فهرست مطالب

Basic Medical Sciences - Volume:24 Issue: 10, Oct 2021

Iranian Journal of Basic Medical Sciences
Volume:24 Issue: 10, Oct 2021

  • تاریخ انتشار: 1400/07/19
  • تعداد عناوین: 17
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  • Mehdi Karimi-Shahri, Hossein Javid, Alireza Sharbaf Mashhad, Shaghayegh Yazdani, Seyed Isaac Hashemy * Pages 1307-1323

    For a long time, mesenchymal stem cells (MSCs) were discussed only as stem cells which could give rise to different types of cells. However, when it became clear that their presence in the tumor microenvironment (TME) was like a green light for tumorigenesis, they emerged from the ashes. This review was arranged to provide a comprehensive and precise description of MSCs’ role in regulating tumorigenesis and to discuss the dark and the bright sides of cancer treatment strategies using MSCs.To gather the details about MSCs, we made an intensive literature review using keywords, including MSCs, tumor microenvironment, tumorigenesis, and targeted therapy. Through transferring cytokines, growth factors, and microRNAs, MSCs maintain the cancer stem cell population, increase angiogenesis, provide a facility for cancer metastasis, and shut down the anti-tumor activity of the immune system. Although MSCs progress tumorigenesis, there is a consensus that these cells could be used as a vehicle to transfer anti-cancer agents into the tumor milieu. This feature opened a new chapter in MSCs biology, this time from the therapeutic perspective. Although the data are not sufficient, the advent of new genetic engineering methods might make it possible to engage these cells as Trojan horses to eliminate the malignant population. So many years of investigation showed that MSCs are an important group of cells, residing in the TME, studying the function of which not only could add a delicate series of information to the process of tumorigenesis but also could revolutionize cancer treatment strategies.

    Keywords: Carcinogenesis, Mesenchymal stem cells, Molecular targeted therapies, Neoplasm Tumor microenvironment
  • Hiva Sharebiani, Sara Hajimiri, Shadi Abbasnia, Saman Soleimanpour, Amir Mohamad Hashem Asnaashari, Narges Valizadeh, Mohammad Derakhshan, Rezvan Pilpa, Arezoo Firouzeh, Kiarash Ghazvini, Saeid Amel Jamehdar, Seyed Abdolrahim Rezaee * Pages 1324-1335
    Objective(s)
    Game theory describes the interactions between two players and the pay-off from winning, losing, or compromising. In the present study, Mycobacterium tuberculosis (Mtb)–host interactions were used as an example for the application of game theory to describe and predict the different outcomes of Mtb-infection and introducing target molecules for use in protection or therapy.
    Materials and Methods
    The gene expression for eight main markers (CCR1, CCR2, IDO, Tbet, TGFβ, iNOS, MMP3, MMP9) of host response and three Mtb virulence factors (Ag85B, CFP-10, ESAT-6) were assessed in broncho-alveolar lavage of TB+ and TB- patients.
    Results
    The players’ strategies in the “Nash equilibrium”, showed that Ag85B is the main virulence factor for Mtb in active phase, and also the most immunogenic factor, if the host can respond by high expression of T-bet and iNOS toward a Th1 response. In this situation, Mtb can express high levels of ESAT-6 and CFP10 and change the game to the latency, in which host responses by medium expression of T-bet and iNOS and medium level of TGF-β and IDO. Consistently, the IDO expression was 134-times higher in TB+s than the TB-s,and the T-bet expression,~200-times higher in the TB-s than the TB+s. Furthermore, Mtb-Ag85B had a strong positive association with CCR2, T-bet and iNOS, but had a negative correlation with IDO.
    Conclusion
    Ag85B and maybe ESAT6 (without its suppressive C-terminal) should be considered for making subunit vaccines. And, preventing IDO formation in dendritic cells might be a novel target for immunotherapy of tuberculosis, to reduce the pressure of immune-suppression on Th1 responses.
