Publications by authors named "Seyed Isaac Hashemy"

75 Publications

Modulatory effect of berberine on plasma lipoprotein (or lipid) profile: a review.

Mol Biol Rep 2022 Aug 8. Epub 2022 Aug 8.

Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.

Berberine is a bioactive isoquinoline alkaloid compound extracted from various medicinal plants, such as Barberry. Berberine shows various pharmacological properties that are mainly attributed to its anti-inflammatory and antioxidant effects. A growing body of evidence has shown that berberine influences cholesterol metabolism, and consequently, may ameliorate dyslipidemias and atherosclerosis. Plasma high-density lipoprotein cholesterol (HDL-C) is known to have an independent negative association with incident cardiovascular disease (CVD). However, several outcomes trials and genetic studies have failed to meet expecting the beneficial effects of elevating plasma HDL-C concentrations. Hence, investigations are currently focused on enhancing the functionality of HDL particles, independent of their plasma concentrations. HDL particles show various qualities because of a heterogeneous composition. Consistent with complex metabolism and composition, various biological functions are found for HDL, such as anti-inflammatory, antioxidant, anti-apoptotic, and anti-thrombotic activities. Protective effects of berberine may impact the functionality of HDL; therefore, the present literature review was intended to determine whether berberine can amplify HDL function. It was concluded that berberine may regulate markers of HDL activity, such as apo-AI, cholesterol efflux, LCAT, PON1, and S1P activities and levels. Consequently, berberine may recuperate conditions with dysfunctional HDL and, therefore, have the potential to emerge as a therapeutic agent. However, further human trials of berberine are warranted to evaluate its impact on HDL function and cholesterol metabolism.
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http://dx.doi.org/10.1007/s11033-022-07623-7DOI Listing
August 2022

Selenium Effects on Oxidative Stress-Induced Calcium Signaling Pathways in Parkinson's Disease.

Indian J Clin Biochem 2022 Jul 15;37(3):257-266. Epub 2022 Apr 15.

Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.

Parkinson's disease (PD) is a neurological disorder in which oxidative stress and reactive oxygen species productions are proposed to be involved in its pathogenesis. Despite considerable advancement in Selenium's (Se) molecular biology and metabolism, we do not know much about the cell type-specific pattern of Se distribution in the brain of PD humans and experimental animals. Although, there is plenty of evidence around the role of Se deficiency in PD's pathogenesis impacting lipid peroxidation and reducing glutathione (GSH) and glutathione peroxidase (GPX). It has been suggested that Se has an inducible role in selenium-dependent GPX activity in PD animals and humans. However, calcium as a second messenger regulates the neuron cells' essential activities, but its overloading leads to cellular oxidative stress and apoptosis. Therefore, Se's antioxidant role can affect calcium signaling and alleviate its complications. There are signs of Se and Selenoproteins incorporation in protecting stress oxidative in various pathways. In conclusion, there is convincing proof for the crucial role of Se and Calcium in PD pathogenesis.

Supplementary Information: The online version contains supplementary material available at 10.1007/s12291-022-01031-1.
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http://dx.doi.org/10.1007/s12291-022-01031-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9300809PMC
July 2022

The substance P/ neurokinin-1 receptor signaling pathway mediates metastasis in human colorectal SW480 cancer cells.

Mol Biol Rep 2022 Jun 16;49(6):4893-4900. Epub 2022 Apr 16.

Surgical Oncology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.

Background: The substance P (SP)/neurokinin-1 receptor (NK1R) system, a critical metastatic signaling pathway, can be targeted by substance P antagonists to prevent its cancer-progressive impacts. In the current study, we aimed to investigate the carcinogenic activity of the SP/NK1R system in human SW480 colorectal cancer cells and study the antagonistic impact of aprepitant (AP) by measuring MMP-2 and MMP-9 enzymatic activity.

Methods: Different concentrations of SP, alone or mixed by AP, were utilized to treat SW480 cells to investigate the cells' viability and metastasis by applying Resazurin and Gelatin Zymography methods, respectively. The cells' metastatic response was analyzed by measuring the MMP-2 and MMP-9 in transcriptional and translational levels. Finally, the Scratch assay was carried out to evaluate the cells' metastatic response following the SP/AP treatment.

