L-carnitine treatment attenuates renal tubulointerstitial fibrosis induced by unilateral ureteral obstruction

( Hai Yan Zhao ),( Hui Ying Li ),( Jian Jin ),( Ji Zhe Jin ),( Long Ye Zhang ),( Mei Ying Xuan ),( Xue Mei Jin ),( Yu Ji Jiang ),( Hai Lan Zheng ),( Ying Shun Jin ),( Yong Jie Jin ),( Bum Soon Choi ) 대한내과학회 2021 The Korean Journal of Internal Medicine Vol.36 No.0

Background/Aims: Accumulating evidence indicates that L-carnitine (LC) protects against multiorgan damage through its antioxidant properties and preservation of the mitochondria. Little information is available about the effects of LC on renal fibrosis. This study examined whether LC treatment would provide renoprotection in a rat model of unilateral ureteral obstruction (UUO) and in vitro. Methods: Sprague-Dawley rats that underwent UUO were treated daily with LC for 7 or 14 days. The influence of LC on renal injury caused by UUO was evaluated by histopathology, and analysis of gene expression, oxidative stress, mitochondrial function, programmed cell death, and phosphatidylinositol 3-kinase (PI3K)/ AKT/forkhead box protein O 1a (FoxO1a) signaling. In addition, H₂O₂-exposed human kidney cells (HK-2) were treated with LC. Results: LC treatment inhibited expression of proinflammatory and profibrotic cytokines, and was followed by a significant attenuation of tubulointerstitial inflammation and fibrosis. The increased oxidative stress caused by UUO was associated with mitochondrial dysfunction and excessive apoptosis and autophagy via PI3K/AKT/FoxO1a-dependent signaling, and this was abrogated by administration of LC. In H₂O₂-exposed HK-2 cells, LC decreased intracellular production of reactive oxygen species, and suppressed expression of profibrotic cytokines and reduced the number of apoptotic cells. Conclusions: LC protects against the progression of tubulointerstitial fibrosis in an obstructed kidney.

Effects of Systemic and Focal Hypoxia on the Activities of Rostral Ventrolateral Medullary Neurons in Cats

Yan, Hai-Dun,Kim, Charn,Kim, Ji-Mok,Lim, Won-Il,Kim, Sang-Jeong,Kim, Jun The Korean Physiological Society 1996 대한생리학회지 Vol.30 No.1

Rendering the brain ischemic would evoke the cerebral ischemic reflex which is characterized by an arterial pressor response, apnea and bradycardia. Since the rostral ventrolateral medulla (RVLM) is known to play a key role in the maintenance of normal cardiopulmonary activity, during the cerebral ischemic reflex some cardiac related cells should be excited and respiration related cells inhibited. In this context, the responses of RVLM neurons to systemie and focal hypoxia were analyzed in the present study. Twenty-five adult cats of either sex were anesthetized with ${\alpha}-chloralose$ and the single neuronal activities were identified from RVLM area. For the induction of focal hypoxia in the recording site, sodium cyanide was applied iontophoretically and for systemic hypoxia the animal was ventilated with nitrogen gas for a twenty-second period. Cellular activities were analyzed in terms of their discharge pattern and responses to the hypoxia by using post-stimulus time and single-pass time histograms. Of eighteen cardiac related cells recorded from the RVLM area, twelve cells were excited by iontophoresed sodium cyanide and of twenty-five respiration related cells, fourteen cells were excited by iontophoresed sodium cyanide. Remaining cells were either inhibited or unaffected. Eight of fifteen cells tested with iontophoresed sodium lactate were excited and remaining seven cells were inhibited. Systemic hypoxia induced by nitrogen gas inhalation elevated the arterial blood pressure, but excited, inhibited or unaffected the single neuronal activities. Some cells showed initial excitation followed by inhibition during the systemic hypoxia. Bilateral vagotomy resulted in a decrease of arterial pressor response to the systemic hypoxia, and a slight decrease in the rhythmicity related to cardiac and/or respiratory rhythms. The single neuronal responses to either systemic or focal hypoxia were not affected qualitatively by vagotomy. From the above results, it was concluded that the majority of the cardiac- and respiration- related neurons in the rostral ventrolateral medulla be excited by hypoxia, not through the mediation of peripheral chemoreceptors, and along with the remaining inhibited cells, all these cells be involved in the mediation of cerebral ischemic reflex.

