PBMC and exosome-derived Hotair is a critical regulator and potent marker for rheumatoid arthritis.

Song, Jinsoo,Kim, Dongkyun,Han, Jiyeon,Kim, Yunha,Lee, Myeungsu,Jin, Eun-Jung Springer-Verlag Italia 2015 Clinical and experimental medicine Vol.15 No.1

<P>Despite growing importance of long non-coding RNAs (lncRNAs) in normal physiological and disease conditions, our knowledge of RA-related lncRNAs remains limited. Therefore, we aimed to identify lncRNA signatures that have prognostic values in RA. There was a notably high expression level of Hotair in blood mononuclear cells and serum exosome of rheumatoid arthritis (RA) patients, leading the migration of active macrophage. In contrast, markedly lower level of Hotair was detected in differentiated osteoclasts and rheumatoid synoviocytes and enforced expression of Hotair led to significantly decreased levels of MMP-2 and MMP-13. This exploratory study provides novel empirical evidence that Hotair could be one of potential biomarkers for diagnosing RA.</P>

Programmed death-1 (PD-1)-dependent functional impairment of CD4(+) T cells in recurrent genital papilloma.

Chang, Dong-Yeop,Song, Sang Hoon,You, Sooseong,Lee, Jino,Kim, Jihye,Racanelli, Vito,Son, Hwancheol,Shin, Eui-Cheol Springer-Verlag Italia 2014 Clinical and experimental medicine Vol.14 No.3

<P>Genital papilloma is caused by human papilloma virus (HPV) infection and recurs frequently. Although T cells are known to play a critical role in the control of HPV infection and papilloma development, the function and phenotype of these cells in the lesion remain to be elucidated. In the present study, we examined the function and phenotype of CD4(+) T cells isolated from the lesions of primary (n = 9) and recurrent (n = 11) genital papillomas. In recurrent papillomas, the frequency of proliferating (Ki-67(+)) CD4(+) T cells was significantly reduced compared with primary papillomas. Cytokine production was evaluated by intracellular cytokine staining in anti-CD3/anti-CD28-stimulated CD4(+) T cells. CD4(+) T cells from recurrent lesions showed impaired production of IL-2, IFN-γ, and TNF-α. Of interest, the frequency of cytokine-producing CD4(+) T cells significantly correlated with the frequency of Ki-67(+)CD4(+) T cells. We also studied expression of programmed death-1 (PD-1), a T-cell exhaustion marker. The frequency of PD-1(+)CD4(+) T cells was significantly increased in recurrent lesions and inversely correlated with the frequency of cytokine-producing CD4(+) T cells. The functional significance of PD-1 expression was determined in blocking assays with anti-PD-L1, which restored cytokine production of CD4(+) T cells from recurrent lesions. Taken together, in recurrent genital papilloma lesions, proliferation, and cytokine production by CD4(+) T cells are impaired and the PD-1/PD-L1 interaction is responsible for the functional impairment of CD4(+) T cells.</P>

Apocynin regulates cytokine production of CD8(+) T cells.

Nam, Seung-Joo,Oh, In Soo,Yoon, Young Ha,Kwon, Bo In,Kang, Wonseok,Kim, Hee Ja,Nahm, Seung Hoon,Choi, Youn-Hee,Lee, Seung-Hyo,Racanelli, Vito,Shin, Eui-Cheol Springer-Verlag Italia 2014 Clinical and experimental medicine Vol.14 No.3

