Bioimpacts最新文献

Introduction: COVID-19 has spread out all around the world and seriously interrupted human activities. Being a newfound disease, not only many aspects of the disease are unknown, but also there is not an effective medication to cure the disease. Besides, designing a drug is a time-consuming process and needs large investment. Hence, drug repurposing techniques, employed to discover the hidden benefits of the existing drugs, maybe a useful option for treating COVID-19. Methods: The present study exploits the drug repositioning concepts and introduces some candidate drugs which may be effective in controlling COVID-19. The suggested method consists of three main steps. First, the required data such as the amino acid sequences of targets and drug-target interactions are extracted from the public databases. Second, the similarity score between the targets (protein/enzymes) and genome of SARS-COV-2 is computed using the proposed fuzzy logic-based method. Since the classical approaches yield outcomes which may not be useful for the real-world applications, the fuzzy technique can address the issue. Third, after ranking targets based on the obtained scores, the usefulness of drugs affecting them is examined for managing COVID-19. Results: The results indicate that antiviral medicines, designed for curing hepatitis C, may also cure COVID-19. According to the findings, ribavirin, simeprevir, danoprevir, and XTL-6865 may be helpful in controlling the disease. Conclusion: It can be concluded that the similarity-based drug repurposing techniques may be the most suitable option for managing emerging diseases such as COVID-19 and can be applied to a wide range of data. Also, fuzzy logic-based scoring methods can produce outcomes which are more consistent with the real-world biological applications than others.

Introduction: Inflammation is one of the most important mechanisms involved in cisplatin-induced acute kidney injury (AKI). Mesenchymal stromal/stem cells (MSCs) exhibit anti-inflammatory and immunomodulatory abilities. Human endometrial stromal/stem cells (hEnSCs) exhibit similar properties to MSCs. These cells secrete immunoregulators, so we investigated the inflammatory aspect of hEnSCs in the treatment of cisplatin-induced AKI in Wistar rats. Methods: Each group consisted of 6 male Wistar rats. Groups were as follows: sham, model (5 mg/kg cisplatin, IP), and treatment (1 million hEnSCs, IV, 3 hours after cisplatin). Renal function, histopathology, proliferation rate, infiltration of CD3⁺ T cell, and expression of Il-10 and cystatin c (Cst3) were assessed on day 5. DiI-labeled cells were tracked in kidney and liver on days 4 and 14. Results: HEnSC transplantation improved cisplatin-induced injuries such as renal dysfunction and tissue damage. The highest levels of pathologic scores and hyaline cast formation were observed in the model group while hEnSCs transplantation resulted in their reduction (154.00 ± 14.95, 8.00 ± 1.41 vs. 119.40 ± 5.43, 2.50 ± 1.05). The percentage of Ki-67 positive cells in the treatment group increased while cisplatin decreased proliferation (39.91 ± 5.33 vs. 23.91 ± 3.57 in glomeruli and 39.07 ± 2.95 vs. 16.61 ± 3.25 in tubules). The expression of Cst3 and Il-10 was higher in the model and treatment groups, respectively. DiI-labeled cells were observed in the renal tubules and liver lobes on days 4 and 14. Conclusion: HEnSCs may ameliorate cisplatin-induced AKI through anti-inflammatory and immunomodulatory effects and/or through paracrine effects.

Introduction: Hypoxia context is highly specific for tumors and represents a unique niche which is not found elsewhere in the body. Clostridium novyi is an obligate anaerobic bacterium. It has a potential to treat tumors. The aim of this study was to produce the C. novyi nontoxic spores and to investigate its oncolytic effect on breast cancer in mice model. Methods: Primarily, the lethal toxin gene in C. novyi type B was removed. Colonies were isolated using PCR testing. To assure the removal of alpha-toxin, plasmid extraction and in vivo assay were conducted. Next, to treat breast cancer model in different sizes of tumors, a single dose of spores of C. novyi nontoxic was tested. Results: The results denoted that C. novyi nontoxic lost lethal toxin and a--ppeared to be safe. For smaller than 1000 mm³ tumors, a single dose of C. novyi nontoxic was able to cure 100% of mice bearing breast tumors. Hence the mice remained free of tumor relapse. Tumors larger than 1000 mm³ were not cured by a single dose- of C. novyi nontoxic treatment. Conclusion: The experiment concluded that the C. novyi nontoxic might be a suitable and safe candidate, a novel therapeutic approach to encounter such hypoxic regions in the center of tumors. Research also showed that bacteriolytic therapy by C. novyi nontoxic could lead to regression in small tumor.