Results: A significant metastatic activity was observed in SW480 cells following incubation with the increasing SP doses by detecting MMP-2/MMP-9 enzyme activity, genes overexpression, and enhanced cell migration. This is while the AP treatment meaningfully diminished all the SP-mediated metastatic effects (p-Value < 0.001).

Conclusions: According to the results, the SP/NKR1 signaling pathway can be considered one of the main metastatic effectors in human colorectal cancer. Therefore, AP might be suggested to be used as the SP antagonist and an efficient anti-metastatic drug.
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http://dx.doi.org/10.1007/s11033-022-07348-7DOI Listing
June 2022

Acetyl-11-Keto--Boswellic Acid (AKBA) Prevents Lipopolysaccharide-Induced Inflammation and Cytotoxicity on H9C2 Cells.

Evid Based Complement Alternat Med 2022 30;2022:2620710. Epub 2022 Mar 30.

Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.

Acetyl-11-keto-beta-boswellic acid (AKBA), the major component of , exhibits anti-inflammatory activities. This in vitro study investigated the protective effects of AKBA against lipopolysaccharide (LPS)-induced cardiac dysfunction. In this study, the H9C2 cardiomyocytes were pretreated with AKBA (2.5, 5, and 10 M for 24 h), and then cotreated with LPS for another 24 h. The MTT assay, ELISA test kits, and quantitative real-time PCR analysis assessed the cell viability, levels of proinflammatory factors (IL-, IL-6, TNF- , and PGE2), and the gene expression of IL-, IL-6, TNF- , iNOS, and COX-2, respectively. The nitric oxide (NO) and thiol levels were also measured using a biochemical assay. The results indicated that LPS exposure markedly reduced cell viability and total thiol content, but increased the inflammatory cytokines, NO metabolites, and gene expression of proinflammatory mediators in H9C2 cells. AKBA pretreatment significantly altered the mentioned factors induced by LPS. Our results demonstrated that AKBA might be a promising therapeutic agent for treating sepsis-related cardiac dysfunction in the future.
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http://dx.doi.org/10.1155/2022/2620710DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8986374PMC
March 2022

The Therapeutic Potential of Aprepitant in Glioblastoma Cancer Cells through Redox Modification.

Biomed Res Int 2022 3;2022:8540403. Epub 2022 Mar 3.

Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.

Although there is no doubt regarding the involvement of oxidative stress in the development of glioblastoma, many questions remained unanswered about signaling cascades that regulate the redox status. Given the importance of the substance P (SP)/neurokinin 1 receptor (NK1R) system in different cancers, it was of particular interest to evaluate whether the stimulation of this cascade in glioblastoma-derived U87 cells is associated with the induction of oxidative stress. Our results showed that SP-mediated activation of NK1R not only increased the intracellular levels of malondialdehyde (MDA) and reactive oxygen species (ROS) but also reduced the concentration of thiol in U87 cells. We also found that upon SP addition, there was a significant reduction in the cells' total antioxidant capacity (TAC), revealing that the SP/NK1R axis may be involved in the regulation of oxidative stress in glioblastoma cells. The significant role of SP/NK1R in triggering oxidative stress in glioblastoma has become more evident when we found that the abrogation of the axis using aprepitant reduced cell survival, probably through exerting antioxidant effects. The results showed that both MDA and ROS concentrations were significantly reduced in the presence of aprepitant, and the number of antioxidant components of the redox system increased. Overall, these findings suggest that aprepitant might exert its anticancer effect on U87 cells through shifting the balance of oxidant and antioxidant components of the redox system.
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http://dx.doi.org/10.1155/2022/8540403DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8913111PMC
April 2022

The redox modulatory effects of SP/NK1R system: Implications for oxidative stress-associated disorders.

Life Sci 2022 May 2;296:120448. Epub 2022 Mar 2.

Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran; Surgical Oncology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran. Electronic address:

Oxidative stress which refers to redox imbalance with increased generation of reactive oxygen species (ROS) has been associated with the pathophysiology of diverse disease conditions. Recently, a close, yet not fully understood, relation between oxidative stress and neuropeptides, in particular, substance P (SP), has been reported in certain conditions. SP has been shown to affect the cellular redox environment through activation of neurokinin-1receptor (NK1R). It seems that SP/NK1R system and oxidative stress can act either synergistically or antagonistically in a context-dependent manner, thereby, influencing the pathology of various clinical disorders either destructively or protectively. Importantly, the interactions between oxidative stress and SP/NK1R system can be pharmacologically targeted. Therefore, a better understanding of the redox modulatory properties of SP/NK1R signaling will pave the way for identifying new therapeutic possibilities for attenuating oxidative stress-mediated damage. Towards this end, we performed a comprehensive search through PubMed/Medline and Scopus databases and discussed all related existing literature regarding the interplay between oxidative stress and SP/NK1R system as well as their implication in various clinical disorders, to provide a clear view and hence better management of oxidative damage.
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http://dx.doi.org/10.1016/j.lfs.2022.120448DOI Listing
May 2022

SP/NK1R system regulates carcinogenesis in prostate cancer: Shedding light on the antitumoral function of aprepitant.

Biochim Biophys Acta Mol Cell Res 2022 05 5;1869(5):119221. Epub 2022 Feb 5.

Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran; Surgical Oncology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran. Electronic address:

Aims: Prostate cancer continues to be one of the main global health issues in men. Neuropeptide substance P (SP) acting via neurokinin-1receptor (NK1R) promotes tumorigenicity in many human malignant tumors. However, its pro-tumorigenic functions and the therapeutic effects of its inhibition in prostate cancer remain unclear.

Methods: MTT assay was employed for measuring cellular proliferation and cytotoxicity. mRNAs and proteins expression levels were evaluated by qRT-PCR and western blot assay, respectively. Gelatinase activity was assessed by zymography. The migration ability was defined using wound-healing assay. Flow cytometry was employed to evaluate the cell cycle distribution. We also performed an in vivo experiment in a mouse model of prostate cancer to confirm the in vitro therapeutic effect of targeting the SP/NK1R system.

Results: We found a noticeable increase in the expression of the truncated isoform of NK1R as an oncogenic NK1R splice variant in tumor cells. We also demonstrated that SP promotes both proliferative and migrative phenotypes of prostate cancer through modifying cell cycle-related proteins (c-Myc, cyclin D1, cyclin B1, p21), and apoptosis-related genes (Bcl-2 and Bax), promoting cell migration and increasing MMP-2 and MMP-9 expression and activity, while aprepitant administration could remarkably reverse these effects. SP also stimulated tumor growth in vivo, which was correlated with shorter survival times, while aprepitant reversed this effect and led to significantly longer survival time.

Significance: Our findings suggest that SP/NK1R system may serve as a novel therapeutic target in prostate cancer and support the possible candidacy of aprepitant in future prostate cancer therapy.
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http://dx.doi.org/10.1016/j.bbamcr.2022.119221DOI Listing
May 2022

Mesenchymal stem cells in cancer therapy; the art of harnessing a foe to a friend.

Iran J Basic Med Sci 2021 Oct;24(10):1307-1323

Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of ‎Medical Sciences, Mashhad, Iran.

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.
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http://dx.doi.org/10.22038/IJBMS.2021.58227.12934DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8769515PMC
October 2021

Evaluation of the salivary glutaredoxin-1 levels in oral lichen planus and oral squamous cell carcinoma.

Gulf J Oncolog 2021 May;1(36):14-20

General Dentist, Mashhad, Iran.

Background: Glutaredoxin-1, as a component of antioxidant system, plays a crucial role in pathogenesis of some cancers and pre-malignant lesions. The aim of this study is to assess salivary levels of glutaredoxin-1 in oral lichen planus (OLP) and oral squamous cell carcinoma (OSCC) patients compared with healthy controls.

Methods & Materials: This cross-sectional study was conducted on 28 OLP patients, 20 OSCC cases, and 40 healthy subjects. Their salivary glutaredoxin-1 was assessed by the enzyme-linked immunosorbent assay (ELISA).

