Activation of GPR120 in podocytes ameliorates kidney fibrosis and inflammation in diabetic nephropathy.

Diabetic nephropathy (DN) is one of the most common causes of end-stage renal disease worldwide. ω3-Fatty acids (ω3FAs) were found to attenuate kidney inflammation, glomerulosclerosis, and albuminuria in experimental and clinical studies of DN. As G protein-coupled receptor 120 (GPR120) was firstly identified as the receptor of ω3FAs, we here investigated the function of GPR120 in DN. We first examined the renal biopsies of DN patients, and found that GPR120 expression was negatively correlated with the progression of DN. Immunofluorescence staining analysis revealed that GPR120 protein was mainly located in the podocytes of the glomerulus. A potent and selective GPR120 agonist TUG-891 (35 mg · kg-1 · d-1, ig) was administered to db/db mice for 4 weeks. We showed that TUG-891 administration significantly improved urinary albumin excretion, protected against podocyte injury, and reduced collagen deposition in the glomerulus. In db/db mice, TUG-891 administration significantly inhibited the mRNA and protein expression of fibronectin, collagen IV, α-SMA, TGF-ß1, and IL-6, and downregulated the phosphorylation of Smad3 and STAT3 to alleviate glomerulosclerosis. Similar results were observed in high-glucose-treated MPC5 podocytes in the presence of TUG-891 (10 µM). Furthermore, we showed that TUG-891 effectively upregulated GPR120 expression, and suppressed TAK1-binding protein-1 expression as well as the phosphorylation of TAK1, IKKß, NF-κB p65, JNK, and p38 MAPK in db/db mice and high-glucose-treated MPC5 podocytes. Knockdown of GPR120 in MPC5 podocytes caused the opposite effects of TUG-891. In summary, our results highlight that activation of GPR120 in podocytes ameliorates renal inflammation and fibrosis to protect against DN.

Cost-Effectiveness of First-Line Atezolizumab versus Chemotherapy in Non-Small-Cell Lung Cancer Patients Ineligible for Platinum-Containing Regimens.

Purpose: The IPSOS study provided evidence supporting the efficacy and tolerability of first-line atezolizumab compared to single-agent chemotherapy for non-small-cell lung cancer (NSCLC) patients ineligible for treatment with a platinum-containing regimen. This study aimed to assess the cost-effectiveness of atezolizumab specifically in this population, considering the perspective of the Chinese healthcare system. Patients and Methods: In this analysis, a three-state Markov model was utilized. The survival data were derived from the IPSOS clinical trial. Direct medical costs and utility values were collected from national authoritative database and published literature. The primary outcomes were costs, quality-adjusted life-years (QALYs) and incremental cost-effectiveness ratio (ICER). To ensure the robustness of our model, both one-way and probabilistic sensitivity analyses were conducted. Results: Atezolizumab monotherapy led to an increase in costs of $4139.23 compared to single-agent chemotherapy. Additionally, it resulted in a gain of 0.14 QALYs, leading to an ICER of $29,365.79 per QALY, which was below the willingness-to-pay threshold of $36,066 per QALY used in the model. One-way sensitivity analyses revealed cost of atezolizumab and utility of progressive disease (PD) as major influencing factors for ICER. Furthermore, probabilistic sensitivity analyses confirmed our base-case results. Conclusion: From the perspective of the Chinese healthcare system, atezolizumab emerges as a cost-effective choice for the first-line treatment of NSCLC patients ineligible for platinum-based chemotherapy.

High-sensitivity naphthalene-based two-photon fluorescent probe suitable for direct bioimaging of H2S in living cells.

H2S is the third endogenously generated gaseous signaling compound and has also been known to involve a variety of physiological processes. To better understand its physiological and pathological functions, efficient methods for monitoring of H2S in living systems are desired. Although quite a few one photon fluorescence probes have been reported for H2S, two-photon (TP) probes are more favorable for intracellular imaging. In this work, by employing a donor-π-acceptor-structured naphthalene derivative as the two-photon fluorophore and an azide group as the recognition unit, we reported a new two-photon bioimaging probe 6-(benzo[d]thiazol-2'-yl)-2-azidonaphthalene (NHS1) for H2S with improved sensitivity. The probe shows very low background fluorescence in the absence of H2S. In the presence of H2S, however, a significant enhancement for both one photon and TP excited fluorescence were observed, resulting in a high sensitivity to H2S in aqueous solutions with a detection limit of 20 nM observed, much lower than the previously reported TP probe. The probe also exhibits a wide linear response concentration range (0-5 µM) to H2S with high selectivity. All these features are favorable for direct monitoring of H2S in complex biological samples. It was then applied for direct TP imaging of H2S in living cells with satisfactory sensitivity, demonstrating its value of practical application in biological systems.

Ethyl 2,4-dimethyl-pyrido[1,2-a]benz-imidazole-3-carboxyl-ate.

The title compound, C(16)H(16)N(2)O(2), was synthesized using a novel tandem annulation reaction between 1-(1H-benzo[d]imidazol-2-yl)ethanone and ethyl (E)-4-bromo-but-2-enoate under mild conditions. The dihedral angles formed by the mean plane of the five-membered imidazole ring with the dihydro-pyridin and benzene rings are 1.54 (9) and 1.85 (9)°, respectively.

MMP-9, Vertebrobasilar Ectasia and Vertebral Artery Dominance in Vertigo or Dizziness Patients With Vascular Risk Factors.