Safety of Brucea javanica and Cantharidin Combined with Chemotherapy for Treatment of NSCLC Patients

Ji, Zhu-Qing,Huang, Xin-En,Wu, Xue-Yan,Liu, Jin,Wang, Lin,Tang, Jin-Hai Asian Pacific Journal of Cancer Prevention 2014 Asian Pacific journal of cancer prevention Vol.15 No.20

Objective: To assess the safety of Brucea javanica and Cantharidin combined with chemotherapy in treating patients with non-small-cell lung carcinoma. Method: A consecutive cohort of patients with NSCLC were divided into four groups: experimental group A treated with Brucea javanica injection combined with chemotherapy; experimental group B with Cantharidin injection combined with chemotherapy; experimental group C treated with Brucea javanica and Cantharidin injection combined with chemotherapy; and the control group receiving only chemotherapy. After more than two courses of treatment, safety, quality of life and side effects were evaluated. Results: The incidences of myelosuppression in groups A, B and C were lower than that in Control group (p<0.05), but without significant differences among A, B and C. Adverse effects on the gastrointestinal tract also were lower than in controls (p<0.05) without variation amnog the combined treatment groups. Conclusions: Brucea javanica or Cantharidin combined with chemotherapy could in both cases improve quality of life in our cohort of NSCLC patients without any increase in toxicity. However, further clinical experiments should be conducted to evaluate the efficacy of Brucea javanica and Cantharidin combined with chemotherapy for patients with NSCLC.

Nicotine exacerbates tacrolimus-induced renal injury by programmed cell death

( Yu Ji Jiang ),( Sheng Cui ),( Kang Luo ),( Jun Ding ),( Qi Yan Nan ),( Shang Guo Piao ),( Mei Ying Xuan ),( Hai Lan Zheng ),( Yong Jie Jin ),( Ji Zhe Jin ),( Jung Pyo Lee ),( Byung Ha Chung ),( Bum 대한내과학회 2021 The Korean Journal of Internal Medicine Vol.36 No.6

Background/Aims: Cigarette smoking is an important modifiable risk factor in kidney disease progression. However, the underlying mechanisms for this are lacking. This study aimed to assess whether nicotine (NIC), a major toxic component of cigarette smoking, would exacerbates tacrolimus (TAC)-induced renal in-jury. Methods: Sprague-Dawley rats were treated daily with NIC, TAC, or both drugs for 4 weeks. The influence of NIC on TAC-caused renal injury was examined via renal function, histopathology, oxidative stress, mitochondria, endoplasmic reticulum (ER) stress, and programmed cell death (apoptosis and autophagy). Results: Both NIC and TAC significantly impaired renal function and histopathology, while combined NIC and TAC treatment aggravated these parameters beyond the effects of either alone. Increased oxidative stress, ER stress, mitochondrial dysfunction, proinflammatory and profibrotic cytokine expressions, and programmed cell death from either NIC or TAC were also aggravated by the two combined. Conclusions: Our observations suggest that NIC exacerbates chronic TAC nephrotoxicity, implying that smoking cessation may be beneficial for transplant smokers taking TAC.

Rs895819 within miR-27a Might be Involved in Development of Non Small Cell Lung Cancer in the Chinese Han Population

Ma, Ji-Yong,Yan, Hai-Jun,Yang, Zhen-Hua,Gu, Wei Asian Pacific Journal of Cancer Prevention 2015 Asian Pacific journal of cancer prevention Vol.16 No.5

MicroRNA-27a (miR-27a) is deemed to be an oncogene that plays an important role in development of various cancers, and single nucleotide polymorphism (SNP) of miR-27a can influence the maturation or aberrant expression of hsa-miR27a, resulting in increased risk of cancer and poor prognosis for non-small cell lung cancer (NSCLC). This study aimed to assess the effects of rs895819 within miR-27a on susceptibility and prognosis of NSCLC patients in 560 clinical confirmed cases and 568 healthy check-up individuals. Adjusted odds/hazard ratios (ORs/HRs) and 95% confidential intervals (CIs) were calculated to evaluate the association between rs895819 and the risk and prognosis of NSCLC. The results showed that allele A and genotype GG of rs895819 were significantly associated with an increased risk of NSCLC (38.9% vs 30.8%, adjusted OR=1.26, 95%CI=1.23-1.29 for allele G vs A; 18.1% vs 11.7%, adjusted OR=1.67, 95%CI=1.59-1.75 for genotype GG vs AA). Moreover, positive associations were also observed in dominant and recessive models (53.7% vs 49.9%, adjusted OR=1.17, 95%CI=1.13-1.20 for GG/AG vs AA; 18.1% vs 11.7%, adjusted=1.65, 95%CI=1.58-1.73). However, no significant association was found between rs895819 and the prognosis of NSCLC in genotype, dominant and recessive models. These results suggested that miR-27a might be involved in NSCLC carcinogenesis, but not in progression of NSCLC. The allele G, genotype GG and allele G carrier (GG/AG vs AA) of rs895819 might be genetic susceptible factors for NSCLC. Further multi-central, large sample size and well-designed prospective studies as well as functional studies are warranted to verify our findings.