Introduction: Recent studies showed that rapamycin, as a mammalian target of rapamycin (mTOR) inhibitor, could have beneficial therapeutic effects for the central nervous system (CNS) related diseases. However, the immunosuppressive effect of rapamycin as an adverse effect, the low water solubility, and the rapid in vivo degradation along with the blood-brain barrier-related challenges restricted the clinical use of this drug for brain diseases. To overcome these drawbacks, a transferrin (Tf) decorated nanostructured lipid carrier (NLC) containing rapamycin was designed and developed. Methods: Rapamycin-loaded cationic and bare NLCs were prepared using solvent diffusion and sonication method and well characterized. The optimum cationic NLCs were physically decorated with Tf. For in vitro study, the MTT assay and intracellular uptake of nanoparticles on U-87 MG glioblastoma cells were assessed. The animal biodistribution of nanoparticles was evaluated by fluorescent optical imaging. Finally, the in vivo effect of NLCs on the immune system was also studied. Results: Spherical NLCs with small particle sizes ranging from 120 to 150 nm and high entrapment efficiency of more than 90%, showed ≥80% cell viability. More importantly, Tf-decorated NLCs in comparison with bare NLCs, showed a significantly higher cellular uptake (97% vs 60%) after 2 hours incubation and further an appropriate brain accumulation with lower uptake in untargeted tissue in mice. Surprisingly, rapamycin-loaded NLCs exhibited no immunosuppressive effect. Conclusion: Our findings proposed that the designed Tf-decorated NLCs could be considered as a safe and efficient carrier for targeted brain delivery of rapamycin which may have an important value in the clinic for the treatment of neurological disorders.

Introduction: Acute kidney injury (AKI) may have a negative effect on mitochondrial hemostasis and bioenergetics as well as coenzyme Q₁₀ (CoQ₁₀) content. PGC-1α, AMPK, sirtuin 1 (Sirt1), and Sirt3, as the key metabolic regulators under nutritional stress, stimulate energy production via mitochondrial biogenesis during AKI. However, no report is available on the relationship between CoQ₁₀ level and nutrient sensors in the pathophysiology of AKI caused by Hemiscorpius lepturus scorpion envenomation. Methods: Three doses of venoms (1, 5, and 10 mg/kg) were administered by subcutaneous (SC) injection to male albino mice. The animals were sacrificed 1 day or 7 days after administration of venom and their kidneys were collected to analyze gene expression involved in AKI, nutrient sensors, and apoptosis signaling activation by real-time polymerase chain reaction (PCR) and the measurement of CoQ₁₀ level using the High-performance liquid chromatography (HPLC) method. Results: The data indicated a significant decrease in CoQ₁₀ level after the administration of venom in 5 and 10 mg/kg. In addition, 1 day after the treatment, a significant over-expression of Sirt1 (5 and 10 mg/kg) was observed compared with normal mice. Overexpression of Sirt3 occurred 1 day and 7 days after treatment only at the dose of 5.0 mg/kg of venom. Furthermore, over-expression of AMPK as an important mitochondrial energetic sensor happened 1 day and 7 days after the injection of venom (5 mg/kg) (P < 0.01). The significant increase in the gene expression of caspase-9 and 3 after the injection of venom (5 and 10 mg/kg) confirmed the role of cell death signaling. Conclusion: The venom-induced energy-sensing pathways have a key role in gene expression of PGC-1α, AMPK, Sirt3, and CoQ₁₀ content after venom-induced AKI.

