The renin-angiotensin system (RAS) and its active peptide angiotensin II (AngII) have major involvements not only in hypertension but also in mood and anxiety disorders. Substantial evidence supports the notion that AngII acts as a neuromodulator in the brain. In this review, we provide an overview of the link between the RAS and anxiety or mood disorders, and focus on recent advances in the understanding of AngII-linked, NADPH oxidase-derived oxidative stress in the central nervous system, which may underlie pathogenesis of mood and anxiety disorders.
Autism spectrum disorder (ASD) is a group of neurodevelopmental disorders characterized by impairment in social communication/interaction and inflexible/repetitive behavior. Several lines of evidence support genetic factors as a predominant cause of ASD. Among those autism susceptibility genes that have been identified, the PTEN tumor suppressor gene, initially identified as predisposing to Cowden heritable cancer syndrome, was found to be mutated in a subset of ASD patients with extreme macrocephaly. However, the ASD-relevant molecular mechanism mediating the effect of PTEN mutations remains elusive.We developed a Pten knock-in murine model to study the effects of Pten germline mutations, specifically altering subcellular localization, in ASD. Proteins were isolated from the hemispheres of the male littermates, and Western blots were performed to determine protein expression levels of tyrosine hydroxylase (TH). Immunohistochemical stains were carried out to validate the localization of TH and dopamine D2 receptors (D2R). PC12 cells ectopically expressing either wild-type or missense mutant PTEN were then compared for the differences in TH expression.Mice carrying Pten mutations have high TH and D2R in the striatum and prefrontal cortex. They also have increased phosphorylation of cAMP response element-binding protein (CREB) and TH. Mechanistically, PTEN downregulates TH production in PC12 cells via inhibiting the phosphoinositide 3-kinase (PI3K)/CREB signaling pathway, while PTEN reduces TH phosphorylation via suppressing MAPK pathway. Unlike wild-type PTEN but similar to the mouse knock-in mutant Pten, three naturally occurring missense mutations of PTEN that we previously identified in ASD patients, H93R, F241S, and D252G, were not able to suppress TH when overexpressed in PC12 cells. In addition, two other PTEN missense mutations, C124S (pan phosphatase dead) and G129E (lipid phosphatase dead), failed to suppress TH when ectopically expressed in PC12 cells.Our data reveal a non-canonical PTEN-TH pathway in the brain that may work as a core regulator of dopamine signaling, which when dysfunctional is pathogenic in ASD.
Background: First-episode schizophrenia (FES) and anti-NMDAR encephalitis are different disorders with similar psychiatric symptoms, and both diseases are associated with the inflammatory system. In this study, we compared hematological parameters and inflammation ratios in anti-NMDAR encephalitis, FES, and healthy control. Methods: We enrolled 106 patients (53 FES patients and 53 anti-NMDAR encephalitis patients) and 59 healthy controls. The values of the neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), monocyte-lymphocyte ratio (MLR), and systemic immune-inflammation index (SII) were used to evaluate inflammation. Other parameters such as the white blood cell (WBC), platelet (PLT), uric acid (UA), total bilirubin (TBIL), total bile acid (TBA), and serum albumin counts were also used to compare inflammation ratios between these two diseases. Results: SII, NLR, PLR, MLR, and serum albumin levels were statistically significantly different between these three groups (p < 0.05). The values of SII, NLR, PLR, and MLR were significantly higher in the anti-NMDAR encephalitis group than those in the FES group (p < 0.05), and the values in both diseases were more increased than those in HC (p < 0.05). The serum albumin level was significantly lower in anti-NMDAR encephalitis than in FES (p < 0.05). WBC, neutrophil, lymphocyte, and monocyte counts showed significantly higher levels in the anti-NMDAR encephalitis group and FES group separately (p < 0.05). Other parameters like TBA, TBIL, and UA showed no difference between groups. Conclusion: In summary, this is a relatively new study that is innovative by comparing some inflammation markers of peripheral blood in two diseases with clinically psychotic symptoms. These two diseases are related to the inflammatory system, proving that NMDAR dysfunction is related to psychotic symptoms. Besides, NLR, PLR, MLR, and serum albumin can be used as biomarkers to distinguish the two diseases. The serum albumin level in patients with anti-NMDAR encephalitis was lower than that in patients with schizophrenia.
Triple-negative breast cancer (TNBC) is a highly heterogeneous cancer lacking actionable targets. Using a phenotypic screen of TNBC cells, we discovered a novel multiple kinase inhibitor tinengotinib (TT-00420) that strongly inhibited Aurora A/B, FGFR1/2/3, VEGFRs, JAK1/2, and CSF1R in biochemical assays. Exposure to tinengotinib specifically inhibited proliferation across all subtypes of TNBC in vitro and in vivo, while leaving luminal breast cancer cells intact. Incubation of HCC1806 with tinengotinib led to dose-dependent downregulation of genes essential for TNBC cell growth and proliferation. Studies revealed that the potential mechanism of action of tinengotinib involved, predominantly, inhibition of Aurora A or B kinase activity, while inhibition of other pathways contributed to suppression of potency and activity. In vitro treatment of TNBC cell lines or in vivo administration in a syngeneic model with tinengotinib resulted in up-regulation of CXCL10 and 11 or diminished tumor-associated macrophage (TAM) infiltration. Tinengotinib represents a novel combinatorial inhibitory mechanism to treat TNBC. The phase I trial of tinengotinib was completed (ClinicalTrials.gov identifier: NCT03654547).
