Iranian Journal of Basic Medical Sciences
Volume:22 Issue: 8, Aug 2019

Metastasis means the dissemination of the cancer cells from one organ to another which is not directly connected to the primary site. Metastasis has a crucial role in the prognosis of cancer patients. A few theories, different types of cell and several molecular pathways have been proposed to explain the mechanism of metastasis. In this work, the related articles in the limited period of time, 2000–mid -2018 were reviewed, through search in PubMed, Google Scholar and Scopus database. The articles published in the last two decades related to the biology of cancer metastasis were selected and the most important factors were discussed. Metastasis is critical factor to predict survival in patients with advanced cancer and prognosis determines the treatment plan. Many different cell types and various signaling pathways control the metastatic process. Metastasis is a multistep process. Many signaling pathways and molecules are involved in metastasis. Increasing knowledge about the mechanism of metastasis can help in finding the promising targets of cancer therapy.

Acoustic cavitation which occurs at high intensities of ultrasound waves can be fatal for tumor cells. The existence of dissolved gases and also the presence of nanoparticles (NPs) in a liquid, irradiated by ultrasound, decrease the acoustic cavitation onset threshold and the resulting bubbles collapse. On the other hand, due to unique capabilities and optical properties of gold nanoparticles (GNPs), they have been emphasized as effective NPs in the field of tumor therapy. Absorption of the laser light by GNPs causes the water molecules around the NPs to evaporate and produces vapor cavities. In this paper, we have reviewed published studies in the fields of ultrasound therapy, sonodynamic therapy (SDT) and synergism of low-level ultrasound and also laser radiation in the presence of GNPs.

Neurodegeneration is an outcome of Methamphetamine (METH) abuse. Studies have emphasized on the neuroprotective properties of lithium. The current study is designed towards evaluating the role of Akt-1/GSK3 and CREB-BDNF signaling pathways in mediating lithium neuroprotection against METH-induced neurodegeneration in rats. Sixty adult male rats were randomly divided into five groups: control group (received 0.7 ml normal saline per rat for 28 days), METH group (given 10 mg/kg of METH intraperitoneally for 28 days), groups 3, 4, and 5 (given  METH (10 mg/kg) and lithium (75, 150, and 300 mg/kg intraperitoneally, individually for 28 days). Morris water maze (MWM) was used to assess mental functions. In addition to hippocampal neurodegeneration, Brain-derived neurotrophic factor (BDNF), cAMP response element binding (CREB), Glycogen synthase kinase 3 (GSK3), and Protein kinase B (Akt-1) were assessed in isolated hippocampus. METH abuse caused marked disorders in learning and memory that were dramatically improved with various doses of lithium. Furthermore, METH increased lipid peroxidation and the levels of oxidized form of interleukin 1 beta (IL-1β), glutathione (GSSG), Bax, tumor necrosis factor alpha (TNF-α), and GSK3,  while attenuating the extent of glutathione (reduced form (GSH)), P-CREB, Bcl-2, BDNF,  and Akt-1 in the hippocampus. Moreover, METH declined superoxide dismutase (SOD), glutathione reductase (GR), and glutathione peroxidase (GPx) activity in the hippocampus. Conversely, lithium attenuated METH-stimulated apoptosis, oxidative stress, and inflammation; while improving the extent of BDNF and P-CREB. Probably lithium possesses neuroprotection against METH-stimulated neurodegeneration in the hippocampus via Akt-1/GSK3β and CREB/BDNF signaling pathways.

