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Background: Alisol A can ameliorate glucose metabolism disorders, however, there is no data regarding its role in diabetic nephropathy (DN). The present work evaluates the role of Alisol A in DN and the underlying mechanism. Methods: RNA expression of circ_0001831, miR‐346, and lin‐28 homolog B (LIN28B) was detected by qRT‐PCR. Cell viability and proliferation were investigated by MTT assay and EdU assay, respectively. The inflammatory cytokines were examined by ELISAs. Oxidative stress was evaluated by the commercial kits. Protein expression was detected by western blotting. The interactions among circ_0001831, miR‐346, and LIN28B were identified by dual‐luciferase reporter assay and RIP assay. DN mouse model assay was used to analyse the effect of Alisol A on renal injury of diabetic mice. Results: HG treatment promoted HRMC proliferation, fibrosis, inflammation, and oxidative stress; however, these effects were reversed after Alisol A treatment. Alisol A treatment ameliorated STZ‐induced renal injury of diabetic mice. Additionally, circ_0001831 or LIN28B overexpression or miR‐346 downregulation relieved Alisol A‐induced effects under HG conditions. Mechanistically, circ_0001831 acted as a miR‐346 sponge, and LIN28B was identified as a target gene of miR‐346. Further, the regulation of circ_0001831 in HG‐induced HRMC dysfunction involved LIN28B. Conclusion: Alisol A ameliorated HG‐induced HRMC fibrosis, inflammation, and oxidative stress and STZ‐induced renal injury of diabetic mice by regulating the circ_0001831/miR‐346/LIN28B pathway. [ABSTRACT FROM AUTHOR]

Baicalin (BCL) has been found to have neuroprotective effects in ischemic stroke (IS), but its underlying molecular mechanisms are unknown. SK‐N‐SH cells were treated with BCL and then induced by oxygen–glucose deprivation/reoxygenation (OGD/R). Cell proliferation, apoptosis, inflammation, and ferroptosis were detected. Protein levels were examined by western blot. The expression levels of microRNA (miR)‐556‐3p and ACSL4 were tested via quantitative real‐time PCR. MiR‐556‐3p and Acyl‐CoA synthetase long‐chain family member 4 (ACSL4) interaction was confirmed via dual‐luciferase reporter assay and RNA pull‐down assay. Middle cerebral artery occlusion (MCAO) mice model was constructed to assess the role of BCL on brain injury in vivo. Our study showed that BCL treatment alleviated OGD/R‐induced SK‐N‐SH cell apoptosis, inflammation and ferroptosis. MiR‐556‐3p was decreased in OGD/R‐induced SK‐N‐SH cells, and BCL treatment enhanced its expression. MiR‐556‐3p could target ACSL4, and its overexpression relieved OGD/R‐induced SK‐N‐SH cell injury by targeting ACSL4. Besides, miR‐556‐3p inhibitor or ACSL4 overexpression reversed the inhibitory effect of BCL on OGD/R‐induced SK‐N‐SH cell injury. In vivo, BCL alleviated brain injury in MCAO mice through miR‐556‐3p/ACSL4 axis. In conclusion, BCL alleviated OGD/R‐induced SK‐N‐SH cell injury and relieved brain injury in MCAO mice by regulating miR‐556‐3p/ACSL4 axis. [ABSTRACT FROM AUTHOR]

Myocardial ischemia/reperfusion injury (MIRI) is a significant challenge in the management of myocardial ischemic disease. Extensive evidence suggests that the macrophage-mediated inflammatory response may play a vital role in MIRI. Mesenchymal stem cells and, in particular, exosomes derived from these cells, may be key mediators of myocardial injury and repair. However, whether exosomes protect the heart by regulating the polarization of macrophages and the exact mechanisms involved are poorly understood. The present study aimed to determine whether exosomes secreted by bone marrow mesenchymal stem cells (BMSC-Exo) harboring miR-25-3p can alter the phenotype of macrophages by affecting the JAK2/STAT3 signaling pathway, which reduces the inflammatory response and protects against MIRI. An in vivo MIRI model was established in rats by ligating the anterior descending region of the left coronary artery for 30 min followed by reperfusion for 120 min, and BMSC-Exo carrying miR-25-3p (BMSC-Exo-25-3p) were administered through tail vein injection. A hypoxia-reoxygenation model of H9C2 cells was established, and the cells were cocultured with BMSC-Exo-25-3p in vitro. The results of the present study demonstrated that BMSC-Exo or BMSC-Exo-25-3p could be taken up by cardiomyocytes in vivo and H9C2 cells in vitro. BMSC-Exo-25-3p demonstrated powerful cardioprotective effects by decreasing the cardiac infarct size, reducing the incidence of malignant arrhythmias and attenuating myocardial enzyme activity, as indicated by lactate dehydrogenase and creatine kinase levels. It induced M1-like macrophage polarization after myocardial ischemia/reperfusion (I/R), as evidenced by the increase in iNOS expression through immunofluorescence staining and upregulation of proinflammatory cytokines through RT-qPCR, such as interleukin-1β (IL-1β) and interleukin-6 (IL-6). As hypothesized, BMSC-Exo-25-3p inhibited M1-like macrophage polarization and proinflammatory cytokine expression while promoting M2-like macrophage polarization. Mechanistically, the JAK2/STAT3 signaling pathway was activated after I/R in vivo and in LPS-stimulated macrophages in vitro, and BMSC-Exo-25-3p pretreatment inhibited this activation. The results of the present study indicate that the attenuation of MIRI by BMSC-Exo-25-3p may be related to JAK2/STAT3 signaling pathway inactivation and subsequent inhibition of M1-like macrophage polarization. [ABSTRACT FROM AUTHOR]