Background and Purpose: Although vertebrobasilar ectasia (VBE) is diagnosed with increasing frequency, it is not clear whether this is because of altered hemodynamics caused by the effects of matrix metalloproteinases (MMPs) and/or vertebral artery dominance (VAD). Therefore, we investigate the relationship between plasma levels of MMPs and VBE in patients with vertigo or dizziness who also have vascular risk factors, in order to determine whether high levels of MMPs in VBE are independent of VAD. Methods: We prospectively studied 285 patients with vertigo or dizziness and at least one vascular risk factor. Plasma levels of MMPs, tissue inhibitor of metalloproteinases (TIMPs) and cathepsin L were measured. Subjects were classified as VBE-negative or VBE-positive, who were further classified based on the presence of VAD with magnetic resonance angiography. Acute ischemic stroke was screened by diffusion-weighted imaging, generally after bedside evaluation and the drawing of blood samples. Receiver operating characteristic (ROC) curves were applied to evaluate the utility of these potential biomarkers in predicting risk for ischemic stroke. Results: The prevalence of VBE in patients with vertigo or dizziness was 16.5%. Of the 82 patients with ischemic stroke, 14 strokes involved the cortex or subcortex. MMP-9 levels were significantly higher in the VBE-positive group than in the VBE-negative group (P = 0.022). There was a significant difference in the risk of posterior circulation ischemic stroke between the VBE-positive group and the VBE-negative group (P = 0.002). Levels of MMP-2 and cathepsin L tended to be higher in the VBE-negative group (P = 0.054, P = 0.060, respectively). Compared with the non-VAD subgroup, levels of MMP-2,-3,-9, TIMP-1,-2, and cathepsin L were similar in the VAD subgroup. ROC analysis showed that MMP-9 predicted risk for ischemic stroke (AUC = 0.582, 95%CI, 0.510-0.654, P = 0.030). Conclusions: MMP-9 was associated with VBE and independent of VAD. High levels of MMP-9 may predict risk for ischemic stroke in patients with vertigo or dizziness who also have vascular risk factors.

Basilar Artery Tortuosity Is Associated With White Matter Hyperintensities by TIMP-1.

BACKGROUND AND PURPOSE: To test the hypothesis that the imbalance between matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinases (TIMPs) may play a potential role in bridging vertebrobasilar dolichoectasia (VBD) with lacunar infarction (LI) and white matter hyperintensities (WMH). METHODS: We studied 212 patients with vertigo who underwent multimodal magnetic resonance imaging (MRI) tests for VBD, LI, and WMH identification. We investigated biomarkers of VBD with magnetic resonance angiography (MRA) via various physical characteristics of the vertebrobasilar arteries (VBAs). Similarly, LI and WMH biomarkers were extracted using T2-weighted and fluid attenuated inversion recovery (FLAIR) images. We first determined which of these neuroimaging markers were significant identifiers of VBD, LI and the different grades of WMH. We then sought to draw potential mechanistic conclusions from these MRI-derived parameters, by associating the aforementioned biomarkers with MMP and TIMP serum levels in patient blood samples using non-parametric statistical tests. RESULTS: MMP-9 serum level was significantly higher in vertigo patients with VBAs dilation and basilar artery (BA) elongation compared to those with healthy arterial size, and the ratio of MMP-9/TIMP-1 level were higher in those patients. TIMP-1 level was also markedly higher in vertigo patients with BA tortuosity than those without BA tortuosity. The bending length (BL) of the BA was positively correlated with TIMP-1. The length, BL, and tortuosity index of the BA, as well as serum levels of TIMP-1 were greater in patients with higher WMH grades compared to those with low WMH grades. The vertebral artery and BA diameters, and the levels of MMP-2, -3, -9, TIMP-2 and cathepsin L were similar in patients with different WMH grades. CONCLUSION: In vertigo patients, we found various probably associations between MMP-9 and TIMP-1 with arterial alterations linked to both VBD and WMH that may help with the diagnosis and treatment of such diseases in the future.

Correlation of HLA-DP/DQ polymorphisms with transplant etiologies and prognosis in liver transplant recipients.

Previous study has identified that the genetic variants in the human leukocyte antigen (HLA)-DP/DQ region were strongly associated with hepatitis B virus (HBV) infection. But their roles in liver function recovery after hepatic transplantation were still obscure. This study aimed to investigate whether HLA-DP/DQ polymorphisms were associated with post-transplant etiologies and prognosis in Chinese liver transplant recipients.A total of 144 liver transplant recipients were enrolled, which were divided into 2 groups according to the transplant etiology: HBV-related disease and non-HBV-related disease. HBV-related disease includes 3 subgroups: liver cirrhosis, hepatocellular carcinoma, and progressive HBV hepatitis. Three single-nucleotide polymorphisms HLA-DP (rs3077 and rs9277535) and HLA-DQ (rs7453920) were studied in all recipients by high-resolution melting curve analysis. Liver function indices (albumin, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, gamma-glutamyltranspeptidase, direct bilirubin, total bilirubin) and coagulation indices (prothrombin time, platelet, international normalized ratio, fibrinogen) were routinely tested. After transplant, 10 recipients who were positive for HBsAg or with elevation in HBV virus load were regarded as HBV recurrence.No significant association of HLA-DP/DQ polymorphisms with HBV recurrence or transplant etiology was observed (P < .05). Recipients with HLA-DQ (rs7453920) AG and AA genotype had lower direct bilirubin levels than GG genotype individuals, especially on the 14th day after surgery (17.80 vs. 5.35, P  =  .038). Patients with A alleles displayed earlier liver function recovery than patients with G alleles (7 vs. 6 months). No significant correlation was shown in HLA-DP rs3077 and rs9277535 with HBV infection or liver function recovery (P < .05).Our study concluded that HLA-DP (rs3077 and rs9277535) and HLA-DQ (rs7453920) were not significantly associated with HBV recurrence or HBV susceptibility, but HLA-DQ rs7453920 was related to prognosis of liver transplant recipients. HLA-DQ rs7453920 A might be used as an indicator of earlier recovery and better prognosis after transplantation.