Dysregulated long non-coding RNAs participate in the development of diabetic cerebral ischemia. This study aimed to investigate the underlying mechanism of lncRNA MALAT1 in diabetic cerebral ...ischemia.
Middle cerebral artery occlusion (MCAO) was performed to establish diabetic cerebral I/R in vivo. TTC and neurological deficits assessment were performed to assess cerebral ischemic injury. LDH was conducted to detect cytotoxicity. RT-qPCR and western blotting assays were applied to determine mRNA and protein expression. Flow cytometry was performed to detect the pyroptosis of BV2 cells. Immunofluorescence and FISH were conducted for subcellular localization of MALAT1 and STAT1. ELISA was performed to determine cytokine release. Dual luciferase reporter, RIP, and ChIP assays were used to validate the interaction between STAT1 and MALAT1/NLRP3. Diabetes aggravated cerebral injury in vivo and in vitro. Diabetic cerebral ischemia induced inflammatory response and inflammation-induced cell pyroptosis.
MALAT1 was overexpressed in diabetic cerebral ischemia models in vivo and in vitro. However, knockdown of MALAT1 suppressed inflammatory response and the pyroptosis of BV2 cells. Moreover, MALAT1 interacted with STAT1 to transcriptionally activate NLRP3. Knockdown of STAT1 significantly reversed the effects of MALAT1. Furthermore, STAT1 promotes the MALAT1 transcription. MALAT1 interacts with STAT1 to promote the pyroptosis of microglias induced by diabetic cerebral ischemia through activating NLRP3 transcription.
Thus, knockdown of MALAT1 may be a potential promising therapy target for diabetic cerebral ischemia.
With the advent of isogeometric analysis, the modeling of spline solids became an important topic. In this paper, we present a discrete volume parameterization method for tetrahedral (tet) mesh ...models and an iterative fitting algorithm with a B-spline solid. The discrete volume parameterization method maps the vertices of a tet mesh into a parameter domain by solving a system of linear equations. Each equation is explicitly constructed for an inner vertex in terms of the geometric information adjacent to the inner vertex. Moreover, we show the validity of the parameterization system of linear equations thus constructed. Next, because the number of tet mesh vertices is usually very large, we develop an iterative algorithm for fitting a tet mesh with a B-spline solid. The iterative algorithm exploits the geometric information of the control hexahedral (hex) mesh and the local support property of the spline function, so the total amount of computation in each iteration is unchanged when the number of control hex mesh vertices of the B-spline solid is increased. Therefore, the iterative fitting algorithm performs very well in incremental fitting of a tet mesh with a large number of vertices. Finally, four experimental examples presented in this paper show the efficiency and effectiveness of the developed algorithms.
Intracerebral hemorrhage (ICH) has a high mortality and disability rate. Numerous basic studies on pathogenesis and therapeutics have been performed in mice. However, the consistency of the ...experimental mouse model and the human ICH patient remains unclear. This has slowed progress in translational medicine. Furthermore, effective therapeutic targets and reliable regulatory networks for ICH are needed. Therefore, we determined the differentially expressed (DE) messenger RNAs (mRNAs), microRNAs (miRNAs) and circular RNAs (circRNAs) before and after murine ICH and analyzed their regulatory relationships. Subsequently, data on mRNAs from human peripheral blood after ICH were obtained from the Gene Expression Omnibus database. The DE mRNAs after human ICH were compared with those of the mouse. Finally, we obtained seven genes with translational medicine research value and verified them in mice. Then the regulatory network of these genes was analyzed in humans. Similarly, species homologies of these regulatory pathways were identified. In conclusion, we found that the mouse ICH model mimics the human disease mainly in terms of chemokines and inflammatory factors. This has important implications for future research into the mechanisms of ICH injury and repair.
Neuronal pentraxin 2 (Nptx2), a member of the synaptic protein family linked to excitatory synaptic formation, is found to be upregulated in epileptic mice, yet its role in epilepsy has been unclear. ...In vivo, we constructed a mouse model of epilepsy by using kainic acid induction. In vitro experiments, a Mg
-free medium was used to induce epileptiform discharges in neurons. The results showed that the Nptx2 was upregulated in epileptic mice. Moreover, Nptx2 knockdown reduced the number of seizures and seizure duration. Knocking down Nptx2 not only reduced the number and duration of seizures but also showed a decrease in electroencephalogram amplitude. Behavioral tests indicated improvements in learning and memory abilities after Nptx2 knockdown. The Nissl staining and Timms staining revealed that Nptx2 silencing mitigated epilepsy-induced brain damage. The immunofluorescence staining revealed that Nptx2 absence resulted in a reduction of apoptosis. Nptx2 knockdown reduced Bax, cleaved caspase3, and cleaved caspase9 expression, while increased Bcl-2 expression. Notably, Nptx2 knockdown inhibited GluA1 phosphorylation at the S831 site and reduced the GluA1 membrane expression. The PSD95 expression declined in the epilepsy model, while the Nptx2 knockdown reversed it. Collectively, our study indicated that Nptx2 silencing not only alleviated brain damage and neuron apoptosis but also improved learning and memory ability in epileptic mice, suggesting Nptx2 as a promising target for epilepsy treatment.
