bluuebunny/crossref_metadata_2025 huggingface dataset:
Metabolic changes in adipose tissues in response to β3‐adrenergic receptor activation in mice
Authors: Fujimoto Yusuke , Hashimoto Osamu , Shindo Daichi , Sugiyama Makoto , Tomonaga Shozo , Murakami Masaru , Matsui Tohru , Funaba Masayuki
Published: September 2018

Brown and beige adipocytes dissipate energy as heat. Thus, the activation of brown adipocytes and the emergence of beige adipocytes in white adipose tissue (WAT) are suggested to be useful for preventing and treating obesity. Although β3‐adrenergic receptor activation is known to stimulate lipolysis and activation of brown and beige adipocytes, fat depot–dependent changes in metabolite concentrations are not fully elucidated. The current study examined the effect of treatment with CL‐316,243, a β3‐adrenergic receptor agonist, on the relative abundance of metabolites in interscapular brown adipose tissue (iBAT), inguinal WAT (ingWAT), and epididymal WAT (epiWAT). Intraperitoneal injection of CL‐316,243 (1 mg/kg) for 3 consecutive days increased the relative abundance of several glycolysis‐related metabolites in all examined fat depots. The cellular concentrations of metabolites involved in the citric acid cycle and of free amino acids were also increased in epiWAT by CL‐316,243. CL‐316,243 increased the expression levels of several enzymes and transporters related to glucose metabolism and amino acid catabolism in ingWAT and iBAT but not in epiWAT. CL‐316,243 also induced the emergence of more beige adipocytes in ingWAT than in epiWAT. Furthermore, adipocytes surrounded by macrophages were detected in the epiWAT of mice given CL‐316,243. The current study reveals the fat depot–dependent modulation of cellular metabolites in CL‐316,243‐treated mice, presumably resulting from differential regulation of cell metabolism in different cell populations.
Effects of calpain inhibitor on the apoptosis of hepatic stellate cells induced by calcium ionophore A23187
Authors: Li Yanan , Yan Yu , Liu Fang , Wang Luguang , Feng Fumin , Xiao Yonghong
Published: September 2018

We previously showed that changes in calcium concentrations were related to cell apoptosis in vitro. The endoplasmic reticulum (ER) is the main component of calcium storage and signal transduction, and disrupting the balance of intracellular Ca2+ can cause endoplasmic reticulum stress (ERS). In this process, the ER releases stored Ca
2+ into the cytoplasm and activates calpain‐2. To further investigate the effect of calpain in hepatic stellate cells (HSCs), in the current study, we examine the effect of
N‐acetyl‐leu‐leu‐norleucinal (ALLN) on apoptosis resulting from calcium ionophore A23187–induced ERS. Our findings indicate that calpain inhibition reduces calcium ionophore A23187–induced apoptosis of HSCs and decreases the expression of ER stress proteins that may be related to the calpain/caspase signaling pathway.
Bone marrow–derived mesenchymal stem cells–derived exosomes prevent oligodendrocyte apoptosis through exosomal miR‐134 by targeting caspase‐8
Authors: Xiao Yilei , Geng Fengyang , Wang Guifang , Li Xueyuan , Zhu Jianxin , Zhu Weijie
Published: September 2018

Ischemic stroke causes severe brain damage and remains one of the leading causes of morbidity and mortality worldwide. The microRNA‐134 (miR‐134) is involved in regulating the process of ischemia injury in neural cells and brain with ischemia stroke. The role of miR‐134 in ischemic stroke remains poorly understood. The purpose of the current study was to investigate the effect of bone marrow–derived mesenchymal stem cells (BMSCs)‐derived exosomal miR‐134 on rat oligodendrocytes (OLs) apoptosis and its underlying mechanism of action. The results demonstrated that levels of miR‐134 in BMSCs‐exosome decreased but increased incaspase‐8 after oxygen‐glucose deprivation (OGD) treatment. Exosomal miR‐134 significantly inhibited apoptosis by decreasing caspase‐8 expression and activity in OGD‐treated group cultured with BMSCs‐exosome and OLs. In addition, the miR‐134 mimics decreased caspase‐8 expression in OGD‐treated OLs, whereas miR‐134 inhibitors exacerbated the changes in the expression of the procaspase‐8 and caspase‐8 cleaved product proteins caused by OGD. The caspase‐8 knockdown using caspase‐8 small interfering RNA decreased OLs apoptosis, reversing the improvements that the miR‐134 inhibited cells apoptosis by targeting caspase‐8. Taken together, these results demonstrated that BMSCs‐derived exosomes suppressed OLs apoptosis through exosomal miR‐134 by negatively regulating the caspase‐8‐dependent apoptosis pathway and may, therefore, be a novel potential therapeutic target for ischemic stroke treatment.
Long noncoding RNA H19 competitively binds miR‐93‐5p to regulate STAT3 expression in breast cancer
Authors: Li Jia‐Peng , Xiang Yuan , Fan Li‐Juan , Yao Ao , Li Hui , Liao Xing‐Hua
Published: September 2018

The long noncoding RNA H19 is overexpressed in many cancers and acts as an oncogene. Here, we explored the role of H19 in breast cancer cells, including the effect of H19 on proliferation, migration, and invasion of breast cancer cells. We also investigated the relation of H19 to microRNA miR‐93‐5p and signal transducers and activators of transcription 3 (STAT3), the target gene of miR‐93‐5p. Ectopic expression of H19 in MCF‐7 cells and knockdown of H19 in MDA‐MB‐231 cells showed that overexpression of H19 promoted proliferation, migration, and invasion, whereas knockdown of H19 reduced proliferation, migration, and invasion in vitro. Dual‐luciferase reporter assays and RNA‐binding protein immunoprecipitation assays proved that H19 was a target of miR‐93‐5p. In addition, H19 antagonized the downregulation of miR‐93‐5p on its target STAT3 and antagonized miR‐93‐5p‐mediated cell proliferation. Our study revealed a new network in the expression of STAT3 involving H19 and miR‐93‐5p, which may contribute to a better understanding of breast cancer pathogenesis and provide new insights into the treatment of this disease.
Pharmacophore modeling and molecular dynamics approach to identify putative DNA Gyrase B inhibitors for resistant tuberculosis
Authors: Kashyap Aanchal , Singh Pankaj Kumar , Satpati Suresh , Verma Himanshu , Silakari Om
Published: September 2018

