CircPVT1 promotes ER-positive breast tumorigenesis and drug resistance by targeting ESR1 and MAVS.

The molecular mechanisms underlying estrogen receptor (ER)-positive breast carcinogenesis and endocrine therapy resistance remain incompletely understood. Here, we report that circPVT1, a circular RNA generated from the lncRNA PVT1, is highly expressed in ERα-positive breast cancer cell lines and tumor samples and is functionally important in promoting ERα-positive breast tumorigenesis and endocrine therapy resistance. CircPVT1 acts as a competing endogenous RNA (ceRNA) to sponge miR-181a-2-3p, promoting the expression of ESR1 and downstream ERα-target genes and breast cancer cell growth. Furthermore, circPVT1 directly interacts with MAVS protein to disrupt the RIGI-MAVS complex formation, inhibiting type I interferon (IFN) signaling pathway and anti-tumor immunity. Anti-sense oligonucleotide (ASO)-targeting circPVT1 inhibits ERα-positive breast cancer cell and tumor growth, re-sensitizing tamoxifen-resistant ERα-positive breast cancer cells to tamoxifen treatment. Taken together, our data demonstrated that circPVT1 can work through both ceRNA and protein scaffolding mechanisms to promote cancer. Thus, circPVT1 may serve as a diagnostic biomarker and therapeutic target for ERα-positive breast cancer in the clinic.

Dual electronic effects achieving a high-performance Ni(II) pincer catalyst for CO2 photoreduction in a noble-metal-free system.

A carbazolide-bis(NHC) NiII catalyst (1; NHC, N-heterocyclic carbene) for selective CO2 photoreduction was designed herein by a one-stone-two-birds strategy. The extended π-conjugation and the strong σ/π electron-donation characteristics (two birds) of the carbazolide fragment (one stone) lead to significantly enhanced activity for photoreduction of CO2 to CO. The turnover number (TON) and turnover frequency (TOF) of 1 were ninefold and eightfold higher than those of the reported pyridinol-bis(NHC) NiII complex at the same catalyst concentration using an identical Ir photosensitizer, respectively, with a selectivity of ∼100%. More importantly, an organic dye was applied to displace the Ir photosensitizer to develop a noble-metal-free photocatalytic system, which maintained excellent performance and obtained an outstanding quantum yield of 11.2%. Detailed investigations combining experimental and computational studies revealed the catalytic mechanism, which highlights the potential of the one-stone-two-birds effect.

Expression and prognostic value of APOBEC2 in gastric adenocarcinoma and its association with tumor-infiltrating immune cells.

BACKGROUND: Apolipoprotein B mRNA editing enzyme catalytic polypeptide-like 2 (APOBEC2) is associated with nucleotide alterations in the transcripts of tumor-related genes which are contributed to carcinogenesis. Expression and prognosis value of APOBEC2 in stomach adenocarcinoma (STAD) remains unclear. METHODS: The APOBEC2 gene alteration frequency of STAD and APOBEC2 gene expression in STAD and normal tissues were investigated in cBioportal and GEPIA, respectively. We detected expression of APOBEC2, infiltration of CD66b+ tumor-associated neutrophils and CD163+ tumor-associated macrophages in tissue microarrays by immunohistochemistry. APOBEC2 gene expression was explored by western blot and qRT-PCR. Relationships between APOBEC2 and CD66b, CD163, and other clinicopathological characteristics were investigated. Associations among APOBEC2 expression status and patient survival outcome were further analyzed. RESULTS: APOBEC2 gene alteration frequency was 5%, and APOBEC2 gene was downexpressed in STAD compared to normal tissues (P < 0.05). APOBEC2 expression status were associated with the infiltration of CD66b+ TANs, differentiation grade, TNM stage, histological type and gender (all P < 0.05) in STAD. Little or no APOBEC2 expression was detected in STAD and adjacent normal tissues by western blot. We failed to show that APOBEC2 was an independent risk factor for OS (Hazard Ratio 0.816, 95%CI 0.574-1.161, P = 0.259) or DFS (Hazard Ratio 0.821, 95%CI 0.578-1.166, P = 0.270) in STAD by multivariate Cox regression analysis, but APOBEC2 negative subgroup has a worse OS and DFS among patients with adjuvant chemotherapy. CONCLUSIONS: APOBEC2 correlates with CD66b, differentiation grade, TNM stages, histological classification, and gender in STAD. APOBEC2 is not an independent prognostic factor for STAD, our results suggest that patients with positive APOBEC2 can benefit from postoperative chemotherapy, and combination of APOBEC2 and CD66b is helpful to further stratify patients into different groups with distinct prognoses.

