Sodium tanshinone IIA sulfonate protects vascular relaxation in ApoE-knockout mice by inhibiting the SYK-NLRP3 inflammasome-MMP2/9 pathway.

BACKGROUND: Hyperlipidemia damages vascular wall and serves as a foundation for diseases such as atherosclerosis, hypertension and stiffness. The NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome is implicated in vascular dysfunction associated with hyperlipidemia-induced vascular injury. Sodium tanshinone IIA sulfonate (STS), a well-established cardiovascular protective drug with recognized anti-inflammatory, antioxidant, and vasodilatory properties, is yet to be thoroughly investigated for its impact on vascular relaxant imbalance induced by hyperlipidemia. METHODS: In this study, we treated ApoE-knockout (ApoE-/-) mouse with STS and assessed the activation of the NLRP3 inflammasome, expression of MMP2/9, integrity of elastic fibers, and vascular constriction and relaxation. RESULTS: Our findings reveal that STS intervention effectively preserves elastic fibers, significantly restores aortic relaxation function in ApoE-/- mice, and reduces their excessive constriction. Furthermore, STS inhibits the phosphorylation of spleen tyrosine kinase (SYK), suppresses NLRP3 inflammasome activation, and reduces MMP2/9 expression. CONCLUSIONS: These results demonstrate that STS protects vascular relaxation against hyperlipidemia-induced damage through modulation of the SYK-NLRP3 inflammasome-MMP2/9 pathway. This research provides novel insights into the mechanisms underlying vascular relaxation impairment in a hyperlipidemic environment and uncovers a unique mechanism by which STS preserves vascular relaxation, offering valuable foundational research evidence for its clinical application in promoting vascular health.

Does the addition of drugs targeting the vascular endothelial growth factor pathway to first-line chemotherapy increase complete response? A meta-analysis of randomized clinical trials.

Drugs targeting the vascular endothelial growth factor (VEGF) and its receptor (VEGFR) signaling (anti-VEGF/VEGFR drugs) are the most validated anti-angiogenic strategies for cancer treatment. Complete response (CR) is a rare event in cancer patients receiving chemotherapy. A meta-analysis was conducted to determine whether adding anti-VEGF/VEGFR drugs to chemotherapy can further increase the chance of CR in the first-line therapy. Relevant databases were systematically searched for the period 2000-2015. Eligible studies were selected according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. The incidence, relative risk (RR), and 95 % confidence intervals (CIs) were calculated using random-effects or fixed-effects models based on the heterogeneity of selected studies. A total of 12,453 patients from 28 randomized controlled trials were included. The overall incidence of CR in patients treated with anti-VEGF/VEGFR drugs plus chemotherapy was 1.5 % (95 % CI, 1.0-2.0 %) compared to 1.1 % (95 % CI, 0.7-1.4 %) in the chemotherapy-alone arm. Adding anti-VEGF/VEGFR drugs was associated with significant improvement of CR (RR, 1.52, 95 % CI, 1.18-1.95, P = 0.001). When stratified by drug type, adding VEGFR tyrosin kinase inhibitors (TKIs) did not increase the chance of CR (RR, 0.87, 95 % CI, 0.51-1.49; P = 0.614). The addition of bevacizumab with 7.5 mg/kg every 3 weeks, but not 15 mg/kg every 3 weeks, significantly improves the CR (7.5 mg, RR, 2.43, 95 % CI, 1.64-3.60, P = 0.000; 15 mg, RR, 1.07, 95 % CI, 0.63-1.81, P = 0.799). In subgroup analysis, a significant improvement of CR by the addition of anti-VEGF/VEGFR drugs was observed in patients with colorectal cancer (RR, 2.10, 95 % CI 1.21-3.63, P = 0.008), ovarian cancer (RR, 3.07; 95 % CI, 1.68-5.62, P = 0.000), and patients who are treated with platinum-based regimens (RR, 1.78, 95 % CI, 1.23-2.59, P = 0.002). Low-dose bevacizumab, rather than VEGFR TKIs or high-dose bevacizumab, can increase the chance of CR in patients receiving chemotherapy.