The purpose of this study is to determine the efficacy and molecular mechanism of the effect of schisandrin b (SCHB) on treating erectile dysfunction (ED) in a rat model with bilateral cavernous crushing nerve injury. The ED rat model was established with bilateral cavernous nerve crushing, and then confirmed by apomorphine. Fifty healthy eight-week-old ED rats were randomly assigned into five group, including control group (sham surgery), bilateral cavernous nerve crushing injury group (BCNC), BCNC with low SCHB (100 mg/d), BCNC with medium SCHB (200 mg/d) and BCNC with high SCHB (400 mg/d). For the last three groups, SCHB was given for 2 months. Then, we examined intracavernosal pressure (ICP), cyclic nucleotides (cAMP, cGMP), endothelial nitric oxide synthase (eNOS) and neuronal NOS (nNOS) in all groups. In the study of ICP, SCHB was able to improve ED in a dose-dependent manner. In addition, as compared to the BCNC group, the relative expression of eNOS and nNOS in medium and high concentration of SCHB-treated groups are higher than BCNC group. Moreover, all groups treated with SCHB showed a significant higher expression level of cAMP and cGMP. These results suggested that SCHB were able to significantly improve the ED on rat model through the NO-cGMP and cAMP- protein kinase A (PKA) pathway.

Stenotrophomonas maltophilia has emerged as an important opportunistic nosocomial pathogen due to its intrinsic and acquired resistance to a wide range of antimicrobial agents. The present study aimed to investigate the occurrence of antibiotic resistance and resistance mechanisms among clinical isolates of S. maltophilia from Iranian patients. This cross-sectional study was performed on 44 S. maltophilia isolates that were recovered from different clinical specimens in 2015 and 2016. Conventional microbiologic methods were used for primary identification of isolates and confirmed by specific polymerase chain reaction (PCR) primers. Minimum inhibitory concentrations (MICs) were determined by the E-test. PCR was applied to determine antibiotic resistance genes. All of S. maltophilia isolates were susceptible to trimethoprim/sulfamethoxazole (TMP/SMX) and colistin. Moreover, the susceptibility rates of isolates toward ceftazidime and ciprofloxacin were 93.2%, and 84.1%, respectively. Class 1 integrons was detected in 24 (54.5%) isolates by the presence of int1 gene. Moreover, the prevalence of antibiotic resistance genes sul1, sul2, and Smqnr were found in 16 (36.4%), 15 (34.1%), and 29 (65.9%) isolates, respectively. In summary, the prevalence of sul and Smqnr genes in integrons-contained isolates point out the significant risk of sulfonamides and fluoroquinolones resistance among clinical isolates of S. maltophilia in our region.

MicroRNAs (miRNAs) could regulate many cellular processes such as proliferation and differentiation. let-7a miRNA is one of the key regulators in the developmental transition of retinal progenitor cells into differentiated cells. Current evidence suggests that mesenchymal stem cells (MSCs) can isolate from various tissues such as bone marrow and conjunctiva. In this study, we investigated the effect of let-7a overexpression on induced differentiation of conjunctiva mesenchymal stem cells (CJMSCs) into photoreceptor-like cells. After isolation and characterization, CJMSCs were transduced with lentiviruses containing let-7a or empty vector. The effect of let-7a overexpression on expression of photoreceptor-specific markers was evaluated by quantitative real-time PCR (RT-qPCR) after 28 and 42 days of transduction. The relative expression of rhodopsin and recoverin genes was evaluated by RT-qPCR in let-7a overexpressing cells, control vector transduced cells and untransduced CJMSCs (control cells). Our results indicated that following overexpression of let-7a, after 28 and 42 days of transduction, significant up-regulation in the expression of recoverin (574.7 and 43.9 folds) and rhodopsin (3334.7 and 53.1 folds) were observed, respectively. Our findings indicate that overexpression of let-7a microRNA can increase the expression of photoreceptor-specific genes in CJMSCs. Moreover, it is prospective that let-7a overexpression can use as an alternative protocol for the differentiation of mesenchymal stem cells into photoreceptors. It seems that the effect of let-7a on the differentiation of CJMSCs into photoreceptors is also time-dependent.