Electronic Effect Promoted Visible-Light-Driven CO2-to-CO Conversion in a Water-Containing System.

The design of unsaturated nonprecious metal complexes with high catalytic performance for photochemical CO2 reduction is still an important challenge. In this paper, four coordinatively unsaturated Co-salen complexes 1-4 were explored in situ using o-phenylenediamine derivatives and 5-methylsalicylaldehyde as precursors of the ligands in 1-4. It was found that complex 4, bearing a nitro substituent (-NO2) on the aromatic ring of the salen ligand, exhibits the highest photochemical performance for visible-light-driven CO2-to-CO conversion in a water-containing system, with TONCO and CO selectivity values of 5300 and 96%, respectively. DFT calculations and experimental results revealed that the promoted photocatalytic activity of 4 is ascribed to the electron-withdrawing effect of the nitro group in 4 compared to 1-3 (with -CH3, -F, and -H groups, respectively), resulting in a lower reduction potential of active metal centers CoII and lower barriers for CO2 coordination and C-O cleavage steps for 4 than those for catalysts 1-3.

Intestinal obstruction caused by mesodiverticular band in children: a cohort study.

OBJECTIVE: To explore clinical characteristics, pathogenesis, diagnosis and treatment of intestinal obstruction due to mesodiverticular band (MDB) in children in a single center in China. METHODS: The clinical data of 20 children with acute intestinal obstruction due to MDB between 1998 and 2020 were retrospectively analyzed. RESULTS: The male-to-female ratio was 14:6 in 20 cases. Except one case of 7-month pregnant stillbirth, the cases were aged from 7 days to 14 years, at the median age of 4.31 years. The common symptoms were vomiting, abdominal pain and/or abdominal distension. About 40% (8/20) of patients had both MDB and Meckel's Diverticulum (MD), while 60% (12/20) of patients had MDB only. Only one case died because of total colonic aganglionosis, while other children recovered after surgery treatment. MDB led to the strangulation of necrotic bowel in six cases, intestinal perforation in one case, and intestinal rupture in one case. Pathologic examination showed thick-walled arteries and or thick venous vascular structures in the cord. All cases had no complications during 1-year follow-up. CONCLUSION: MDB results from the remnant of vitelline vessel, and often causes acute intestinal obstruction without special clinical symptoms. Unexplained abdominal pain and distension without surgery history should be paid attention, especially for strangulated intestinal obstruction. Timely surgical exploration is beneficial to avoid intestinal necrosis or even sudden death, and the pathological examination is important for the diagnosis.

Distribution of type VI secretion system (T6SS) in clinical Klebsiella pneumoniae strains from a Chinese hospital and its potential relationship with virulence and drug resistance.

