Macrophage KLF15 prevents foam cell formation and atherosclerosis via transcriptional suppression of OLR-1.

BACKGROUND: Macrophage-derived foam cells are a hallmark of atherosclerosis. Scavenger receptors, including lectin-like oxidized low-density lipoprotein (LDL) receptor-1 (OLR-1), are the principal receptors responsible for the uptake and modification of LDL, facilitating macrophage lipid load and the uptake of oxidized LDL by arterial wall cells. Krüppel-like factor 15 (KLF15) is a transcription factor that regulates the expression of genes by binding to the promoter during transcription. Therefore, this study aimed to investigate the precise role of macrophage KLF15 in atherogenesis. METHODS: We used two murine models of atherosclerosis: mice injected with an adeno-associated virus (AAV) encoding the Asp374-to-Tyr mutant version of human PCSK9, followed by 12 weeks on a high-fat diet (HFD), and ApoE-/-- mice on a HFD. We subsequently injected mice with AAV-KLF15 and AAV-LacZ to assess the role of KLF15 in the development of atherosclerosis in vivo. Oil Red O, H&E, and Masson's trichome staining were used to evaluate atherosclerotic lesions. Western blots and RT-qPCR were used to assess protein and mRNA levels, respectively. RESULTS: We determined that KLF15 expression was downregulated during atherosclerosis formation, and KLF15 overexpression prevented atherosclerosis progression. KLF15 expression levels did not affect body weight or serum lipid levels in mice. However, KLF15 overexpression in macrophages prevented foam cell formation by reducing OLR-1-meditated lipid uptake. KLF15 directly targeted and transcriptionally downregulated OLR-1 levels. Restoration of OLR-1 reversed the beneficial effects of KLF15 in atherosclerosis. CONCLUSION: Macrophage KLF15 transcriptionally downregulated OLR-1 expression to reduce lipid uptake, thereby preventing foam cell formation and atherosclerosis. Thus, our results suggest that KLF15 is a potential therapeutic target for atherosclerosis.

Impaired long contact white matter fibers integrity is related to depression in Parkinson's disease.

AIMS: Depression is one of the most common nonmotor symptoms in Parkinson's disease (PD). But the pathogenesis is still unclear. Studies have shown that depression in PD is closely related to the white matter abnormalities, but the number of studies is still very small and lack of whole brain white matter lesions study. METHODS: In this study, we investigated whole brain white matter integrity in 31 depressed PD patients and 37 nondepressed PD patients by diffusion tensor imaging. RESULTS: There was no difference in age, gender, age of onset, disease duration, Hoehn-Yahr scale, Unified Parkinson's Disease Rating Scale scores-III, and Mini-Mental State Examination scores between the two groups. The only difference was the Hamilton Depression Rating Scale. Depressed PD patients showed reduced fractional anisotropy values in the left anterior corona radiata, left posterior thalamic radiation, left cingulum, left superior longitudinal fasciculus, left sagittal stratum (including inferior longitudinal fasciculus and inferior fronto-occipital fasciculus), and left uncinate fasciculus. In patients with depression, the Hamilton Depression Rating Scale (HDRS) was negatively correlated with the FA value in the left cingulum (r = -0.712, P = .032) and left superior longitudinal fasciculus (r = -0.699, P = .025). CONCLUSIONS: This study suggested depression in PD was related to impaired white matter integrity especially the long contact fibers in the left hemisphere. These findings may be helpful for further understanding the potential mechanisms underlying depression in PD.

Safety and efficacy of umbilical cord mesenchymal stem cell therapy in hereditary spinocerebellar ataxia.

Hereditary spinocerebellar ataxia (SCA) is a devastating, incurable disease. Stem-cell-based therapies represent new promise for clinical research in neurology. The objectives of this study were to assess the feasibility, efficacy, and potential toxicity of human umbilical cord mesenchymal stem cells (UCMSCs) therapy in patients with SCA. Sixteen genomically diagnosed SCA patients were enrolled and received intravenous and intrathecal infusion of UCMSCs. Clinical, laboratory, and radiographic evaluations were conducted to assess the safety of UCMSC therapy. Efficacy was evaluated by the Berg Balance Scale (BBS) and International Cooperative Ataxia Rating Scale (ICARS) scores. Among the 16 cases, there were no serious transplant-related adverse events happened in 12 months follow-up. The majority of patients showed improved BBS and ICARS scores continuing for at least 6 months which indicated UCMSC therapy could alleviate SCA symptoms. This study suggested that UCMSC transplantation was safe and might delay the progression of SCA. This may represent a new therapeutic strategy for SCA and other genetic neurological diseases.