<P>Apocynin is known to suppress the production of reactive oxygen species (ROS) by inhibiting NADPH oxidases, specifically phagocytic NADPH oxidase (PHOX or NOX2). Given the pro-inflammatory effects of ROS, apocynin has been studied extensively for its use as a therapeutic agent in various disease models. While the effects of apocynin on neutrophils and monocytes have been investigated, it remains to be elucidated whether apocynin modulates the effector function of T cells. In the present study, we examined the effect of apocynin on CD8(+) T cells and further investigated its mechanism of action. We found that apocynin directly inhibited the production of pro-inflammatory cytokines such as TNF-α, IFN-γ, and IL-2 in anti-CD3/anti-CD28-stimulated CD8(+) T cells. The action of apocynin was upstream of the protein kinase C and calcium signaling in the T cell receptor signaling pathway because apocynin did not inhibit cytokine production in phorbol 12-myristate 13-acetate/ionomycin-stimulated CD8(+) T cells. Electrophoretic mobility shift assays revealed that apocynin attenuated anti-CD3/anti-CD28-induced NF-κB activation in CD8(+) T cells. In the experiments with NOX2-deficient mice, we demonstrated that apocynin inhibited TNF-α production of CD8(+) T cells in a NOX2-independent manner. Taken together, we demonstrated that apocynin, a well-known NOX2 inhibitor, suppressed the cytokine production of CD8(+) T cells. We also showed the NOX2-independent action of apocynin in the inhibition of TNF-α production in CD8(+) T cells.</P>

Hedgehog signaling regulates proliferation of prostate cancer cells via stathmin1.

Chung, Moon-Kee,Kim, Hyun-Jung,Lee, Young-Suk,Han, Myoung-Eun,Yoon, Sik,Baek, Sun-Yong,Kim, Bong-Seon,Kim, Jae-Bong,Oh, Sae-Ock Springer-Verlag Italia 2010 Clinical and experimental medicine Vol.10 No.1

<P>Hedgehog (Hh) signaling is an essential pathway in embryonic development of prostate. Hh also plays roles in the proliferation of progenitor cells and cancer cells of adult prostate. However, how Hh signaling contributes to carcinogenesis of prostate is poorly understood. Stathmin1 is a microtubule-regulating protein that plays an important role in the assembly and disassembly of the mitotic spindle. Stathmin1 is expressed in normal developing mouse prostate and in prostate cancer. The expression pattern of stathmin1 is similar to that of Shh in prostate development and cancer, suggesting a connection between these two proteins. In this study, we examined the relationship between stathmin1 and Hh signaling. Here, we show that stathmin1 expression is regulated by Hh signaling in prostate cancer cells. Cyclopamine, a specific inhibitor of Hh signaling, reduced the expression of stathmin1 in prostate cancer cells. However, the Shh peptide induced stathmin1 expression. Overexpression of Gli1 further confirmed the relationship. Co-expression of stathmin1 and Patched 1, a receptor for Hh signaling was observed in prostate cancer tissues. Cyclopamine and stathmin1 siRNA both decreased proliferation of prostate cancer cells but did not produce an additive effect, suggesting a common pathway. These results suggest that Hh signaling regulates proliferation of prostate cancer cells by controlling stathmin1 expression.</P>

Analysis of differentially expressed genes in human rectal carcinoma using suppression subtractive hybridization.

Choi, So-Young,Jang, Jun Hyeog,Kim, Kyung Rae Springer-Verlag Italia 2011 Clinical and experimental medicine Vol.11 No.4

<P>The existence and treatment of rectal cancer are important for the function of defecation and the quality of life. However, the precise mechanisms of rectal carcinogenesis remain unclear. To screen the overexpressed gene in rectal carcinoma, we performed suppressive subtractive hybridization (SSH) on rectal carcinoma cells and the corresponding normal rectal cells. A total of 64 recombinant clones were subjected to DNA sequencing analysis, and 9 known genes were found to overexpressed in the tumors compared with those of the normal tissues. The genes are ST3 beta-galactoside alpha-2,3-sialyltransferase (ST3GAL5), interferon-induced transmembrane protein 3 (IFITM3), platelet-derived growth factor A-associated protein 1 (PDAP1), AlkB alkylating repair homolog 3 (ALKBH3), nucleoside diphosphate linked moiety X (Nudix)-type motif 14 (NUDT14), calponin 2 (CNN2), mitogen-activated protein kinase 14 (MAPK14), aconitase 1 (ACO1), and selenophosphate synthetase 1 (SEPHS1). The expression profiles of the genes were further confirmed in rectal carcinoma cells and the corresponding normal rectal cells of 12 patients by quantitative real-time RT-PCR. Our results revealed that ST3GAL5, IFITM3, PDAP1, ALKBH3, NUDT14, CNN2, MAPK14, ACO1, and SEPHS1 may be involved in rectal carcinogenesis.</P>

Ipsilateral hemiparesis and spontaneous horizontal nystagmus caused by middle cerebral artery territory infarct in a patient with agenesis of the corpus callosum.