    Keywords: Game theory, M. tuberculosis antigens, Mycobacterium tuberculosis, Th1, Tuberculosis
  • Sheng-Ta Tsai, Tzu-Hsuan Wei, Yu-Wan Yang, Ming-Kuei Lu, Shao San, Chon-Haw Tsai, Yi-Wen Lin * Pages 1336-1345
    Objective(s)
    Parkinson’s disease (PD) is a common progressive neurodegeneration disease. Its incidence increases with age and affects about 1% of people over 60. Incidentally, transient receptor potential V1 (TRPV1) and its relation with neuroinflammation in mouse brain has been widely reported.
    Materials and Methods
    We used 6-hydroxydopamine (6-OHDA) to induce PDD in mice. We then used the Morris water maze and Bio-Plex to test learning and inflammatory mediators in mouse plasma. Western blotting and immunostaining were used to examine TRPV1 pathway in the hippocampus and medial prefrontal cortex (mPFC).
    Results
    On acquisition days 3 (Control = 4.40 ± 0.8 sec, PDD = 9.82 ± 1.52 sec, EA = 5.04 ± 0.58 sec, Riva = 4.75 ± 0.87 sec; P=0.001) and 4, reversal learning days 1, 2, 3 (Control = 2.86 ± 0.46 sec, PDD = 9.80 ± 1.83 sec, EA = 4.6 ± 0.82 sec, Riva = 4.6 ± 1.03 sec; P=0.001) and 4, PDD mice showed significantly longer escape latency than the other three groups. Results showed that several cytokines were up-regulated in PDD mice and reversed by EA and rivastigmine. TRPV1 and downstream molecules were up-regulated in PDD mice and further reversed by EA and rivastigmine. Interestingly, α7 nicotinic receptors and parvalbumin levels in both the hippocampus and prefrontal cortex increased in EA-treated mice, but not in rivastigmine-treated mice.
    Conclusion
    Our results showed that TRPV1 played a role in the modulation of neuroinflammation of PDD, and could potentially be a new target for treatment.
    Keywords: Electroacupuncture, Hippocampus, Neuroinflammation, Parkinson’s disease dementia, Rivastigmine, Transient receptor potential V1
  • Tahmineh Sohrabi, Maryam Asadzadeh-Lotfabad, Zahra Shafie, Zeinab Tehranizadeh, Mohammad-Reza Saberi, Jamshidkhan Chamani * Pages 1346-1357
    Objective(s)
    Small molecules can bind to DNA via covalent or non-covalent interactions, which results in altering or inhibiting the function of DNA. Thus, understanding the interaction patterns of medicines or other small molecules can be very crucial. In this study, the interaction between malathion and calf thymus DNA (ctDNA), in the absence and presence of electromagnetic field (EMF) at low and high frequencies, was investigated through various spectroscopies and viscosity measurements.
    Materials and Methods
    The interaction studies were performed by means of absorbance, circular dichroism, fluorescence spectroscopy, viscosity, thermal melting, and molecular modeling techniques.
    Results
    The fluorescence intensity of the ctDNA-malathion complex in the presence of EMF, has revealed quenching of fluorescence emission curves. The dynamic interaction and RLS studies have implied the changes in ctDNA-malathion complex throughout the presence of EMF which suggested that hydrophobic forces play the main role in the binding. Studies have revealed that malathion does not have any effect on binding ethidium bromide to ctDNA, which signifies the groove binding. The viscosity of ctDNA increased as the malathion concentration was enlarged. The circular dichroism technique suggested that the ellipticity values of the ctDNA-malathion complex have not increased with enhancing the malathion concentration. Molecular docking and dynamics studies have indicated a potent electrostatic interaction between ctDNA and malathion in the groove binding site.  
    Conclusion
    The results of spectroscopic studies reinforced a potent interaction between malathion and ctDNA in the absence and presence of EMF which can help us for further pharmaceutical drug discoveries.
    Keywords: ctDNA, Electromagnetic Field, Groove binding, Spectroscopy, Viscosity
  • Zhe Zhang, Xing Wang, Linlin Yang, Linquan Yang, Huijuan Ma * Pages 1358-1365
    Objective(s)
    Liraglutide, a well-established drug for treating diabetes mellitus (DM), has recently gained attention for its cardiovascular benefits in diabetes via multiple cellular activities; however, whether liraglutide improves myocardial damage by inhibiting pyroptosis and the mechanisms of these potential effects remain unknown.