Diabetes mellitus causes brain microvascular endothelial cell (MEC) damage, inducing dysfunctional angiogenic response and disruption of the blood-brain barrier (BBB). Canagliflozin is a ...revolutionary hypoglycemic drug that exerts neurologic and/or vascular-protective effects beyond glycemic control; however, its underlying mechanism remains unclear. In the present study, we hypothesize that canagliflozin ameliorates BBB permeability by preventing diabetes-induced brain MEC damage. Mice with high-fat diet/streptozotocin-induced diabetes received canagliflozin for 8 weeks. We assessed vascular integrity by measuring cerebrovascular neovascularization indices. The expression of specificity protein 1 (Sp1), as well as tight junction proteins (TJs), phosphorylated AMP-activated protein kinase (p-AMPK), and adenosine A2A receptors was examined. Mouse brain MECs were grown in high glucose (30 mM) to mimic diabetic conditions. They were treated with/without canagliflozin and assessed for migration and angiogenic ability. We also performed validation studies using AMPK activator (AICAR), inhibitor (Compound C), Sp1 small interfering RNA (siRNA), and adenosine A2A receptor siRNA. We observed that cerebral pathological neovascularization indices were significantly normalized in mice treated with canagliflozin. Increased Sp1 and adenosine A2A receptor expression and decreased p-AMPK and TJ expression were observed under diabetic conditions. Canagliflozin or AICAR treatment alleviated these changes. However, this alleviation effect of canagliflozin was diminished again after Compound C treatment. Either Sp1 siRNA or adenosine A2A receptor siRNA could increase the expression of TJs. Luciferase reporter assay confirmed that Sp1 could bind to the adenosine A2A receptor gene promoter. Our study identifies the AMPK/Sp1/adenosine A2A receptor pathway as a treatment target for diabetes-induced cerebrovascular injury.
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There are few effective preventive or therapeutic strategies to mitigate the effects of catastrophic intracerebral hemorrhage (ICH) in humans. Heme oxygenase is the rate-limiting enzyme in heme ...metabolism; heme oxygenase-2 (HO-2) is a constitutively expressed heme oxygenase. We explored the involvement of HO-2 in a collagenase-induced mouse model of ICH in C57BL/6 wild-type and HO-2 knockout mice. We assessed oxidative stress injury, blood-brain barrier permeability, neuronal damage, late-stage angiogenesis, and hematoma clearance using im-munofluorescence, Western blot, MRi, and special staining methods. Our results show that HO-2 reduces brain injury volume and brain edema, alleviates cytotoxic injury, affects vascular function in the early stage of iCH, and improves hematoma absorbance and angiogenesis in the late stage of ICH in this model. Thus, we found that HO-2 has a protective effect on brain injury after iCH. Key Words: Angiogenesis, Heme oxygenase-2, Intracerebral hemorrhage, Neuronal damage, Oxidative stress.
The hexahedral mesh (hex mesh) is usually preferred to the tetrahedral mesh (tet mesh) in finite element methods for numerical simulation. In finite element analysis, a valid hex mesh requires that ...the scaled Jacobian value at each mesh vertex is larger than 0. However, the hex mesh produced by lots of prevailing hex mesh generation methods cannot be guaranteed to be a valid hex mesh. In this paper, we develop a constrained volume iterative fitting (CVIF) algorithm to fill a given triangular mesh model with an all-hex volume mesh. Starting from an initial all-hex mesh model, which is generated by voxelizing the given triangular mesh model, CVIF algorithm fits the boundary mesh of the initial all-hex mesh to the given triangular mesh model by iteratively adjusting the boundary mesh vertices. In each iteration, the movements of the boundary mesh vertices are diffused to the inner all-hex mesh vertices. After the iteration stops, an all-hex volume mesh that fills the given triangular mesh model can be generated. In the CVIF algorithm, the movement of each all-hex mesh vertex is constrained to ensure that the scaled Jacobian value at each mesh vertex is larger than 0, etc. Therefore, the all-hex mesh generated by the CVIF algorithm is guaranteed to be a valid all-hex mesh.
