Expression of human dCTP pyrophosphatase 1 (DCTPP1) and its association with cisplatin resistance characteristics in ovarian cancer.

Cisplatin (DDP) resistance is a major challenge in treating ovarian cancer patients. A recently discovered enzyme called dCTP pyrophosphatase 1 (DCTPP1) has been implicated in regulating cancer characteristics, including drug responses. In this study, we aimed to understand the role of DCTPP1 in cancer progression and cisplatin response. Using publicly available databases, we analysed the expression and clinical significance of DCTPP1 in ovarian cancer. Our bioinformatics analysis confirmed that DCTPP1 is significantly overexpressed in ovarian cancer and is closely associated with tumour progression and poor prognosis after cisplatin treatment. We also found that DCTPP1 located in oxidoreductase complex and may be involved in various biological processes related to cisplatin resistance, including pyrimidine nucleotide metabolism, the P53 signalling pathway and cell cycle signalling pathways. We observed higher expression of DCTPP1 in cisplatin-resistant cells (SKOV3/DDP) and samples compared to their sensitive counterparts. Additionally, we found that DCTPP1 expression was only enhanced in SKOV3/S cells when treated with cisplatin, indicating different expression patterns of DCTPP1 in cisplatin-sensitive and cisplatin-resistant cancer cells. Our study further supports the notion that cisplatin induces intracellular reactive oxygen species (ROS) and triggers cancer cell death through excessive oxidative stress. Knocking out DCTPP1 reversed the drug resistance of ovarian cancer cells by enhancing the intracellular antioxidant stress response and accumulating ROS. Based on our research findings, we conclude that DCTPP1 has prognostic value for ovarian cancer patients, and targeting DCTPP1 may be clinically significant in overcoming cisplatin resistance in ovarian cancer.

Identifying Network Biomarkers in Early Diagnosis of Hepatocellular Carcinoma via miRNA-Gene Interaction Network Analysis.

BACKGROUND: Hepatocellular carcinoma (HCC) is a highly heterogeneous cancer at the histological level. Despite the emergence of new biological technology, advanced-stage HCC remains largely incurable. The prediction of a cancer biomarker is a key problem for targeted therapy in the disease. METHODS: We performed a miRNA-gene integrated analysis to identify differentially expressed miRNAs (DEMs) and genes (DEGs) of HCC. The DEM-DEG interaction network was constructed and analyzed. Gene ontology enrichment and survival analyses were also performed in this study. RESULTS: By the analysis of healthy and tumor samples, we found that 94 DEGs and 25 DEMs were significantly differentially expressed in different datasets. Gene ontology enrichment analysis showed that these 94 DEGs were significantly enriched in the term "Liver" with a statistical p-value of 1.71 × 10-26. Function enrichment analysis indicated that these genes were significantly overrepresented in the term "monocarboxylic acid metabolic process" with a p-value = 2.94 × 10-18. Two sets (fourteen genes and five miRNAs) were screened by a miRNA-gene integrated analysis of their interaction network. The statistical analysis of these molecules showed that five genes (CLEC4G, GLS2, H2AFZ, STMN1, TUBA1B) and two miRNAs (hsa-miR-326 and has-miR-331-5p) have significant effects on the survival prognosis of patients. CONCLUSION: We believe that our study could provide critical clinical biomarkers for the targeted therapy of HCC.

Investigating efficacy of "microbiota modulation of the gut-lung Axis" combined with chemotherapy in patients with advanced NSCLC: study protocol for a multicenter, prospective, double blind, placebo controlled, randomized trial.