OBJECTIVES: The type VI secretion system (T6SS) in Klebsiella pneumoniae strains isolated from the bloodstream, intestinal, the pyogenic liver abscess has been reported. Here we aimed to characterize T6SS in 248 Klebsiella pneumoniae isolates with all kinds of specimens from a Chinese hospital and to investigate the potential association of T6SS with virulence and drug resistance. METHODS: T6SS genes, capsular serotyping genes, drug resistance genes, and virulence genes were identified by polymerase chain reaction (PCR). Antibiotic susceptibilities were examined by the disk diffusion method. To assess biofilm formation of these clinical Klebsiella pneumoniae isolates, 96-well microtiter plate assays were performed. MLST was used to analyze the genotypes of these Klebsiella pneumoniae isolates. RESULTS: The frequency of T6SS genes among the clinical Klebsiella pneumoniae isolates was 72.2%. The T6SS-positive isolates displayed higher resistance to piperacillin-tazobactam, ciprofloxacin, levofloxacin, meropenem than the T6SS-negative isolates (P < 0.05). The T6SS-positive isolates formed significantly more biofilm mass than the T6SS-negative isolates (mean ± standard deviation [SD], 0.3 ± 0.09 vs.0.16 ± 0.06; P < 0.01). Compared to the T6SS-negative isolates, the T6SS-positive isolates had a higher frequency of virulence genes (rmpA, fimH, entB, kfu, ybtS) and the pLVPK-like plasmid (P < 0.05). CONCLUSION: In conclusion, the prevalence of the type VI secretion system is high in clinical Klebsiella pneumoniae isolates in a Chinese teaching hospital. T6SS-positive strains show higher biofilm-forming activity with high drug resistance and exhibit higher virulence potential.

Highly Efficient Visible-Light-Driven CO2-to-CO Conversion by Coordinatively Unsaturated Co-Salen Complexes in a Water-Containing System.

The development of cost-effective catalysts for CO2 reduction is highly desired but remains a significant challenge. The unsaturated coordination metal center in a catalyst is favorable for the process of catalytic CO2 reduction. In this paper, two asymmetric salen ligands were used to synthesize two coordinatively unsaturated Co-salen complexes. The two Co-salen complexes exhibit an unsaturated coordination pattern and display high activity and CO selectivity for visible-light-driven CO2 reduction in a water-containing system. The photocatalytic performance of 2 is higher than that of 1 because the reduction potential of the catalytic CoII center and the energy barrier of the catalytic transition states of 2 are lower than those of 1, with turnover numbers (TONCO), turnover frequencies (TOF), and CO selectivity values of 8640, 0.24 s-1, and 97% for 2, respectively. The photocatalytic reduction of CO2 to CO for 2 is well supported by control experiments and density functional theory (DFT) calculations.

A giant enhancement in the up-conversion luminescence and high temperature sensitivity of Bi3+ doped ZnMoO4:Er3+ up-conversion phosphor.

Luminescence intensity is a critical factor for upconversion (UC) oxides with high phonon energy. Herein, an effective enhancement in UC luminescence is achieved in the ZnMoO4:Er3+ phosphor via Bi3+ doping. UV-vis-NIR diffuse reflectance spectroscopy verifies the fact that the absorption at 980 nm is enhanced by the introduction of Bi3+. The physical mechanism is that Bi3+ doping affects the transition probability between the f-levels of Er3+. Therefore, the green and red emission intensities are increased 82.4 and 37 times, respectively. The dependence of luminescence intensity on the power of Bi3+-doped ZnMoO4:Er3+ combined with density functional theory (DFT) calculations also confirms the proposed energy transfer mechanism. Based on the excellent green emission, the 980 nm excited optical temperature sensing property of the synthesized sample is realized in a wide temperature range by monitoring the intensity of UC luminescence. The theoretically calculated absolute sensitivity of the optical temperature sensor was SA = 3.04% K-1 at 1253 K. This work paves a new way for enhancing UC luminescence and will arouse extensive interest in noncontact temperature-sensing applications.

Enhanced Hydrogen Evolution Reactivity of T'-Phase Tungsten Dichalcogenides (WS2, WSe2, and WTe2) Materials: A DFT Study.