One of the major mechanisms followed by the therapeutic agents to target the causative organism of TB, mycobacterium tuberculosis (Mtb), involves disruption of the replication cycle of the pathogen DNA. The process involves two steps that occur simultaneously, ie, breakage and reunion of DNA at gyrase A (GyrA) domain and ATP hydrolysis at gyrase B (GyrB) domain. Current therapy for multi‐drug resistant TB involves FDA approved, Fluoroquinolone‐based antibiotics, which act by targeting the replication process at GyrA domain. However, resistance against fluoroquinolones due to mutations in the GyrA domain has limited the use of this therapy and shifted the focus of the research community on the GyrB domain. Thus, this study involves in silico designing of chemotherapeutic agents for resistant TB by targeting GyrB domain. In the current study, a pharmacophore model for GyrB domain was generated using reported inhibitors. It was utilized as a query search against three commercial databases to identify GyrB domain inhibitors. Additionally, a qualitative Hip‐Hop pharmacophore model for GyrA was also developed on the basis of some marketed fluoroquinolone‐based GyrA inhibitors, to remove non‐selective gyrase inhibitors obtained in virtual screening. Further, molecular dynamic simulations were carried out to determine the stability of the obtained molecules in complex with both the domains. Finally, Molecular mechanics with generalized Born and surface area solvation score was calculated to determine the binding affinity of obtained molecule with both domains to determine the selectivity of the obtained molecules that resulted in seven putative specific inhibitors of GyrB domain.
Association between rs2278426 (C/T) and rs892066 (C/G) variants of ANGPTL8 (betatrophin) and susceptibility to type2 diabetes mellitus
Authors: Ghasemi Hassan , Karimi Jamshid , Khodadadi Iraj , Saidijam Massoud , Tavilani Heidar
Published: September 2018

Background

Angiopoietin‐like protein 8 (ANGPTL8) is a hormone that mainly secreted from the liver and adipose tissue and plays an important role in the proliferation of pancreatic beta cells and lipid metabolism. Therefore, we studied the association of ANGPTL8 rs2278426 (C/T) and rs892066 (C/G) polymorphisms with the risk of type 2 diabetes mellitus (T2DM) and their association with biochemical parameters.

Methods

Two hundred and eighty‐eight subjects (controls; n = 138 and type 2 diabetic patients; n = 150) were enrolled in this study. Direct haplotyping was performed using amplification‐refractory mutation system (ARMS)‐RFLP‐PCR.

Results

The CT genotype frequency of rs2278426 (C/T) variant was significantly higher in T2DM patients compared to the controls group (P = 0.02), and there was a significant association between this genotype and increased risk of T2DM (OR: 2.41, CI: 1.26‐4.59, P = 0.007). In addition, there was a significant relationship between CT genotype of this variant and high‐density lipoprotein cholesterol (HDL‐C), fasting blood sugar (FBS), insulin, insulin resistance and glycated hemoglobin (P < 0.05). Furthermore, bioinformatics analysis revealed that arginine (Arg) to tryptophan (Trp) substitution at rs2278426 position causes structural instability of ANGPTL8 protein. Genotype and allele distribution of rs892066 (C/G) was not statistically significant in T2DM patients compared to the control group. The distribution of haplotypes had no significant difference between controls and T2DM patients (P = 0.24).

Conclusion

Our results suggest that the rs2278426 (C/T) variant is associated with increased risk of T2DM and may cause dyslipidemia due to its effect on decreasing HDL‐C levels.
MicroRNA‐384‐3p inhibits retinal neovascularization through targeting hexokinase 2 in mice with diabetic retinopathy
Authors: Xia Fei , Sun Juan‐Juan , Jiang Ya‐Qin , Li Cheng‐Fang
Published: September 2018

Diabetic retinopathy (DR) presents a microvascular complication of diabetes, which may contribute to visual impairment. The treatment of DR is still controversial. Accumulating studies have reported the role of microRNAs (miRs) in DR. This study aims to explore the functions of microRNA‐384‐3p (miR‐384‐3p) in retinal neovascularization by targeting hexokinase 2 (HK2) in mice with DR. A total of 43 C57BL/6 male mice were selected and divided into normal (
n = 16) and DR (
n = 27) groups. Retinal microvascular endothelial cells (RMECs) were collected from the normal and DR mice and mainly treated with a miR‐384‐3p mimic, a miR‐384‐3p inhibitor, small interfering RNA (siRNA) against HK2 and HK2 overexpression plasmids to understand the underlying regulatory mechanisms of miR‐384‐3p. The relationship between miR‐384‐3p and HK2 was determined by dual‐luciferase reporter assay. The miR‐384‐3p expression and the mRNA and the protein expressions of HK2 and CD31 in retinal tissues and cells were evaluated using reverse transcription quantitative polymerase chain reaction (RT‐qPCR) and western blot assay. Cell proliferation was assessed by 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide assay. Tube formation was observed by conducting a tube formation experiment. HK2 is a target gene of miR‐384‐3p. The DR mice showed higher expression of HK2 and CD31 but lower expression of miR‐384‐3p. The miR‐384‐3p mimic and siRNA‐HK2 reduced the expression of HK2, decreased cell proliferation and tube formation of RMECs, whereas the miR‐384‐3p inhibitor could reverse these trends. Our study demonstrates that overexpression of miR‐384‐3p inhibits retinal neovascularization in DR mice via inhibition of HK2.
DUSP1 recuses diabetic nephropathy via repressing JNK‐Mff‐mitochondrial fission pathways
Authors: Sheng Junqin , Li Hongyan , Dai Qin , Lu Chang , Xu Min , Zhang Jisheng , Feng Jianxun
Published: September 2018