BACKGROUND: Most NSCLCs metastasised out of the lungs at the time of diagnosis and cannot be surgically removed . Cytotoxic chemotherapy drugs have become the main treatment in recent decades, especially in patients with NSCLC without EGFR, ALK, and ROS gene mutations. The prognosis of lung cancer is poor, and the overall 5-year survival rate is only 9-13%. Therefore the treatment of advanced NSCLC remains a significant medical need. Recent studies have shown a significant relationship between the gut-lung axis microecology and malignant tumors. Intestinal probiotics are likely to play a role in inhibiting tumorigenesis through "intestinal-pulmonary axis microecological regulation". This study will seek to investigate the efficacy of "Microbiota modulation of the Gut-Lung Axis" combined with chemotherapy in patients with advanced NSCLC. METHODS: The research is a multicenter, prospective, double blind, placebo controlled, randomized trial. Based on the theoretical basis of "intestinal and lung axis microecological adjustment", combined with traditional platinum-containing two-drug chemotherapy, the efficacy of the new therapy on patients with advanced NSCLC was observed. Collect the basic information of the patient, and study the effect of platinum-based combined chemotherapy on the diversity of intestinal flora in patients with lung cancer after receiving chemotherapy treatment, feces before and after chemotherapy, and the status and extent of adverse reactions during chemotherapy . A total of 180 subjects were included, divided into a control group (platinum-containing dual-drug chemotherapy) and an intervention group (platinum-containing dual-drug chemotherapy combined with Bifico), and were randomly assigned to the group 1:1. DISCUSSION: As a result, intestinal-pulmonary microecological balance could become a new target for the treatment of lung cancer. This study explores the combination of intestinal microecological regulation and chemotherapy to provide new treatment strategies and basis for lung cancer patients. It can help prolong the survival time of lung cancer patients and improve the quality of life, thereby generating huge economic and social benefits. The results can be promoted and applied to units engaged in the treatment of lung cancer. TRIAL REGISTRATION NUMBER: NCT03642548, date: August 22, 2018, the first version protocol. The URL of trial registry record: https://clinicaltrials.gov/ct2/show/NCT03642548?term=NCT03642548&draw=2&rank=1 .

Melatonin inhibits lung cancer development by reversing the Warburg effect via stimulating the SIRT3/PDH axis.

Recently, the morbidity and mortality from lung cancer have continued to increase. Mitochondrial dysfunction plays a key role in apoptosis, proliferation, and the bioenergetic reprogramming of cancer cells, especially for energy metabolism. Herein, we investigated the ability of melatonin (MLT) to influence lung cancer growth and explored the association between mitochondrial functions and the progression of lung tumors. The deacetylase, sirtuin 3 (Sirt3), is a pivotal player in maintenance of mitochondrial function, among participating in ATP production by regulating the acetylone and pyruvate dehydrogenase complex (PDH). We initially found that MLT inhibited lung cancer growth in the Lewis mouse model. Similarly, we observed that MLT inhibited the proliferation of lung cancer cells (A549, PC9, and LLC cells), and the underlying mechanism of MLT was related to reprogramming cancer cell metabolism, accompanied by a shift from cytosolic aerobic glycolysis to oxidative phosphorylation (OXPHOS). These changes were accompanied by higher ATP production, an elevated ATP production-coupled oxygen consumption rate (QCR), higher ROS levels, higher mito-ROS levels, and lower lactic acid secretion. Additionally, we observed that MLT improved mitochondrial membrane potential and the activities of complexes Ⅰ and Ⅳ in the electron transport chain. Importantly, we also found and verified that the foregoing changes resulted from activation of Sirt3 and PDH. As a result of these changes, MLT significantly enhanced mitochondrial energy metabolism to reverse the Warburg effect via increasing PDH activity with stimulation of Sirt3. Collectively, these findings suggest the potential use of melatonin as an anti-lung cancer therapy and provide a mechanistic basis for this proposal.

Study of Circulating Natural Antibodies Against CD25 and FOXP3 in Type-2 Diabetes.

BACKGROUND: Natural antibodies are critical components for maintaining homeostasis of the immune system. Regulatory T (Treg) cells have indispensable effects on immunosuppressive function and peripheral immune tolerance. Both CD25 and FOXP3 are specifically expressed in Treg cells and their natural antibodies may protect against the development of type-2 diabetes (T2D). The present study aimed to test whether circulating antibodies against CD25 and FOXP3 were altered in first-episode patients with T2D. METHODS: An enzyme-linked immunosorbent assay (ELISA) was developed in-house to detect the levels of plasma IgG antibodies against five linear peptide antigens with three derived from CD25 (named CD25a, CD25b, CD25c) and two derived from FOXP3 (called FOXP3a and FOXP3b) among 200 first-episode patients with T2D and 220 healthy controls. RESULTS: Mann-Whitney U test showed a significant decrease in anti-CD25a IgG levels in patients with T2D as compared with the healthy controls (Z = -3.438, p = 0.0006), male patients mainly contributing to the decreased levels of anti-CD25a IgG levels (Z = -3.065, p = 0.002). The other four IgG tests demonstrated a lower level of plas-ma IgG antibodies in the patient group than the control group, but failed to show statistical significance (p > 0.01). ROC curve analysis indicated that the anti-CD25a IgG assay had the best sensitivity of 19.5% against the specificity of 90%. CONCLUSIONS: Decreased anti-CD25 IgG levels in the circulation may represent a reduction in the number of Treg cells and detection of such antibodies may be beneficial to the understanding of immunological changes in T2D patients.