Kang, Kyusik,Choi, Nack-Cheon Springer-Verlag Italia 2012 Neurological sciences Vol.33 No.5

<P>Ipsilateral hemiparesis and spontaneous nystagmus have rarely been reported after a cerebral lesion. A 35-year-old man with agenesis of the corpus callosum developed ipsilateral hemiparesis and spontaneous horizontal nystagmus after an infarct in the right middle cerebral artery territory. Magnetic resonance imaging revealed the presence of an acute infarct in the right middle and inferior frontal gyrus, supramarginal gyrus, insular gyrus, internal capsule, head of caudate nucleus, putamen, and globus pallidus. Transcranial stimulation of the hand area of the cerebral motor cortex produced motor-evoked potentials in the abductor pollicis brevis muscle exclusively on the ipsilateral side. No motor-evoked potentials were evoked in the abductor pollicis brevis muscle contralateral to the stimulation. The motor-evoked potentials and magnetic resonance imaging findings in our case suggest that anomalies of the decussation of the corticospinal tracts can be found in agenesis of the corpus callosum.</P>

VPL-DBS on neuropathic pain rat model is effective in mechanical allodynia than cold allodynia.

Kim, Jaehyung,Kim, Jinhyung,Min, Kyou Sik,Lee, Sung Eun,Kim, Sung June,Chang, Jin Woo Springer-Verlag Italia 2012 Neurological sciences Vol.33 No.6

<P>Recently, deep brain stimulation (DBS) is widely used in various types of neurodegenerative disorders for minimal invasiveness and safety of the procedure. Deep brain stimulation is consistently applied for the treatment of patients with neuropathic pain even though the success rate is not as high as other neurodegenerative disorders. Furthermore, it is also unclear how DBS improves neuropathic pain. In this study, we investigated the role of DBS following the stimulation parameter for analgesic effect on mechanical allodynia and cold allodynia in neuropathic pain rats. We used a sciatic nerve injury model to induce neuropathic pain, and observed responses to mechanical and cold stimulation by the von Frey test and acetone test, respectively. We classified the rats into four groups: na?ve (na?ve, n = 10), na?ve + DBS (N + DBS, n = 10), neuropathic pain (NP, n = 10), and neuropathic pain + DBS (NP + DBS, n = 10). We inserted the DBS electrode into the ventral posterolateral nucleus (VPL) into the rats (VPL-DBS). The score for mechanical allodynia was significantly decreased in NP + DBS group (p < 0.01). However, the score for cold allodynia did not significantly drop in any groups including NP + DBS group (p > 0.05). In this study, we found that the electrical stimulation of the VPL works more effectively with mechanical allodynia than cold one, and pain signal induced by mechanical stimulus and cold stimulus may be processed through different pathways in the brain.</P>

Exercise-induced downbeat nystagmus in a Korean family with a nonsense mutation in CACNA1A.

Choi, Jae-Hwan,Seo, Jae-Deuk,Choi, Yu Ri,Kim, Min-Ji,Shin, Jin-Hong,Kim, Ji Soo,Choi, Kwang-Dong Springer-Verlag Italia 2015 NEUROLOGICAL SCIENCES Vol.36 No.8

<P>Episodic ataxia type 2 (EA2) is characterized by recurrent attacks of vertigo and ataxia lasting hours triggered by emotional stress or exercise. Although interictal horizontal gaze-evoked nystagmus and rebound nystagmus are commonly observed in patients with EA2, the nystagmus has been rarely reported during the vertigo attack. To better describe exercise-induced nystagmus in EA2, four affected members from three generations of a Korean family with EA2 received full neurological and neuro-otological evaluations. Vertigo was provoked in the proband with running for 10?min to record eye movements during the vertigo attack. We performed a polymerase chain reaction-based direct sequence analysis of all coding regions of CACNA1A in all participants. The four affected members had a history of exertional vertigo, imbalance, childhood epilepsy, headache, and paresthesia. The provocation induced severe vertigo and imbalance lasting several hours, and oculography documented pure downbeat nystagmus during the attack. Genetic analyses identified a nonsense mutation in exon 23 which has been registered in dbSNP as a pathogenic allele (c.3832C>T, p.R1278X) in all the affected members. Ictal downbeat nystagmus in the studied family indicates cerebellar dysfunction during the vertigo attack in EA2. In patients with episodic vertigo and ataxia, the observation of exercise-induced nystagmus would provide a clue for EA2.</P>