    Materials and Methods
    In this study, high-fat diet feeding and low-dose streptozotocin (STZ) injection were used to construct a rat DM model. Rats with fasting blood glucose (FBG) levels >16.7 mmol/l received subcutaneous injections of liraglutide (0.2 mg/kg) for 4 weeks. Metabolic parameters, the heart weight/body weight (HW/BW) ratio, and histopathology were examined. Protein levels of inflammatory, pyroptosis, and NOD-like receptor protein 3 (NLRP3) inflammasome markers were assessed via Western blotting. In in vitro studies, a sirtuin 1 (Sirt1) inhibitor (EX 527, 200 nM) and an AMP-activated protein kinase (AMPK) inhibitor (compound C, 20 µM) were used to inhibit Sirt1 and AMPK pathways, respectively.
    Results
    Liraglutide significantly attenuated cardiac hypertrophy, pathological changes, inflammation, pyroptosis, and NLRP3 inflammasome activation, accompanied by increased Sirt1 and AMPK activation. Consistent with the in vivo results, liraglutide attenuated high glucose (HG)-induced pyroptosis and NLRP3 inflammasome activation along with enhanced Sirt1 and AMPK activation. After blockade of Sirt1 and AMPK signaling, the protective effect of liraglutide was restrained. Notably, EX 527 abolished the stimulatory effect of liraglutide on Sirt1 and AMPK signaling, whereas compound C blunted AMPK signaling without affecting Sirt1 signaling. 
    Conclusion
    Liraglutide may protect against myocardial damage by activating the Sirt1/AMPK signaling pathways to inhibit cellular pyroptosis in DM.
    Keywords: Cardiovascular Disease, Diabetes Mellitus, Inflammasomes, Rats, Sirtuin 1
  • Masoumeh Abbasi, Asghar Tanomand *, Farshid Kafilzadeh, Samaneh Zolghadri, Hasan Hosainzadegan Pages 1366-1372
    Objective(s)
    Pseudomonas aeruginosa is an opportunistic pathogen that is an important cause of nosocomial infections. This bacterium produces various virulence factors, among which exotoxin A is significantly involved in mortality and morbidity. In this study, we evaluated the immunogenicity of native exotoxin A extracted from the P. aeruginosa and its conjugation with gold nanoparticles in the animal model.
    Materials and Methods
    Exotoxin A was first extracted and purified from the culture medium of P. aeruginosa PAO1 by selective precipitation and dialysis. The gold nanoparticles were prepared using the Turkevich method and conjugated to the prepared exotoxin A by electrostatic force. The size and conjugation were confirmed using electron microscopy and Fourier transform infrared spectrometry (FTIR), respectively. The immunogenicity of prepared ExoA-gold nanoparticles was investigated in the mice model.
    Results
    The results indicated that nano-gold particles can be conjugated to the native exotoxin A with high efficiency. Immunogenicity investigation demonstrated that antibody titers produced against native exotoxin A and its conjugate to nano-gold particles are significant in a mouse model (P<0.005). Moreover, significant protection against 2×LD50 P. aeruginosa infection was observed in animals immunized with nano-gold-exotoxin A as compared with control groups (P=0.00).
    Conclusion
    Our study indicated that exotoxin A can be produced with acceptable purity in the laboratory, and conjugated to gold nanoparticles. Based on these results nano-gold-exotoxin A conjugate is highly immunogenic and can be considered a potential vaccine candidate for P. aeruginosa infections.
    Keywords: Exotoxin A, Gold Nanoparticles, Immunization, Pseudomonas aeruginosa, Vaccine candidate
  • Maria Muddassir, Sadaf Munir, Almas Raza, Ahmad Basirat, Muddassir Ahmed, Umar Farooq, Syed Shoaib Ahmed, Syed Zeeshan Haider Naqvi * Pages 1373-1379
    Objective(s)
    Isolates producing Metallo-β-lactamase (MBL) have a significant impact on therapeutic and diagnostic layouts, plus their increased frequency has been reported globally. Determination of incidence of clinical isolates of Pseudomonas aeruginosa that are capable of producing MBL and AmpC-β-lactamases making them resistant to imipenem and cefoxitin.