Role of miR-124 and miR-141 in the regulation of vascular reactivity and the relationship to RhoA and Rac1 after hemorrhage and hypoxia.

Recent studies show that hypoxia can alter expression levels of microRNAs (miRNAs). Whether hypoxia or hemorrhage-induced vascular hyporeactivity is related to miRNAs and the underlying mechanisms of this process is not clear. Using hypoxia-treated superior mesenteric arteries (SMAs) and vascular smooth muscle cells (VSMCs) of rats that underwent hemorrhage, we observed the regulatory effects of miR-124/miR-141 on vascular reactivity, the relationship of these miRNAs to RhoA and Rac1, and the mutual regulation of miR-124 and miR-141. The contractile responses of SMAs and VSMCs showed an increase in early stages and a decrease in late stages of hypoxia and hemorrhage. Forty-five miRNAs appeared to have been significantly changed in SMAs after hypoxia, and miR-124 and miR-141 underwent the most change. Overexpressed miR-124 or miR-141 and their antisenses appeared to alter both vascular reactivity and expression of the proteins RhoA and Rac1 after hypoxia. miR-124 inhibited Rac1 by acting at the Rac1 mRNA 3'-untranslated region (UTR), but it led to an increase in RhoA by inhibiting miR-141. miR-141 inhibited RhoA by acting at the RhoA mRNA 3'-UTR, but it led to an increase in Rac1 by inhibiting miR-124. Further study found that miR-124 inhibited miR-141 via transcription factor early growth response gene-1 (Egr-1), whereas miR-141 inhibited miR-124 via transcription of nuclear factor erythroid 2-related factor 2 (Nrf-2). These results suggest that miR-124 and miR-141 participate in the regulation of vascular reactivity after hypoxia and hemorrhage by regulating expression of the RhoA and Rac1 proteins, and in doing so, miR-124 and miR-141 are mutually regulated. These findings provide potential targets for restoring vascular function as part of the treatment protocol for hemorrhagic shock and some other critical illness.

4-Phenylbutyric Acid Reveals Good Beneficial Effects on Vital Organ Function via Anti-Endoplasmic Reticulum Stress in Septic Rats.

OBJECTIVES: Sepsis and septic shock are the common complications in ICUs. Vital organ function disorder contributes a critical role in high mortality after severe sepsis or septic shock, in which endoplasmic reticulum stress plays an important role. Whether anti-endoplasmic reticulum stress with 4-phenylbutyric acid is beneficial to sepsis and the underlying mechanisms are not known. DESIGN: Laboratory investigation. SETTING: State Key Laboratory of Trauma, Burns and Combined Injury. SUBJECTS: Sprague-Dawley rats. INTERVENTIONS: Using cecal ligation and puncture-induced septic shock rats, lipopolysaccharide-treated vascular smooth muscle cells, and cardiomyocytes, effects of 4-phenylbutyric acid on vital organ function and the relationship with endoplasmic reticulum stress and endoplasmic reticulum stress-mediated inflammation, apoptosis, and oxidative stress were observed. MEASUREMENTS AND MAIN RESULTS: Conventional treatment, including fluid resuscitation, vasopressin, and antibiotic, only slightly improved the hemodynamic variable, such as mean arterial blood pressure and cardiac output, and slightly improved the vital organ function and the animal survival of septic shock rats. Supplementation of 4-phenylbutyric acid (5 mg/kg; anti-endoplasmic reticulum stress), especially administered at early stage, significantly improved the hemodynamic variables, vital organ function, such as liver, renal, and intestinal barrier function, and animal survival in septic shock rats. 4-Phenylbutyric acid application inhibited the endoplasmic reticulum stress and endoplasmic reticulum stress-related proteins, such as CCAAT/enhancer-binding protein homologous protein in vital organs, such as heart and superior mesenteric artery after severe sepsis. Further studies showed that 4-phenylbutyric acid inhibited endoplasmic reticulum stress-mediated cytokine release, apoptosis, and oxidative stress via inhibition of nuclear factor-κB, caspase-3 and caspase-9, and increasing glutathione peroxidase and superoxide dismutase expression, respectively. CONCLUSIONS: Anti-endoplasmic reticulum stress with 4-phenylbutyric acid is beneficial to septic shock. This beneficial effect of 4-phenylbutyric acid is closely related to the inhibition of endoplasmic reticulum stress-mediated oxidative stress, apoptosis, and cytokine release. This finding provides a potential therapeutic measure for clinical critical conditions, such as severe sepsis.

