MTHFD2-mediated redox homeostasis promotes gastric cancer progression under hypoxic conditions.

OBJECTIVES: Cancer cells undergo metabolic reprogramming to adapt to high oxidative stress, but little is known about how metabolic remodeling enables gastric cancer cells to survive stress associated with aberrant reactive oxygen species (ROS) production. Here, we aimed to identify the key metabolic enzymes that protect gastric cancer (GC) cells from oxidative stress. METHODS: ROS level was detected by DCFH-DA probes. Multiple cell biological studies were performed to identify the underlying mechanisms. Furthermore, cell-based xenograft and patient-derived xenograft (PDX) model were performed to evaluate the role of MTHFD2 in vivo. RESULTS: We found that overexpression of MTHFD2, but not MTHFD1, is associated with reduced overall and disease-free survival in gastric cancer. In addition, MTHFD2 knockdown reduces the cellular NADPH/NADP+ ratio, colony formation and mitochondrial function, increases cellular ROS and cleaved PARP levels and induces in cell death under hypoxia, a hallmark of solid cancers and a common inducer of oxidative stress. Moreover, genetic or pharmacological inhibition of MTHFD2 reduces tumor burden in both tumor cell lines and patient-derived xenograft-based models. DISCUSSION: our study highlights the crucial role of MTHFD2 in redox regulation and tumor progression, demonstrating the therapeutic potential of targeting MTHFD2.

A Chinese patent medicine's long-term efficacy on non-dialysis patients with CKD stages 3-5: a retrospective cohort study.

Background: Chinese patent medicine is commonly used in China as an important treatment mechanism to thwart the progression of chronic kidney disease (CKD) stages 3-5, among which Niaoduqing granules are a representative Chinese patent medicine; however, its long-term efficacy on CKD prognosis remains unclear. Methods: Patients were grouped according to Niaoduqing granule prescription duration (non-Niaoduqing granule (non-NDQ) group vs Niaoduqing granule (NDQ) group). Serum creatinine (SCr) variation was compared using a generalized linear mixed model (GLMM). Multivariate Cox regression models were constructed, adjusting for confounding factors, to explore the risk of composite outcomes (receiving renal replacement therapy (RRT) or having an estimated glomerular filtration rate (eGFR)<5 mL/min/1.73 m2, ≥50% decline in the eGFR from the baseline, and doubling of SCr) in individuals consuming Niaoduqing granules. Results: A total of 1,271 patients were included, with a median follow-up duration of 29.71 (12.10, 56.07) months. The mean SCr Z-scores for the non-NDQ group and NDQ group were -0.175 and 0.153, respectively, at baseline (p = 0.015). The coefficients of the NDQ group from visit 1 to visit 5 were -0.207 (95% CI: -0.346, -0.068, p = 0.004), -0.214 (95% CI: 0.389, -0.039, p = 0.017), -0.324 (95% CI: 0.538, -0.109, p = 0.003), -0.502 (95% CI: 0.761, -0.243, p = 0.000), and -0.252 (95% CI: 0.569, 0.065, p = 0.119), respectively. The survival probability was significantly higher in the NDQ group (p = 0.0039). Taking Niaoduqing granules was a significant protective factor for thwarting disease progression (model 1: HR 0.654 (95% CI 0.489-0.875, p = 0.004); model 2: HR 0.646 (95% CI 0.476, 0.877, p = 0.005); and model 3: HR 0.602 (95% CI 0.442, 0.820, p = 0.001)). Conclusion: The long-term use of Niaoduqing granules improved SCr variation and lowered the risk of CKD progression by 39.8%.

Comparison of Radiation Dose and Image Quality Between Split-Filter Twin Beam Dual-Energy Images and Single-Energy Images in Single-Source Contrast-Enhanced Chest Computed Tomography.