    Materials and Methods
    Out of 1159 collected samples of urine, wound swabs, blood, tissue, and pus, the isolation rate of P. aeruginosa in the period of March 2020 to February 2021 was 22.0% (255/1159). Bacterial strains that were resistant towards imipenem were further processed for detecting the β-lactamase group of genes followed by statistical analysis of risk factors done based on clinical sample, gender, plus department of sample collection.
    Results
    The percentage of resistance against imipenem was found to be 53%. Out of 135 strains, phenotypic tests revealed MBLs incidence to be 61.5% by combination disc test and 81.5% by Modified Hodge test (MHT). Frequencies of blaIMP-1, blaVIM, blaSHV, blaTEM, and blaOXA genes were calculated to be 13%, 15%, 32%, 43%, and 21%, respectively. Co-expressions of blaMBLs (blaVIM and blaIMP-1) plus blaESBL (blaSHV, blaOXA, blaTEM) were detected using simplex and multiplex PCR. blaTEM, blaSHV, and blaOXA co-existed in 7.5% of clinical isolates. 5.5% of the isolates exhibited simultaneous expression of MBL/ESBL genes. 15% of the isolates resistant to cefoxitin were positive for the blaAmpC gene (17/114).
    Conclusion
    This is a pioneer report from Pakistan that concomitantly presents expression of blaVIM and blaIMP-1 with blaTEM, blaOXA, blaSHV, and blaAmpC in isolates of P. aeruginosa.
    Keywords: Antibiotic resistance, Beta-lactamases, Infections, MDR genes, Pseudomonas aeruginosa
  • Chuan-Ying Li, Zhen Qin, Shaohua Mei, Yan Hu, Cheng Wu * Pages 1380-1387
    Objective(s)
    A2 adenosine receptor (A2AR) is a novel promising target for the treatment of inflammatory and allergic diseases. However, its role in the development of cow’s milk protein allergy (CMPA) has not been elucidated. The present study was designed to investigate the function of A2AR in CMPA development.
    Materials and Methods
    BALB/c mice were sensitized and challenged with ovalbumin (OVA) to induce allergic responses. The model was assessed by detecting allergic responses and plasma-specific IgE levels. The levels of A2AR were measured by PCR and flow cytometry. The subpopulation of Treg cells was analysed.
    Results
    The mice sensitized and challenged with OVA showed classic allergic symptoms, such as acute allergic skin responses, increased anaphylactic shock symptom scores, and higher levels of total IgE, OVA-specific IgE, IgG1 and IgG2a. OVA-sensitized mice and CMPA patients showed decreased levels of A2AR and Treg cells. Interestingly, we observed a positive correlation between A2AR expression and Treg levels in CMPA patients. Further study showed that the A2AR agonist CGS21680 blocked OVA-induced allergic reactions, and the A2AR antagonist KW-6002 amplified allergic responses. Interestingly, CGS21680 not only activated the A2AR-mediated signalling pathway but also caused an increase in the population of Treg cells. In contrast, KW-6002 therapy decreased the levels of Tregs in allergic mice.
    Conclusion
    A2AR expression is downregulated in CMPA. The A2AR-mediated pathway negatively regulates the development of CMPA, at least in part, by amplifying the differentiation of Tregs.
    Keywords: Adenosine receptor, Allergic response, Cow’s milk protein allergy, FOXP3, Regulatory T cells
  • Manijeh Motevalian, Neda Tekyemaroof, Mohammad Hadi Nematollahi, Fatemeh Khajehasani, Iman Fatemi * Pages 1388-1394
    Objective(s)
    Atorvastatin (AT), a competitive inhibitor of 3-hydroxymethyl-3-glutaryl-coenzyme-A reductase, is a cholesterol-lowering drug. AT has been shown to have neuroprotective, antioxidant, and anti-inflammatory properties. Previously, we have reported that AT could attenuate the behavioral, renal, and hepatic manifestations of aging. To clarify further the mechanisms involved, the present study was designed to evaluate the effect of AT on the expression of some aging-related genes in the brain of aging mice induced by D-galactose (DG).