Diabetes and hyperlipidemia induce dysfunction of VSMCs: contribution of the metabolic inflammation/miRNA pathway.

Vascular endothelial cell injury is considered to be the major factor inducing vascular complications in metabolic diseases and plays an important role in other organ damage. With diabetic and hyperlipidemic rats and cultured VSMCs, the present study was aimed at investigating whether the early damage of VSMCs during metabolic diseases plays a critical role in vascular dysfunction and the underlying mechanisms and would be a promising treatment target. With diabetic and hyperlipidemic rats and cultured VSMCs, the changes and relationships of vascular relaxation and contractile function to the vital organ damage and the underlying mechanisms were investigated; meanwhile, the protective and preventive effects of lowering blood lipid and glucose and inhibition of diabetes and hyperlipidemia-induced vascular hyperreactivity were observed. Diabetic and hyperlipidemic rats presented hyperreactivity in vascular contractile response in the early stages. Hyperglycemia and hyperlipidemia directly affected the contractile function of VSMCs. Early application of fasudil, a specific antagonist of Rho kinase, significantly alleviated diabetes and hyperlipidemia-induced organ damage by inhibiting vascular hyperreactivity. Diabetes and hyperlipidemia-induced inflammatory response could upregulate the expression of connexins and Rho kinase by selective downregulation of the expression of miR-10a, miR-139b, miR-206, and miR-222. These findings suggest that hyperglucose and lipid may directly impair VSMCs and induce vascular hyperreactivity in the early stages. Metabolic inflammation-induced changes in the miRNA-connexin/Rho kinase regulatory pathway are the main mechanism for vascular hyperreactivity and organ damage. Measures inhibiting vascular hyperreactivity are promising for the prevention of organ damage induced by metabolic diseases.

Identification of ideal resuscitation pressure with concurrent traumatic brain injury in a rat model of hemorrhagic shock.

BACKGROUND: Traumatic brain injury (TBI) is often associated with uncontrolled hemorrhagic shock (UHS), which contributes significantly to the mortality of severe trauma. Studies have demonstrated that permissive hypotension resuscitation improves the survival for uncontrolled hemorrhage. What the ideal target mean arterial pressure (MAP) is for TBI with UHS remains unclear. METHODS: With the rat model of TBI in combination with UHS, we investigated the effects of a series of target resuscitation pressures (MAP from 50-90 mm Hg) on animal survival, brain perfusion, and organ function before hemorrhage controlled. RESULTS: Rats in 50-, 60-, and 70-mm Hg target MAP groups had less blood loss and less fluid requirement, a better vital organ including mitochondrial function and better cerebral blood flow, and animal survival (8, 6, and 7 of 10, respectively) than 80- and 90-mm Hg groups. The 70-mm Hg group had a better cerebral blood flow and cerebral mitochondrial function than in 50- and 60-mm Hg groups. In contrast, 80- and 90-mm Hg groups resulted in an excessive hemodilution, a decreased blood flow, an increased brain water content, and more severe cerebral edema. CONCLUSIONS: A 50-mm Hg target MAP is not suitable for the resuscitation of TBI combined with UHS. A 70 mm Hg of MAP is the ideal target resuscitation pressure for this trauma, which can keep sufficient perfusion to the brain and keep good organ function including cerebral mitochondrial function.

DNA synthesis during endomitosis is stimulated by insulin via the PI3K/Akt and TOR signaling pathways in the silk gland cells of Bombyx mori.