The hydrogen evolution reaction (HER) plays a crucial role in hydrogen gas production. Layers of transition-metal dichalcogenides (TMDs) possess adjustable electronic structures, and TMDs with H-phase structures have been proposed as substitute HER catalysts. Nonetheless, there are few systematic theoretical analyses of the HER catalytic properties of TMDs with T'-phase structures. Using a DFT calculation, we investigated the electrocatalytic properties of W-based dichalcogenides (WS2, WSe2, and WTe2) through defect engineering. It was found that the interaction of H atoms with the basal plane can be tuned using non-metallic atomic doping, especially with P, thereby enhancing catalytic activity. Furthermore, the computation results demonstrated that high P-doping concentrations can enhance the number of active sites and exhibit a suitable ΔGH*.

Sleep Quality Improvement Enhances Neuropsychological Recovery and Reduces Blood Aß42/40 Ratio in Patients with Mild-Moderate Cognitive Impairment.

Background and objectives: Alzheimer's disease is a progressive brain degeneration and is associated with a high prevalence of sleep disorders. Amyloid ß peptide-42/40 (Aß42/40) and Tau-pT181 are the core biomarkers in cerebrospinal fluid and blood. Accumulated data from studies in mouse models and humans demonstrated an aberrant elevation of these biomarkers due to sleep disturbance, especially sleep-disordered breathing (SDB). However, it is not clear if sleep quality improvement reduces the blood levels of Ab42/40 ratio and Tau-pT181 in Alzheimer's disease patients. Materials and Methods: In this prospective study, a longitudinal analysis was conducted on 64 patients with mild-moderate cognition impairment (MCI) due to Alzheimer's disease accompanied by SDB. Another 33 MCI cases without sleep-disordered breathing were included as the control group. Sleep quality was assessed using the Pittsburgh Sleep Quality Index (PSQI) score system. Neuropsychological assessments were conducted using the Montreal Cognitive Assessment (MoCA), Geriatric Depression Scale (GDS), Clinical Dementia Rating (CDR), 24-h Hamilton Rating Scale for Depression (HRSD-24), and Hamilton Anxiety Rating Scale (HAMA) scoring systems. Aß42, Aß40, and Tau-pT181 protein levels in blood specimens were measured using ELISA assays. All patients received donepezil treatment for Alzheimer's disease. SDB was managed with continuous pressure ventilation. Results: A significant correlation was found among PSQI, HRSD-24, HAMA, Aß42/40 ratio, and Tau-pT181 level in all cases. In addition, a very strong and negative correlation was discovered between education level and dementia onset age. Compared to patients without SDB (33 non-SD cases), patients with SDB (64 SD cases) showed a significantly lower HRSD-24 score and a higher Aß42/40 ratio Tau-pT181 level. Sleep treatment for patients with SDB significantly improved all neuropsychological scores, Aß42/40 ratio, and Tau-pT181 levels. However, 11 patients did not completely recover from a sleep disorder (PSQI > 5 post-treatment). In this subgroup of patients, although HAMA score and Tau-pT181 levels were significantly reduced, MoCA and HRSD-24 scores, as well as Aß42/40 ratio, were not significantly improved. ROC analysis found that the blood Aß42/40 ratio held the highest significance in predicting sleep disorder occurrence. Conclusions: This is the first clinical study on sleep quality improvement in Alzheimer's disease patients. Sleep quality score was associated with patient depression and anxiety scores, as well as Aß42/40 ratio and Tau-pT181 levels. A complete recovery is critical for fully improving all neuropsychological assessments, Aß42/40 ratio, and Tau-pT181 levels. Blood Aß42/40 ratio is a feasible prognostic factor for predicting sleep quality.

M2 macrophage-derived exosomal miR-25-3p improves high glucose-induced podocytes injury through activation autophagy via inhibiting DUSP1 expression.

