Zhilong Huoxue Tongyu capsule attenuates intracerebral hemorrhage induced redox imbalance by modulation of Nrf2 signaling pathway

Background: One of the severely debilitating and fatal subtypes of hemorrhagic stroke is intracerebral hemorrhage (ICH), which lacks an adequate cure at present. The Zhilong Huoxue Tongyu (ZLHXTY) capsule has been utilized effectively since last decade to treat ICH, in some provinces of China but the scientific basis for its mechanism is lacking. Purpose: To investigate the neuroprotective role of ZLHXTY capsules for ICH-induced oxidative injury through the regulation of redox imbalance with the Nrf2 signaling pathway.Methods: Autologous blood injection model of ICH in C57BL/6J mice was employed. Three treatment groups received ZLHXTY once daily through oral gavage at doses 0.35 g/kg, 0.7 g/kg, and 1.4 g/kg, started after 2 h and continued for 72 h of ICH induction. The neurological outcome was measured using a balance beam test. Serum was tested for inflammatory markers IL-1β, IL-6, and TNF-α through ELISA, oxidative stress through hydrogen peroxide content assay, and antioxidant status by total antioxidant capacity (T-AOC) assay. Nuclear extract from brain tissue was assayed for Nrf2 transcriptional factor activity. RT-qPCR was performed for Nfe2l2, Sod1, Hmox1, Nqo1, and Mgst1; and Western blotting for determination of protein expression of Nrf2, p62, Pp62, Keap, HO1, and NQO1. Fluoro-jade C staining was also used to examine neuronal damage.Results: ZLHXTY capsule treatment following ICH demonstrated a protective effect against oxidative brain injury. Neurological scoring showed improvement in behavioral outcomes. ELISA-based identification demonstrated a significant decline in the expression of serum inflammatory markers. Hydrogen peroxide content in serum was found to be reduced. The total antioxidant capacity was also reduced in serum, but the ZLHXTY extract showed a concentration-dependent increase in T-AOC speculating at its intrinsic antioxidant potential. Nrf2 transcriptional factor activity, mRNA and protein expression analyses revealed normalization of Nrf2 and its downstream targets, which were previously elevated as a result of oxidative stress induced by ICH. Neuronal damage was also reduced markedly after ZLHXTY treatment as revealed by Fluoro-jade C staining. Conclusion: ZLHXTY capsules possess an intrinsic antioxidant potential that can modulate the ICH-induced redox imbalance in the brain as revealed by the normalization of Nrf2 and its downstream antioxidant targets

Circular RNA circNOL10 Inhibits Lung Cancer Development by Promoting SCLM1-Mediated Transcriptional Regulation of the Humanin Polypeptide Family

circNOL10 is a circular RNA expressed at low levels in lung cancer, though its functions in lung cancer remain unknown. Here, the function and molecular mechanism of circNOL10 in lung cancer development are investigated using in vitro and in vivo studies, and it is shown that circNOL10 significantly inhibits the development of lung cancer and that circNOL10 expression is co‐regulated by methylation of its parental gene Pre‐NOL10 and by splicing factor epithelial splicing regulatory protein 1 (ESRP1). circNOL10 promotes the expression of transcription factor sex comb on midleg‐like 1 (SCML1) by inhibiting transcription factor ubiquitination and thus also affects regulation of the humanin (HN) polypeptide family by SCML1. circNOL10 also affects mitochondrial function through regulating the humanin polypeptide family and affecting multiple signaling pathways, ultimately inhibiting cell proliferation and cell cycle progression, and promoting the apoptosis of lung cancer cells, thereby inhibiting lung cancer development. This study investigates the functions and molecular mechanisms of circNOL10 in the development of lung cancer and reveals its involvement in the transcriptional regulation of the HN polypeptide family by SCML1. The results also demonstrate the inhibitory effect of HN on lung cancer cells growth. These findings may identify novel targets for the molecular therapy of lung cancer

Moringa oleifera leaf alleviates functional constipation via regulating the gut microbiota and the enteric nervous system in mice

Moringa oleifera Lam. leaf is not only a new food resource in China, but also a traditional medicinal plant. It is commonly used in the folk to alleviate constipation, but its laxative mechanism is not fully understood. Hence we investigated it in loperamide-induced functional constipation (FC) mice. The results showed that MOAE significantly regulated not only gastrointestinal hormones and neurotransmitters in serum but also important gastrointestinal motility factors in the enteric nervous system (ENS)-interstitial cells of Cajal (ICCs)-smooth muscle cell (SMC) network. Meanwhile, MOAE attenuated intestinal inflammation, increased cecal short-chain fatty acid levels and colonic antimicrobial peptide expression, and improved the impaired intestinal barrier function in loperamide-induced FC mice. In addition, MOAE also increased fecal water content by inhibiting the mRNA expression of colonic aquaporins (Aqp3 and Aqp4) in FC mice. Interestingly and importantly, MOAE affected the intestinal microbiota by inhibiting some key “constipation-causing” microbiota, such as Bacteroidaceae, Clostridiaceae, Bacteroides, and Ruminococcus, and promoting the growth of other important “constipation-curing” microbiota, such as Butyricoccus, Tyzzerella, and Desulfovibrio. These important taxa are significantly associated with a variety of indicators of constipation. These findings suggest that MOAE can promote defecation through its rich chemical composition to modulate the ENS-ICCs-SMCs network and the gut microecosystem

Coexistence of superconductivity with exotic ferromagnetic state in pressurized non-superconducting UTe2_2