Testicular torsion/detorsion (T/D) is a well-known cause for infertility. Pioglitazone is an agonist of peroxisome proliferator activated receptor-gamma (PPAR-γ). Previous studies have shown that pioglitazone has anti-inflammatory, antioxidant and antiapoptotic properties. The present study hypothesized that pioglitazone may be protective against the testicular T/D tissue insults, and the possible pathophysiological mechanisms involved in this effect were also investigated. Rats were randomly divided into four groups: sham group, T/D group where testicular torsion was performed for 4 hr followed by 4 hr of detorsion and two pioglitazone-treated groups (1 mg/kg and 3 mg/kg, by single intraperitoneal injection 30 min prior to detorsion). At the end of reperfusion period, blood, ipsilateral and contralateral testicular tissue samples were obtained for biochemical and histopathological examination. Pioglitazone reduced oxidative tissue damages, inflammatory mediators, and apoptotic markers and enhanced the total antioxidant status, and AMP-activated protein kinase level. Moreover, pioglitazone improved spermatogenesis evidenced by increased Johnsen’s score and reversed the histopathological damages induced by testicular T/D. The effects of pioglitazone were higher with the dose of 3 mg/kg. Pioglitazone exhibited a protective effect against the deleterious actions of testicular T/D. This beneficial potential of pioglitazone may be attributed to its antioxidant, anti-inflammatory and antiapoptotic properties, which was more obvious with the dose of 3 mg/kg. Pioglitazone may be a promising therapy for testicular T/D.

A new strategy in recent studies is using effective tuberculosis (TB) subunit vaccines combined with appropriate carriers and adjuvants which have shown promising results in preclinical and clinical studies. The aim of the present study was to evaluate the PLGA:DDA hybrid nanoparticles (NPs) for subcutaneous delivery of a novel multistage subunit vaccine along with MPLA adjuvant against Mycobacterium tuberculosis (M. tuberculosis). PLGA and PLGA:DDA NPs containing HspX/EsxS fusion protein and MPLA were prepared by double emulsion method (w/o/w). After characterization, these NPs were subcutaneously administered to BALB/c mice aged 6-8 weeks old. Immunogenicity of formulations were assessed by measuring the level of IFN-γ, IL-4, IL-17 and TGF-β cytokines as well as IgG1, IgG2a and IgA antibodies using ELISA. Both particles had spherical shape and smooth surface with 316.7 ± 12.7 nm in size, surface charge of -33 ± 1.7 mV, and encapsulation efficiency of 92.2 ± 2% for PLGA NPs and 249.7 ± 16.7 nm in size, surface charge of 39 ± 1.8 mV, and encapsulation efficiency of 35.7 ± 1.4% for PLGA:DDA NPs. The highest IFN-γ response and also IgG2a and IgG1 antibodies titers were observed in groups immunized with PLGA:DDA/HspX/EsxS/MPLA and PLGA:DDA/HspX/EsxS/MPLA as booster as well as PLGA:DDA/HspX/EsxS and PLGA:DDA/HspX/EsxS as booster. With regard to effective induction of IFN-γ and IgG2a immune responses, PLGA:DDA hybrid NP along with MPLA adjuvant have good potentials for improving the immunogenicity of HspX/EsxS multistage subunit vaccine as well as promoting BCG efficacy as a BCG prime-boost.

Toxoplasma gondii is an obligate intracellular protozoan parasite that causes toxoplasmosis in humans and animals. Micronemes (MICs) are effective candidates for DNA vaccine. In this study, we evaluated the immune response of BALB/c mice against MIC3 gene of Toxoplasma gondii and interleukin 12 (IL-12) as DNA vaccine. The MIC3 gene was cloned into the PTZ57R/T vector before sub-cloning in pcDNA3. Recombinant pc-MIC3 was transformed into Escherichia coli (TOP10 strain). The pc-MIC3 plasmid was then transfected into Chinese Hamster Ovary (CHO) cells, and the expression of the MIC3 gene was evaluated by SDS-PAGE and Western blotting. Sixty female BALB/c mice were divided into 6 groups. Each group received 3 intramuscular immunizations on days 0, 21st and 42nd using one of the following stimulants: phosphate-buffered saline, pcDNA3, pCAGGS-IL12, pc-MIC3 (100 µg), pc-MIC3 (50 µg), or combined pCAGGS-IL12 (50 µg) and pc-MIC3 (50 µg). The enzyme-linked immunosorbent assays was applied to evaluate  interferon gamma (IFN-γ) and IL-4 cytokines excretion of lymphocytes stimulated with tachyzoites lysate antigen, as well as the total levels of immunoglobulin G (IgG), IgG2a and IgG1 in immunized mice sera. Our results showed that mice challenged with pc-MIC3 (100 µg) had the highest longevity and quantity of immunoglobulin. Moreover, the highest expression level of IFN-γ was found in mice injected with combined pcMIC3 and pCAGGS-IL12 (P<0.05). The MIC3 gene can be an efficient DNA vaccine candidate against toxoplasmosis. While, the single-gene vaccine can confer partial protection to mice against toxoplasmosis, the multigene vaccine can significantly enhance immune responses.