Results: Regarding the glutaredoxin-1 level, there was no significant difference between the three studied groups (p=0.073); however, the salivary glutaredoxin-1levels were higher in the healthy subjects than the OLP and OSCC patients. Among OSCC patients, the salivary glutaredoxin-1 levels were significantly higher in the males (p=0.03). According to glutaredoxin-1 levels, the difference between keratotic and non-keratotic OLP lesions were not significant (p=0.98). Furthermore, there was no significant difference between various clinical manifestations and grades of OSCC, (p=0.08, p=0.56, respectively).

Conclusion: Salivary glutaredoxin-1 levels were lower in OLP and OSCC patients compared to the normal volunteers; therefore the role of glutaredoxin-1 in the pathogenesis of these diseases could be proposed.
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May 2021

Aprepitant Promotes Caspase-Dependent Apoptotic Cell Death and G2/M Arrest through PI3K/Akt/NF-B Axis in Cancer Stem-Like Esophageal Squamous Cell Carcinoma Spheres.

Biomed Res Int 2021 9;2021:8808214. Epub 2021 Dec 9.

Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.

The antagonists of the neurokinin-1 receptor (NK1R) are known for their anti-inflammatory, anxiolytic, antiemetic, and anticancer activities. Aprepitant, a nonpeptide NK1R antagonist, is used in nausea and vomiting, the most common side effects of cancer chemotherapy in patients. It has been established that NK1R activation by substance P (SP), which links cancer promotion and progression to a neurokinin-mediated environment, became one mechanism that corresponds to the mitogenesis of tumor cells. Therefore, this study is aimed at explaining and evaluating the anticancer impacts of aprepitant on esophageal squamous cancer cell (ESCC) spheres by using in vitro experiments, such as resazurin, ROS, annexin-V binding, RT-PCR, and Western blot analysis. As a result, we showed that aprepitant had strong antiproliferative and cytotoxic effects on ESCC cell spheres. Also, aprepitant caused significant G2-M cell cycle arrest depending on concentration increase. Further, exposure of cells to this agent resulted in caspase -8/-9-dependent apoptotic pathway activation by modifying the expression of genes involved in apoptosis. Besides, treatment of the cells by aprepitant abrogates of the PI3K/Akt pathway, as shown by reducing the level of Akt, induces apoptotic cell death. In summary, pharmacological inhibition of NK1R with aprepitant seems to have a significant chance of treating ESCC as a single agent or in conjunction with other chemotherapeutic drugs.
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http://dx.doi.org/10.1155/2021/8808214DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8677400PMC
January 2022

The SP/NK1R System-Mediated ROS Generation in GBM Cells through Inhibiting Glutaredoxin Protein.

Neurol Res Int 2021 7;2021:9966000. Epub 2021 Dec 7.

Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.

Altered redox balance is among the main contributing factors developing glioblastoma multiforme (GBM), a highly aggressive grade IV brain tumor. Neuropeptide substance P (SP) plays a key role in modifying the cellular redox environment by activating the neurokinin-1 receptor (NK1R). In this study, we aimed to investigate the redox-modulating properties of both SP and a commercially available NK1R antagonist, aprepitant in GBM cells. To detect the effect of aprepitant on the viability of U87 glioblastoma cells, resazurin assay was applied. The level of intracellular ROS was assessed using 2',7'-dichlorodihydrofluorescein diacetate (H2DCFDA) assay. The expression of glutaredoxin, a well-known redox-active protein, was measured by quantitative real-time polymerase chain reaction (qRT-PCR). Concurrently, the activity of glutaredoxin was also analyzed by a commercial kit (ZellBio GmbH). We found that SP increased the intracellular levels of reactive oxygen species (ROS) in U87 GBM cells, and aprepitant remarkably decreased this effect. We also explored the effects of SP/NK1R signaling on the glutaredoxin system as a major cellular redox buffer in GBM cells. SP reduced both expression and enzymatic activity of glutaredoxin, and these effects were significantly decreased by aprepitant. In conclusion, our results suggest a possible involvement of SP/NK1R signaling in GBM pathogenesis through oxidative stress and offering new insight for the application of aprepitant as a redox-modulating strategy in GBM patients.
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http://dx.doi.org/10.1155/2021/9966000DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8670971PMC
December 2021

Potential in vitro therapeutic effects of targeting SP/NK1R system in cervical cancer.

