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   Table of Contents - Current issue
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March-April 2020
Volume 15 | Issue 2
Page Nos. 107-208

Online since Monday, May 11, 2020

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REVIEW ARTICLE  

Aptamer-based approaches for in vitro molecular detection of cancer Highly accessed article p. 107
Hadi Bakhtiari, Abbas Ali Palizban, Hossein Khanahmad, Mohammad Reza Mofid
DOI:10.4103/1735-5362.283811  
Cancer is typically associated with abnormal production of various tumor-specific molecules known as tumor markers. Probing these markers by utilizing efficient approaches could be beneficial for cancer diagnosis. The current widely-used biorecognition probes, antibodies, suffer from some undeniable shortcomings. Fortunately, novel oligonucleotide-based molecular probes named aptamers are being emerged as alternative detection tools with distinctive advantages compared to antibodies. All of the existing strategies in cancer diagnostics, including those of in vitro detection, can potentially implement aptamers as the detecting moiety. Several studies have been performed in the field of in vitro cancer detection over the last decade. In order to direct future studies, it is necessary to comprehensively summarize and review the current status of the field. Most previous studies involve only a few cancer diagnostic strategies. Here, we thoroughly review recent significant advances on the applications of aptamer in various in vitro detection strategies. Furthermore, we will discuss the status of diagnostic aptamers in clinical trials.
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ORIGINAL ARTICLES Top

Enhancement of dissolution of atorvastatin through preparation of polymeric solid dispersions using supercritical fluid technology p. 123
Bashar Altaani, Rana Obaidat, Walaa Malkawi
DOI:10.4103/1735-5362.283812  
Background and purpose: This study aimed at preparation of solid dispersions in order to enhance dissolution of poorly water-soluble atorvastatin using supercritical CO2 technology. Atorvastatin has poor bioavailability of 12%, mainly due to poor water solubility and dissolution. Dispersion of drugs in various hydrophilic carriers using supercritical fluid technology has been found to be an outstanding method to prepare solid dispersion. Experimental approach: Four different polymers were employed. These were polyvinyl pyrrolidone K30 (PVP), polyethylene glycol 6000 (PEG), Soluplus® and chitosan. Full physicochemical characterizations were performed in addition to in vitro dissolution study. Findings / Results: The used polymers enhanced the dissolution rate of atorvastatin. However, supercritical parameters affected the dissolution profile and drug loading efficiency of the prepared dispersions. High performance liquid chromatography assay indicated the stability of the prepared PEG, Soluplus® andchitosan-based dispersions. On the other hand, PVP solid dispersions were not stable and formed sticky paste. Powder X-ray diffraction showed similar patterns for PEG-based dispersions after exposure to storage condition, while the intensity of atorvastatin peaks increased after three months of storage of Soluplus® and chitosan dispersions. Conclusion and implications: Supercritical fluid technology proved to have great potential to prepare dispersions for biopharmaceutics classification system (BCS) class II drugs. Dissolution enhancement of atorvastatin was achieved through successful preparation of polymeric dispersions of the drug using the supercritical technology without further addition of solvents.
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Vitamin E in the prevention of vancomycin-induced nephrotoxicity p. 137
Rasool Soltani, Farzin Khorvash, Mohsen Meidani, Shirinsadat Badri, Sajedeh Alaei, Shahram Taheri
DOI:10.4103/1735-5362.283813  
Background and purpose: The use of vancomycin, as a key therapeutic choice for treatment of hazardous infections, may be associated with nephrotoxicity. The proposed mechanism is the indirect production of reactive oxygen species and oxidative stress. The purpose of this study was to investigate the effect of vitamin E asan antioxidant agent in the prevention of vancomycin-induced nephrotoxicity. Experimental approach: In a matched-groups interventional study, patients who received vancomycin for any indication were assigned to vitamin E (n = 30) and control (n = 60) groups. The patients in experimental group received 400 units of oral vitamin E per day for 10 days started concurrently with vancomycin, while the patients in control group received vancomycin alone. Serum level of creatinine, blood urea nitrogen (BUN), creatinine clearance (CrCl), and 24-h urine output were determined and recorded before the start of interventions, every other day during therapy, and 12 h after the last dose of vancomycin in 10[th] day of therapy for all patients. Also, the rate of acute kidney injury (AKI) in the two groups was recorded. Finally, the mean values of the measured parameters were compared between the groups. Findings / Results: Treatment with vitamin E for 10 days resulted in a significant reduction of BUN (from 17.5 ± 7.8 mg/dL at baseline to 11.4 ± 4.8mg/dL at the end; P < 0.001) along with slightly non-significant increase of CrCl (from 84.7 ± 18.9 mL/min at baseline to 91.3 ± 19.5 mL/min at the end; P = 0.301) in comparison to the control group. However, CrCl decreased significantly in the control group. Vitamin E had no significant effect on24-h urine output. Regarding vancomycin-induced AKI, 12 cases were observed in the control group, while no case was reported in experimental group (P = 0.041). Conclusion and implications: This study showed the beneficial effect of add-on therapy of vitamin E besides vancomycin in reducing AKI, which could be considered as a new potential prophylactic therapy for vancomycin-induced nephrotoxicity.