Excessive mitochondrial fission has been identified as the pathogenesis of diabetic nephropathy (DN), although the upstream regulatory signal for mitochondrial fission activation in the setting of DN remains unknown. In the current study, we found that dual‐specificity protein phosphatase‐1 (DUSP1) was actually downregulated by chronic hyperglycemia stimulus. Lower DUSP1 expression was associated with glucose metabolism disorder, renal dysfunction, kidney hypertrophy, renal fibrosis, and glomerular apoptosis. At the molecular level, defective DUSP1 expression activated JNK pathway, and the latter selectively opened mitochondrial fission by modulating mitochondrial fission factor (Mff) phosphorylation. Excessive Mff‐related mitochondrial fission evoked mitochondrial oxidative stress, promoted mPTP opening, exacerbated proapoptotic protein leakage into the cytoplasm, and finally initiated mitochondria‐dependent cellular apoptosis in the setting of diabetes. However, overexpression of DUSP1 interrupted Mff‐related mitochondrial fission, reducing hyperglycemia‐mediated mitochondrial damage and thus improving renal function. Overall, we have shown that DUSP1 functions as a novel malefactor in diabetic renal damage that mediates via modifying Mff‐related mitochondrial fission. Thus, finding strategies to regulate the balance of the DUSP1‐JNK‐Mff signaling pathway and mitochondrial homeostasis may be a therapeutic target for treating diabetic nephropathy in clinical practice.
Defective bone repair in diclofenac treated C57Bl6 mice with and without lipopolysaccharide induced systemic inflammation
Authors: Ramirez‐Garcia‐Luna Jose L. , Wong Timothy H. , Chan Daniel , Al‐Saran Yazeed , Awlia Ayman , Abou‐Rjeili Mira , Ouellet Suzie , Akoury Elie , Lemarié Catherine A. , Henderson Janet E. , Martineau Paul A.
Published: September 2018

Bone repair after trauma or surgical intervention involves a tightly regulated cascade of events that starts with hemostasis and an inflammatory response, which are critical for successful healing. Nonsteroidal anti‐inflammatory drugs (NSAID) are routinely prescribed for pain relief despite their potential inhibitory effect on bone repair. The goal of this study was to determine the impact of administration of the non‐selective NSAID diclofenac in the inflammatory phase of bone repair in mice with or without lipopolysaccharide‐induced systemic inflammation. Repair of femoral window defects was characterized using micro computed tomography imaging and histological analyses at 2 weeks postoperative. The data indicate (a) impaired bone regeneration associated with reduced osteoblast, osteoclast, and macrophage activity; (b) changes in the number, activity, and distribution of mast cells in regenerating bone; and (c) impaired angiogenesis due to a direct toxic effect of diclofenac on vascular endothelial cells. The results of this study provide strong evidence to support the conjecture that administration of NSAIDs in the first 2 weeks after orthopaedic surgery disrupts the healing cascade and exacerbates the negative effects of systemic inflammation on the repair process.
MicroRNA‐10b expression predicts long‐term survival in patients with solid tumor
Authors: Zhang Yi , Wang Li‐Juan , Yang He‐Quan , Wang Rong , Wu Hua‐Jun
Published: September 2018

Background

Numerous studies have evaluated the significance of the microRNA‐10b (miR‐10b) in the development and progression of many cancers. Their findings revealed that increased expression of miR‐10b is associated with unfavorable prognosis in patients with cancer.

Results

A total of 1,834 patients from 19 studies were included in this study. A significantly shorter overall survival was observed in patients with increased expression of miR‐10b (hazard ratio [HR] = 1.99, 95% confidence interval [CI]: 1.51–2.61). Statistical significance was also observed in subgroup meta‐analysis stratified by the cancer type, cutoff value, analysis type, and sample size. Also, patients with a high expression level of miR‐10b had a poorer disease‐free survival rate (HR = 1.18, 95% CI: 1.05–1.33). In addition, the pooled odds ratios (ORs) showed that increased miR‐10b was also associated with positive lymph node metastasis (OR = 2.09, 95% CI: 1.45–3.03), distant metastasis (OR = 2.40, 95% CI: 1.57–3.67), tumor size (OR = 3.86, 95% CI: 2.25–6.64), and poor clinical stage (OR = 5.02, 95% CI: 3.37–7.47).

Materials and Methods

A systematic literature search was conducted on a number of electronic databases, including PubMed, Embase, Web of Science, China National Knowledge Infrastructure, Springer, Google Scholar, and Gene expression omnibus. We retrieved the relevant articles to examine the association between the miR‐10b expression levels and patients’ prognosis. The meta‐analysis was conducted using the RevMan 5.2 software and Stata SE12.0 software.

Conclusions

High miR‐10b expression was correlated with poor clinical outcome, which indicated the potential clinical use of miR‐10b as a molecular biomarker for cancer, particularly in assessing prognosis for patients with cancers. Further studies should be performed to verify the clinical utility of miR‐10b in human solid tumors.
Proteomic identification of hippocalcin and its protective role in heatstroke‐induced hypothalamic injury in mice
Authors: Ji Jingjing , Hong Xinxin , Su Lei , Liu Zhifeng
Published: September 2018