Silk gland cells undergo multiple endomitotic cell cycles during silkworm larval ontogeny. Our previous study demonstrated that feeding is required for continued endomitosis in the silk gland cells of silkworm larvae. Furthermore, the insulin signaling pathway is closely related to nutritional signals. To investigate whether the insulin signaling pathway is involved in endomitosis in silk gland cells, in this study, we initially analyzed the effects of bovine insulin on DNA synthesis in endomitotic silk gland cells using 5-bromo-2'-deoxyuridine (BrdU) labeling technology, and found that bovine insulin can stimulate DNA synthesis. Insulin signal transduction is mainly mediated via phosphoinositide 3-kinase (PI3K)/Akt, the target of rapamycin (TOR) and the extracellular signal-regulated kinase (ERK) pathways in vertebrates. We ascertained that these three pathways are involved in DNA synthesis in endomitotic silk gland cells using specific inhibitors against each pathway. Moreover, we investigated whether these three pathways are involved in insulin-stimulated DNA synthesis in endomitotic silk gland cells, and found that the PI3K/Akt and TOR pathways, but not the ERK pathway, are involved in this process. These results provide an important theoretical foundation for the further investigations of the mechanism underlying efficient endomitosis in silk gland cells.

One-tube B7-H3 detection based on isothermal exponential amplification and dendritic hybridization chain reaction.

We have developed a one-tube fluorescence strategy for the detection of B7-H3 based on a proximity hybridization-mediated protein-to-DNA signal transducer, isothermal exponential amplification (EXPAR), and dendritic hybridization chain reaction (D-HCR). In this assay, a protein signal transducer was employed to convert the input protein to output single-stranded DNA with a nicking site. Antibody-conjugated DNA1 was first hybridized with the output DNA (DNA3). The binding of antibodies conjugated DNA1 and DNA2 to the same protein was able to increase the local concentrations, resulting in strand displacement between DNA3 and DNA2. DNA3 with a nicking endonuclease recognition sequence at the 5' end then hybridized with hairpin probe 1 to mediate EXPAR in the presence of nicking endonuclease and DNA polymerase. A large number of single-strand DNA were produced in the circle of nicking, polymerization, and strand displacement. The resulting ssDNA products were further amplified by D-HCR to produce many large-molecular concatemers. The resulting DNA products can be monitored in real-time fluorescence signaling. Our proposed assay can realize one-tube detection due to the same reaction temperature of the protein-to-DNA signal transducer, EXPAR, and DHCR. This assay has a linear range from 100 fg mL-1 to 1 µg mL-1 with a detection limit down to 100 fg mL-1. This work shows a good performance in clinical specimen detection.

Cofilin aggregation blocks intracellular trafficking and induces synaptic loss in hippocampal neurons.

Cofilin is an actin-binding protein and a major actin depolymerization factor in the central nervous system (CNS). Cofilin-actin aggregates are associated with neurodegenerative disorders, but how cofilin-actin aggregation induces pathological effects in the CNS remains unclear. Here, we demonstrated that cofilin rods disrupted dendritic microtubule integrity in rat hippocampal cultures. Long term time-lapse imaging revealed that cofilin rods block intracellular trafficking of both mitochondria and early endosomes. Importantly, cofilin rod formation induced a significant loss of SV2 and PSD-95 puncta as well as dendritic spines. Cofilin rods also impaired local glutamate receptor responses. We discovered an inverse relationship between the number of synaptic events and the accumulation of cofilin rods in dendrites. We also detected cofilin rods in aging rat brains in vivo. These results suggest that cofilin aggregation may contribute to neurodegeneration and brain aging by blocking intracellular trafficking and inducing synaptic loss.

Anticancer peptidylarginine deiminase (PAD) inhibitors regulate the autophagy flux and the mammalian target of rapamycin complex 1 activity.

Tumor suppressor genes are frequently silenced in cancer cells by enzymes catalyzing epigenetic histone modifications. The peptidylarginine deiminase family member PAD4 (also called PADI4) is markedly overexpressed in a majority of human cancers, suggesting that PAD4 is a putative target for cancer treatment. Here, we have generated novel PAD inhibitors with low micromolar IC(50) in PAD activity and cancer cell growth inhibition. The lead compound YW3-56 alters the expression of genes controlling the cell cycle and cell death, including SESN2 that encodes an upstream inhibitor of the mammalian target of rapamycin complex 1 (mTORC1) signaling pathway. Guided by the gene expression profile analyses with YW3-56, we found that PAD4 functions as a corepressor of p53 to regulate SESN2 expression by histone citrullination in cancer cells. Consistent with the mTORC1 inhibition by SESN2, the phosphorylation of its substrates including p70S6 kinase (p70S6K) and 4E-BP1 was decreased. Furthermore, macroautophagy is perturbed after YW3-56 treatment in cancer cells. In a mouse xenograft model, YW3-56 demonstrates cancer growth inhibition activity with little if any detectable adverse effect to vital organs, whereas a combination of PAD4 and histone deacetylase inhibitors further decreases tumor growth. Taken together, our work found that PAD4 regulates the mTORC1 signaling pathway and that PAD inhibitors are potential anticancer reagents that activate tumor suppressor gene expression alone or in combination with histone deacetylase inhibitors.