[Study on mineral elements distribution in soil of Angelica sinensis producing regions and its relationship with altitude and soil types].

OBJECTIVE: To investigate the distribution characteristics of mineral elements in the soil of Angelica sinensis producing regions and its relationship with altitude and soil types. METHODS: The contents of 15 mineral elements in 103 batches of soil from 13 counties were determined by ICP-MS or AAS. Pearson correlation analysis, partial correlation analysis and systematical cluster analysis were used to analyze the data. RESULTS: Pearson correlation analysis showed that the content of Mg in soil and altitude showed significant positive correlation(P <0. 01), the content of Cd in soil and altitude showed significant negative correlation(P <0. 05), and the con- tents of Pb, Cd, As, Cu, Cr as well as Ni in soil and altitude showed negative correlation. The result of systematic cluster analysis showed that 103 batches of soil were clustered into 5 groups. The main soil types of group I were black soil, haplic kastanozems and black sandy-soil, group II was loess, group III was cinnamon soil, group IV were red soil and grey cinnamon soil, and group V were black soil, haplic kastanozems, grey cinnamon soil and cinnamon soil. CONCLUSION: The distribution of mineral elements in soil is closely related to altitude and soil types.

Genetic variation in the triosephosphate isomerase gene of the fall armyworm and its distribution across China.

The fall armyworm (FAW), Spodoptera frugiperda, has colonized and caused consistent damage in the Eastern hemisphere. The identification of various FAW strains is essential for developing precise prevention and control measures. The triosephosphate isomerase (Tpi) gene is recognized as an effective marker closely linked to FAW subpopulations. However, most current studies primarily focus on the comparison of variations in specific gene sites of this gene. In this study, we conducted full-length sequencing of the Tpi genes from 5 representative FAW groups. Our findings revealed that the Tpi genes varied in length from 1220 to 1420 bp, with the primary variation occurring within 4 introns. Notably, the exon lengths remained consistent, at 747 bp, with 37 observed base variations; however, no amino acid variations were detected. Through sequence alignment, we identified 8 stable variation sites that can be used to distinguish FAW strains in the Eastern hemisphere. Additionally, we performed strain identification on 1569 FAW samples collected from 19 provinces in China between 2020 and 2021. The extensive analysis indicated the absence of the rice strain in the samples. Instead, we only detected the presence of the corn strain and the Zambia strain, with the Zambia strain being distributed in a very low proportion (3.44%). Furthermore, the corn strain could be further categorized into 2 subgroups. This comprehensive study provides a valuable reference for enhancing our understanding of FAW population differentiation and for improving monitoring and early warning efforts.

Sulfasalazine ameliorates lipopolysaccharide-induced acute lung injury by inhibiting oxidative stress and nuclear factor-kappaB pathways.

Acute lung injury/acute respiratory distress syndrome (ALI/ARDS) has a high mortality rate and incidence of complications. The pathophysiology of ALI/ARDS is still not fully understood. The lipopolysaccharide (LPS)-induced mouse model of ALI has been widely used to study human ALI/ARDS. Sulfasalazine (SASP) has antibacterial and anti-inflammatory effects and is used for treating inflammatory bowel and rheumatic diseases. However, the effect of SASP on LPS-induced ALI in mice has not yet been reported. Therefore, we aimed to investigate the effect of SASP on LPS-induced ALI in mice. Mice were intraperitoneally injected with SASP 2 h before or 4 h after LPS modeling. Pulmonary pathological damage was measured based on inflammatory factor expression (malondialdehyde and superoxide dismutase levels) in the lung tissue homogenate and alveolar lavage fluid. The production of inflammatory cytokines and occurrence of oxidative stress in the lungs induced by LPS were significantly mitigated after the prophylactic and long-term therapeutic administration of SASP, which ameliorated ALI caused by LPS. SASP reduced both the production of inflammatory cytokines and occurrence of oxidative stress in RAW264.7 cells, which respond to LPS. Moreover, its mechanism contributed to the suppression of NF-κB and nuclear translocation. In summary, SASP treatment ameliorates LPS-induced ALI by mediating anti-inflammatory and antioxidant effects, which may be attributed to the inhibition of NF-κB activation and promotion of antioxidant defenses. Thus, SASP may be a promising pharmacologic agent for ALI therapy.