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Design, construction, and expression of recombinant human interferon beta gene in CHO-s cell line using EBV-based expression system p. 144
Mohadeseh Shayesteh, Fahimeh Ghasemi, Fatemeh Tabandeh, Bagher Yakhchali, Mehdi Shakibaie
DOI:10.4103/1735-5362.283814  
Background and purpose: Codon optimization has been considered as a powerful strategy to increase the expression level of protein therapeutics in mammalian cells. As an empirical approach to study the effects of the codon usage and GC content on heterologous gene expression in suspension adapted Chinese hamster ovary (CHO-s) cells, we redesigned the recombinant human interferon beta (rhIFN- β) gene based on the codon preference of the CHO cell in a way to increase the GC content in the third position of each codon. Experimental approach: The nucleotide sequence of the codon-optimized rhIFN-β was synthesized in parallel with the wild-type and expressed transiently inCHO-s cells using Epstein-Bar virus (EBV)-based expression system. The protein expression of the rhIFN-β by codon-optimized and wild-type genes were quantified using ELISA test. Findings / Results: The results indicated a 2.8-fold increase in the expression level of the biologically active form of the rhIFN-β by codon-optimized sequence. Conclusion and implications: These results shed light on the capability of codon optimization to create a stable CHO cell for scaling up the production of recombinant therapeutics such as rhIFN-β.
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Synthesis and cytotoxic effect of a few N-heteroaryl enamino amides and dihydropyrimidinethiones on AGS and MCF-7 human cancer cell lines p. 154
Sajjad Tavangar, Shahab Bohlooli, Nima Razzaghi-Asl
DOI:10.4103/1735-5362.283815  
Background and purpose: Cancer prevalence has increased in the last century posing psychological, social, and economic consequences. Chemotherapy uses chemical molecules to control cancer. New studies have shown that dihydropyrimidinethione (DHPMT) derivatives have the potential of being developed into anticancer agents. Experimental approach: New derivatives of DHPMTs and a few acyclic bioisosters were synthesized via Biginelli reaction and assessed for their toxicity against gastric (AGS) and breast cancer (MCF-7) cell lines through MTT method. Findings / Results: Chemical structures of all synthesized N-heteroaryl enamino amides and DHPMTs were confirmed by spectroscopic methods. Result of biological assessment exhibited that none of the tested agents was more cytotoxic than cis-platin against AGS and MCF-7 cell lines and compound 2b was the most cytotoxic agent against AGS (IC50 41.10 μM) and MCF-7 (IC50 75.69 μM). Cytotoxic data were mostly correlated with the number of H-bond donors within gastric and breast cancer cells. Conclusion and implications: It was realized that DHPMTs were able to inhibit the growth of cancer cells much better than acyclic enamino amides and moreover;N-(4-methylbenzothiazol-2-yl) DHPMT derivative (2b) supposed possible interaction with a poor electron site of target due to the lipophilic nature of benzothiazole ring and also less electron rich nature than isoxazole. Similar scenario was observed with acyclic enamino amides in which incorporation of sulfur and nitrogen containing heterocycles doubled the cytotoxic effects. Results of the present contribution might assist in extending the scope of DHPMTs as privileged medicinal scaffolds.