Expression and Clinical Significance of HIF-1α in Follicular Fluid and Granulosa Cells in Infertile PCOS Patients.

The present study aimed to determine the clinical predictive significance of HIF-1α in follicular development and assisted reproductive technology (ART). We collected follicular fluid (FF) and granulosa cells (GCs) from PCOS (polycystic ovary syndrome) patients (experimental group) and other patients who were infertile due to tubal factors or male factors (control group) with IVF/ICSI-ET. The localization and expression of HIF-1α in GCs were determined by immunofluorescence staining. HIF-1α protein and mRNA expression were detected by enzyme-linked immunosorbent assay and quantitative real-time PCR, respectively. To clarify the regulation of HIF-1α by TGF-ß1, we added the HIF-1α-specific blocker YC-1 to GCs. The serum AMH, LH, LH/FSH, testosterone, BMI and the number of oocytes retrieved in the PCOS group were significantly higher, while the cleavage rate was significantly lower, than those in the control group. HIF-1α protein was expressed in the cytoplasm of GCs. The expression of HIF-1α protein in the FF of the PCOS group was significantly lower than that in the control group. However, the expression of HIF-1α protein in GCs between the two groups was not significantly different. HIF-1α protein was highly expressed in large FF (follicular diameter ≥ 14 mm). Compared with the control group, the expression of HIF-1α mRNA in GCs of the PCOS group was significantly lower. The results showed a significant positive correlation between HIF-1α and TGF-ß1 expression. We found that both HIF-1α and TGF-ß1 were involved in the development of PCOS follicular development. The mutual regulation of HIF-1α and TGF-ß1 may be one of the important mechanisms of the occurrence and development of PCOS.

Comparisons of Two-dimensional Echocardiographic Aortic Dimensions between Chinese, Japanese, and Europeans.

PURPOSE: We aimed to investigate the impacts of age, gender, and race on aortic dimensions in healthy adults. METHODS: We analyzed data from 3 large population-based sample studies, including Chinese Echocardiographic Measurements in Normal Chinese Adults, Japanese the Normal Values for Echocardiographic Measurements Project, and European Normal Reference Ranges for Echocardiography, to compare the two-dimensional echocardiography-derived aortic diameters at different levels and to explore the effects of age, gender, and race on aortic measurements. We also compared the values corrected by body surface area (BSA) or height. RESULTS: The results are as follows: (1) Aortic diameters showed positive correlations with age (r=0.12-0.42, P<0.05), and there were significant inter-age group differences before and after indexing to BSA (P<0.05); (2) Men had greater measurements of aortic diameters than women, with the differences being the same when indexed to height. However, indexing to BSA reversed the differences; (3) The aortic diameters at annulus (Ao-a) and sinus (Ao-s) levels were very close with minor differences between the Chinese and Japanese regardless of whether BSA was used for correction; and (4) The aortic measurements at Ao-s and proximal ascending aorta (Ao-asc) levels in the Chinese were significantly lower than in the Europeans for both genders, with the differences remaining the same even after indexing to BSA or height (P<0.05). CONCLUSION: Aortic dimensions vary with age and gender, and there are significant differences between races or ethnicities even when stratified by gender and age. The indexation by BSA or height cannot eliminate these differences. Therefore, age-specific, gender-specific, race-specific, and nationality-specific reference values may be more appropriate at present for clinical practice to avoid misdiagnosis and misclassification of aortic dilation.

Case report: Different clinical manifestations of the rare Loeffler endocarditis.