Sodium Tanshinone IIA Sulfonate alleviates vascular senescence in diabetic mice by modulating the A20-NFκB-NLRP3 inflammasome-catalase pathway.

Diabetes accelerates vascular senescence, which is the basis for atherosclerosis and stiffness. The activation of NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome and oxidative stress are closely associated with the deteriorative senescence in endothelial cells (ECs) and vascular smooth muscle cells (VSMCs). For decades, Sodium Tanshinone IIA Sulfonate (STS) has been utilized as a cardiovascular medicine with acknowledged anti-inflammatory and anti-oxidative properties. Nevertheless, the impact of STS on vascular senescence remains unexplored in diabetes. Diabetic mice, primary ECs and VSMCs were transfected with the NLRP3 overexpression/knockout plasmid, the tumor necrosis factor alpha-induced protein 3 (TNFAIP3/A20) overexpression/knockout plasmid, and treated with STS to detect senescence-associated markers. In diabetic mice, STS treatment maintained catalase (CAT) level and vascular relaxation, reduced hydrogen peroxide probe (ROSgreen) fluorescence, p21 immunofluorescence, Senescence ß-Galactosidase Staining (SA-ß-gal) staining area, and collagen deposition in aortas. Mechanistically, STS inhibited NLRP3 phosphorylation (serine 194), NLRP3 dimer formation, NLRP3 expression, and NLRP3-PYCARD (ASC) colocalization. It also suppressed the phosphorylation of IkappaB alpha (IκBα) and NFκB, preserved A20 and CAT levels, reduced ROSgreen density, and decreased the expression of p21 and SA-ß-gal staining in ECs and VSMCs under HG culture. Our findings indicate that STS mitigates vascular senescence by modulating the A20-NFκB-NLRP3 inflammasome-CAT pathway in hyperglycemia conditions, offering novel insights into NLRP3 inflammasome activation and ECs and VSMCs senescence under HG culture. This study highlights the potential mechanism of STS in alleviating senescence in diabetic blood vessels, and provides essential evidence for its future clinical application.

Interactions of CyMe4 -BTBP ligand with lanthanides and actinides: Insights from ESI-MS and DFT calculations.

Electrospray Ionization Mass Spectrometry (ESI-MS) technique and density functional theory (DFT) calculations were combined to study the formation of the complexes of lanthanides (Ln = La, Ce, Nd, Sm, Eu, Yb) and actinides (UO2 2+ , Th4+ ) with CyMe4 -BTBP (6,6'-bis(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-benzo-[1,2,4-]triazin-3-yl)-[2,2']bipyridine) to understand the mechanisms during the extraction process. Mass spectrometry titrations showed the formation of the complexation in acetonitrile. For lanthanides, only 1:2 complexes ([Ln(L)2 ]3+ , [Ln(L)2 (CH3 CN)]3+ ), [Ln(L)2 (NO3 )]2+ ) were found at low [Ln]/[L] concentration ratios, whereas the 1:1 complexes ([Ln(L)(NO3 )2 ]+ ) were observed when the [Ln]/[L] concentration ratio reached 1.0. For uranyl complexes, 1:1 complex ([UO2 L(NO3 )]+ ) was the only species within the measuring range. Th4+ complexes had two compositions: 1:1 and 1:2, in which 1:2 species was the dominant complex. Collision-induced dissociation (CID) was employed to characterize the fragmentation process. The fragmentation process was unfolded sequentially on both sides of CyMe4 -BTBP ligand with the loss of alkyl groups and cleavage of triazinyl rings. The CID results of CyMe4 -BTBP complexes revealed a slight difference depending on the metal center. The DFT calculations showed that the stable complexes formed in acetonitrile solution were consistent with the ESI-MS results.