    Materials and Methods
    For this purpose, AT (0.1 and 1 mg/kg/p.o.) was administrated daily in DG-received (500 mg/kg/p.o.) mice model of aging for six weeks. At the end of the experiment, mice were decapitated to remove the brains. Then, the expression profiles of sirtuin 1 (Sirt1), P53, P21, Bcl-2, Bax, superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), interleukin 1 beta (IL1β), tumor necrosis factor-alpha (TNFα), inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and brain-derived neurotrophic factor (BDNF) were assessed using the real-time PCR method.
    Results
    The present study shows that DG decreases the expression of Sirt1, Bcl-2, CAT, GPx, and BDNF while increasing the expression of P53, P21, Bax, IL-1β, iNOS, COX-2, and TNF-α. According to the findings of the present study, AT (more potentially at the dose of 1 mg/kg) modulates the expression of these aging-related genes in the brain of aging mice.
    Conclusion
    The results of the present study confirmed our previous reports on the anti-aging effects of AT at the gene level, the precise mechanisms and underlying pathways need further studies.
    Keywords: Aging, Animal model, Apoptosis, Gene expression, Inflammation
  • Xingfeng Liu, Jingxin He, Zhi Xiao * Pages 1395-1403
    Objective(s)
    Clinically effective analgesia treatment for patients afflicted with osteocarcinoma lessens the intensity of pain. The midbrain periaqueductal gray (PAG) plays a critical role in pain modulation, and activation of P2X3 receptors in this region mediates pain processing. Neurotropin is a small molecule drug used for analgesic treatment of a number of chronic pain conditions. The present study aims at determining whether P2X3 receptor activation in PAG is responsible for the analgesic effect of neurotropin in rats with osteocarcinoma pain. 
    Materials and Methods
    The tibia of female Sprague-Dawley rats was inoculated with breast carcinoma cells to establish the osteocarcinoma pain model. The effects of intraperitoneal injection of 6, 12, and 18 neurotropin units (NU)/kg on pain threshold and receptor expression of P2X3 in the ventrolateral PAG (vlPAG) were assessed. The P2X3 receptor antagonist A-317491 (1.5 nmol/0.3 µl) was administered into vlPAG with a high-dose neurotropin (18 NU/kg) to determine the role of this receptor in the analgesic effect. 
    Results
    The pain thresholds of the rats with osteocarcinoma pain continuously decreased, whereas P2X3 receptor expression in vlPAG only slightly increased after osteocarcinoma cell inoculation. Neurotropin substantially elevated the pain threshold and P2X3 receptor expression in vlPAG in a dose-dependent manner. A-317491 microinjection into vlPAG significantly reduced the analgesic effects of neurotropin in the rats with osteocarcinoma pain.
    Conclusion
    Through these findings, it is shown that vlPAG P2X3 receptor activation participates in neurotropin-mediated analgesia mechanism in osteocarcinoma pain.
    Keywords: A-317491, Bone, Neurotropin, Osteocarcinoma Pain, P2X3 receptor, Periaqueductal gray
  • Samaneh Bayat, Akram Rabbani Zabihi, Sara Amel Farzad, Jebreel Movafagh, Ezzat Hashemi, Sepideh Arabzadeh, Maryam Hashemi * Pages 1404-1412
    Objective(s)
    Bromelain, a mixture of proteolytic enzymes from pineapple (Ananas comosus) is known as a potential debriding agent in burn treatment. In this research, the debridement efficiency of chitosan hydrogel loaded by sodium alginate-chitosan nanoparticles (NPs) containing bromelain (Br 10%-AG-CS NPs) was evaluated in animal models. 
    Materials and Methods
    The NPs were prepared using the ionic gelation technique and their properties were identified. Then, the debridement effect of bromelain NPs incorporated into chitosan hydrogel was evaluated 4 hr after wound treatment in animal models. 