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Rational design of a new mutant of tobacco etch virus protease in order to increase the in vitro solubility p. 164
Hossein Mohammadian, Karim Mahnam, Hamid Mirmohammad Sadeghi, Mohamad Reza Ganjalikhany, Vajihe Akbari
DOI:10.4103/1735-5362.283816  
Background and purpose: Tobacco etch virus (TEV) protease is a protease with high sequence specificity which is useful for the cleavage of fusion proteins. A major limitation of this enzyme is its relatively poor solubility. This study aimed to investigate the effects of some suggested mutations by online tools and molecular dynamics simulation to improve the solubility of TEV protease in vitro. Experimental approach: We designed a rational multi-stage process to determine the solubilizing mutations of TEV protease. At the first stage, all the possible mutations were predicted using online tools such as PoPMuSiC and Eris servers, in which five mutations include N23F, N23L, Q74L, Q74V, and Q74I were suggested for further studies. In the next step, the three dimensional structure of the wild type (WT) and the best mutations were subjected to molecular dynamic simulations to evaluate the dynamic behaviour of the obtained structures. The selected mutation was introduced into the structure using site-directed mutagenesis and expressed in Escherichia coli BL21DE3. After purification, solubility and activity of the purified mutant and WT-TEV proteases were assayed. Findings /Results: By considering the analysis of various factors such as structural and solubility properties, one mutant, N23F, was selected for in vitro studies which led to a 1.5 times increase in the solubility compared to the WT while its activity was decreased somewhat. Conclusion and implications: We propose N23F mutation, according to computational and experimental analyses for TEV proteases which resulted in a 150% increase in solubility compared to the WT.
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The effects of two types of renin-angiotensin system inhibitors on the hypertension induced by new pressor protein associated with beta-factor XIIa in rats p. 174
Akbar Pejhan, Ali Gohari, Mohammad Hassan Rakhshani, Peter C Papageorgiou, Muhammad Ibrar Mustafa, Rahim Golmohammadi
DOI:10.4103/1735-5362.283817  
Background and purpose: New pressor protein (NPP) is a human plasma enzyme, which is structurally related to the beta-fragment of activated factor XII. The present study aimed to compare the effects of angiotensin converting enzyme inhibitors (captopril) and angiotensin type 1 receptor blocker (losartan) on the hypertension induced by NPP injection in normal (sham-2NX) and bilaterally nephrectomized rats (2NX). Experimental approach: In total, 60 male Wistar rats were sham operated or bilaterally nephrectomized under anesthesia. After 24 h of anesthesia with Inactin® (100 mg/kg), their systolic blood pressure (SBP), diastolic blood pressure (DBP), and heart rate (HR) were measured before and after the intravenous administration of captopril, losartan, and NPP. Findings / Results: In the sham-2NX group, after NPP injection, changes were observed in SBP (145.99 ± 3.6 mmHg), DBP (93.9 ± 3.87 mmHg), and HR (400.29 ± 12.78 bpm). In the captopril group, SBP and DBP had no significant changes, while HR increased significantly (P = 0.001). In the losartan group, SBP and DBP decreased (P = 0.001 and P = 0.000, respectively), while HR had no significant changes. In the 2NX group, after NPP injection,changes were denoted in SBP (127.89 ± 9.03 mmHg), DBP (65.86 ± 5.69 mmHg), and HR (333.35 ± 11.47 bpm). In addition, captopril injection increased DBP(P = 0.016) and HR (P = 0.036) in response to NPP injection, while losartan injection had no significant effects in this regard. Conclusion and implications: It could be concluded that losartan could improve hypertension in normal rats, while captopril deteriorated hypertension in bilaterally nephrectomized rats in this hypertension model.