Co-occurrence of m.15992A>G and m.15077G>A Is Associated With a High Penetrance of Maternally Inherited Hypertension in a Chinese Pedigree.

BACKGROUND: Mitochondrial DNA (mtDNA) pathogenic variants have been identified to be associated with maternally inherited essential hypertension (MIEH). However, the distinctive clinical features and molecular pathogenesis of MIEH are not fully understood. METHODS: In this study, we collected a Chinese MIEH family with extraordinary higher penetrance of essential hypertension (88.89%) and early ages of onset (31-40 years old), and performed clinical and genetic characterization for this family. The complete mitochondrial genome of the proband was sequenced and analyzed. RESULTS: The maternally related members in this family were presented with severe increased blood pressure, left ventricular remodeling, and metabolic abnormalities. Through sequencing the entire mtDNA of the proband and performing systematic analysis of the mtDNA variants with a phylogenic approach, we identified a potentially pathogenic tRNA variant (m.15992A>G in the MT-TP gene) that may account for the MIEH in this family. One nonsynonymous variant (m.15077G>A in the MT-CYB gene) was identified to play a synergistic role with m.15992A>G to cause a high penetrance of MIEH. CONCLUSIONS: Our results, together with previous findings, have indicated that tRNA pathogenic variants in the mtDNA could act important roles in the pathogenesis of MIEH through reducing mitochondrial translation and disturbing mitochondrial function.

A Retrospective Study of Biliary Drainage Strategies for Patients with Malignant Hilar Biliary Strictures.

PURPOSE: The main aim of this study was to compare the efficacy and safety of different biliary drainage strategies, including percutaneous transhepatic biliary drainage (PTBD) versus endoscopic biliary stenting (EBS) and unilateral versus bilateral stenting, in patients with unresectable malignant hilar biliary strictures (MHBSs). PATIENTS AND METHODS: This was a retrospective review of patients with inoperable MHBSs who underwent biliary drainage by either EBS or PTBD. Efficacy and safety were compared between the two pathways and between unilateral and bilateral stenting in the EBS group. The survival duration was analyzed with K-M curves and Log rank tests. RESULTS: From January 2015 to December 2019, a total of 206 (126: EBS and 80: PTBD) patients with MHBSs were enrolled in our study and underwent 270 procedures (173: EBS and 97: PTBD). Bilateral stenting was superior to unilateral stenting in terms of clinical success (69.6% vs 50.6%, p=0.039), especially for patients with Bismuth type IV (70.0% vs 30.3%, p=0.002). A higher decrease in bilirubin was seen with PTBD in patients with Bismuth types III-IV (66.9 vs 36.7, p=0.006). A survival advantage was seen in successful drainage (227 days vs 82 days, p<0.001), lower tumor-node-metastasis (TNM) scores (I-II) (195 days vs 139 days, p=0.012), and cholangiocarcinoma (184 days vs 84 days, p=0.001). CONCLUSION: For patients with advanced MHBSs, bilateral stenting may achieve a better drainage effect than unilateral stenting, and PTBD may have a better performance in relieving cholestasis than EBS. Successful drainage and cholangiocarcinoma may provide greater long-term survival benefits.

Low-dose irradiation inhibits proliferation of the p53null type human prostate cancer cells through the ATM/p21 pathway.

Low-dose ionizing radiation (LDIR) induces hormesis, exerts an adoptive effect on normal mammalian cells and stimulates cell proliferation; however, this effect is absent in cancer cells. Little is known on the molecular mechanisms underlying this differential response between normal and cancer cells. In the present study, it was demonstrated that the human prostate cancer cell line PC-3 and the normal prostate cell line RWPE-1 exhibited differential biological responses to LDIR. Through cell cycle analyses, it was demonstrated that LDIR inhibited cell growth and arrested the cell cycle at the S and G2/M phases in PC-3 cells, but not in RWPE-1 cells. Using western blotting, it was demonstrated that LDIR at 75 mGy induced the expression of ataxia-telangiectasia mutated (ATM) protein in PC-3 as well as RWPE-1 cells. However, the ATM̸p21 pathway was activated in PC-3, but not in RWPE-1 cells. Although the expression of p53 was not affected by 75 mGy LDIR in RWPE-1 cells, the ATM̸p21 pathway was activated when RWPE-1 cells lost p53 function. In addition, when using ATM inhibitors, the ATM̸p21 pathway was inactivated in both cell lines, and the LDIR-induced cell proliferation inhibition was also abolished. These findings suggested that the ATM/p21 pathway directly participated in the LDIR-induced cell proliferation inhibition in p53null type prostate tumor cells, whereas this mechanism was absent in normal prostate cells. Thus, p53 may affect cell stability following LDIR, and plays a crucial role in regulating the ATM/p21 pathway activated by LDIR.