A novel M2e-multiple antigenic peptide providing heterologous protection in mice

Feng Wen,Ji-Hong Ma,Hai Yu,Fu-Ru Yang,Meng Huang,Yan-Jun Zhou,Ze-Jun Li,Xiu-Hui Wang,Guo-Xin Li,Yi-Feng Jiang,Wu Tong,Guangzhi Tong 대한수의학회 2016 Journal of Veterinary Science Vol.17 No.1

Swine influenza viruses (SwIVs) cause considerable morbidity and mortality in domestic pigs, resulting in a significant economic burden. Moreover, pigs have been considered to be a possible mixing vessel in which novel strains loom. Here, we developed and evaluated a novel M2e-multiple antigenic peptide (M2e-MAP) as a supplemental antigen for inactivated H3N2 vaccine to provide cross-protection against two main subtypes of SwIVs, H1N1 and H3N2. The novel tetra-branched MAP was constructed by fusing four copies of M2e to one copy of foreign T helper cell epitopes. A high-yield reassortant H3N2 virus was generated by plasmid based reverse genetics. The efficacy of the novel H3N2 inactivated vaccines with or without M2e-MAP supplementation was evaluated in a mouse model. M2e-MAP conjugated vaccine induced strong antibody responses in mice. Complete protection against the heterologous swine H1N1 virus was observed in mice vaccinated with M2e-MAP combined vaccine. Moreover, this novel peptide confers protection against lethal challenge of A/Puerto Rico/8/34 (H1N1). Taken together, our results suggest the combined immunization of reassortant inactivated H3N2 vaccine and the novel M2e-MAP provided cross-protection against swine and human viruses and may serve as a promising approach for influenza vaccine development.

Protective efficacy of a high-growth reassortant swine H3N2 inactivated vaccine constructed by reverse genetic manipulation

Feng Wen,Ji-Hong Ma,Hai Yu,Fu-Ru Yang,Meng Huang,Yan-Jun Zhou,Ze-Jun Li,Guangzhi Tong 대한수의학회 2014 JOURNAL OF VETERINARY SCIENCE Vol.15 No.3

Novel reassortant H3N2 swine influenza viruses (SwIV)with the matrix gene from the 2009 H1N1 pandemic virushave been isolated in many countries as well as duringoutbreaks in multiple states in the United States, indicatingthat H3N2 SwIV might be a potential threat to public health. Since southern China is the world’s largest producer of pigs,efficient vaccines should be developed to prevent pigs fromacquiring H3N2 subtype SwIV infections, and thus limit thepossibility of SwIV infection at agricultural fairs. In thisstudy, a high-growth reassortant virus (GD/PR8) wasgenerated by plasmid-based reverse genetics and tested as acandidate inactivated vaccine. The protective efficacy of thisvaccine was evaluated in mice by challenging them withanother H3N2 SwIV isolate [A/Swine/Heilongjiang/1/05(H3N2) (HLJ/05)]. Prime and booster inoculation withGD/PR8 vaccine yielded high-titer serum hemagglutinationinhibiting antibodies and IgG antibodies. Completeprotection of mice against H3N2 SwIV was observed, withsignificantly reduced lung lesion and viral loads invaccine-inoculated mice relative to mock-vaccinatedcontrols. These results suggest that the GD/PR8 vaccine mayserve as a promising candidate for rapid intervention ofH3N2 SwIV outbreaks in China.

K _Ca 3.1 upregulation preserves endothelium‐dependent vasorelaxation during aging and oxidative stress

Choi, Shinkyu,Kim, Ji Aee,Li, Hai‐,yan,Shin, Kyong‐,Oh,Oh, Goo Taeg,Lee, Yong‐,Moon,Oh, Seikwan,Pewzner‐,Jung, Yael,Futerman, Anthony H.,Suh, Suk Hyo BLACKWELL PUBLISHING 2016 AGING CELL Vol.15 No.5