Diabetic nephropathy (DN) is the primary reason of chronic kidney disease. The aim of our study is to explore the role and action mechanism of M2 macrophage-derived exosomes in high glucose (HG)-induced podocytes injury. Here, 30 mmol/L of HG was used to induce podocytes injury. Annexin V-FITC/PI double staining was performed to measure podocytes apoptosis, and western blot was carried out to ensure proteins expression. The shape of exosomes was identified using TEM. Besides, the expression of miR-25-3p was determined by qRT-PCR, FAM-labeled miR-25-5p combined with DiI-labeled exosomes were utilized to explore the uptake of podocytes to exosomes. Relationship between miR-25-3p and DUSP family members was ensued by luciferase activity assay. In the beginning, we found that M2 macrophage ameliorated HG-induced podocytes apoptosis and epithelial-mesenchymal transition through secreting exosomes. Subsequently, highly expressed miR-25-3p was found in M2 macrophage-derived exosomes that effectively improved HG-induced podocytes injury. Furthermore, inhibition of miR-25-3p in M2 macrophage inefficiently repressed HG-induced podocytes injury, thus we proposed that M2 macrophage attenuated podocytes injury through secreting exosomal miR-25-3p. Then, we used an autophagy inhibitor to stimulate podocytes, and demonstrated that M2 macrophage-derived exosomal miR-25-3p improved HG-induced podocytes injury through activating autophagy. Finally, DUSP1 was proved to be a downstream target and mediated the inhibition of exosomal miR-25-3p to HG-induced podocytes injury. Our results indicated that M2 macrophage could improve HG-induced podocytes injury via secreting exosomal miR-25-3p to activate autophagy of the cells through suppressing DUSP1 expression. We proved a newly potential therapy strategy for DN treatment.

Perineural Invasion is a Better Prognostic Indicator than Lymphovascular Invasion and a Potential Adjuvant Therapy Indicator for pN0M0 Esophageal Squamous Cell Carcinoma.

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) at pN0M0 can be more locally aggressive and disseminated than those with lymph node and distant metastasis. Perineural invasion (PNI) is reported as a poor prognostic factor in cancer and is thought to be related to regional tumor spread and metastasis. However, its clinicopathological role and meaning for treatment in pN0M0 ESCC are unknown. PATIENTS AND METHODS: We applied scoring methods of PNI and lymphatic and vascular invasion (LI, VI) based on immunohistochemistry staining on tumor tissues of pN0M0 ESCC patients. ROC analyses, Kaplan-Meier analyses, Cox regression, and χ2 test were performed for survival analysis, comparison of PNI with LI and VI, and exploration of the relevance between PNI and other clinicopathological features. RESULTS: Presence of PNI was significantly associated with poor survival in pN0M0 patients, whereas LI and VI were not predictive of outcome (P > 0.05). Neural invasion index (NII), defined as the ratio of the number of tumor-invaded nerves to the total number of nerves per tumor microsection, was the most consistent measure of PNI (P = 0.006, HR = 6.892, 1.731-27.428). Postoperative radiotherapy significantly improved survival in high-NII patients (P = 0.035, HR = 0.390, 0.163-0.936). CONCLUSIONS: PNI is an important risk factor for the outcome of pN0M0 ESCC patients. NII can be used for risk assessment and to tailor adjuvant radiotherapy in this population.

The angiotensin-converting enzyme 2/angiotensin (1-7)/mas axis protects against pyroptosis in LPS-induced lung injury by inhibiting NLRP3 activation.