Introduction: Circulating tumor cells (CTCs) are the transformed tumor cells that can penetrate into the bloodstream and are available at concentrations as low as 1-100 cells per milliliter. To trap CTCs in the blood, one valid and mature technique that has been developed is the magnetophoresis-based separation in a microfluidic channel. Recently, nanostructured platforms have also been developed to trap specific targeted and marker cells in the blood. We aimed to integrate both in one platform to improve trapping. Methods: Here, we developed a numerical scheme and an integrated device that considered the interaction between drag and magnetic forces on paramagnetic labeled cells in the fluid as well as interaction of these two forces with the adhesive force and the surface friction of the nanowires substrate. We aimed on developing a more advanced technique that integrated the magnetophoretic property of some Fe₃O₄ paramagnetic nanoparticles (PMNPs) with a silicon nanowires (SiNWs) substrate in a microfluidic device to trap MDA-MB231 cell lines as CTCs in the blood. Results: Simulation indicated assuming that the nanoparticles adhere perfectly to the white blood cells (WBCs) and the CTCs, the magnetic moment of the CTCs was almost one order of magnitude larger than that of the WBCs, so its attraction by the magnetic field was much higher. In general with significant statistics, the integrated device can trap almost all of the CTCs on the SiNWs substrate. In the experimental section, we took advantage of the integrated trapping techniques, including micropost barriers, magnetophoresis, and nanowires-based substrate to more effectively isolate the CTCs. Conclusion: The simulation indicated that the proposed device could almost trap all of the CTCs onto the SiNWs substrate, whereas trapping in flat substrates with magnetophoretic force was very low. As a result of the magnetic field gradient, magnetophoretic force was applied to the cells through the nanoparticles, which would efficiently drive down the nanoparticle-tagged cells. For the experimental validation, anti-EpCAM antibodies for specific binding to tumor cells were used. Using this specific targeting method and by statistically counting, it was shown that the proposed technique has excellent performance and results in the trapping efficiency of above 90%.

Introduction: Breast cancer cells produce exosomes that promote tumorigenesis. The anticancer properties of gallic acid have been reported. However, the mechanism underlying its anticancer effect on the exosomal secretory pathway is still unclear. We investigated the effect of gallic acid on exosome biogenesis in breast cancer cell lines. Methods: The cytotoxic effect of gallic acid on MCF-10a, MCF-7, and MDA-MD-231 cells was measured by MTT assay after 48 hours treatment. Expression of miRNAs including miRNA-21, -155, and 182 as well as exosomal genes such as Rab27a, b, Rab11, Alix, and CD63; along with HSP-70 (autophagy gene), was determined using Q-PCR. The subcellular distribution of it was monitored by flow cytometry analysis. Isolated exosomes were characterized by transmission and scanning electron microscopes and flow cytometry. Acetylcholinesterase activity is used to measure the number of exosomes in supernatants. In addition, autophagy markers including LC3 and P62 were measured by ELISA. Results: Data showed that gallic acid was cytotoxic to cells (P < 0.05). Gallic acid modulated expression of miRNAs and down-regulated transcript levels of exosomal genes and up-regulated the HSP-70 gene in three cell lines (P < 0.05). The surface CD63/total CD63 ratio as well as acetylcholinesterase activity decreased in treated cells (P < 0.05). The protein level of LC3 was increased in three cell lines, while the expression of P62 increased in MCF-7 and MDA-MB-231 cancer cell lines. Conclusion: Together, gallic acid decreased the activity of the exosomal secretory pathway in breast cancer cell lines, providing evidence for its anti-cancer effects.