Background: Loeffler endocarditis is a rare and fatal disease, which is prone to be misdiagnosed, owing to its various clinical manifestations. Consequently, an early identification of Loeffler endocarditis and its effective treatment are crucial steps to be undertaken for good prognosis. Case presentation: This report describes two cases of Loeffler endocarditis with different etiologies and clinical manifestations. Case 1 was caused by idiopathic eosinophilia and presented with a thrombus involving the tricuspid valve and right ventricular inflow tract (RVIT). The patient suffered from recurrent syncope following activity. After the patient underwent tricuspid valve replacement and thrombectomy, he took oral prednisone and warfarin for 2 years, consequent to which he discontinued both drugs. However, the disease recurred 6 months later, this time manifesting as edema of both legs. Echocardiography showed that a thrombus had reappeared in the RVIT. Thus, oral prednisone and warfarin therapy was readministered. Three months later, the thrombus had dissolved. Low-dose prednisone maintenance therapy was provided long term. Case 2 involved a patient who presented with recurrent fever, tightness in the chest, and asthma, and whose condition could not be confirmed, despite multiple local hospitalizations. In our hospital, echocardiography revealed biventricular apical thrombi. After comprehensive examinations, the final diagnosis was eosinophilic granulomatosis polyangiitis (EGPA) involving multiple organs, including the heart (Loeffler endocarditis), lungs, and kidneys. After administration of corticosteroid, anticoagulant, and immunosuppressive agents along with drugs to improve cardiac function, the patient's symptoms improved significantly. Conclusion: In Loeffler endocarditis due to idiopathic eosinophilia, long-term corticosteroid use may be required. Diverse and non-specific symptoms cause Loeffler endocarditis to be easily misdiagnosed. So, when a patient shows a persistent elevation of the eosinophil count with non-specific myocardial damage, the possibility of this disease, should always be considered. Furthermore, even when an invasive clinical procedure such as endomyocardial biopsy (EMB) is not available or acceptable, corticosteroids should be administered promptly to bring the eosinophil count back to the normal range, thereby halting the progression of disease and reducing patient mortality.

[Relationship between spinal ventricular septal angle by computer tomographic pulmonary angiography and right cardiac functions, N-terminal brain natriuretic peptide in chronic thromboembolic pulmonary hypertension].

OBJECTIVE: To explore the relationship of spinal ventricular septal angle (SVSA) measured by computer tomographic pulmonary angiography (CTPA) and right cardiac functions, N-terminal brain natriuretic peptide (NT-proBNP) in the patients with chronic thromboembolic pulmonary hypertension (CTEPH). METHODS: Forty-four CTEPH patients, 26 males and 18 females aged (52 ± 12) years old on average, at our hospital from January 2008 to January 2010 were retrospectively reviewed. SVSA and such pulmonary artery obstruction indices as Qanadli and Mastora indices were evaluated by two independent radiologists. The parameters of right heart functions were evaluated by echocardiography and right-heart catheterization. The level of NT-proBNP was measured by enzyme linked immunosorbent assay (ELISA). RESULTS: SVSA was (63 ± 11)° in CTEPH and (40 ± 7)° in the control group. The differences were significant (t = 12.320, P = 0.000). SVSA had a moderately positive correlation with the level of NT-proBNP (r = 0.704, P = 0.000). A positive correlation existed between SVSA and right atrium transverse diameter (r = 0.381, P = 0.002), right atrium long axis diameter (r = 0.437, P = 0.000) and right ventricular transverse diameter (r = 0.449, P = 0.000) on echocardiography. But there was no correlation between SVSA and right ventricular ejection fraction (r = -0.175, P = 0.365, n = 24). Also there was a negative correlation between SVSA and cardiac output (r = -0.337, P = 0.025), cardiac index (r = -0.351, P = 0.020), right cardiac work (r = -0.307, P = 0.043) and right ventricular stroke work (r = -0.384, P = 0.010). CONCLUSION: Spinal ventricular septal angle measured on CTPA may serve as a better predictor for evaluating the level of NT-proBNP and right cardiac functions in CTEPH.

Host metabolic shift during systemic Salmonella infection revealed by comparative proteomics.