Previous studies have suggested that pyroptosis may play an important role in LPS-induced acute lung injury (ALI), but the exact mechanism of pyroptosis induction and the role of Angiotensin-converting enzyme 2 (ACE2)/Ang (1-7)/Mas axis in pyroptosis has not been investigated yet. The present study aimed to establish a mice model of ALI and clarify the involvement of pyroptosis and ACE2/Ang (1-7)/Mas axis. The results showed that LPS induced pyroptosis in lung, demonstrated by increased expression of Gasdermin D (GSDMD), cleaved GSDMD, IL-1ß, and Caspase-1. Treatment of Ang (1-7) significantly reduced the severity of ALI and pyroptosis, while AngII significantly exaggerated them. Furthermore, ACE2 activator resorcinolnaphthalein (RES) significantly reduced the severity of ALI and pyroptosis, but ACE2 inhibitor MLN-4760 and Mas inhibitor A779 significantly exaggerated them, suggesting that the ACE2/Ang (1-7)/Mas axis was involved in the pyroptosis in LPS-induced ALI. In addition, Ang (1-7) and RES significantly decreased the levels of NLRP3, which were increased by AngII and A779. NLRP3 knockout significantly reduced the severity of ALI and pyroptosis. In conclusion, pyroptosis played an important role in ALI induced by LPS. The ACE2/Ang (1-7)/Mas axis negatively regulated the pyroptosis and protected mice against LPS-induced ALI through NLRP3 inhibition. The present study expanded our understating of the role of ACE2/Ang (1-7)/Mas axis in ALI by providing a novel explanation that it may regulate the pyroptosis in ALI.

Encapsulation of Single Iron Sites in a Metal-Porphyrin Framework for High-Performance Photocatalytic CO2 Reduction.

Efficient CO2 reduction with earth-abundant photocatalysts is a highly attractive but very challenging process for chemists. Herein, we synthesized an indium-porphyrin framework, In(H2TCPP)(1-n)[Fe(TCPP)(H2O)](1-n)[DEA](1-n) (In-FenTCPP-MOF; H2TCPP = tetrakis(4-benzoic acid)porphyrine; DEA = diethylamine), with a porphyrin ring supporting the single-site iron for the high-performance visible-light-driven conversion of CO2 to CO. A high CO yield of 3469 µmol g-1 can be achieved by a 24 h photocatalytic reaction with a high CO selectivity (ca. 99.5%). This activity was much higher than that of its cobalt analogues or the Fe-free indium-based metal-organic framework (MOF). Systematic experimental and theoretical studies indicate that the porphyrin-supported iron centers in the MOF matrix serve as efficient active sites, which can accept electrons from the photoexcited MOFs in order to mediate CO2 reduction.

Microbiological evidences for gastric cardiac microflora dysbiosis inducing the progression of inflammation.

BACKGROUND AND AIM: Nowadays, anti-inflammation treatment is a promising approach for preventing tumorigenesis, and human microflora is closely related to inflammation. This study aimed to investigate the gastric cardiac microbiome and identify inflammation-related microorganisms for gastric cardiac inflammation. METHODS: We performed 16S rRNA sequencing on a total of 11 healthy individuals and 89 individuals with different degree of gastric cardiac inflammation. Immunohistochemistry was used for verifying candidate bacteria. Phylogenetic reconstruction of unobserved states (picrust) was used for predicting the pathways involved by cardiac microflora. RESULTS: The resident phyla in normal were Proteobacteria, Firmicutes, Bacteroides, and Actinobacteria, and the dominant genus in normal were Halomonas, shewanella, and Comamonas. In the progression of gastric cardiac inflammation, the diversity of cardiac microflora did not change (P > 0.05). However, the composition structure of cardiac microflora varied between healthy and inflamed tissues (P < 0.05). Meanwhile, there were 64 species parallel increased with inflammation degree, especially Helicobacter pylori, Lactobacillus spp. Additionally, inflammation-related species were detected (P < 0.05), including H. pylori, Acinetobacter ursingii, and Streptococcus agalactiae. Higher H. pylori colonization was positively related to the progression of cardiac inflammation (γ coefficient = 0.678, P < 0.001), and it also influenced the cardiac microbial community structure. Cardiac microflora also participated in DNA repair pathways and is affected by the relative abundance of H. pylori (P < 0.0001). CONCLUSIONS: Cardiac microflora dysbiosis, especially the increasing of the relevant abundance of H. pylori, promotes the progression of cardiac inflammation.

SHOX CNE9/10 Knockout in U2OS Osteosarcoma Cells and Its Effects on Cell Growth and Apoptosis.