Association of overexpression of hexokinase II with chemoresistance in epithelial ovarian cancer.

Suh, Dong Hoon,Kim, Min A,Kim, Haeryoung,Kim, Mi-Kyung,Kim, Hee Seung,Chung, Hyun Hoon,Kim, Yong-Beom,Song, Yong Sang Springer-Verlag Italia 2014 Clinical and experimental medicine Vol.14 No.3

<P>This aim of this study was to evaluate the relationship between hexokinase II expression and chemoresistance in epithelial ovarian cancer. One hundred and eleven paraffin-embedded specimens from patients with epithelial ovarian cancer were immunohistochemically stained for hexokinase II. Subsequently, the association between hexokinase II overexpression and clinicopathologic characteristics including chemoresistance was assessed. Survival analyses were also performed for evaluating the prognostic value of hexokinase II overexpression. Tumor recurrence within 6 months after termination of first-line chemotherapy was considered to indicate chemoresistance. Hexokinase II overexpression was associated with chemoresistance (p = 0.029) and was an independent risk factor for chemoresistance [odds ratio (OR) 3.37; 95 % confidence interval (CI) 1.07-10.62; p = 0.038] along with non-optimal debulking surgery (OR 4.93; 95 % CI 1.43-16.98; p = 0.011). Hexokinase II overexpression was significantly associated with decreased progression-free survival (p = 0.002) and showed a similar trend for overall survival (p = 0.101). Cox regression analysis revealed that hexokinase II overexpression was an independent prognostic factor for early recurrence (hazard ratio 2.63; 95 % CI 1.40-4.92; p = 0.002). Our findings suggest that hexokinase II overexpression is associated with short progression-free survival, which could be associated with chemoresistance in epithelial ovarian cancer.</P>

Decreased GABABR expression and increased neuronal cell death in developing rat brain after PTZ-induced seizure.

Naseer, Muhammad Imran,Ullah, Ikram,Al-Qahtani, Mohammed H,Karim, Sajjad,Ullah, Najeeb,Ansari, Shakeel Ahmed,Kim, Myeong Ok,Bibi, Fehmida Springer-Verlag Italia 2013 Neurological sciences Vol.34 No.4

<P>The objective of this study was to evaluate the PTZ-induced seizures effects on GABAB receptor (R) expression and to observe its neurodegenerative effect in hippocampal part of developing rat brain. In the present study, high dose of pentylenetetrazol (PTZ 40 mg/kg) was injected in developing rats of age 5 weeks having average weight of 60-65 g for 4 days. Further, baclofen (B 3 mg/kg i.p) agonist and phaclofen (P 30 μg/rat) antagonist of GABABR were injected along with PTZ. Western blot analysis was used to elucidate expression of GABABR protein upon PTZ, baclofen and phaclofen exposure in the developing rat brain. Furthermore, PTZ-induced apoptotic neurodegeneration was also observed through the release of caspase-3 antibody and propidium iodide (PI) staining using confocal microscopy. Seizure was confirmed using electroencephalography (EEG) data obtained from the Laxtha EEG-monitoring device in the EEG recording room and EEG was monitored 5-15 min after PTZ injection. The results of the present study showed that PTZ-induced seizure significantly decreased GABABR expression and induced neuronal apoptosis in cortical and hippocampal part of brain. While, baclofen reverse the effect of PTZ by increasing the expression of GABABR as compared to the PTZ- , PTZ plus B- and PTZ plus P-treated groups. Our findings indicated that PTZ-induced seizure showed not only decrease in GABABR expression but also cause neuronal apoptosis in the developing rat brain.</P>