Heatstroke is a devastating condition that is characterized by severe hyperthermia and central nervous system dysfunction. However, the mechanism of thermoregulatory center dysfunction of the hypothalamus in heatstroke is unclear. In this study, we established a heatstroke mouse model and a heat‐stressed neuronal cellular model on the pheochromocytoma‐12 (PC12) cell line. These models revealed that HS promoted obvious neuronal injury in the hypothalamus, with high pathological scores. In addition, PC12 cell apoptosis was evident by decreased cell viability, increased caspase‐3 activity, and high apoptosis rates. Furthermore, 14 differentially expressed proteins in the hypothalamus were analyzed by fluorescence two‐dimensional difference gel electrophoresis and identified by matrix‐assisted laser desorption ionization time‐of‐flight mass spectrometry. Expression changes in hippocalcin (HPAC), a downregulated neuron‐specific calcium‐binding protein, were confirmed in the hypothalamus of the heatstroke mice and heat‐stressed PC12 cells by immunochemistry and western blot. Moreover, HPAC overexpression and HPAC‐targeted small interfering RNA experiments revealed that HPAC functioned as an antiapoptotic protein in heat‐stressed PC12 cells and hypothalamic injury. Lastly, ulinastatin (UTI), a cell‐protective drug that is clinically used to treat patients with heatstroke, was used in vitro and in vivo to confirm the role of HPAC; UTI inhibited heat stress (HS)‐induced downregulation of HPAC expression, protected hypothalamic neurons and PC12 cells from HS‐induced apoptosis and increased heat tolerance in the heatstroke animals. In summary, our study has uncovered and demonstrated the protective role of HPAC in heatstroke‐induced hypothalamic injury in mice.
The potential prognostic and therapeutic application of tissue and circulating microRNAs in cervical cancer
Authors: Hasanzadeh Malihe , Movahedi Mehraneh , Rejali Marzieh , Maleki Faezeh , Moetamani‐Ahmadi Mehrdad , Seifi Sima , Hosseini Zeinab , Khazaei Majid , Amerizadeh Forouzan , Ferns Gordon A. , Rezayi Majid , Avan Amir
Published: September 2018

Cervical cancer (CC) is a common malignancy in women and a major cause of cancer‐related mortality globally. Some novel biomarkers may enable the early diagnosis and monitoring of CC. MicroRNAs (miRNAs) are small noncoding RNAs that control gene translation at a posttranscriptional level. Hence the deregulation of these molecules can cause many diseases. There appears to be an association between aberrant miRNA expression and CC, but the molecular mechanisms involved in the development of CC remain unknown. The upregulation of some circulating miRNAs, for example, miRNA‐20a, miRNA‐203, miRNA‐21, miRNA‐205, miRNA‐218, and miR‐485‐5, as well as tissue‐specific miRNAs, for example, miR‐7, miR‐10a, miR‐17‐5p, miR‐135b, miR‐149, and miR‐203 have been found in patients with CC. There is also growing evidence for the importance of miRNAs in the development of drug resistance. This review therefore highlights recently published preclinical and clinical investigation performed on tissue specific and circulating miRNAs, as potential biomarkers for the detection of patients at early stages of CC, in the prediction of prognosis, and monitoring of their response to therapy.
Retracted: Role of CXCL12–CXCR4 axis in ovarian cancer metastasis and CXCL12–CXCR4 blockade with AMD3100 suppresses tumor cell migration and invasion in vitro
Authors: Liu Yan , Ren Chen‐Chen , Yang Li , Xu Yi‐Ming , Chen Yan‐Nan
Published: September 2018

Ovarian cancer (OC) is a lethal gynecologic tumor, which brings its mortality to the head. CXCL12 and its receptor chemokine receptor 4 (
CXCR4) have been found to be highly expressed in OC and contribute to the disease progression by affecting tumor cell proliferation and invasion. Here, in this study, we aim to explore whether the blockade of CXCL12–CXCR4 axis with AMD3100 (a selective CXCR4 antagonist) has effects on the progression of OC. On the basis of the gene expression omnibus database of OC gene expression chips, the OC differentially expressed genes were screened by microarray analysis. OC (nonmetastatic and metastatic) and normal ovarian tissues were collected to determine the expressions of CXCL12 and CXCR4. A series of AMD3100, shRNA against CXCR4, and pCNS‐CXCR4 were introduced to treat CAOV3 cells with the highest CXCR4 was assessed. Cell viability, apoptosis, migration, and invasion were all evaluated. The microarray analysis screened out the differential expression of CXCL12–CXCR4 in OC. CXCL12 and CXCR4 expressions were increased in OC tissues, particularly in the metastatic OC tissues. Downregulation of CXCR4 by AMD3100 or shRNA was observed to have a critical role in inhibiting cell proliferation, migration, and invasion of the CAOV3 OC cell line while promoting cell apoptosis. Overexpressed CXCR4 brought significantly promoting effects on the proliferation and invasiveness of OC cells. These results reinforce that the blockade of CXCL12–CXCR4 axis with AMD3100 inhibits the growth of OC cells. The antitumor role of the inhibition of CXCL12–CXCR4 axis offers a preclinical validation of CXCL12–CXCR4 axis as a therapeutic target in OC.
Immune responsive resolvin D1 programs peritoneal macrophages and cardiac fibroblast phenotypes in diversified metabolic microenvironment
Authors: Kain Vasundhara , Halade Ganesh V.
Published: September 2018

Bioactive lipid mediators derived from n‐3 and
n‐6 fatty acids are known to modulate leukocytes. Metabolic transformation of essential fatty acids to endogenous bioactive molecules plays a major role in human health. Here we tested the potential of substrates; linoleic acid (LA) and docosahexaenoic acid (DHA) and their bioactive products; resolvin D1 (RvD1) and 12‐
S‐hydroxyeicosatetraenoic acids (HETE) to modulate macrophage plasticity and cardiac fibroblast phenotype in presence or absence of lipid metabolizing enzyme 12/15‐lipoxygenase (LOX). Peritoneal macrophages and cardiac fibroblasts were isolated from wild‐type (C57BL/6J) and 12/15LOX
−/− mice and treated with DHA, LA, 12(S)‐HETE, and RvD1 for 4, 8, 12, and 24 hr. LA, DHA, 12(S)‐HETE, and RvD1 elicited mRNA expression of proinflammatory markers; tumor necrosis factor‐α (
Tnf‐α), interleukin 6 (
IL‐6), chemokine (C–C motif) ligand 2 
(Ccl2), and
IL‐1β in wild type (WT) and in 12/15LOX
−/− macrophages at early time point (4 hr). Bioactive immunoresolvent RvD1 lowered the levels of
Tnf‐α, IL‐6, and
IL‐1β at 24 hr time point. Both DHA and RvD1 stimulated the proresolving markers such as arginase 1 (
Arg‐1), chitinase‐like protein 3 (
Ym‐1), and mannose receptor C‐type 1 in WT macrophage. RvD1 induced proresolving phenotype
Arg‐1 expression in both WT 12/15LOX
−/− macrophages even in presence of 12(S)‐HETE. RvD1 peaked 5LOX expression in both WT and 12/15LOX
−/− at 24 hr time point compared with DHA. RvD1 diminished cyclooxygenase‐2 but upregulated 5LOX expression in fibroblast compared with DHA. In summary, the feed‐forward enzymatic interaction with fatty acids substrates and direct mediators (RvD1 and 12(S)‐HETE) are responsive in determining macrophages phenotype and cardiac fibroblast plasticity. Particularly, macrophages and fibroblast phenotypes are responsive to milieu and RvD1 governs the milieu‐dependent chemokine signaling in presence or absence of 12/15LOX enzyme to resolve inflammation.
Heme oxygenase 1 regulates apoptosis induced by heat stress in bovine ovarian granulosa cells via the ERK1/2 pathway
Authors: Wang Yi‐Ru , Chen Kun‐Lin , Li Cheng‐Min , Li Lian , Wang Gen‐Lin
Published: September 2018