BACKGROUND Osteosarcoma is a common malignant tumor of musculoskeletal stromal cells. Osteosarcoma clinical behavior depends mostly on the histologic grade, the site of primary tumor, the response to chemotherapy, and the presence of pulmonary metastases. The aim of this study was to knockout SHOX CNE9/10 in U2OS osteosarcoma cells and to analyze the effects on cell growth and apoptosis. MATERIAL AND METHODS U2OS cells with CNE9 knockout and U2OS cells with CNE10 knockout were established via the CRISPR/Cas9 system. Sanger sequencing was used to detect the success of the knockdown experiment. Western blotting and quantitative polymerase chain reaction were used to detect the expression levels of short stature homeobox-containing gene (SHOX) protein and messenger RNA (mRNA) after knockdown of CNE9 and CNE10. The cell viability and apoptotic rate were detected by the Cell Counting Kit-8 method and by flow cytometry. RESULTS The Sanger sequencing results showed that the knockdown experiment was successful. The levels of SHOX mRNA and protein were significantly reduced after knocking down CNE9 and CNE10. Knockdown of CNE9 and CNE10 significantly increased the growth and inhibited the apoptosis of U2OS osteosarcoma cells. CNE9/CNE10 knockdown U2OS cells were successfully constructed. CONCLUSIONS Knockdown of CNE9 and CNE10 promoted U2OS cell growth and inhibited apoptosis by decreasing SHOX expression. This CNE9/CNE10 knockout U2OS cell model could provide a bridge for the research on SHOX and CNEs in osteosarcoma.

Angiotensin-converting enzyme 2 regulates autophagy in acute lung injury through AMPK/mTOR signaling.

Autophagy exerts a dual role in promoting cell death or survival. Recent studies have shown that it may play an important role in lipopolysaccharide (LPS)-induced acute lung injury (ALI). It was also suggested that angiotensin converting enzyme 2 (ACE2) may participate in the regulation of autophagy. The present study aims to investigate the role of autophagy in ALI and the involvement of ACE2. The regulation of the APMK/mTOR pathway was explored to clarify the underlying mechanism. The results showed that autophagy played an important role in ALI induced by LPS, as the autophagy inhibitor 3-methyladenine (3-MA) mitigated the severity of ALI. ACE2 activator resorcinolnaphthalein and inhibitor MLN-4760 significantly affected the histological appearance and wet/dry (W/D) ratio of the lung and altered the ACE2 activity of the lung, tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß) levels in bronchoalveolar lavage fluid (BALF) and myeloperoxidase (MPO) levels in lung tissue. Furthermore, LPS, resorcinolnaphthalein and MLN-4760 significantly affected the expression of autophagy proteins Beclin-1, LC3-I and LC3-II. To explore the mechanism of ACE2 on lung autophagy, we measured the phosphorylation of AMPK/mTOR after mice were treated with LPS and resorcinolnaphthalein or MLN-4760. The results revealed that resorcinolnaphthalein and MLN-4760 both significantly altered the phosphorylation of AMPK/mTOR. Finally, we found that AMPK inhibitor (8-bAMP) and mTOR activator (propranolol) both abolished the effects of ACE2 activator (resorcinolnaphthalein) on the expression of lung autophagy proteins Beclin-1, LC3-I and LC3-II. In conclusion, these findings suggest that ACE2 could alleviate the severity of ALI, inflammation and autophagy in lung tissue through the AMPK/mTOR pathway.

MiR-101a ameliorates AngII-mediated hypertensive nephropathy by blockade of TGFß/Smad3 and NF-κB signalling in a mouse model of hypertension.