Icariin enhances neuronal survival after oxygen and glucose deprivation by increasing SIRT1.

It has been reported that icariin protects neurons against ischemia/reperfusion injury. In this study, we found that icariin could enhance neuronal viability and suppress neuronal death after oxygen and glucose deprivation (OGD). Further study showed that neuroprotection by icariin was through the induction of Sirtuin type 1 (SIRT1), an effect that was reversed by SIRT1 inhibitor III and P38 inhibitor SB203580. SIRT1 is an endogenous gene of longevity, which increased neuronal viability and could be activated by stimulating the mitogen-activated protein kinase (MAPK) pathway. However, this study found that icariin activated the MAPK/P38 pathway, not the extracellular signal-regulated kinase (MAPK/ERK) or c-Jun N-terminal protein kinase (MAPK/JNK) to regulate SIRT1 expression. The results suggest that icariin may be developed into a neuroprotectant for ischemia-related brain injury.

Opening of microglial K(ATP) channels inhibits rotenone-induced neuroinflammation.

As activated microglia (MG) is an early sign that often precedes and triggers neuronal death, inhibition of microglial activation and reduction of subsequent neurotoxicity may offer therapeutic benefit. The present study demonstrates that rat primary cultured MG expressed Kir6.1 and SUR2 subunits of K(ATP) channel, which was identical to that expressed in BV-2 microglial cell line. The classic K(ATP) channel opener pinacidil and selective mitochondrial K(ATP) (mito-K(ATP)) channel opener diazoxide prevented rotenone-induced microglial activation and production of pro-inflammatory factors (tumour necrosis factor[TNF]-alpha and prostaglandin E(2)[PGE(2)]). And the effects of pinacidil and diazoxide were reversed by mito-K(ATP) blocker 5-hydroxydecanoate (5-HD), indicating that mito-K(ATP) channels participate in the regulation of microglial activation. Moreover, the underlying mechanisms involved the stabilization of mitochodrial membrane potential and inhibition of p38/c-Jun-N-terminal kinase (JNK) activation in microglia. Furthermore, the in vivo study confirmed that diazoxide exhibited neuroprotective effects against rotenone along with the inhibition of microglial activation and neuroinflammation. Thus, microglial mito-K(ATP) channel might be a novel prospective target for the treatment of neuroinflammation-related degenerative disorders such as Parkinson's disease.

Enhancement of glutamate uptake in 1-methyl-4-phenylpyridinium-treated astrocytes by trichostatin A.

Histone deacetylases (HDAC) inhibitors have been emerging as neuroprotective agents by acting on neurons and microglia. In this study, we found trichostatin A (TSA), a HDAC inhibitor, could inhibit the elevation of glutamate in 150 microM 1-methyl-4-phenylpyridinium (MPP+)-treated primary cultured astrocytes medium when its concentration reached 132 nM. TSA of 132 nM or more could promote the uptake of [3H]-D, L-glutamate by astrocytes. Further study showed the downregulation of glutamate transporter 1 and glutamate/aspartate transporter induced by MPP+ were prevented by TSA. Therefore, these findings suggested TSA could alleviate MPP+-induced impairment of astrocytic glutamate uptake, which might be a novel mechanism contributing to neuroprotection by HDAC inhibitors.

Iptakalim alleviates rotenone-induced degeneration of dopaminergic neurons through inhibiting microglia-mediated neuroinflammation.

