro. RESULTS: Pharmacokinetics studies showed that Sophora flavescens alkaloids, primarily composed with matrine, are the key component of XJEK. And, through bioinformatic analysis, we speculated JAK2 could be the potential target for XJEK, and could form stable hydrogen bonds with matrine. Administration of XJEK and matrine significantly improved heart function and reduced apoptosis of cardiomyocytes by increasing the phosphorylation of JAK2 and STAT3. The anti-apoptosis effect of XJEK and matrine was also observed on AC16 cells, and could be reversed by co-treatment with JAK2 inhibitor AG490 or knock-down of JAK2. CONCLUSION: XJEK exerts cardioprotective effect on MIR injury, which may be associated with the activation of JAK2/STAT3 signaling pathway.

Xin-Ji-Er-Kang protects heart from ischemia-reperfusion injury by rebalancing lipid metabolism.

Background and Purpose: We have previously reported a cardioprotective effect with Xin-Ji-Er-Kang (XJEK) treatment in mice with myocardial infarction (MI)-induced heart failure, but no report about its potential functions in myocardial ischemia-reperfusion (MIR) injury. Here we studied the therapeutic effects of XJEK on MIR injury and investigated the mechanisms involved. Experimental Approach: MIR model of Balb/c mice induced by left anterior descending coronary artery ligation for half an hour, followed by reperfusion, was utilized to study the potential therapeutic effects of XJEK on MIR-induced cardiac injury. Ultra-performance liquid chromatography tandem Orbitrap mass spectrometry platform was used for studying serum lipid metabolic signatures. Key Results: MIR caused cardiac dysfunctions, cardiac injury, myocardial fibrosis, and increased inflammation, and all the observed abnormalities caused by MIR were largely corrected by XJEK treatment. Mechanistically, XJEK exerts its cardioprotective effect in the context of MIR injury by suppressing MIR-induced inflammation and dysregulation of serum lipid metabolism. Conclusion and Implications: We have demonstrated for the first time that XJEK protects heart from MIR injury by restoring dysregulated lipidomics. Our data provide new evidence to support a therapeutic effect for XIEK on MIR-induced cardiac injury, and pave the way for exploring the therapeutic potential of XJEK in large animal study and early clinical trial.

Mangiferin Inhibits Human Lung Adenocarcinoma by Suppressing MiR-27b and MiR-92a.

Lung adenocarcinoma (LUAD) is one of the most prevalent malignancies. However, its mechanism and therapeutic strategy remain to be clarified. Mangiferin is a flavonoid derived from the leaves of mango trees of the lacquer family that has many pharmacological and physiological effects. This research aimed to elucidate the biological effect of mangiferin in LUAD cell lines and clarify the in vitro mechanism of mangiferin. Mangiferin was shown to significantly restrain the proliferation of LUAD cells (A549, H1299, and H2030 cells) in a dose- and time-dependent manner. Furthermore, mangiferin was capable of stimulating apoptosis, and more cells were blocked in G1 and S phase in the mangiferin-treated cells than in those not treated with mangiferin. Microarrays and micro-RNA sequencing data suggested that there is a higher level of miR-27b and miR-92a in LUAD tissues than in non-LUAD tissues. Additional experiments indicated that mangiferin may be related to the downregulated levels of miR-92a and miR-27b. In conclusion, mangiferin likely regulates proliferation and apoptosis in LUAD cells by reducing the expression levels of miR-92a and miR-27b.