Hypertensive nephropathy, clinically characterized by progressive renal fibrosis and inflammation, is a severe complication of hypertension. The objectives of this study were to investigate the roles of miR-101a in relieving angiotensin II (Ang II)-mediated hypertensive nephropathy and uncover the possible underlying mechanisms. A hypertensive mouse model was established via continuous 28-day AngII infusion. Systolic blood pressure (SBP), ratio of urine albumin to creatinine, blood urea nitrogen (BUN), serum creatinine (Scr) and glomerular filtration rate (GFR) were evaluated. Dual luciferase reporter assay was used to explore the target of miR-101a. mRNA levels of miR-101a, TGFßRI, fibrotic markers (Collagen I and α-SMA) and pro-inflammatory cytokines (IL-1ß and TNF-α) were determined by real-time PCR. Protein levels of TGFßRI, Collagen I, α-SMA, IL-1ß, TNF-α, t-p65, P-p65, t-Smad3, P-Smad3, t-IκBα and P-IκBα were detected by western blot. MiR-101a mimics significantly improved GFR and inhibited AngII-induced increase in the ratio of urine albumin to creatinine, BUN and Scr. MiR-101a mimics partially abolished AngII-induced increase in the mRNA and protein level of fibrotic markers by targeting TGFßRI and inhibiting TGFß/Smad3 pathway. Moreover, TGFßRI inhibitor galunisertib inhibited AngII-mediated renal injury in mice with hypertensive nephropathy. Additionally, miR-101a overexpression blocked AngII-induced up-regulation of pro-inflammatory markers via suppressing NF-κB pathway. MiR-101a exhibited protective effects against hypertensive nephropathy via inhibiting TGFß/Smad3 and NF-κB signalling pathways.

A Molecular Cobalt Hydrogen Evolution Catalyst Showing High Activity and Outstanding Tolerance to CO and O2.

There is a demand to develop molecular catalysts promoting the hydrogen evolution reaction (HER) with a high catalytic rate and a high tolerance to various inhibitors, such as CO and O2 . Herein we report a cobalt catalyst with a penta-dentate macrocyclic ligand (1-Co), which exhibits a fast catalytic rate (TOF=2210 s-1 ) in aqueous pH 7.0 phosphate buffer solution, in which proton transfer from a dihydrogen phosphate anion (H2 PO4 - ) plays a key role in catalytic enhancement. The electrocatalyst exhibits a high tolerance to inhibitors, displaying over 90 % retention of its activity under either CO or air atmosphere. Its high tolerance to CO is concluded to arise from the kinetically labile character of undesirable CO-bound species due to the geometrical frustration posed by the ligand, which prevents an ideal trigonal bipyramid being established.

Farnesoid X receptor ablation sensitizes mice to hepatitis b virus X protein-induced hepatocarcinogenesis.

Chronic hepatitis B virus infection is a major risk factor for hepatocellular carcinoma (HCC). Hepatitis B virus X protein (HBx) is a hepatitis B virus protein that has multiple cellular functions, but its role in HCC pathogenesis has been controversial. Farnesoid X receptor (FXR) is a nuclear receptor with activities in anti-inflammation and inhibition of hepatocarcinogenesis. However, whether or how FXR can impact hepatitis B virus/HBx-induced hepatocarcinogenesis remains unclear. In this study, we showed that HBx can interact with FXR and function as a coactivator of FXR. Expression of HBx in vivo enhanced FXR-responsive gene regulation. HBx also increased the transcriptional activity of FXR in a luciferase reporter gene assay. The HBx-FXR interaction was confirmed by coimmunoprecipitation and glutathione S-transferase pull-down assays, and the FXR activation function 1 domain was mapped to bind to the third α helix in the C terminus of HBx. We also found that the C-terminally truncated variants of HBx, which were found in clinical HCC, were not effective at transactivating FXR. Interestingly, recruitment of the full-length HBx, but not the C-terminally truncated HBx, enhanced the binding of FXR to its response element. In vivo, FXR ablation markedly sensitized mice to HBx-induced hepatocarcinogenesis. CONCLUSIONS: We propose that transactivation of FXR by full-length HBx may represent a protective mechanism to inhibit HCC and that this inhibition may be compromised upon the appearance of C-terminally truncated HBx or when the expression and/or activity of FXR is decreased. (Hepatology 2017;65:893-906).