Parkinson disease (PD) is the second most common neurodegenerative disorder after Alzheimer disease and is caused by genetics, environmental factors and aging, with few treatments currently available. Apoptosis and macroautophagy/autophagy play critical roles in PD pathogenesis; as such, modulating their balance is a potential treatment strategy. BCL2 (B cell leukemia/lymphoma 2) is a key molecule regulating this balance. Piperlongumine (PLG) is an alkaloid extracted from Piper longum L. that has antiinflammatory and anticancer effects. The present study investigated the protective effects of PLG in rotenone-induced PD cell and mouse models. We found that PLG administration (2 and 4 mg/kg) for 4 wk attenuated motor deficits in mice and prevented the loss of dopaminergic neurons in the substantia nigra induced by oral administration of rotenone (10 mg/kg) for 6 wk. PLG improved cell viability and enhanced mitochondrial function in primary neurons and SK-N-SH cells. These protective effects were exerted via inhibition of apoptosis and induction of autophagy through enhancement of BCL2 phosphorylation at Ser70. These results demonstrate that PLG exerts therapeutic effects in a rotenone-induced PD models by restoring the balance between apoptosis and autophagy.Abbreviations: 6-OHDA, 6-hydroxydopamine; ACTB, actin, beta; BafA1, bafilomycin A1; BAK1, BCL2-antagonist/killer 1; BAX, BCL2-associated X protein; BCL2, B cell leukemia/lymphoma2; BECN1, Beclin 1, autophagy related; CoQ10, coenzyme Q10; COX4I1/COX IV, cytochrome c oxidase subunit 4I1; CsA, cyclosporine A; ED50, 50% effective dose; FITC, fluorescein isothiocyanate; GFP, green fluorescent protein; HPLC, high-performance liquid chromatography; JC-1, tetraethylbenz-imidazolylcarbocyanine iodide; LC3, microtubule-associated protein 1 light chain3; LC-MS/MS, liquid chromatography-tandem mass spectrometry; LDH, lactate dehydrogenase; l-dopa, 3, 4-dihydroxyphenyl-l-alanine; MAPK8/JNK1, mitogen-activated protein kinase 8; MMP, mitochondrial membrane potential; mPTP, mitochondrial permeability transition pore; mRFP, monomeric red fluorescent protein; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; NFE2L2/NRF2, nuclear factor, erythroid derived 2, like 2; PD, Parkinson disease; PLG, piperlongumine; pNA, p-nitroanilide; PI, propidium iodide; PtdIns3K, phosphatidylinositol 3-kinase; PtdIns3P, phosphatidylinositol-3-phosphate; PTX, paclitaxel; Rap, rapamycin; SQSTM1/p62, sequestosome 1; TH, tyrosine hydroxylase; TUNEL, terminal deoxynucleotidyl transferase dUTP nick end labeling; WIPI2, WD repeat domain, phosphoinositide interacting 2; ZFYVE1/DFCP1, zinc finger, FYVE domain containing 1.

Reduced basal ganglia function has been associated with fatigue in neurologic disorders, as well as in patients exposed to chronic immune stimulation. Patients with chronic fatigue syndrome (CFS) have been shown to exhibit symptoms suggestive of decreased basal ganglia function including psychomotor slowing, which in turn was correlated with fatigue. In addition, CFS patients have been found to exhibit increased markers of immune activation. In order to directly test the hypothesis of decreased basal ganglia function in CFS, we used functional magnetic resonance imaging to examine neural activation in the basal ganglia to a reward-processing (monetary gambling) task in a community sample of 59 male and female subjects, including 18 patients diagnosed with CFS according to 1994 CDC criteria and 41 non-fatigued healthy controls. For each subject, the average effect of winning vs. losing during the gambling task in regions of interest (ROI) corresponding to the caudate nucleus, putamen, and globus pallidus was extracted for group comparisons and correlational analyses. Compared to non-fatigued controls, patients with CFS exhibited significantly decreased activation in the right caudate (p = 0.01) and right globus pallidus (p = 0.02). Decreased activation in the right globus pallidus was significantly correlated with increased mental fatigue (r2 = 0.49, p = 0.001), general fatigue (r2 = 0.34, p = 0.01) and reduced activity (r2 = 0.29, p = 0.02) as measured by the Multidimensional Fatigue Inventory. No such relationships were found in control subjects. These data suggest that symptoms of fatigue in CFS subjects were associated with reduced responsivity of the basal ganglia, possibly involving the disruption of projections from the globus pallidus to thalamic and cortical networks.