The discovery of superconductivity in heavy Fermion UTe$_2$, a candidate topological and triplet-paired superconductor, has aroused widespread interest. However, to date, superconductivity has only been reported in nonstoichiometric crystals of UTe$_2$ with a Te deficit. Here, we demonstrate that the application of uniaxial pressure induces superconductivity in stoichiometric UTe$_2$ crystals. Measurements of resistivity, magnetoresistance and susceptibility reveal that uniaxial pressure results in a suppression of the Kondo coherent state seen at ambient pressure, leading to the emergence of superconductivity initially at 1.5 GP, followed by the development of bulk superconductivity at 4.8 GPa. The superconducting state coexists with an exotic ferromagnetically ordered (FM) state that develops just below the onset temperature of the superconducting transition. High-pressure synchrotron x-ray diffraction measurements performed at 20 K indicate that no structural phase transition occurs over the measured pressure range. Our results not only demonstrate the coexistence of superconductivity with an exotic ferromagnetic state in pressurized stoichiometric UTe$_2$, but also highlight a vital role of Te deficiency in developing superconductivity at ambient pressures.Comment: 17 pages, 4 figure

Pressure-induced coevolution of transport properties and lattice stability in CaK(Fe1-xNix)4As4 (x= 0.04 and 0) superconductors with and without spin-vortex crystal state

Here we report the first investigation on correlation between the transport properties and the corresponding stability of the lattice structure for CaK(Fe1-xNix)4As4 (x=0.04 and 0), a new type of putative topological superconductors, with and without a spin-vortex crystal (SVC) state in a wide pressure range involving superconducting to non-superconducting transition and the half- to full-collapse of tetragonal (h-cT and f-cT) phases, by the complementary measurements of high-pressure resistance, Hall coefficient and synchrotron X-ray diffraction. We identify the three critical pressures, P1 that is the turn-on critical pressure of the h-cT phase transition and it coincides with the critical pressure for the sign change of Hall coefficient from positive to negative, a manifestation of the Fermi surface reconstruction, P2 that is the turn-off pressures of the h-cT phase transition, and P3 that is the critical pressure of the f-cT phase transition. By comparing the high-pressure results measured from the two kinds of samples, we find a distinct left-shift of the P1 for the doped sample, at the pressure of which its SVC state is fully suppressed, however the P2 and the P3 remain the same as that of the undoped one. Our results not only provide a consistent understanding on the results reported before, but also demonstrate the importance of the Fe-As bonding in stabilizing the superconductivity of the iron pnictide superconductors through the pressure window

An immune-related gene prognostic risk index for pancreatic adenocarcinoma

ObjectiveOur goal is to construct an immune-related gene prognostic risk index (IRGPRI) for pancreatic adenocarcinoma (PAAD), and to clarify the immune and molecular features in IRGPRI-defined PAAD subgroups and the benefit of immune checkpoint inhibitors (ICIs) therapy.MethodThrough differential gene expression analysis, weighted gene co-expression network analysis (WGCNA), and univariate Cox regression analysis, 16 immune-related hub genes were identified using the Cancer Genome Atlas (TCGA) PAAD dataset (n = 182) and immune gene set. From these genes, we constructed an IRGPRI with the Cox regression method and the IRGPRI was verified based on the Gene Expression Omnibus (GEO) dataset (n = 45). Then, we analyzed the immune and molecular features and the benefit of ICI therapy in IRGPRI-defined subgroups.ResultsFive genes, including S100A16, CD40, VCAM1, TNFRSF4 and TRAF1 were used to construct IRGPRI. As with the results of the GEO cohort, the overall survival (OS) was more favorable in low IRGPRI patients versus high IRGPRI patients. The composite results pointed out that low IRGPRI was associated with immune response-related pathways, high level of CTLA4, low KRAS and TP53 mutation rate, more infiltration of activated memory CD4+ T cells, CD8+ T cells, and more benefits from ICIs therapy. In comparison, high IRGPRI was associated with cancer-related pathways, low expression of CTLA4, high KRAS and TP53 mutation rate, more infiltration of M2 macrophages, and less benefit from ICIs therapies.ConclusionThis IRGPRI is an encouraging biomarker to define the prognosis, immune and molecular features, and benefits from ICIs treatments in PAAD

Evaluation of progression of chronic kidney disease in dogs with myxomatous mitral valve disease

IntroductionCardiovascular and renal diseases are known to affect each other in the cardiovascular renal axis disorder (CvRD). Although CvRD, which includes myxomatous mitral valve disease (MMVD) and chronic kidney disease (CKD), has been described in dogs, there are only a few reports on the progression of CKD in accordance with the severity of MMVD. The aim of this study was to evaluate whether the presence of MMVD is associated with the rate of progression of CKD in dogs. The time from the initial diagnosis to the worsening of the International Renal Interest Society (IRIS) stage and the time for the occurrence of hyperphosphatemia and isosthenuria were evaluated.Materials and methodsIn this retrospective study, CKD progression was determined as an increase in the IRIS stage by at least one level and the development of hyperphosphatemia or isosthenuria. The CKD progression was compared in dogs with and without comorbid MMVD.ResultsDogs with CKD were divided into two groups: dogs with and without MMVD (n = 63, concurrent group; n = 52, CKD group, respectively). The concurrent group was further divided into two subgroups based on the American College of Veterinary Internal Medicine guidelines (B1 group, n = 24; B2 group, n = 39). The time for progression of CKD from IRIS stage 1 to IRIS stage 2 was significantly shorter in the concurrent group than in the CKD group (log-rank test, p < 0.001). MMVD was associated with an increased risk of progression from stage 1 to stage 2 (hazard ratio, 6.442; 95% confidence interval (CI), 2.354 to 18.850; p < 0.001). The timing of the onset of hyperphosphatemia or isosthenuria in the concurrent group and the CKD group was not significantly different.ConclusionThe results of this study suggest that MMVD could be a risk factor for the progression of CKD. Our findings may help predict the prognosis of dogs with both CKD and MMVD compared to CKD only