<P><B>Summary</B></P><P>Endothelial oxidative stress develops with aging and reactive oxygen species impair endothelium‐dependent relaxation (EDR) by decreasing nitric oxide (NO) availability. Endothelial K<SUB>Ca</SUB>3.1, which contributes to EDR, is upregulated by H<SUB>2</SUB>O<SUB>2</SUB>. We investigated whether K<SUB>Ca</SUB>3.1 upregulation compensates for diminished EDR to NO during aging‐related oxidative stress. Previous studies identified that the levels of ceramide synthase 5 (CerS5), sphingosine, and sphingosine 1‐phosphate were increased in aged wild‐type and CerS2 mice. In primary mouse aortic endothelial cells (MAECs) from aged wild‐type and CerS2 null mice, superoxide dismutase (SOD) was upregulated, and catalase and glutathione peroxidase 1 (GPX1) were downregulated, when compared to MAECs from young and age‐matched wild‐type mice. Increased H<SUB>2</SUB>O<SUB>2</SUB> levels induced Fyn and extracellular signal‐regulated kinases (ERKs) phosphorylation and K<SUB>Ca</SUB>3.1 upregulation. Catalase/GPX1 double knockout (catalase<SUP>−/−</SUP>/GPX1<SUP>−/−</SUP>) upregulated K<SUB>Ca</SUB>3.1 in MAECs. NO production was decreased in aged wild‐type, CerS2 null, and catalase<SUP>−/−</SUP>/GPX1<SUP>−/−</SUP>MAECs. However, K<SUB>Ca</SUB>3.1 activation‐induced, NG‐nitro‐<SMALL>L</SMALL>‐arginine‐, and indomethacin‐resistant EDR was increased without a change in acetylcholine‐induced EDR in aortic rings from aged wild‐type, CerS2 null, and catalase<SUP>−/−</SUP>/GPX1<SUP>−/−</SUP> mice. CerS5 transfection or exogenous application of sphingosine or sphingosine 1‐phosphate induced similar changes in levels of the antioxidant enzymes and upregulated K<SUB>Ca</SUB>3.1. Our findings suggest that, during aging‐related oxidative stress, SOD upregulation and downregulation of catalase and GPX1, which occur upon altering the sphingolipid composition or acyl chain length, generate H<SUB>2</SUB>O<SUB>2</SUB> and thereby upregulate K<SUB>Ca</SUB>3.1 expression and function via a H<SUB>2</SUB>O<SUB>2</SUB>/Fyn‐mediated pathway. Altogether, enhanced K<SUB>Ca</SUB>3.1 activity may compensate for decreased NO signaling during vascular aging.</P>

Altering sphingolipid composition with aging induces contractile dysfunction of gastric smooth muscle via KC _a 1.1 upregulation

Choi, Shinkyu,Kim, Ji Aee,Kim, Tae Hun,Li, Hai‐,yan,Shin, Kyong‐,Oh,Lee, Yong‐,Moon,Oh, Seikwan,Pewzner‐,Jung, Yael,Futerman, Anthony H.,Suh, Suk Hyo BLACKWELL PUBLISHING 2015 AGING CELL Vol.14 No.6

<P><B>Summary</B></P><P>KC<SUB>a</SUB>1.1 regulates smooth muscle contractility by modulating membrane potential, and age‐associated changes in KC<SUB>a</SUB>1.1 expression may contribute to the development of motility disorders of the gastrointestinal tract. Sphingolipids (SLs) are important structural components of cellular membranes whose altered composition may affect KC<SUB>a</SUB>1.1 expression. Thus, in this study, we examined whether altered SL composition due to aging may affect the contractility of gastric smooth muscle (GSM). We studied changes in ceramide synthases (CerS) and SL levels in the GSM of mice of varying ages and compared them with those in young CerS2‐null mice. The levels of C16‐ and C18‐ceramides, sphinganine, sphingosine, and sphingosine 1‐phosphate were increased, and levels of C22, C24:1 and C24 ceramides were decreased in the GSM of both aged wild‐type and young CerS2‐null mice. The altered SL composition upregulated KC<SUB>a</SUB>1.1 and increased KC<SUB>a</SUB>1.1 currents, while no change was observed in KC<SUB>a</SUB>1.1 channel activity. The upregulation of KC<SUB>a</SUB>1.1 impaired intracellular Ca2+ mobilization and decreased phosphorylated myosin light chain levels, causing GSM contractile dysfunction. Additionally, phosphoinositide 3‐kinase, protein kinase C<SUB>ζ</SUB>, c‐Jun N‐terminal kinases, and nuclear factor kappa‐B were found to be involved in KC<SUB>a</SUB>1.1 upregulation. Our findings suggest that age‐associated changes in SL composition or CerS2 ablation upregulate KC<SUB>a</SUB>1.1 via the phosphoinositide 3‐kinase/protein kinase C<SUB>ζ</SUB>/c‐Jun N‐terminal kinases/nuclear factor kappa‐B‐mediated pathway and impair Ca2+ mobilization, which thereby induces the contractile dysfunction of GSM. CerS2‐null mice exhibited similar effects to aged wild‐type mice; therefore, CerS2‐null mouse models may be utilized for investigating the pathogenesis of aging‐associated motility disorders.</P>

Altered Redox State Modulates Endothelial K_Ca2.3 and K_Ca3.1 Levels in Normal Pregnancy and Preeclampsia

Choi, Shinkyu,Kim, Ji Aee,Li, Hai-yan,Lee, Sae-Jin,Seok, Ye Seon,Kim, Tae Hun,Han, Ki-Hwan,Park, Mi Hye,Cho, Geum Joon,Suh, Suk Hyo Mary Ann Liebert 2018 ANTIOXIDANTS AND REDOX SIGNALING Vol. No.