Introduction: Paclitaxel (PTX) is a cornerstone in the treatment of breast cancer, the most common type of cancer in women. However, this drug has serious limitations, including lack of tissue-specificity, poor water solubility, and the development of drug resistance. The transport of PTX in a polymeric nanoformulation could overcome these limitations. Methods: In this study, PLGA-PTX nanoparticles (NPs) were assayed in breast cancer cell lines, breast cancer stem cells (CSCs) and multicellular tumor spheroids (MTSs) analyzing cell cycle, cell uptake (Nile Red-NR-) and α-tubulin expression. In addition, PLGA-PTX NPs were tested in vivo using C57BL/6 mice, including a biodistribution assay. Results: PTX-PLGA NPs induced a significant decrease in the PTX IC50 of cancer cell lines (1.31 and 3.03-fold reduction in MDA-MB-231 and E0771 cells, respectively) and CSCs. In addition, MTSs treated with PTX-PLGA exhibited a more disorganized surface and significantly higher cell death rates compared to free PTX (27.9% and 16.3% less in MTSs from MCF-7 and E0771, respectively). PTX-PLGA nanoformulation preserved PTX's mechanism of action and increased its cell internalization. Interestingly, PTX-PLGA NPs not only reduced the tumor volume of treated mice but also increased the antineoplastic drug accumulation in their lungs, liver, and spleen. In addition, mice treated with PTX-loaded NPs showed blood parameters similar to the control mice, in contrast with free PTX. Conclusion: These results suggest that our PTX-PLGA NPs could be a suitable strategy for breast cancer therapy, improving antitumor drug efficiency and reducing systemic toxicity without altering its mechanism of action.

Immunotherapy is considered a promising approach for cancer treatment. An important strategy for cancer immunotherapy is the use of cancer vaccines, which have been widely used for cancer treatment. Despite the great potential of cancer vaccines for cancer treatment, their therapeutic effects in clinical settings have been limited. The main reason behind the lack of significant therapeutic outcomes for cancer vaccines is believed to be the immunosuppressive tumor microenvironment (TME). The TME counteracts the therapeutic effects of immunotherapy and provides a favorable environment for tumor growth and progression. Therefore, overcoming the immunosuppressive TME can potentially augment the therapeutic effects of cancer immunotherapy in general and therapeutic cancer vaccines in particular. Among the strategies developed for overcoming immunosuppression in TME, the use of toll-like receptor (TLR) agonists has been suggested as a promising approach to reverse immunosuppression. In this paper, we will review the application of the four most widely studied TLR agonists including agonists of TLR3, 4, 7, and 9 in cancer immunotherapy.

Introduction: Malignant breast cancer (BC) frequently contains a rare population of cells called cancer stem cells which underlie tumor relapse and metastasis, and targeting these cells may improve treatment options and outcomes for patients with BC. The aim of the present study was to determine the effect of silibinin on the self-renewal capacity, tumorgenicity, and metastatic potential of mammospheres. Methods: The effect of silibinin on viability and proliferation of MCF-7, MDA-MB-231 mammospheres, and MDA-MB-468 cell aggregation was determined after 72-120 hours of treatment. Colony and sphere formation ability, and the expression of stemness, differentiation, and epithelial-mesenchymal-transition (EMT)-associated genes were assessed by reverse transcription-quantitative polymerase chain reaction (qRT-PCR) in mammospheres treated with an IC₅₀ dose of silibinin. Additionally, the antitumor capacity of silibinin was assessed in vivo, in mice. Results: The results of the present study showed that silibinin decreased the viability of all mammospheres derived from MCF-7, MDA-MB-231, and MDA-MB-468 cell aggregation in a dose-dependent manner. Colony and sphere-forming ability, as well as the expression of genes associated with EMT were reduced in mammospheres treated with silibinin. Additionally, the expression of genes associated with stemness and metastasis was also decreased and the expression of genes associated with differentiation were increased. Intra-tumoral injection of 2 mg/kg silibinin decreased tumor volumes in mice by 2.8 fold. Conclusion: The present study demonstrated that silibinin may have exerted its anti-tumor effects in BC by targeting the BC stem cells, reducing the tumorgenicity and metastasis. Therefore, silibinin may be a potential adjuvant for treatment of BC.