Mol Biol Rep 2022 Feb 12;49(2):1067-1076. Epub 2021 Nov 12.

Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.

Background: Cervical cancer, an aggressive gynecological cancer, seriously threatens women's health worldwide. It is recently reported that neuropeptide substance P (SP) regulates many tumor-associated processes through neurokinin-1 receptor (NK1R). Therefore, we used cervical cancer cell line (HeLa) to investigate the functional relevance of the SP/NK1R system in cervical cancer pathogenesis.

Methods: Cellular proliferation and cytotoxicity were analyzed by colorimetric MTT assay. Quantitative real-time PCR (qRT-PCR) was used to measure mRNA expression levels of desired genes. Cell cycle distribution and apoptosis were evaluated by flow cytometry. A wound-healing assay was employed to assess migration ability.

Results: We found that the truncated isoform of NK1R(NK1R-Tr) is the dominantly expressed form of the receptor in Hela cells. We also indicated that that SP increased HeLa cell proliferation while treatment with NK1R antagonist, aprepitant, inhibited HeLa cell viability in a dose and time-dependent manner. SP also alters the levels of cell cycle regulators (up-regulation of cyclin B1 along with downregulation of p21) and apoptosis-related genes (up-regulation of Bcl-2 along with downregulation of Bax) while aprepitant reversed these effects. Aprepitant also induced arrest within the G2 phase of the cell cycle and subsequent apoptosis. Furthermore, SP promoted the migrative phenotype of HeLa cells and increased MMP-2 and MMP-9 expression while aprepitant exposure significantly reversed these effects.

Conclusion: Collectively, our results indicate the importance of the SP / NK1R system in promoting both proliferative and migrative phenotypes of cervical cancer cells and suggest that aprepitant may be developed as a novel treatment for combating cervical cancer.
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http://dx.doi.org/10.1007/s11033-021-06928-3DOI Listing
February 2022

Investigation of the Role of Neurokinin-1 Receptor Inhibition Using Aprepitant in the Apoptotic Cell Death through PI3K/Akt/NF-B Signal Transduction Pathways in Colon Cancer Cells.

Biomed Res Int 2021 2;2021:1383878. Epub 2021 Aug 2.

Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.

Background: Colorectal cancer (CRC) is recognized as one of the most common malignancies with a high mortality rate worldwide, supporting the necessity for an effective novel antitumor drug to improve current therapy's effectiveness. Substance P (SP) is the essential member of the tachykinins (TKs) family, which binds to the specific receptors, known as neurokinin-1 receptor (NK1R), exerting its multiple influences such as tumor cell proliferation, angiogenesis, and metastasis. Aprepitant, as a specific NK1R antagonist, is suggested as a novel antitumor agent, promoting apoptotic processes in tumor cells; however, the exact antitumor mechanism of aprepitant on molecular signaling in CRC is not entirely known.

Method: The resazurin assay was conducted to assess the cytotoxic effects of aprepitant on the viability of the CRC cell line (SW480). The level of reactive oxygen species (ROS) was measured after 24-hour treatment with SP and aprepitant. PI/annexin V-FITC staining was conducted to assess apoptosis. Also, the expression of NF-B antiapoptotic target genes and proapoptotic p53 target genes was measured by real-time- (RT-) PCR assay. Western blotting assay was performed to determine the expression of PI3k/AKT/NF-B proteins.

Results: We found that aprepitant stimulates apoptotic cell death and attenuates the PI3K/Akt pathway and its downstream proapoptotic target gene, including NF-B in SW480 cells. Also, the obtained results from the quantitative RT-PCR assay showed that aprepitant could decrease the level of mRNA of NF-B antiapoptotic target genes.