Inhibition of microglia-mediated neuroinflammation has been regarded as a prospective strategy for treating neurodegenerative disorders, such as Parkinson's disease (PD). In the present study, we demonstrated that systematic administration with iptakalim (IPT), an adenosine triphosphate (ATP)-sensitive potassium channel (K(ATP)) opener, could alleviate rotenone-induced degeneration of dopaminergic neurons in rat substantia nigra along with the downregulation of microglial activation and mRNA levels of tumor necrosis factor-alpha (TNF-alpha) and cyclooxygenase-2 (COX-2). In rat primary cultured microglia, pretreatment with IPT suppressed rotenone-induced microglial activation evidenced by inhibition of microglial amoeboid morphological alteration, declined expression of ED1 (a marker for activated microglia), and decreased production of TNF-alpha and prostaglandin E2 (PGE(2)). These inhibitory effects of IPT could be reversed by selective mitochondrial K(ATP) (mitoK(ATP)) channel blocker 5-hydroxydecanoate (5-HD). Furthermore, pretreatment with IPT prevented rotenone-induced mitochondrial membrane potential loss and p38/c-jun N-terminal kinase (JNK) mitogen-activated protein kinase (MAPK) activation in microglia, which might in turn regulate microglial activation and subsequent production of TNF-alpha and PGE(2). These data strongly suggest that the K(ATP) opener IPT may be a novel and promising neuroprotective drug via inhibiting microglia-mediated neuroinflammation.

Activation of Group II/III metabotropic glutamate receptors attenuates LPS-induced astroglial neurotoxicity via promoting glutamate uptake.

Altered glial function that leads to oxidative stress and excitotoxicity may contribute to the initiation or progression of neuronal death in neurodegenerative diseases. We report the pivotal role of astroglial Group II and III metabotropic glutamate receptors (mGluR) against neurotoxicity. Activation of Group II or III mGluR on astrocytes with selective agonists DCG-IV or L-AP4 respectively inhibited astroglial lipopolysaccharide (LPS)-conditioned medium induced apoptosis of primary cultured mesencephalic neurons. Specific Group II or III mGluR antagonists APICA or MSOP completely abolished the neuroprotective effects of DCG-IV and L-AP4. Morphologic analysis showed that DCG-IV or L-AP4 could also attenuate the astroglial neurotoxicity to dopaminergic neurons. Measurement of extracellular glutamate concentration and [(3)H]-glutamate uptake showed that the restoration of glutamate uptake capability in LPS-treated astrocytes might be involved in the neuroprotective effects of activating astroglial Group II or III mGluR. Furthermore, we found that the repression of astroglial uptake function could be revived by GSH, and both Group II and III mGluR agonists could recover the endogenous reduced glutathione (GSH) level in LPS-treated astrocytes. These results suggested that the possible mechanisms of neuroprotection by either Type II or Type III mGluR activation may involve restoration of endogenous GSH, in turn affording recovery of astroglial capability to take up glutamate.

The regulation of rotenone-induced inflammatory factor production by ATP-sensitive potassium channel expressed in BV-2 cells.

Our previous studies have demonstrated that activating ATP-sensitive potassium channel (K(ATP) channel), not only improved Parkinsonian behavior and neurochemical symptoms, but also reduced iNOS activity and mRNA levels in striatum and nigra of rotenone rat model of Parkinson's disease (PD). In this study, it was first shown that the subunits of K(ATP) channels are expressed in BV-2 cells, and then it was investigated whether K(ATP) channel was involved in regulating inflammatory factor production from BV-2 cells activated by rotenone. It was found that K(ATP) channel was expressed in BV-2 cell and formed by the combination of Kir 6.1 and SUR 2A/2B. K(ATP) channel openers (KCOs) including pinacidil, diazoxide and iptakalim (Ipt) exerted beneficial effects on rotenone-induced morphological alterations of BV-2 cells, decreased tumor necrosis factor alpha (TNF-alpha) production and the expression and activity of inducible isoform of nitric oxide synthase (iNOS). Either glibenclamide or 5-hydroxydecanoate acid (a selective mitochondrial K(ATP) channel blocker) could abolish the effects of KCOs, suggesting that K(ATP) channels, especially mitochondrial ATP-sensitive potassium channels (mitoK(ATP) channels), played a crucial role in preventing the activation of BV-2 cells, and subsequently the production of a variety of proinflammatory factors. Therefore, activation of K(ATP) channel might be a new therapeutic strategy for treating neuroinflammatory and neurodegenerative disorders.