Salmonella enterica serovar Typhimurium (S. Typhimurium) is a food-borne bacterium that causes acute gastroenteritis in humans and typhoid fever in mice. Salmonella pathogenicity island II (SPI-2) is an important virulence gene cluster responsible for Salmonella survival and replication within host cells, leading to systemic infection. Previous studies have suggested that SPI-2 function to modulate host vesicle trafficking and immune response to promote systemic infection. However, the molecular mechanism and the host responses triggered by SPI-2 remain largely unknown. To assess the roles of SPI-2, we used a differential proteomic approach to analyse host proteins levels during systemic infections in mice. Our results showed that infection by WT S. Typhimurium triggered the reprogramming of host cell metabolism and inflammatory response. Salmonella systemic infection induces an up-regulation of glycolytic process and a repression of the tricarboxylic acid (TCA) cycle. WT-infected tissues prefer to produce adenosine 5'-triphosphate (ATP) through aerobic glycolysis rather than relying on oxidative phosphorylation to generate energy. Moreover, our data also revealed that infected macrophages may undergo both M1 and M2 polarization. In addition, our results further suggest that SPI-2 is involved in altering actin cytoskeleton to facilitate the Salmonella-containing vacuole (SCV) biogenesis and perhaps even the release of bacteria later in the infection process. Results from our study provide valuable insights into the roles of SPI-2 during systemic Salmonella infection and will guide future studies to dissect the molecular mechanisms of how SPI-2 functions in vivo.

α-Lipoic Acid Targeting PDK1/NRF2 Axis Contributes to the Apoptosis Effect of Lung Cancer Cells.

As an antioxidant, α-lipoic acid (LA) has attracted much attention to cancer research. However, the exact mechanism of LA in cancer progression control and prevention remains to be unclear. In this study, we demonstrated that α-lipoic acid has inhibitory effects on the proliferation, migration, and proapoptotic effects of non-small-cell lung cancer (NSCLC) cell lines A549 and PC9. LA-induced NSCLC cell apoptosis was mediated by elevated mitochondrial reactive oxygen species (ROS). Further study confirmed that it is by downregulating the expression of PDK1 (the PDH kinase), resulted in less phospho-PDH phenotype which could interact with Keap1, the negative controller of NRF2, directly leading to NRF2 decrease. Thus, by downregulating the NRF2 antioxidant system, LA plays a role in promoting apoptosis through the ROS signaling pathway. Moreover, LA could enhance other PDK inhibitors with the proapoptosis effect. In summary, our study shows that LA promotes apoptosis and exerts its antitumor activity against lung cancer by regulating mitochondrial energy metabolism enzyme-related antioxidative stress system. Administration of LA to the tumor-bearing animal model further supported the antitumor effect of LA. These findings provided new ideas for the clinical application of LA in the field of cancer therapy.

Melatonin enhances radiofrequency-induced NK antitumor immunity, causing cancer metabolism reprogramming and inhibition of multiple pulmonary tumor development.

Surgery is the common treatment for early lung cancer with multiple pulmonary nodules, but it is often accompanied by the problem of significant malignancy of other nodules in non-therapeutic areas. In this study, we found that a combined treatment of local radiofrequency ablation (RFA) and melatonin (MLT) greatly improved clinical outcomes for early lung cancer patients with multiple pulmonary nodules by minimizing lung function injury and reducing the probability of malignant transformation or enlargement of nodules in non-ablated areas. Mechanically, as demonstrated in an associated mouse lung tumor model, RFA not only effectively remove treated tumors but also stimulate antitumor immunity, which could inhibit tumor growth in non-ablated areas. MLT enhanced RFA-stimulated NK activity and exerted synergistic antitumor effects with RFA. Transcriptomics and proteomics analyses of residual tumor tissues revealed enhanced oxidative phosphorylation and reduced acidification as well as hypoxia in the tumor microenvironment, which suggests reprogrammed tumor metabolism after combined treatment with RFA and MLT. Analysis of residual tumor further revealed the depressed activity of MAPK, NF-kappa B, Wnt, and Hedgehog pathways and upregulated P53 pathway in tumors, which was in line with the inhibited tumor growth. Combined RFA and MLT treatment also reversed the Warburg effect and decreased tumor malignancy. These findings thus demonstrated that combined treatment of RFA and MLT effectively inhibited the malignancy of non-ablated nodules and provided an innovative non-invasive strategy for treating early lung tumors with multiple pulmonary nodules. Trial registration: www.chictr.org.cn , identifier ChiCTR2100042695, http://www.chictr.org.cn/showproj.aspx?proj=120931 .