Heat stress can inhibit follicular development in dairy cows, and thus can affect their reproductive performance. Follicular granulosa cells can synthesize estrogen, that affects the development and differentiation of follicles by apoptosis. Heme oxygenase 1 (HO‐1/heat shock protein 32) plays an antiapoptotic and cytoprotective role in various cells during stress‐induced apoptosis, but little is known about its definitive function in bovine (ovarian) granulosa cells (bGCs). In our study, the roles and mechanism of HO‐1 on the heat stress‐induced apoptosis of bGCs were studied. Our results show that the expression of HO‐1 was significantly increased under heat stress. Moreover, HO‐1 silencing increased apoptosis, whereas its overexpression dampened apoptosis by regulating the expression of Bax/Bcl‐2 and the levels of cleaved caspase‐3. In addition, HO‐1 can also play a cytoprotective role by affecting estrogen levels and decomposing heme to produce biologically active metabolite carbon monoxide (CO). Meanwhile, CO significantly increased the level of HO‐1, decreased Bax/Bcl‐2 levels, and inhibited the activation of extracellular signal‐regulated kinase 1/2 (ERK1/2) signaling pathway. The apoptosis of ovarian GCs can affect the secretion of estrogen and lead to disorder of the ovarian microenvironment, thus affecting the normal function of the ovary. Our results indicate that HO‐1 acts as a cytoprotective enzyme and plays a protective role in heat‐induced apoptosis of bGCs. In conclusion, HO‐1 and its metabolite CO inhibit the apoptosis of bGCs induced by heat stress through the ERK1/2 pathway. The results of this study provide a valuable clue for improving the fertility of heat stressed cows in summer.
PD‐1/PD‐L1 immune checkpoint: Potential target for cancer therapy
Authors: Dermani Fatemeh K. , Samadi Pouria , Rahmani Golebagh , Kohlan Alisa K. , Najafi Rezvan
Published: September 2018

Recent studies show that cancer cells are sometimes able to evade the host immunity in the tumor microenvironment. Cancer cells can express high levels of immune inhibitory signaling proteins. One of the most critical checkpoint pathways in this system is a tumor‐induced immune suppression (immune checkpoint) mediated by the programmed cell death protein 1 (PD‐1) and its ligand, programmed death ligand 1 (PD‐L1). PD‐1 is highly expressed by activated T cells, B cells, dendritic cells, and natural killer cells, whereas PD‐L1 is expressed on several types of tumor cells. Many studies have shown that blocking the interaction between PD‐1 and PD‐L1 enhances the T‐cell response and mediates antitumor activity. In this review, we highlight a brief overview of the molecular and biochemical events that are regulated by the PD‐1 and PD‐L1 interaction in various cancers.
Phosphorylation of nucleolin is indispensable to upregulate miR‐21 and inhibit apoptosis in cardiomyocytes
Authors: Tong Zhongyi , Tang Yuting , Jiang Bimei , Wu Yanyang , Liu Yanjuan , Li Yuanbin , Xiao Xianzhong
Published: September 2018

Nucleolin is a multifunctional phosphoprotein and is involved in protecting from myocardial ischemia/reperfusion (I/R) injury. The function of nucleolin is regulated by posttranslational modifications, including phosphorylation and glycosylation. To study whether phosphorylation of nucleolin (P‐nucleolin) was involved in the protection from myocardial I/R injury. We investigated the expression pattern of P‐nucleolin (Thr‐76 and 84) in hearts subjected to I/R injury, or rat cardiac myoblast cells (H9C2) subjected to hydrogen peroxide (H
2O
2). The results showed that the expression of P‐nucleolin and the ratio of P‐nucleolin/nucleolin were significantly increased both in vivo and in vitro. Mutant nucleolin was obtained by site directed mutagenesis in vitro: threonine at 76 and 84 was replaced by alanine, and we found that the protective effect of nucleolin on apoptosis induced by oxidative stress was dependent on its phosphorylation at 76 and 84 in H9C2 cells. Furthermore, the cardio‐protective roles of P‐nucleolin (Thr‐76 and 84) in H9C2 cardiomyocytes, were attributable to the upregulation of microRNA (miR)‐21. Further analysis found that P‐nucleolin (Thr‐76 and 84) could bind to miR‐21, and P‐nucleolin colocalized with argonaute 2 (Ago2) in cytoplasm and could interact with Ago2 in a RNA‐independent manner under cell oxidative stress. The current study revealed that P‐nucleolin (Thr‐76 and 84) increased in I/R injury myocardium, P‐nucleolin was indispensable to upregulate miR‐21 and inhibited apoptosis induced by H
2O
2 in H9C2 cardiomyocytes. These findings provided new insight into the molecular mechanisms of nucleolin in myocardial I/R injury and oxidative stress cells.
Hepatocyte growth factor promotes the proliferation of human embryonic stem cell derived retinal pigment epithelial cells
Authors: Karamali Fereshteh , Esfahani Mohammad‐Hossein Nasr , Hajian Mehdi , Ejeian Fatemeh , Satarian Leila , Baharvand Hossein
Published: September 2018

