A novel compound alleviates oxidative stress via PKA/CREB1-mediated DJ-1 upregulation.

Oxidative stress is one of the major culprits causing dopaminergic neuron loss in Parkinson's disease (PD). DJ-1 is a protein with multiple actions against oxidative stress, apoptosis, neuroinflammation, etc. DJ-1 expression is decreased in sporadic PD, therefore increasing DJ-1 expression might be beneficial in PD treatment. However, drugs known to upregulate DJ-1 are still lacking. In this study, we identified a novel DJ-1-elevating compound called ChemJ through luciferase assay-based high-throughput compound screening in SH-SY5Y cells and confirmed that ChemJ upregulated DJ-1 in SH-SY5Y cell line and primary cortical neurons. DJ-1 upregulation by ChemJ alleviated MPP+-induced oxidative stress. In exploring the underlying mechanisms, we found that the transcription factor CREB1 bound to DJ-1 promoter and positively regulated its expression under both unstressed and 1-methyl-4-phenylpyridinium-induced oxidative stress conditions and that ChemJ promoted DJ-1 expression via activating PKA/CREB1 pathway in SH-SY5Y cells. Our results demonstrated that ChemJ alleviated the MPP+-induced oxidative stress through a PKA/CREB1-mediated regulation of DJ-1 expression, thus offering a novel and promising avenue for PD treatment.

Summary of best evidence for prevention and management of frailty.

BACKGROUND: Frailty in older people can seriously affect their quality of life and increase the demand for long-term care and health care expenses. Aims of this study are to provide an evidence-based basis for clinical practice of frailty in older people by systematically searching for the best current evidence on interventions for the prevention and management of frailty. METHODS: According to the '6S' evidence resource model, evidence retrieval is searched from the top-down and collected relevant guidelines, best practices, evidence summaries, systematic reviews and expert consensus. The retrieval time limit was from the database establishment to 20 March 2023. Two reviewers independently screened and evaluated the literature, and then extracted and summarised the evidence according to the JBI grading of evidence and recommendation system. RESULTS: A total of 44 publications were finally included, including 12 guidelines, 5 best practices, 4 expert consensus, 5 evidence summaries and 18 systematic reviews. Through the induction and integration of the evidence, the evidence was finally summarised from eight aspects: frailty screening, frailty assessment, exercise intervention, nutrition intervention, multi-domain intervention, drug administration, social support and health education, and 43 best evidences were formed. CONCLUSIONS: This study summarised the best evidence for the prevention and management of frailty from eight aspects, which can provide guidance for clinical or community medical staff to develop and apply frailty intervention and practice programmes for older people and improved the clinical outcome and quality of life of older people.

SHOOT MERISTEMLESS participates in the heterophylly of Hygrophila difformis (Acanthaceae).

In heterophyllous plants, leaf shape shows remarkable plasticity in response to environmental conditions. However, transgenic studies of heterophylly are lacking and the molecular mechanism remains unclear. Here, we cloned the KNOTTED1-LIKE HOMEOBOX family gene SHOOT MERISTEMLESS (STM) from the heterophyllous plant Hygrophila difformis (Acanthaceae). We used molecular, morphogenetic, and biochemical tools to explore its functions in heterophylly. HdSTM was detected in different organs of H. difformis, and its expression changed with environmental conditions. Heterologous, ectopic expression of HdSTM in Arabidopsis (Arabidopsis thaliana) increased leaf complexity and CUP-SHAPED COTYLEDON (CUC) transcript levels. However, overexpression of HdSTM in H. difformis did not induce the drastic leaf change in the terrestrial condition. Overexpression of HdSTM in H. difformis induced quick leaf variations in submergence, while knockdown of HdSTM led to disturbed leaf development and weakened heterophylly in H. difformis. HdCUC3 had the same spatiotemporal expression pattern as HdSTM. Biochemical analysis revealed a physical interaction between HdSTM and HdCUC3. Our results provide genetic evidence that HdSTM is involved in regulating heterophylly in H. difformis.

Inhibition of ACSS2 attenuates alcoholic liver steatosis via epigenetically regulating de novo lipogenesis.