    Results
    The particle size of positively charged Br-AG-Cs NPs was about 390±25 nm. The encapsulation efficiency of bromelain into AG-CS NPs was about 92%. The in vitro release profile showed that the maximum release of bromelain from NPs occurred during the first 4 hr (70%). The hydrogel structure did not significantly affect the profile release of bromelain in the formulation. After 6 months of storage at 4 and 25 °C, the synthesized NPs indicated no significant changes in bromelain activity. It was found that Br 10%-Ag-Cs NPs-CS hydrogel had the most beneficial effects on reducing necrotic tissues and resulted in re-epithelialization compared with other treated groups (negative and positive control, CS hydrogel, and Br 10%-CS hydrogel). 
    Conclusion
    Therefore, using this novel formulation can be considered a potential debridement agent.
    Keywords: Bromelain, Chitosan, Debridement, Nanoparticles, Sodium alginate
  • Ulker Tunca *, Mustafa Saygin, Ozlem Ozmen, Rahime Aslankoc, Arzu Yalcin Pages 1413-1420
    Objective(s)
    The purpose of this study was to evaluate the effect of moderate-intensity swimming exercise on learning and memory by the Morris water maze test. Changes in the expressions of cyclic AMP-response element-binding protein (CREB) and brain-derived neurotrophic factor (BDNF) proteins alternative pathway which were activated by sirtuin-1 (SIRT-1) were investigated.
    Materials and Methods
    The study included thirty-two male Sprague-Dawley rats (350-500 g, 11-12 and 15–16 months old). The rats were randomly divided into four groups with 8 rats in each group. The groups were designed as follows:  Control-1 (11-12 months), Exercise-1 (11-12 months), Control-2 (15-16 months), Exercise-2 (15-16 months). Moderate-intensity exercise was assigned for 30 min/day, 5 days/week, for the whole training period of 8 weeks.
    Results
    There were statistically significant differences between the groups on the third day (P=0.005) when swim speeds increased in the exercise groups. There was a statistically significant difference between Exercise 1 and Exercise 2 groups, the entries in the platform zone decreased in Exercise 2 group (P=0.026). While there were no histopathological findings observed in any group, increased  SIRT-1, BNDF, and CREB  expressions were seen in exercise groups compared with control groups.
    Conclusion
    In aged rats exercising at moderate intensity, increased expression of CREB and BDNF, and SIRT-1 could improve hippocampal-dependent memory.
    Keywords: BDNF, CREB, Learning-memory, Sirtuin-1, Swimming exercise
  • Ali Mosayebian, Roya Sherkat, Saeid Abediankenari, Monireh Golpour, Alireza Rafiei * Pages 1421-1427
    Objective(s)
    Familial Mediterranean Fever (FMF) is a hereditary auto-inflammatory disorder that is caused by mutations in the Mediterranean fever (MEFV) gene and is associated with an increase in pro-inflammatory cytokines, such as interleukin-1β (IL-1β) and interleukin-18 (IL-18), leading to excess inflammation. Colchicine is a common drug widely used for treatment of FMF attacks, but about 5–15% of the patients show resistance to the regular colchicine treatment. In this study, we used dimethylamino-parthenolide (DMAPT), as a small molecule inhibitor of Nuclear factor-κB (NF-κB), NLR family Pyrin domain containing 3 (NLRP3), and cysteine-aspartic acid protease 1(Caspase-1) on FMF-derived peripheral blood mononuclear cells (PBMCs).
    Materials and Methods
    The effects of DMAPT and colchicine on metabolic activity and apoptosis of FMF-derived PBMCs were evaluated by MTT and Annexin V/PI assays, respectively. Also, the expression levels of NF-κB, NLRP3, MEFV, CASP1, and IL-1β mRNA were investigated using a TaqMan real-time PCR, and the protein levels of IL-1β, IL-18, and IL-37 were assessed via an enzyme-linked immunosorbent assay (ELISA) in LPS/ ATP-stimulated PBMCs.