The Bohai Bay Basin, located on the eastern Asian margin, is the second largest oil-production basin in China. It contains numerous depressions and sags, among which Nanpu Sag has become particularly important because of significant oil discoveries in recent years. Geologically and tectonically, however, the rifting mechanism and geodynamic evolution of the basin remain uncertain. This paper uses detailed volcanic and stratigraphic records obtained through extensive drilling and sampling in Nanpu Sag to interpret tectono-stratigraphic sequences and discuss basin dynamic evolution and crust-mantle interactions of the Bohai Bay Basin. Nanpu Sag contains voluminous volcanic rocks of dominantly alkaline basalts. Drill core samples, well logs, and seismic profiles reveal three volcanic cycles between the Eocene and Miocene Epochs. These basalts were created during a transition from garnet- to spinel-peridotite. Five tectono-stratigraphic sequences produced by episodic continental rifting have been identified, each composed of a basal coarse clastic sequence, a lower volcanic sequence, a middle deep-water clastic sequence, and an upper infilling sequence. Tectonically, Nanpu Sag experienced four evolutionary phases. The first three corresponded to three rifting events revealed by cyclic volcanism and sedimentary depositional features. The fourth phase was marked by extreme thermal subsidence and prograding fluvial deposition fallowed by tectonic inversion. A diapiric upper-mantle upwelling model is proposed to explain the dynamics that controlled the multiple rifting processes, the cyclic volcanism, and the periodic tectonic evolution of Nanpu Sag and the greater Bohai Bay Basin. doi: 10.1130/B30041.1

Although cryptococcosis is widely recognized as infection by Cryptococcus neoformans sensu lato from environmental sources, information concerning the characteristics of environmental isolates of C. neoformans s. l. and how they are related to clinical isolates is very limited, especially in East China. In this study, 61 environmental isolates of C. neoformans were recovered from pigeon (Columba livia) droppings from the Yangtze River Delta region of East China. These isolates were genotyped using the ISHAM-MLST consensus scheme and their antifungal drug susceptibilities were determined following the CLSI M27-A3 guidelines. The 61 isolates were found belonging to 13 sequence types (STs), including several novel STs such as ST254 and ST194. The dominant ST in this environmental sample was ST31, different from that of clinical strains (ST5) in this region. Azole-resistance, such as fluconazole (FLU)-resistance, was observed among our environmental C. neoformans isolates. The findings of this study expand our understanding of ecological niches, population genetic diversity, and azole-resistance characteristics of the yeast in East China. Our research lays the foundation for further comparative analysis the potential mechanisms for the observed differences between environmental and clinical populations of C. neoformans in China. Lay Summary Cryptococcosis is widely recognized as infection by Cryptococcus neoformans sensu lato from environmental sources. However, there is currently limited information about the genetic diversity and antifungal susceptibility of environmental C. neoformans s. l. isolates, including how they may differ from clinical samples. In this study, we collected 61 environmental C. neoformans isolates from domestic pigeon droppings from the Yangtze River Delta region of East China. These isolates were genotyped using multi-locus sequencing. We found a high genotypic diversity in this population of C. neoformans , with several novel genotypes and a distribution of genotypes different from that of clinical strains in this region. Azole-resistance, such as fluconazole (FLU)-resistance, was observed among our environmental C. neoformans isolates. The findings of this study expand our understanding of ecological niches, genetic diversity, and azole-resistance characteristics of the yeast in East China. Our research lays the foundation for phylogenomic analysis investigating why and how disparate population structures of C. neoformans isolates formed between environmental and clinical sources in the region. [ABSTRACT FROM AUTHOR]

SKI-349 is a novel sphingosine kinases (SPHK) inhibitor with anti-tumor effects. This study aimed to assess the effect of SKI-349 on cell biological behaviors, downstream pathways, and its synergistic effect with sorafenib in hepatocellular carcinoma (HCC). HCC cell lines (Huh7 and Hep3B) were treated with SKI-349 at concentrations of 1, 2, 4, or 8 μM. Then, SPHK1/2 activity, cell viability, proliferation, apoptosis, invasion, and protein expressions of phosphorylated-protein kinase B (p-AKT), AKT, phosphorylated-mammalian target of rapamycin (p-mTOR) and mTOR were detected. Combination index values of SKI-349 (0, 1, 2, 4, or 8 μM) and sorafenib (0, 2.5, 5, 10, or 20 μM) were calculated. SKI-349 decreased the relative SPHK1 and SPHK2 activity compared with blank control in a dose-dependent manner in the Huh7 and Hep3B cell lines. Meanwhile, SKI-349 reduced cell viability, 5-ethynyl-2'-deoxyuridine (EdU) positive cells, and invasive cells, while it increased apoptotic cells compared to blank control in a dose-dependent manner in Huh7 and Hep3B cell lines. Based on the western blot assay, SKI-349 decreased the ratio of p-AKT to AKT and that of p-mTOR to mTOR compared with blank control in a dose-dependent manner in the Huh7 and Hep3B cell lines. Additionally, SKI-349 combined with sorafenib declined cell viability with concentration gradient effects compared to SKI-349 sole treatment, and they had synergistic cytotoxic effects in Huh7 and Hep3B cell lines. SKI-349 suppresses SPHK1 and SPHK2 activity, cell viability, invasion, and AKT/mTOR signaling pathway, as well as exhibits a synergistic cytotoxic effect with sorafenib in HCC.