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Targeting of cholera toxin A (ctxA) gene by zinc finger nuclease: pitfalls of using gene editing tools in prokaryotes p. 182
Nafiseh Hosseini, Hossein Khanahmad, Bahram Nasr Esfahani, Mojgan Bandehpour, Laleh Shariati, Nushin Zahedi, Bahram Kazemi
DOI:10.4103/1735-5362.283818  
Background and purpose: The study was launched to use zinc finger nuclease (ZFN) technology to disrupt the cholera toxin gene (ctxA) for inhibiting CT toxin production in Vibrio cholera (V. cholera). Experimental approach: An engineered ZFN was designed to target the catalytic site of the ctxA gene. The coding sequence of ZFN was cloned to pKD46, pTZ57R T/A vector, and E2-crimson plasmid and transformed to Escherichia coli (E. coli) Top10 andV. cholera. The efficiency of ZFN was evaluated by colony counting. Findings/Results: No expression was observed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and western blotting in transformed E. coli. The ctxA gene sequencing did not show any mutation. Polymerase chain reaction on pKD46-ZFN plasmid had negative results. Transformation of E. coli Top10 with T/A vectors containing whole ZFN sequence led to 7 colonies all of which contained bacteria with self-ligated vector. Transformation with left array ZFN led to 24 colonies of which 6 contained bacteria with self-ligated vector and 18 of them contained bacteria with vector/left array. Transformation of V. cholera with E2-crimson vectors containing whole ZFN did not produce any colonies. Transformation with left array vectors led to 17 colonies containing bacteria with vector/left array. Left array protein band was captured using western blot assay. Conclusions and implications: ZFN might have off target on bacterial genome causing lethal double-strand DNA break due to lack of non-homologous end joining (NHEJ) mechanism. It is recommended to develop ZFNs against bacterial genes, engineered packaging host with NHEJ repair system is essential.
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Valproic acid restores the down-regulation of SDF-1 following kidney ischemia; experimental validation of a mathematical prediction p. 191
Kobra Moradzadeh, Seyed Mahdi Nassiri, Yousof Gheisari
DOI:10.4103/1735-5362.283819  
Background and purpose: Stromal-derived factor (SDF)-1, a chemokine recruiting leucocytes and stem cells, plays an essential role in tissue regeneration. In aprevious study, we have unexpectedly found that the expression of this chemokine declines following kidney ischemia reperfusion (IR). To explain this observation, a mathematical model was constructed which proposed histone deacetylase (HDAC) as the main driver of SDF-1 down-regulation. To experimentally verify this prediction, the effect of valproic acid (VPA), a potent HDAC inhibitor, on the kinetics of kidney SDF-1 expression was here assessed. Experimental approach: Adult mice were subjected to IR or sham operation and received VPA or vehicle. Next, SDF-1 expression as well as tissue repair indices were measured in a time course manner. Findings / Results: The transcriptional expressions of Sdf-1 alpha, beta, and gamma isoforms were noisy in the sham groups but the fluctuations disappeared following IR where a continuous declining trend was observed. VPA induced the over-expression of gamma, but not alpha and beta mRNA in IR mice which was accompanied with protein upregulation. Remarkably, VPA deteriorated kidney injury. Conclusion and implications: HDAC inhibition restores SDF-1 down-regulation following kidney IR. The present study is a classic example of the potential of computational modeling for the prediction of biomedical phenomena.
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In silico design of two novel fusion proteins, p28-IL-24 and p28-M4, targeted to breast cancer cells p. 200
Reza Ghavimi, Elmira Mohammadi, Vajihe Akbari, Fatemeh Shafiee, Ali Jahanian-Najafabadi
DOI:10.4103/1735-5362.283820  
Background and purpose: An anticancer peptide P28, has shown to be cytolethal on various cancer cells including breast cancer. Moreover, p28 can be alsoused as a targeting moiety in the structure of fusion proteins. IL-24 (or its truncated form, M4) is a cytokine with anticancer activity against a wide range of tumor cells. We aimed at production of a fusion protein consisted of p28 and either IL-24 or M4 to target breast cancer. However, selection of a proper linker to join the two moieties without intervening each other’s function is a key factor in the construction of fusion proteins. In the present study, the impact of different linkers on construction of the two chimeric proteins (p28-IL-24 and p28-M4) was assessed in silico. Experimental approach: After selection of some linkers with different lengths and characteristics, a small library of the chimeric proteins was created and assessed. Furthermore, following selection of the most suitable linker, the three-dimensional structures and dynamic behavior of both fusion proteins were evaluated byhomology modeling and molecular dynamic simulation, respectively. Findings / Results: Based on the results, a rigid linker having the peptide sequences of AEAAAKEAAAKA showed highest freedom of action for both moieties. Conclusion and implications: Between the p28-IL-24 and p28-M4 fusion proteins, the former showed better stability as well as solubility and might show stronger anticancer effects in vitro and in vivo, because its peptide moieties showed to exert their activities freely.
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