Research that pertains to the molecular mechanisms involved in retinal pigment epithelial (RPE) development can significantly contribute to cell therapy studies. The effects of periocular mesenchymal cells on the expansion of RPE cells remain elusive. We have examined the possible proliferative role of hepatocyte growth factor (HGF) as a mesenchymal cell secretory factor against human embryonic stem cell derived RPE (hESC‐RPE). We found that the conditioned medium of human mesenchymal stem cells from apical papilla and/or exogenous HGF promoted proliferation of the hESC‐RPE cells as single cells and cell sheets, in addition to rabbit RPE sheets in vitro. Blockage of HGF signaling by HGF receptor inhibitor, PHA‐665752, inhibited proliferation of hESC‐RPE cells. However, differentiation of hESCs and human‐induced pluripotent stem cells to a rostral fate and eye‐field specification was unaffected by HGF. Our in vivo analysis showed HGF expression in periocular mesenchymal cells after optic cup formation in chicken embryos. Administration of HGF receptor inhibitor at this developmental stage in chicken embryos led to reduced eye size and disorganization of the RPE sheet. These findings suggested that HGF administration could be beneficial for obtaining higher numbers of hESC‐RPE cells in human preclinical and clinical trials.
The role of microRNAs in 5‐FU resistance of colorectal cancer: Possible mechanisms
Authors: Marjaneh Reyhaneh Moradi , Khazaei Majid , Ferns Gordon A. , Avan Amir , Aghaee‐Bakhtiari Seyed Hamid
Published: September 2018

Colorectal cancer (CRC) is one of the most common cancers globally. Despite recent advances in therapeutic approaches, this cancer continues to have a poor prognosis, particularly when diagnosed late. 5‐Fluorouracil (5‐FU) has been commonly prescribed for patients with CRC, but resistance to 5‐FU is one of the main reasons for failure in the treatment of this condition. Recently, microRNAs (miRNAs) have been established as a means of modifying the signaling pathways involved in initiation and progression of CRC and their role as oncogene or tumor suppressor have been investigated in various studies. Moreover, miRNAs through various mechanisms play an important role in inducing tumor resistance or sensitivity to anticancer drugs. Detecting and targeting these mechanisms may be a new therapeutic approach. This review summarizes the current knowledge about the potential roles of miRNAs in 5‐FU resistance, with particular emphasis on molecular mechanism involved.
Arsenic induces fibrogenic changes in human kidney epithelial cells potentially through epigenetic alterations in DNA methylation
Authors: Chang Yu‐Wei , Singh Kamaleshwar P.
Published: September 2018

Arsenic contamination is a significant public health issue, and kidney is one of the target organ for arsenic‐induced adverse effects. Renal fibrosis is a well‐known pathological stage frequently observed in progressive chronic kidney disease (CKD). Epidemiological studies implicate arsenic exposure to CKD, but the role of arsenic in kidney fibrosis and the underlying mechanism is still unclear. It is in this context that the current study evaluated the effects of long‐term arsenic exposure on the cellular response in morphology, and marker genes expression with respect to fibrosis using human kidney 2 (HK‐2) epithelial cells. Results of this study revealed that in addition to increased growth, HK‐2 cells underwent phenotypic, biochemical and molecular changes indicative of epithelial–mesenchymal transition (EMT) in response to the exposure to arsenic. Most importantly, the arsenic‐exposed cells acquired the pathogenic features of fibrosis as supported by increased expression of markers for fibrosis, such as Collagen I, Fibronectin, transforming growth factor β, and α‐smooth muscle actin. Upregulation of fibrosis associated signaling molecules such as tissue inhibitor of metalloproteinases‐3 and matrix metalloproteinase‐2 as well as activation of AKT was also observed. Additionally, the expression of epigenetic genes (DNA methyltransferases 3a and 3b; methyl‐CpG binding domain 4) was increased in arsenic‐exposed cells. Treatment with DNA methylation inhibitor 5‐Aza‐2′‐dC reversed the EMT properties and restored the level of phospho‐AKT. Together, these data for the first time suggest that long‐term exposure to arsenic can increase the risk of kidney fibrosis. Additionally, our data suggest that the arsenic‐induced fibrotic changes are, at least in part, mediated by DNA methylation and therefore potentially can be reversed by epigenetic therapeutics.
Therapeutic potency of pharmacological adenosine receptors agonist/antagonist on cancer cell apoptosis in tumor microenvironment, current status, and perspectives
Authors: Soleimani Anvar , Bahreyni Amirhossein , Roshan Mostafa K. , Soltani Arash , Ryzhikov Mikhail , Shafiee Mojtaba , Soukhtanloo Mohammad , Jaafari Mahmoud R. , Mashkani Baratali , Hassanian Seyed M.
Published: September 2018

The hypoxic niche of tumor leads to a tremendous increase in the extracellular adenosine concentration through alteration of adenosine metabolism in the tumor microenvironment (TME). This consequently affects cancer progression, local immune responses, and apoptosis of tumor cells. Regulatory effect of adenosine on apoptosis in TME depends on the cancer cell type, pharmacological characteristics of adenosine receptor subtypes, and the adenosine concentration in the tumor niche. Exploiting specific pharmacological adenosine receptor agonist and antagonist inducing apoptosis in cancer cells can be considered as a proper procedure to control cancer progression. This review summarizes the regulatory role of adenosine in cancer cell apoptosis for a better understanding, and hence better management of the disease.
Luteolin attenuates glucocorticoid‐induced osteoporosis by regulating ERK/Lrp‐5/GSK‐3β signaling pathway in vivo and in vitro
Authors: Jing Zheng , Wang Changyuan , Yang Qining , Wei Xuelian , Jin Yue , Meng Qiang , Liu Qi , Liu Zhihao , Ma Xiaodong , Liu Kexin , Sun Huijun , Liu Mozhen
Published: September 2018