BACKGROUND AND AIMS: Steatosis is the early pathological change in alcohol-associated liver disease. However, its precise mechanism is still unclear. The present study is aimed to explore the role and mechanism of acetyl-CoA synthetase 2 (ACSS2) in acute alcohol-induced lipogenesis. METHODS: The increase in ACSS2 nuclear import and histone H3 acetylation were observed in mice after intraperitoneally injected with 2 g/kg ethanol or oral administration of 5 g/kg ethanol and also validated in hepatocytes stimulated with ethanol or acetate. The role of ACSS2 was further explored in liver-specific ACSS2 knockdown mice fed with ethanol-containing diet. RESULTS: Alcohol challenge induced hepatic lipid deposition and upregulated lipogenic genes in mice. It also promoted ACSS2 nuclear import and increased histone H3 acetylation. In hepatocytes, ethanol induced similar phenomena whereas ACSS2 knockdown blocked histone acetylation and lipogenic gene induction. P300/CBP associated factor (PCAF), but not general control nonderepressible 5, CREB-binding protein (CBP) and p300, facilitated H3K9 acetylation responding to ethanol challenge. CUT&RUN assay showed the enrichment of acetylated histone H3K9 surrounding Fasn and Acaca promoters. These results indicated that ethanol metabolism promoted ACSS2 nuclear import to support lipogenesis via H3K9 acetylation. In alcohol-feeding mice, liver-specific ACSS2 knockdown blocked the interaction between PCAF and H3K9 and suppressed lipogenic gene induction in the liver, demonstrating the critical role of ACSS2 in lipogenesis. CONCLUSIONS: Our study demonstrated that alcohol metabolism generated acetyl-CoA in the nucleus dependently on nuclear ACSS2, contributing to epigenetic regulation of lipogenesis in hepatic steatosis. Targeting ACSS2 may be a potential therapeutical strategy for acute alcoholic liver steatosis.

Phaco-goniosynechialysis versus phaco-trabeculectomy in patients with refractory primary angle-closure glaucoma: a comparative study.

PURPOSE: To compare the effects of phacoemulsification with intraocular lens implantation (phaco) combined with goniosynechialysis (phaco + GSL) versus phaco with trabeculectomy (phaco + trab) for the management of primary angle-closure glaucoma (PACG) refractory to peripheral anterior synechiae (PAS) of over 180°. METHODS: This retrospective study followed 77 eyes of 77 patients for at least 6 months. Intraocular pressure (IOP), best-corrected visual acuity (BCVA), number of glaucoma drugs, and PAS were recorded at the preoperative baseline and evaluated at each postoperative follow-up visit. The National Eye Institute Visual Functioning Questionnaire-25 (NEI VFQ-25) was administered to patients enrolled in this study. Pearson's correlation analysis and multivariate linear analysis were performed to identify factors influencing changes in NEI VFQ-25 scores and to identify factors associated with increases in NEI VFQ-25 scores after the operation. RESULTS: In total, seventy-seven eyes were included (43 with phaco + GSL and 34 with phaco + trab). Comparing preoperative baseline and month 6 after surgery measurements revealed that both groups found significant improvements in IOP, PAS, BCVA and the number of glaucoma drugs (P < 0.05). Baseline NEI VFQ-25 scores were similar in the two groups, but there was a significant difference in postoperative NEI VFQ-25 scores (74.47 ± 10.39 in phaco + GSL vs. 69.57 ± 8.54 in phaco + trab, P = 0.048 < 0.05), and the phaco + GSL group had better scores at the time of the last follow-up. The change in preoperative scores and the number of glaucoma drugs was significantly correlated with postoperative scores in the phaco + GSL group. CONCLUSION: Phaco + GSL treatment is as safe and effective as phaco + trab for refractory PACG patients, and patients' subjective experience improved significantly after phaco + GSL surgery.

Pembrolizumab and Trastuzumab in High Tumor Mutational Burden and POLE-Mutated HER2-Positive Refractory Breast Cancer.

Metastatic breast cancer (mBC) is an incurable disease, and it is not sensitive to immunotherapy due to its low immunogenicity. Recently, inactivated DNA polymerase epsilon (POLE) mutations have been found to be associated with high tumor mutational burden (TMB), which is an effective immuno-oncology biomarker. Patients with POLE mutations with different types of cancer have properly responded to immunotherapy. We aimed to report the first case of programmed death-ligand 1 (PD-L1)-negative mBC presenting with high TMB and POLE mutations, in which a complete response to 5 cycles of chemotherapy and 1 year of pembrolizumab and trastuzumab was noted after failing several lines of HER2-targeted therapies. Our findings also suggest that biomarker-driven patient selection is highly significant for further clinical development of combination therapies via anti-HER2 plus immune-checkpoint inhibitors for HER2+ BC patients.

Identification and expression analysis of GARP superfamily genes in response to nitrogen and phosphorus stress in Spirodela polyrhiza.