OBJECTIVE: To compare image quality and radiation dose of split-filter TwinBeam dual-energy (SF-TBDE) with those of single-energy images (SECT) in the contrast-enhanced chest computed tomography (CT). METHODS: Two hundred patients who underwent SF-TBDE (n = 100) and SECT (n = 100) contrast-enhanced chest scanning were retrospectively analyzed. The contrast-to-noise ratio (CNR) and figure of merit (FOM)-CNR of 5 structures (lung, aorta, pulmonary artery, thyroid, and erector spinae) were calculated and subjectively evaluated by 2 independent radiologists. Radiation dose was compared using volume CT dose index and size-specific dose estimate. RESULTS: The CNR and FOM-CNR of lung and erector spinae in SF-TBDE were higher than those of SECT (P < 0.001). The differences in the subjective image quality between the 2 groups were not significant (P = 0.244). Volume CT dose index and size-specific dose estimate of SF-TBDE were lower than those of SECT (6.60 ± 1.56 vs 7.81 ± 3.02 mGy, P = 0.001; 9.25 ± 1.60 vs. 10.55 ± 3.54; P = 0.001). CONCLUSIONS: The SF-TBDE CT can provide similar image quality at a lower radiation dose compared with SECT.

Pioglitazone ameliorates retinal ischemia/reperfusion injury via suppressing NLRP3 inflammasome activities.

AIM: To explore the role of Pioglitazone (Pio) on a mouse model of retinal ischemia/reperfusion (I/R) injury and to elucidate the potential mechanism. METHODS: Retinal ischemia was induced in mice by increasing the intraocular pressure, and Pio was administered 4h though periocular injection before I/R. The number of cells in the ganglion cell layer (GCL) was counted 7d after retinal I/R injury. Glial fibrillary acidic protein (GFAP), nuclear factor-kappa B (NF-κB), p38, phosphorylated-p38, PPAR-γ, interleukin-1ß (IL-1ß), Toll-like receptor 4 (TLR4), NLRP3, cleaved caspase-1, caspase-1 were determined by real-time polymerase chain reaction and Western blotting. RESULTS: Pio promoted the survival of retinal cells in GCL following retinal I/R injury (P<0.05). Besides, retinal I/R injury stimulated the expression of GFAP and TLR4, which were partially reversed by Pio treatment (P<0.05). Retinal I/R injury-upregulated expression of NLRP3, cleaved caspase-1, IL-1ß was attenuated after Pio treatment (P<0.05). Moreover, I/R injury induced activation of NF-κB and p38 were inhibited by Pio treatment (P<0.05). CONCLUSION: Pio promotes retinal ganglion cells survival by suppressing I/R-induced activation of TLR4/NLRP3 inflammasomes via inhibiting NF-κB and p38 phosphorylation.

Hydrogen-rich saline promotes survival of retinal ganglion cells in a rat model of optic nerve crush.

OBJECTIVE: To investigate the effect of molecular hydrogen (H2) in a rat model subjected to optic nerve crush (ONC). METHODS: We tested the hypothesis that after optic nerve crush (ONC), retinal ganglion cell (RGC) could be protected by H2. Rats in different groups received saline or hydrogen-rich saline every day for 14 days after ONC. Retinas from animals in each group underwent measurements of hematoxylin and eosin (H&E) staining, cholera toxin beta (CTB) tracing, gamma synuclein staining, and terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling (TUNEL) staining 2 weeks post operation. Flash visual evoked potentials (FVEP) and pupillary light reflex (PLR) were then tested to evaluate the function of optic nerve. The malondialdehyde (MDA) level in retina was evaluated. RESULTS: H&E, gamma synuclein staining and CTB tracing showed that the survival rate of RGCs in hydrogen saline-treated group was significantly higher than that in saline-treated group. Apoptosis of RGCs assessed by TUNEL staining were less observed in hydrogen saline-treated group. The MDA level in retina of H2 group was much lower than that in placebo group. Furthermore, animals treated with hydrogen saline showed better function of optic nerve in assessments of FVEP and PLR. CONCLUSION: These results demonstrated that H2 protects RGCs and helps preserve the visual function after ONC and had a neuroprotective effect in a rat model subjected to ONC.