Non-small cell lung cancer (NSCLC) has become a serious global health problem in the 21st century, and tumor proliferation and metastasis are the leading causes of death in patients  with lung cancer. The present study aimed to verify the function of miR-96 and miR-96 in relation to competing with endogenous RNA regulatory network in NSCLC progression including proliferation and metastasis. Clinical data of miR-96 expression was collected from StarBase 2.0 developed by Sun Yat-sen University. We used wound-healing, transwell and MTT assays to measure migration, invasion and proliferation of NSCLC cell lines after different treatment. Quantitative real time PCR and western blot were used to test differential genes expression. In order to identify target between genes (FOXO1 and DUSP1) and miR-96, luciferase assay was used. Luciferase activities in FOXO1 and DUSP1 wild type plasmid groups were compared to mutant groups. qRT-PCR and online database results indicated that miR-96 is highly associated with NSCLC when compared to normal patients. In addition, miR-96 indeed induced migration, invasion and proliferation of NSCLC cell line. In addition, FOXO1 and DUSP1 are targets of miR-96 and these three molecules form competing endogenous RNA network. miR-96 related competing endogenous RNA network affects cell metastasis via epidermal growth factor receptor (EGFR) signaling. miR-96 can be considered as one of tumor-inducer and form competing endogenous RNA network with FOXO1 and DUSP1, which affects downstream EGFR signaling.

Systemic and intracerebroventricular (ICV) injection of insulin possess analgesic effects. The raphe magnus nucleus (RMN) is part of the endogenous analgesia system. The objective of the present study was to evaluate the effects of ICV injection of insulin on the levels of monoamines and their related metabolites in the RMN during the formalin test in non-diabetic and short-term diabetic rats. Sixty four adult male rats were used. Diabetes was induced by Streptozotocin (STZ) (60 mg/kg, IP); insulin (5 mU/animal, 5 μl) was injected into the left ventricle. Microdialysis was performed in each rat. Samples were collected at 15 min intervals. After taking the base sample of microdialysis, 50 μl of 2.5% formalin was injected into the plantar surface of the hind paw, and the level of nociception was recorded every 15 sec for 1 hr. Monoamines and their metabolites concentrations were measured using the HPLC-ECD method. Findings showed that ICV injection of insulin in non-diabetic rats increased the concentration of monoamines and their related metabolites in the RMN.  In diabetic rats, injection of insulin decreased the concentrations of monoamines and their related metabolites in the RMN (P<0.5). Our results determined that, at least in part, insulin is associated with antinociceptive effect in non-diabetic rats. Based on the results, it seems that ICV injection of insulin in non-diabetic rats increased the activity of the central pain control pathways leading to antinociceptive response, but this condition was not seen in diabetic rats.

Protection against leishmaniasis, in the murine model, is dependent on developing a potent CD4+ mediated Th1 type response. Liposomes can be applied as immunoadjuvants to stimulate immune responses to different antigens. In the present study, it was investigated whether DOTAP liposomes having SLA and imiquimod adjuvant, can induce a Th1 response and protect against Leishmania major challenge in BALB/c mice. Liposomes were provided applying the lipid film procedure. BALB/C mice were subcutaneously immunized, three times with 2-week intervals, with various formulations. Assessment of lesion development and parasite burden in the foot and spleen after challenge with L. major, assessment of Th1 cytokine (IFN-γ), and titration of IgG isotypes assessed the type of generated immune reaction and the protection extent. The mice immunized with Liposome DOTAP+imiquimod+SLA showed smaller footpad swelling which was meaningfully different (P<0.05) compared with other groups. The highest level of IgG2a was observed with Lip DOTAP+imiquimod+SLA more than the control (P<0.001). Mice immunized with Lip DOTAP+SLA+imiquimod demonstrated the least number of live parasites in the footpad and spleen. Cytokine assay showed that the greatest IFN- γ secretion was seen in the splenocytes of mice immunized with all formulations as compared to the control group (P<0.0001). In contrast, the lowest IL-4 production was detectable in Lip+imiquimod+SLA spleen, which was not significantly different compared with other groups. The results of this study show that liposome DOTAP+SLA+imiquimod formulation generates a cellular immune response that is protective against challenge against L. major.