BACKGROUND: GARP transcription factors perform critical roles in plant development and response to environmental stimulus, especially in the phosphorus (P) and nitrogen (N) sensing and uptake. Spirodela polyrhiza (giant duckweed) is widely used for phytoremediation and biomass production due to its rapid growth and efficient N and P removal capacities. However, there has not yet been a comprehensive analysis of the GRAP gene family in S. polyrhiza. RESULTS: We conducted a comprehensive study of GRAP superfamily genes in S. polyrhiza. First, we investigated 35 SpGARP genes which have been classified into three groups based on their gene structures, conserved motifs, and phylogenetic relationship. Then, we identified the duplication events, performed the synteny analysis, and calculated the Ka/Ks ratio in these SpGARP genes. The regulatory and co-expression networks of SpGARPs were further constructed using cis-acting element analysis and weighted correlation network analysis (WGCNA). Finally, the expression pattern of SpGARP genes were analyzed using RNA-seq data and qRT-PCR, and several NIGT1 transcription factors were found to be involved in both N and P starvation responses. CONCLUSIONS: The study provides insight into the evolution and function of GARP superfamily in S. polyrhiza, and lays the foundation for the further functional verification of SpGARP genes.

Giant dielectric response and relaxation behavior in (Tm + Ta) co-doped TiO2 ceramics.

Dielectric materials with huge dielectric constants are attracting attention due to the growing demand for microelectronics and high energy-storage devices. In this work, Tm + Ta co-doped TiO2 ceramics were prepared by a solid-state reaction (SSR) method, and the microstructure and dielectric behavior were investigated. A ultrahigh permittivity (εr ∼ 2.26 × 104) and very low loss (tan δ ∼ 0.011) are achieved at 1 kHz for (Tm0.5Ta0.5)0.01Ti0.99O2 ceramics. XPS analysis confirms that the high dielectric constant and low dielectric loss are attributed to the electron pinned defect dipole (EPDD) response formed by the coupling of Ti3+ and oxygen vacancies. In addition, impedance analysis and frequency dependent dielectric constant under a DC bias indicate that the presence of the internal barrier layer capacitance (IBLC) response and electrode response at low to medium frequencies (<106 Hz) also contribute significantly to the dielectric constant. The findings reported in this work provide valuable insights into the simultaneous realization of a low dielectric loss and high permittivity in Tm + Ta co-doped TiO2 ceramics and other related dielectric ceramics.

The value of cystatin C in predicting perioperative and long-term prognosis of renal transplantation.

This study aimed to evaluate the value of cystatin C (Cys C) in predicting the perioperative and long-term prognosis of renal transplantation (RT). The clinical data of 198 RT recipients were collected. Blood samples were obtained daily until 7 d after transplantation and then discharge day to determine the serum levels of Cys C. The receiver-operating characteristic (ROC) analysis and the area under the curve (AUC) were used to determine the diagnostic accuracy of Cys C for delayed graft function (DGF). The presence of shrunken pore syndrome (SPS) with a cystatin C-based estimate of glomerular filtration rate less than 70% of a creatinine-based estimate, was also evaluated as a prognostic factor for the development of DGF. The serum Cys C levels of patients with DGF were higher than those of the non-DGF group. Cys C showed a higher AUC (0.928) in the ROC analysis than did sCr (0.862). Compared to the non-SPS group, there were more patients diagnosed with SPS in the DGF group (p < .05). The follow-up data showed that patients diagnosed with SPS had higher levels of sCr and Cys C compared to other patients, suggesting a poor long-term prognosis. Our findings suggest that Cys C is a sensitive indicator of renal function during the perioperative period. Cys C at a concentration of 4.9 mg/L had the highest sum of sensitivity and specificity for prediction of DGF, with a sensitivity of 0.889 and a specificity of 0.8. SPS is associated with the development of DGF and the poor long-term prognosis of RT.

Al2O3 Grain Boundary Segregation in a Thermal Barrier Coating on a Ni-Based Superalloy.

The segregation of reactive elements (REs) along thermally grown oxide (TGO) grain boundaries has been associated to slower oxide growth kinetics and improved creep properties. However, the incorporation and diffusion of these elements into the TGO during oxidation of Ni alloys remains an open question. In this work, electron backscatter diffraction in transmission mode (t-EBSD) was used to investigate the microstructure of TGO within the thermal barrier coating on a Ni-based superalloy, and atom probe tomography (APT) was used to quantify the segregation behavior of REs to α-Al2O3 grain boundaries. Integrating the two techniques enables a higher level of site-specific analysis compared to the routine focused ion beam lift-out sample preparation method without t-EBSD. Needle-shaped APT specimens readily meet the thickness criterion for electron diffraction analysis. Transmission EBSD provides an immediate feedback on grain orientation and grain boundary location within the APT specimens to help target grain boundaries in the TGO. Segregation behavior of REs is discussed in terms of the grain boundary character and relative location in TGO.