Glucocorticoid‐induced osteoporosis (GIO) is a secondary osteoporosis with extensive use of glucocorticoids (GCs). GCs can increase bone fragility and fracture via inhibiting osteoblastic proliferation and differentiation. Luteolin (LUT), a kind of plant flavonoid, has been reported to exhibit the antioxidant activity, but the effects of LUT on GIO still remain unclear. This study aimed to investigate the effects of LUT on GIO both in vivo and in vitro and elaborate the potential molecular mechanisms. LUT increased the superoxide dismutase activity, glutathione level and decreased reactive oxygen species (ROS) level and lactate dehydrogenase release in GIO. Meanwhile, LUT decreased caspase‐3, caspase‐9, and Bax protein expressions and increased Bcl‐2 protein expression in GIO. LUT increased the ratio of osteoprotegerin (OPG)/receptor activator of nuclear factor‐κB Ligand (RANKL) messenger RNA (mRNA) expression and mRNA expression levels of osteogenic markers, including runt‐related transcription factor 2, osterix, collagen type I, and osteocalcin. LUT also enhanced the extracellular signal‐regulated kinases (ERK) phosphorylation, glycogen synthase kinase 3β (GSK‐3β) phosphorylation, mRNA expression levels of lipoprotein‐receptor‐related protein 5 (Lrp‐5) and β‐catenin. Further study revealed that Lrp‐5 small interfering RNA (siRNA )and ERK‐siRNA reduced the effects of LUT on GSK‐3β phosphorylation, alkaline phosphatase (ALP) activity and the ratio of OPG/RANKL mRNA expression. Moreover, ERK‐siRNA decreased Lrp‐5 mRNA expression in vitro. These results indicated that LUT promoted proliferation by attenuating oxidative stress and promoted osteoblastic differentiation by regulating the ERK/Lrp‐5/GSK‐3β pathway in GIO. This study may bring to light the possible mechanisms involved in the action of LUT in GIO treatment, and benefit for further research on GIO.
Adjuvant chemotherapy with melatonin for targeting human cancers: A review
Authors: Najafi Masoud , Salehi Eniseh , Farhood Bagher , Nashtaei Maryam Shabani , Hashemi Goradel Nasser , Khanlarkhani Neda , Namjoo Zeinab , Mortezaee Keywan
Published: September 2018

Melatonin is a multifunctional hormone that has long been known for its antitumoral effects. An advantage of the application of melatonin in cancer therapy is its ability to differentially influence tumors from normal cells. In this review, the roles of melatonin adjuvant therapy in human cancer are discussed. Combination of melatonin with chemotherapy could provide synergistic antitumoral outcomes and resolve drug resistance in affected patients. This combination reduces the dosage for chemotherapeutic agents with the subsequent attenuation of side effects related to these drugs on normal cells around tumor and on healthy organs. The combination therapy increases the rate of survival and improves the quality of life in affected patients. Cancer cell viability is reduced after application of the combinational melatonin therapy. Melatonin does all these functions by adjusting the signals involved in cancer progression, re‐establishing the dark/light circadian rhythm, and disrupting the redox system for cancer cells. To achieve effective therapeutic outcomes, melatonin concentration along with the time of incubation for this indoleamine needs to be adjusted. Importantly, a special focus is required to be made on choosing an appropriate chemotherapy agent for using in combination with melatonin. Because of different sensitivities of cancer cells for melatonin combination therapy, cancer‐specific targeted therapy is also needed to be considered. For this review, the PubMed database was searched for relevant articles based on the quality of journals, the novelty of articles published by the journals, and the number of citations per year focusing only on human cancers.
Inhibition of glycolysis alleviates lipopolysaccharide‐induced acute lung injury in a mouse model
Authors: Zhong Wen‐Jing , Yang Hui‐Hui , Guan Xin‐Xin , Xiong Jian‐Bing , Sun Chen‐Chen , Zhang Chen‐Yu , Luo Xiao‐Qin , Zhang Yan‐Feng , Zhang Jun , Duan Jia‐Xi , Zhou Yong , Guan Cha‐Xiang
Published: September 2018

Gluconic metabolic reprogramming, immune response, and inflammation are intimately linked. Glycolysis involves in the pathologic progress in acute and chronic inflammatory diseases. However, the involvement of glycolysis in the acute lung injury (ALI) is still unclear. This study investigated the role of glycolysis in an animal model of ALI. First, we found that lactate content in serum was remarkably increased in ALI patients and a murine model induced by intratracheal administration of lipopolysaccharide (LPS). The key proteins involving in glycolysis were robustly elevated, including HK2,
PKM2, and
HIF‐1α. Intriguingly, inhibition of glycolysis by 2‐deoxyglucose (2‐DG) pronouncedly attenuated the lung tissue pathological injury, accumulation of neutrophil, oxidative stress, expression of proinflammatory factors in the lung of ALI mice induced by LPS. The 2‐DG treatment also strongly suppressed the activation of the NOD‐like receptor (NLR) family and pyrin domain‐containing protein 3 (NLRP3) inflammasome. Furthermore, we investigated the role of glycolysis in the inflammatory response of primary murine macrophages activated by LPS in vitro. We found that the 2‐DG treatment remarkably reduced the expression of proinflammatory factors induced by LPS, including tumor necrosis factor‐α messenger RNA (mRNA), pro‐interleukin (IL)‐1β mRNA, pro‐IL‐18 mRNA, NLRP3 mRNA, caspase‐1 mRNA, and IL‐1β protein. Altogether, these data provide a novel link between gluconic metabolism reprogramming and uncontrolled inflammatory response in ALI. This study suggests glycolytic inhibition as an effective anti‐inflammatory strategy in treating ALI.
PI3k/AKT signaling pathway: Erythropoiesis and beyond
Authors: Jafari Mahjoobeh , Ghadami Elham , Dadkhah Tahereh , Akhavan‐Niaki Haleh
Published: September 2018