    Results
    DMAPT decreased the expression levels of NFκB (0.38±0.096, P<0.0001), NLRP3 (0.39±0.12, P<0.001), MEFV (0.384±0.145, P<0.001), CASP1 (0.48±0.13, P=0.0023), and IL-1β (0.09±0.09, P<0.0001) and reduced the secretion levels of IL-1β (8.92±5.3 vs. 149.85±20.92, P<0.0001), IL-18 (135±32.1 vs. 192±22.18, P=0.01), and IL-37 (27.5±6.3 vs. 78.19±14.3, P<0.0001) as compared to untreated cells.
    Conclusion
    Given the obtained results in comparison with previous research, the future clinical development of DMAPT could result in the expansion of new anti-inflammatory therapeutics for FMF disorder.
    Keywords: CASP1, Dimethylamino-arthenolide, Familial Mediterranean fever, IL-1β, IL-18, MEFV, NFκB, NLRP3
  • Tian Zhu *, Chao Zhu, Yue Qiu, Qian Li, Xin Yu, Guo Hao, Ping Song, Jian Xu, Peng Li, Ya-Ling Yin Pages 1428-1436
    Objective(s)
    This study aimed to evaluate the effects and the underlying mechanisms of tertiary butylhydroquinone (TBHQ) on diabetic liver steatosis and cell survival.
    Materials and Methods
    We performed streptozocin injection and used a high-sugar-high-fat diet for mice to develop an animal model of type 2 diabetes mellitus (T2DM). Bodyweight, blood glucose levels, and content of insulin were measured on all of the mice. The liver tissues were observed by hematoxylin-eosin staining. Protein levels of the liver were measured by Western blot analysis in mice. Primary hepatocytes were induced by hypochlorous acid (HClO) and insulin to form insulin resistance (IR). Primary hepatocyte apoptosis was observed by Hoechst staining. The PI3K/AKT signaling pathway and β-arrestin-2 factor were evaluated by Western blot assay.
    Results
    TBHQ reduced the blood glucose level and content of insulin in serum, increased body weight, and effectively alleviated liver steatosis in diabetic mice. TBHQ significantly up-regulated the expression of p-PI3K, p-AKT, GLUT4, GSK3β, and β-arrestin-2 in the liver of diabetic mice. Cell experiments confirmed that TBHQ increased the survival ability of primary hepatocytes, and TBHQ improved the expression of p-PI3K, p-AKT, GLUT4, and GSK3β by activating β-arrestin-2 in primary hepatocytes.
    Conclusion
    TBHQ could alleviate liver steatosis and increase cell survival, and the mechanism is due in part to β-arrestin-2 activation.
    Keywords: insulin resistance, Liver Steatosis, Tertiary butylhydroquinone, Type 2 diabetes mellitus, β-arrestin-2
  • Omar Abdel-Salam *, Marwa El-Shamarka, Eman Youness, Nermeen Shaffie Pages 1437-1445
    Objective(s)
    To investigate the potential therapeutic effect of Bougainvillea spectabilis flower decoction on aluminum chloride (AlCl3)-induced neurotoxicity. 
    Materials and Methods
    Rats received daily intraperitoneal injections of AlCl3 at 10 mg/kg for two months and were treated with B. spectabilis decoction at 50 or 100 mg/kg or saline during the 2nd month of the study. The control group received saline. Brain malondialdehyde (MDA), nitric oxide (NO), reduced glutathione (GSH), acetylcholinesterase (AChE), amyloid Aβ peptide, and interleukin-6 (IL-6) concentrations and paraoxonase-1 (PON-1) activity were determined and brain histology was done. Behavioral and neurological testing included Morris water maze (WMZ), Y maze, and wire hanging. 
    Results
    Compared with saline controls, AlCl3 significantly increased brain MDA and NO along with decreased GSH and PON-1 activity. It also increased AChE, IL-6, and amyloid Aβ concentrations. AlCl3 impaired motor strength and memory performance and caused brain neurodegeneration. B. spectabilis decoction given at 50 or 100 mg/kg protected against the biochemical and histopathological alterations evoked by AlCl3 by alleviating the increase in MDA and NO, and decrease in GSH and PON-1 activity.  B. spectabilis decoction showed no significant effect on AChE but markedly decreased IL-6 and amyloid Aβ in the brain of AlCl3-treated rats. It also restored memory performance and motor strength, and protected against AlCl3-induced neurodegeneration.