•An iterative algorithm is developed to fill a triangular mesh with an all-hex mesh.•The Jacobian values of the all-hex mesh are guaranteed to be positive.•The convergence of the iterative algorithm is proved.
Abstract
There are few effective preventive or therapeutic strategies to mitigate the effects of catastrophic intracerebral hemorrhage (ICH) in humans. Heme oxygenase is the rate-limiting enzyme in ...heme metabolism; heme oxygenase-2 (HO-2) is a constitutively expressed heme oxygenase. We explored the involvement of HO-2 in a collagenase-induced mouse model of ICH in C57BL/6 wild-type and HO-2 knockout mice. We assessed oxidative stress injury, blood-brain barrier permeability, neuronal damage, late-stage angiogenesis, and hematoma clearance using immunofluorescence, Western blot, MRI, and special staining methods. Our results show that HO-2 reduces brain injury volume and brain edema, alleviates cytotoxic injury, affects vascular function in the early stage of ICH, and improves hematoma absorbance and angiogenesis in the late stage of ICH in this model. Thus, we found that HO-2 has a protective effect on brain injury after ICH.
Intracerebral hemorrhage (ICH) is a lethal stroke with high mortality or disability. However, effective therapy for ICH damage is generally lacking. Previous investigations have suggested that ...lysosomal protein transmembrane 5 (LAPTM5) is involved in various pathological processes, including autophagy, apoptosis, and inflammation. In this study, we aimed to identify the expression and functions of LAPTM5 in collagenase-induced ICH mouse models and hemoglobin-induced cell models. We found that LAPTM5 was highly expressed in brain tissues around the hematoma, and double immunostaining studies showed that LAPTM5 was co-expressed with microglia cells, neurons, and astrocytes. Following ICH, the mice presented increased brain edema, blood-brain barrier permeability, and neurological deficits, while pathological symptoms were alleviated after the
LAPTM5
knockdown. Adeno-associated virus 9-mediated downregulation of
LAPTM5
also improves ICH-induced secondary cerebral damage, including neuronal degeneration, the polarization of M1-like microglia, and inflammatory cascades. Furthermore, LAPTM5 promoted activation of the nuclear factor kappa-B (NF-κB) pathway in response to neuroinflammation. Further investigations indicated that brain injury improved by
LAPTM5
knockdown was further exacerbated after the overexpression of receptor-interacting protein kinase 1 (
RIP1
), which is revealed to trigger the NF-κB pathway. In vitro experiments demonstrated that
LAPTM5
silencing inhibited hemoglobin-induced cell function and confirmed regulation between RIP1 and LAPTM5. In conclusion, the present study indicates that LAPTM5 may act as a positive regulator in the context of ICH by modulating the RIP1/NF-κB pathway. Thus, it may be a candidate gene for further study of molecular or therapeutic targets.
Gut microbiota dysbiosis is closely involved in intestinal carcinogenesis. A marked reduction in butyrate-producing bacteria has been observed in patients with colorectal cancer (CRC); nevertheless, ...the potential benefit of butyrate-producing bacteria against intestinal tumor development has not been fully investigated. We found that Clostridium butyricum (C. butyricum, one of the commonly used butyrate-producing bacteria in clinical settings) significantly inhibited high-fat diet (HFD)-induced intestinal tumor development in Apcmin/+ mice. Moreover, intestinal tumor cells treated with C. butyricum exhibited decreased proliferation and increased apoptosis. Additionally, C. butyricum suppressed the Wnt/β-catenin signaling pathway and modulated the gut microbiota composition, as demonstrated by decreases in some pathogenic bacteria and bile acid (BA)-biotransforming bacteria and increases in some beneficial bacteria, including short-chain fatty acid (SCFA)-producing bacteria. Accordingly, C. butyricum decreased the fecal secondary BA contents, increased the cecal SCFA quantities, and activated G-protein coupled receptors (GPRs), such as GPR43 and GPR109A. The anti-proliferative effect of C. butyricum was blunted by GPR43 gene silencing using small interfering RNA (siRNA). The analysis of clinical specimens revealed that the expression of GPR43 and GPR109A gradually decreased from human normal colonic tissue to adenoma to carcinoma. Together, our results show that C. butyricum can inhibit intestinal tumor development by modulating Wnt signaling and gut microbiota and thus suggest the potential efficacy of butyrate-producing bacteria against CRC.
•CB inhibited intestinal tumor development via modulating Wnt signaling.•CB altered gut microbiota and microbial-derived metabolites levels.•GPR43 and GPR109A were involved in the efficacy of CB.