Erythropoiesis is a multi‐step process that involves the differentiation of hematopoietic stem cells into mature red blood cells (RBCs). This process is regulated by several signaling pathways, transcription factors and microRNAs (miRNAs). Many studies have shown that dysregulation of this process can lead to hematologic disorders. PI3K/AKT is one of the most important pathways that control many cellular processes including, cell division, autophagy, survival, and differentiation. In this review, we focus on the role of PI3K/AKT pathway in erythropoiesis and discuss the function of some of the most important genes, transcription factors, and miRNAs that regulate different stages of erythropoiesis which play roles in differentiation and maturation of RBCs, prevention of apoptosis, and autophagy induction. Understanding the role of the PI3K pathway in erythropoiesis may provide new insights into diagnosing erythrocyte disorders.
The immunomodulatory role of probiotics in allergy therapy
Authors: Hajavi Jafar , Esmaeili Seyed‐Alireza , Varasteh Abdol‐Reza , Vazini Hossein , Atabati Hadi , Mardani Fatemeh , Momtazi‐Borojeni Amir A. , Hashemi Maryam , Sankian Mojtaba , Sahebkar Amirhossein
Published: September 2018

The increased incidence of allergic disorders may be the result of a relative fall in microbial induction in the intestinal immune system during infancy and early childhood. Probiotics have recently been proposed as viable microorganisms for the prevention and treatment of speciﬁc allergic diseases. Different mechanisms have been considered for this probiotic property, such as generation of cytokines from activated pro‐T‐helper type 1 after bacterial contact. However, the effects of its immunomodulatory potential require validation for clinical applications. This review will focus on the currently available data on the benefits of probiotics in allergy disease.
Antioxidative potential of antidiabetic agents: A possible protective mechanism against vascular complications in diabetic patients
Authors: Yaribeygi Habib , Butler Alexandra E. , Barreto George E. , Sahebkar Amirhossein
Published: September 2018

Many vascular complications are related to exposure of tissues to elevated levels of glucose, a condition that promotes oxidative stress. The primary goal of antidiabetic medication is for normalization of blood glucose. However, antidiabetic medications may have antioxidant effects that go beyond their hypoglycemic influences. Therefore, antidiabetic drugs may be doubly beneficial in preventing diabetic complications. Vascular dysfunction due to uncontrolled diabetes is a serious complication of the disease and one which has a severe impact on quality of life. Readjustment of the oxidative balance in subjects with diabetes, and the positive effects thereof is a topic of intense interest at present. In the current review, we highlight the antioxidant effects of antidiabetic medications which may prevent or delay the onset of vascular dysfunction.
BI1 alleviates cardiac microvascular ischemia‐reperfusion injury via modifying mitochondrial fission and inhibiting XO/ROS/F‐actin pathways
Authors: Zhou Hao , Wang Jin , Hu Shunying , Zhu Hong , Toan Sam , Ren Jun
Published: September 2018

Pathogenesis of cardiac microvascular ischemia‐reperfusion (IR) injury is associated with excessive mitochondrial fission. However, the upstream mediator of mitochondrial fission remains obscure. Bax inhibitor 1 (BI1) is linked to multiple mitochondrial functions, and there have been no studies investigating the contribution of BI1 on mitochondrial fission in the setting of cardiac microvascular IR injury. This study was undertaken to establish the action of BI1 on the cardiac microvascular reperfusion injury and figure out whether BI1 sustained endothelial viability via inhibiting mitochondrial fission. Our observation indicated that BI1 was downregulated in reperfused hearts and overexpression of BI1 attenuated microvascular IR injury. Mechanistically, reperfusion injury elevated the levels of xanthine oxidase (XO), an effect that was followed by increased reactive oxygen species (ROS) production. Subsequently, oxidative stress mediated F‐actin depolymerization and the latter promoted mitochondrial fission. Aberrant fission caused mitochondrial dysfunction and ultimately activated mitochondrial apoptosis in cardiac microvascular endothelial cells. By comparison, BI1 overexpression repressed XO expression and thus neutralized ROS, interrupting F‐actin‐mediated mitochondrial fission. The inhibitory effect of BI1 on mitochondrial fission sustained endothelial viability, reversed endothelial barrier integrity, attenuated the microvascular inflammation response, and maintained microcirculation patency. Altogether, we conclude that BI1 is essential in maintaining mitochondrial homeostasis and alleviating cardiac microvascular IR injury. Deregulated BI1 via the XO/ROS/F‐actin pathways plays a causative role in the development of cardiac microvascular reperfusion injury.
A Comparative Study Between Allometric Scaling and Physiologically Based Pharmacokinetic Modeling for the Prediction of Drug Clearance From Neonates to Adolescents
Authors: Mahmood Iftekhar , Tegenge Million A.
Published: September 2018

The objective of this study was to compare the predictive performance of an allometric model with that of a physiologically based pharmacokinetic (PBPK) model to predict clearance or area under the concentration‐time curve (AUC) of drugs in subjects from neonates to adolescents. From the literature, 10 studies were identified in which clearance or AUC of drugs from neonates to adolescents was predicted by PBPK models. In these published studies, drugs were given to children either by intravenous or oral route. The allometric model was an age‐dependent exponent (ADE) model for the prediction of clearance across the age groups. The predicted clearance or AUC values from the PBPK and ADE models were compared with the experimental values. The acceptable prediction error was the percentage of subjects within an 0.5‐ to 2‐fold or 0.5‐ to 1.5‐fold prediction error. There were 73 drugs with a total of 372 observations. From PBPK and allometric models, 91.1% and 90.6% of observations were within 0.5‐ to 2‐fold prediction error, respectively. For children ≤2 years old (n = 130), PBPK and allometric models had 89% and 87% of observations within the 0.5‐ to 2‐fold prediction error, respectively. This study indicates that the predictive power of PBPK and allometric models was essentially similar for the prediction of clearance or AUC in pediatric subjects ranging from neonates to adolescents.