Morbidity and mortality due to diabetes mellitus (DM) result in exorbitant psycho-economical costs, so there is a strong need to create new strategies and drugs for controlling DM. The aim of the current study was to investigate the anti-diabetic effect of the aqueous extract of Pterocarpus santalinus on streptozotocin (STZ)-induced DM as compared to glustin. Thirty male rats were divided into five groups of six rats each as follows: control; the second group, received the aqueous plant extract (250 mg/kg) orally and daily for three weeks; the third group, was intraperitoneally injected with a single dose of 65 mg/kg of STZ and sacrificed after four weeks; the fourth and fifth groups, were injected with STZ, then after one week these were treated orally with either plant extract or with 3 mg/kg of glustin for three weeks, then sacrificed. HPLC analysis of the plant aqueous extract showed that it contains many polyphenols and flavonoids. Treatment with STZ resulted in significant reductions in body weight, insulin level, and the expression of Fetuin-A and IRS-1. It also caused significant elevations in glucose, HOMA-IR, glycated hemoglobin, urea, and the expression of JNK and SIRT-1. STZ also caused an extensive β-cell degranulation and decreased cellular density. The aqueous extract of red sandalwood was able to abrogate the deleterious effects caused by STZ and improved the histological architecture of pancreas The aqueous extract of P. santalinus ameliorates diabetes mellitus via anti-inflammatory pathways and enhancement of insulin function.

The aim of current study was to evaluate improving effects of pioglitazone as an agonist of peroxisome proliferator-activated receptor gamma (PPARγ), on brain-derived neurotrophic factor (BDNF) and cytokines as well as tissue oxidative damage criteria in the hippocampus in a rat model of lipopolysaccharide (LPS) induced memory impairment. The rats were classified and treated as follows (10 rats per group): (1) vehicle, (2) vehicle before LPS (1 mg/kg, 120 min before memory tests), (3-5) pioglitazone 10, 20 or 30 mg/kg 30 min before LPS. Finally, the hippocampal tissues were collected for biomedical analyses. In the Morris water maze test, the LPS group, had a longer latency to find the platform while they spent a shorter time in the target quadrant in the probe trial. In the passive avoidance test, the animals of the LPS group had shorter delay times to enter the dark compartment than those of the control group. Treatment with 20 and 30 mg of pioglitazone corrected these parameters. In the hippocampus of LPS group interleukin-6, tumor necrosis factor-α, nitric oxide metabolites, and malondialdehyde were higher while  thiol, BDNF, and IL-10 concentrations and the activities of catalase (CAT) and superoxide dismutase (SOD) were lower than the control group. Treatment by both doses of 20 and 30 mg of pioglitazone corrected the biochemical parameters in the hippocampus. The current findings revealed that pioglitazone protected the rats from learning and memory impairment induced by LPS. The effects were associated with improvement of cytokines, oxidative stress criteria, and BDNF.