    Conclusion
    These results suggest that B. spectabilis flower decoction might prove of value in the treatment of Alzheimer’s disease.
    Keywords: Aluminum chloride, Amyloid Aβ, Bougainvillea spectabilis- flowers, Interleukin-6, Neurodegeneration, Oxidative stress, Paraoxonase
  • Mojgan Azadpour, Mohammad Morad Farajollahi, Hassan Dariushnejad, Ali Mohammad Varzi, Amir Varezardi, Mitra Barati * Pages 1446-1454
    Objective(s)
    Silymarin (SM) is a natural antioxidant compound with good anti-inflammatory effects, but its poor water solubility restricts its usage. Today, nanomaterial compounds (such as PLGA Poly D, L-lactic-co-glycolic acid) can provide a proper drug delivery system and help improve the accessibility of bioactive compounds to cells and tissues.
    Materials and Methods
    In this study, PLGA nanoparticles (NPs) containing SM (SM-PLGA) were synthesized and characterized and their biological effects were evaluated on M2 macrophage polarization to regulate inflammation. SM-PLGA NPs were fabricated by the oil in water emulsion (O/W) method. Macrophages (MQs) were isolated from mouse peritoneum by the cold RPMI lavage protocol. Primary mouse MQ cells were treated by SM and SM-PLGA NPs and then stimulated with lipopolysaccharide (LPS). M2 polarization was evaluated by measurements of cytokine secretion levels (TNF-α, IL1-β, and IL-10), flow cytometry markers (F4/80, CD11b, CD38, and CD206), and the expression of specific proteins (M2 Ym1 and Fizz1).
    Results
    SM-PLGA characterization showed that NPs were fabricated in the desired form. SM and SM-PLGA decreased pro-inflammatory cytokines (TNF-α and IL1-β) and increased IL10 as an anti-inflammatory cytokine. On the other hand, the M2-associated markers and proteins increased following treatment with SM and SM-PLGA. Post-hoc analysis indicated that these changes were more pronounced in the SM-PLGA group.
    Conclusion
    This study revealed that SM-PLGA could markedly promote M2 polarization, thereby providing a valuable medical approach against sepsis and septic shock.
    Keywords: Cytokines, Nanoparticles, PLGA compound, Peritoneal macrophages, Silymarin
  • Zhengrong Mei, Ye Hong, Haiyi Yang, Qiongyu Sheng, Bing Situ * Pages 1455-1461
    Objective(s)
    Traumatic brain injury (TBI) is a prominent health problem worldwide and it may lead to cognitive dysfunction, disability, and even death. To date, there is no effective treatment for TBI.  Our previous study showed that Huperzine A (HupA) improved cognitive function in a mouse model of TBI. However, the detailed mechanism of HupA remains unaddressed. In this study, we investigated the possible mechanism of the neuroprotective effect of HupA. 
    Materials and Methods
    C57BL/6 mice were randomly divided into 3 groups as sham, injured with vehicle treatment, and injured with HupA treatment groups. The Morris water maze task was used to evaluate the impairment of special learning and memory. Brain edema was as-sessed by measuring the wet weight to dry weight ratio. Malondialdehyde (MDA) and glutathione peroxidase (GPx) levels were measured for oxidative stress. Protein expressions of nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygen-ase-1(HO-1), and synaptophysin were detected by Western blot. The brain sections were stained with hematoxylin-eosin (H&E) for histology study.
    Results
    We found that HupA therapy improved histology and cognitive functional outcomes after TBI. HupA reduced brain edema in TBI mice. furthermore, HupA inhibited ox-idative stress. HupA promoted nuclear factor erythroid 2-related factor 2 (Nrf2) nu-clear translocation and activated Nrf2 after TBI. 
    Conclusion
    HupA protects against TBI through antioxidative effects via the Nrf2-ARE pathway.
    Keywords: Huperzine A, Neuroprotection, Nrf2-ARE, Oxidative stres, Traumatic brain injuries