Low-dose irradiation promotes proliferation of the human breast cancer MDA-MB-231 cells through accumulation of mutant P53.

Low-dose irradiation (LDIR) has been proven to have differential biological effects on normal mammalian somatic cells and cancer cells. Our previous study showed that p53 gene status is a critical factor regulating the effect of LDIR on cancer cells. We investigated the effect of LDIR on the breast cancer cell line MDA-MB-231 that harbors a mutant p53 gene, and the normal breast fibroblast cell line Hs 578Bst. In the present study, we showed that 150 mGy LDIR pormoted growth of MDA-MB-231 cells but not Hs 578Bst cells. Through cell cycle analyses, we found that LDIR accelerated cell cycle into S phase in MDA-MB-231 cells, but did not affect the cell cycle of Hs 578Bst cells. Using western blotting, we demonstrated that the expression of CDK4, CDK6 and cyclin D1 was upregulated in MDA-MB-231 cells after LDIR. Although LDIR increased ataxia-telangiectasia mutated (ATM) level in both MDA-MB-231 cells and Hs 578Bst cells and activated ATM/p53/p21 pathway, only the mutant type of p53 (mtp53) protein in MDA-MB-231 cells was shown to be accumulated after LDIR. Using ATM inhibitor or lentivirus-mediated small interfering RNA (siRNA) to block the ATM/p53/p21 pathway in MDA-MB-231 cells, the LDIR-induced cell proliferation was abolished. When we introduced wild-type p53 (wtp53) protein into MDA-MB-231 cells, the LDIR-induced cell proliferation was also abolished. These findings suggest that normal p53 function is crucial in ATM/p53/p21 pathway activated by LDIR. The p53 status is the most probable reason leading to differential LDIR biological activities between breast tumor cells and normal breast cells.

Ultrastructural and physiological responses of potato (Solanum tuberosum L.) plantlets to gradient saline stress.

Salinity is one of the major abiotic stresses that impacts plant growth and reduces the productivity of field crops. Compared to field plants, test tube plantlets offer a direct and fast approach to investigate the mechanism of salt tolerance. Here we examined the ultrastructural and physiological responses of potato (Solanum tuberosum L. c.v. "Longshu No. 3") plantlets to gradient saline stress (0, 25, 50, 100, and 200 mM NaCl) with two consequent observations (2 and 6 weeks, respectively). The results showed that, with the increase of external NaCl concentration and the duration of treatments, (1) the number of chloroplasts and cell intercellular spaces markedly decreased, (2) cell walls were thickened and even ruptured, (3) mesophyll cells and chloroplasts were gradually damaged to a complete disorganization containing more starch, (4) leaf Na and Cl contents increased while leaf K content decreased, (5) leaf proline content and the activities of catalase (CAT) and superoxide dismutase (SOD) increased significantly, and (6) leaf malondialdehyde (MDA) content increased significantly and stomatal area and chlorophyll content decline were also detected. Severe salt stress (200 mM NaCl) inhibited plantlet growth. These results indicated that potato plantlets adapt to salt stress to some extent through accumulating osmoprotectants, such as proline, increasing the activities of antioxidant enzymes, such as CAT and SOD. The outcomes of this study provide ultrastructural and physiological insights into characterizing potential damages induced by salt stress for selecting salt-tolerant potato cultivars.