Acute lung injury (ALI) has a high mortality rate and is characterized by damage to pulmonary system giving rise to symptoms such as histological alteration, lung tissue edema and production of proinflammatory cytokine. p-Coumaric acid (p-CA), as a phenolic compound, that is found in many types of fruits and vegetables has been reported to exhibit a therapeutic effect in several inflammatory disorders. The aim of our study was evaluation of pretreatment with p-CA against heart dysfunction, oxidative stress and nuclear factor-erythroid 2 -related factor 2 (Nrf2) modifications following lipopolysaccharide (LPS)-induced acute lung inflammation. The rats were divided into four groups (n=8): Control, LPS (5 mg/kg, it), p-CA (100 mg/kg, IP), and LPS+pCA. Inflammatory response and oxidative stress were evaluated by measurement of interleukin 6 (IL-6), tumor necrosis factor alpha (TNF-α) and malondialdehyde (MDA) levels in heart tissue. For evaluation of the effect of LPS on cardiac response, electrocardiography (ECG) and hemodynamic parameters were recorded. A significant increase in lipid peroxidation (P<0.001, cytokine parameters (TNF-α and IL-6 (P<0.01), gene expression of Nrf2 (P<0.05), and antioxidant activity of superoxide dismutase and glutathione (P< 0.05) in addition to glutathione peroxidase (P<0.01) was demonstrated in heart tissue of ALI rats. LPS can impair cardiac function (in in vitro measurement of hemodynamic parameters by using Langendorff setup, and in in vivo measurement of ECG parameters), and pretreatment with p-CA recovered these parameters to control levels in heart. Pretreatment with p-CA causes modulation of cytokines and MDA level that protected cardiac injury caused by LPS in ALI model. Our results showed anti-inflammatory and antioxidative effect of p-CA on LPS-induced ALI.

The study is aimed to elucidate the impact of antioxidant, anti-inflammatory and antifibrosis properties of Lactobacillus acidophilus (L. acidophilus) on liver and colon in ethephon treated rats through measuring Pro- inflammatory cytokines, oxidative stress index, lysosomal cathepsin-D enzyme activity and fibrosis markers. Rats divided into three groups; Group 1: distilled water control, Group 2: rats at day 16 from experiment beginning were orally received ethephon 50 mg/ kg BW in distilled water once daily for 60 days.  Group 3: rats were orally received L. acidophilus enriched diet 1% (w/w) for 15 days as prophylactic, then received both L. acidophilus enriched diet 1% (w/w) and ethephon 50 mg/kg BW for 60 days. Ethephon exerts hepatic and colonic oxidative stress, inflammatory response and fibrosis through NF-κB activation. On contrary, L. acidophilus supplementation evokes hepatoprotective properties as revealed by decreased serum AST, ALT, γ -GT and increased IGF-1. L. acidophilus exerts antioxidant and anti-inflammatory properties as indicated by decreased TOS, OSI, TNF-α, IL-1β, cathepsins D activity, NF-κB expression and increased TAC, lysosomal membrane stability. L. acidophilus shows antifibrotic activity as demonstrated by down-regulation of TGF-β1, α-SMA, collagen expression. L. acidophilus possess antioxidant, anti -inflammatory and antifibrotic activity through inhibition of NF-kB.

Populus species have various pharmacological properties, including antioxidant activity. In this study, the effects of Populus tomentiglandulosa extract (PTE) on histopathology and antioxidant enzymes in the rat liver and kidney were examined.   Sprague-Dawley rats were assigned to three groups; (1) normal diet fed group, (2) ascorbic acid-containing diet-fed group as a positive control, (3) PTE-containing diet-fed group. The histopathology in the rat liver and kidney was examined by hematoxylin and eosin staining. The effect of PTE was examined in the rat liver and kidney by immunohistochemistry for antioxidant enzymes, such as superoxide dismutases (SOD1 and SOD2), catalase (CAT), and glutathione peroxidase (GPx). No marked histopathological alterations were observed in the liver and kidney of the PTE-containing diet-fed group. In the liver, the mean numbers of SOD1, SOD2, CAT, and GPx immunoreactive cells were significantly increased in the PTE-containing diet-fed rats, compared with those in the normal- and ascorbic acid-containing diet-fed rats. In the kidney, all SOD1, SOD2, CAT, and GPx immunoreactive structures were significantly increased in the PTE-containing diet-fed group, compared with those in the normal- and ascorbic acid-containing diet-fed groups. Results showed that PTE treatment significantly increased antioxidant enzymes in the rat liver and kidney, and we suggest that PTE might have hepato- and nephro-protective potentials against oxidative stress.