Aerobic glycolysis (the Warburg effect) is a robust metabolic hallmark of most tumors, including oral squamous cell carcinoma (OSCC). Glucose transporter 1 (GLUT1), a major glucose transporter regulating the glucose uptake, is upregulated in OSCC and participated in the cell glycolysis of OSCC. The deregulation and function of noncoding RNAs in cancers have been widely reported. Reportedly, hsa_circular RNA (circRNA)_100290 (circ_SLC30A7) is significantly upregulated (fold change = 6.91, p < 0.0000001) in OSCC. According to online tools prediction (miRWalk, miRanda, and Targetscan), miR‐378a could simultaneously target circRNA_100290 and GLUT1. Herein, the expression of circRNA_100290 and GLUT1 remarkably increased in oral tumor tissue specimens and cells. In OSCC cell lines, cell proliferation and glycolysis could be remarkably downregulated by circRNA_100290 silence, which could be rescued by GLUT1 overexpression. Conversely, miR‐378a expression could be remarkably inhibited in tumor tissue specimens and cells. The effect of miR‐378a overexpression on OSCC cells was similar to those of circRNA_100290 silence. miR‐378a directly bound to circRNA_100290 and GLUT1 3′‐untranslated region, circRNA_100290 could remarkably relieve miR‐378a‐induced inhibition on GLUT1 via acting as a competing endogenous RNA (ceRNA). miR‐378a inhibition remarkably attenuated the effect of circRNA_100290 silence on cell proliferation and glycolysis in OSCC cell lines. In summary, circRNA_100290 serves as a ceRNA to counteract miR‐378a‐mediated GLUT1 suppression, thus promoting glycolysis and cell proliferation in OSCC. We provide a reliable experimental basis for understanding the mechanism of cell growth and glycolysis deregulation in OSCC.

BackgroundBone cancer pain (BCP) is one of the most disabling factors in patients suffering from primary bone cancer or bone metastases. Recent studies show several chemokines (for example, CCL2, CXCL10) in the spinal cord are involved in the pathogenesis of BCP. Here we investigated whether and how spinal CXCL1 contributes to BCP.MethodsMouse prostate tumor cell line, RM-1 cells were intramedullary injected into the femur to induce BCP. The mRNA expression of CXCL1 and CXCR2 was detected by quantitative real-time PCR. The protein expression and distribution of CXCL1, NFκB, and CXCR2 was examined by immunofluorescence staining and western blot. The effect of CXCL1 neutralizing antibody, NFκB antagonist, and CXCR2 antagonist on pain hypersensitivity was checked by behavioral testing.ResultsIntramedullary injection of RM-1 cells into the femur induced cortical bone damage and persistent (>21 days) mechanical allodynia and heat hyperalgesia. Tumor cell inoculation also produced CXCL1 upregulation in activated astrocytes in the spinal cord for more than 21 days. Inhibition of CXCL1 by intrathecal administration of CXCL1 neutralizing antibody at 7 days after inoculation attenuated mechanical allodynia and heat hyperalgesia. In cultured astrocytes, TNF-α induced robust CXCL1 expression, which was dose-dependently decreased by NFκB inhibitor. Furthermore, inoculation induced persistent NFκB phosphorylation in spinal astrocytes. Intrathecal injection of NFκB inhibitor attenuated BCP and reduced CXCL1 increase in the spinal cord. Finally, CXCR2, the primary receptor of CXCL1, was upregulated in dorsal horn neurons after inoculation. Inhibition of CXCR2 by its selective antagonist SB225002 attenuated BCP.ConclusionNFκB mediates CXCL1 upregulation in spinal astrocytes in the BCP model. In addition, CXCL1 may be released from astrocytes and act on CXCR2 on neurons in the spinal cord and be involved in the maintenance of BCP. Inhibition of the CXCL1 signaling may provide a new therapy for BCP management.