The blackberry seed was typically removed as a byproduct and waste from blackberry fruits for juices. Developing value-added utilization of berry seeds will significantly expand the market for berry products as well as improve benefit to berry producers. However, the research on blackberry seed is limited. The objective of this paper was to research antithrombotic mechanism of polysaccharides in blackberry seeds. Polysaccharides in blackberry seeds were extracted, purified and identified by high-performance gel permeation chromatography (HPSEC), gas chromatography (GC), fourier transform infrared (FT-IR) spectrometer and nuclear magnetic resonance spectra (NMR). Anticoagulant activities were evaluated in vivo by measuring activated partial thromboplastin time (APTT), thrombin time (TT), prothrombin time (PT), fibrinogen (FIB) and plasma recalcification time (RRT). Four polysaccharides named BSP-1a, BSP-1b, BSP-2 and BSP-3 were isolated from Blackberry ( Rubus spp.) seeds. The results indicated that BSP-1b, BSP-2 and BSP-3 exhibited the anticoagulant activity. Therefore, the anti-thrombosis effects of BSP-1b, BSP-2 and BSP-3 were investigated in vivo by 6-Keto-PGF 1α , thromboxane B 2 (TXB 2 ), endothelial nitric oxide synthase (eNOS), endothelin-1 (ET-1), whole blood viscosity (WBV), plasma viscosity (PV), hematocrit (Hct), erythrocyte sedimentation rate (ESR), APTT, TT, PT and FIB. The results suggested that BSP-1b, BSP-2 and BSP-3 had the inhibition effect on thrombus formation, and the antithrombotic effects were associated with the regulation of vascular endothelium active substance, activating blood flow and anticoagulation effect.
Abstract Background Patients with ulcerative colitis (UC) who are positive for anti-neutrophil cytoplasmic antibodies(ANCA) tend to have a poor response to infliximab(IFX)1-3. We aimed to evaluate the comparative efficacy and safety of rituximab (RTX) versus IFX in moderately to severely active UC patients who are Proteinase 3-ANCA(PR3-ANCA) positive. Methods This retrospective multicentre real-world study encompassed three medical centres in Hubei, China. Patients with moderate to severely active UC who are positive for PR3-ANCA were categorized into the RTX group(100mg or 200mg by intravenous injection every 2 weeks for a total dose between 400mg and 900mg, n=12) and IFX group(5 mg/kg of intravenous at weeks 0, 2, and 6, followed by maintenance doses every 8 weeks, n=26) based on the biological therapy. The Mayo Clinic Score (MCS) was utilised to evaluate the efficacy endpoints at week 22, encompassing clinical remission(primary endpoint), clinical response, endoscopic response, endoscopic improvement, and endoscopic remission. Safety endpoints focused on opportunistic infections and drug-related adverse reactions. Inverse probability of treatment weighting(IPTW) and multifactorial logistic regression analysis(MLRS) were employed to mitigate the effects of potential confounding factors. Results The rates of clinical remission(83.33% vs. 23.08% and 93.20% vs. 25.40%), clinical response(100.00% vs. 65.38% and 100.00% vs. 64.60%), endoscopic response(100.00% vs. 34.62% and 100.00% vs. 36.06), endoscopic improvement(50.00% vs. 11.54% and 75.07% vs. 11.29%), and endoscopic remission(100.00% vs. 34.62% and 100.00% vs. 36.06%) were significantly higher in patients treated with RTX compared with those treated with IFX, both prior to and following IPTW(all P<0.05). In MLRS, RTX was associated with higher odds of achieving clinical remission at week 22 versus IFX before and after IPTW[OR(95%CI): 143.854(1.060-19521.653) and 190.499(4.147-1.000*105), all P<0.05]. In terms of safety endpoints, elevated interferon-gamma release assays(IGRAs) were noted in none of the RTX patients, and 2 IFX patients (7.69%). No patients exhibited elevated EBV-DNA, HBV-DNA, CMV-DNA, or experienced severe infections. Conclusion RTX demonstrated superior efficacy versus IFX in moderately to severely active UC patients with positive PR3-ANCA, with a comparable safety profile. References 1. Yoshida A, Matsuoka K, Ueno F, Morizane T, Endo Y, Hibi T. Serum PR3-ANCA Is a Predictor of Primary Nonresponse to Anti-TNF-α Agents in Patients with Ulcerative Colitis. Inflammatory intestinal diseases. May 2021;6(2):117-122. doi:10.1159/000515361 2. Ferrante M, Vermeire S, Katsanos KH, et al. Predictors of early response to infliximab in patients with ulcerative colitis. Inflammatory bowel diseases. Feb 2007;13(2):123-8. doi:10.1002/ibd.20054 3. Jürgens M, Laubender RP, Hartl F, et al. Disease activity, ANCA, and IL23R genotype status determine early response to infliximab in patients with ulcerative colitis. The American journal of gastroenterology. Aug 2010;105(8):1811-9. doi:10.1038/ajg.2010.95
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