Conclusion: Towards this end, this study suggests that SP/NK1R system plays a vital role in the development of CRC, and pharmaceutical targeting of NK1R using aprepitant might be a promising treatment against CRC.
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http://dx.doi.org/10.1155/2021/1383878DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8355960PMC
September 2021

PD-1 and PD-L1 inhibitors foster the progression of adult T-cell Leukemia/Lymphoma.

Int Immunopharmacol 2021 Sep 18;98:107870. Epub 2021 Jun 18.

Surgical Oncology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran. Electronic address:

Immunotherapy through immune checkpoints blockade and its subsequent clinical application has revolutionized the treatment of a spectrum of solid tumors. Blockade of Programmed cell death protein-1 and its ligand has shown promising results in clinical studies. The clinical trials that enrolled patients with different hematopoietic malignancies including non-Hodgkin lymphoma, Hodgkin lymphoma, and acute myeloid leukemia (AML) showed that anti-PD-1 agents could have potential therapeutic effects in the patients. Adult T-cell leukemia/lymphoma (ATLL) is a non-Hodgkin T-cell Lymphoma that is developed in a minority of HTLV-1-infected individuals after a long latency period. The inhibition of PD-1 as a treatment option is currently being investigated in ATLL patients. In this review, we present a summary of the biology of the PD-1/PD-L1 pathway, the evidence in the literature to support anti-PD-1/PDL-1 application in the treatment of different lymphoid, myeloid, and virus-related hematological malignancies, and controversies related to PD-1/PD-L1 blocking in the management of ATLL patients.
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http://dx.doi.org/10.1016/j.intimp.2021.107870DOI Listing
September 2021

Pathogenic role of the SP/ NK1R system in GBM cells through inhibiting the thioredoxin system.

Iran J Basic Med Sci 2021 Apr;24(4):499-505

Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.

Objectives: Glioblastoma multiforme (GBM), a highly aggressive Grade IV brain tumor, is a significant public health issue due to its poor prognosis and incurability. Neuropeptide substance P (SP) plays a critical role in GBM tumor growth and development via activation of neurokinin-1receptor (NK1R). Moreover, SP is a pro-oxidant factor contributing to oxidative stress in various cell types. However, the link between SP and oxidative stress in cancer cells is not fully investigated. Here, we aimed to identify the effects of SP and NK1R antagonist, aprepitant, on the redox status of GBM cells.

Materials And Methods: Resazurin assay was employed to determine the effect of aprepitant on viability of U87 glioblastoma cells. 2',7'-dichlorodihydrofluorescein diacetate (H2DCFDA) assay was employed to measure the levels of intracellular reactive oxygen species (ROS). A quantitative real-time polymerase chain reaction was applied to measure the expression of proteins of the thioredoxin system. Commercial kits (ZellBio GmbH) were also used to measure the enzymatic activity of these proteins.

Results: We found that SP increased ROS level in U87 GBM cells, and aprepitant significantly reduced this effect. Furthermore, we found that SP could also affect the thioredoxin system, a central antioxidant enzyme defense system. SP reduced both expression and enzymatic activity of the thioredoxin system's proteins, Trx and thioredoxin reductase (TrxR) and these effects were significantly reduced by aprepitant.

Conclusion: Our results indicated that SP activation of NK1R represented a link between oxidative stress and GBM and highlighted the need for further validations in future studies.
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http://dx.doi.org/10.22038/ijbms.2021.52902.11945DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8143719PMC
April 2021

Cross-talk between non-coding RNAs and PI3K/AKT/mTOR pathway in colorectal cancer.

Mol Biol Rep 2021 May 31;48(5):4797-4811. Epub 2021 May 31.

Department of Medical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.

Colorectal cancer (CRC) is the third commonest cancer globally, with metastasis being the reason for cancer-associated mortality. Much is still unknown biochemically about CRC, and with current treatments that are not wholly effective over time, new therapeutics are urgently needed. Emerging evidence has shown the importance of non-coding RNAs such as lncRNAs and miRNAs functions in the development and progression of CRC. However, the exact underlying mechanism of these types of RNAs in CRC is still mostly unknown. PI3K/AKT/mTOR pathway contributes to many cellular processes, and dysregulation of this pathway frequently occurs in cancers. In this review, the authors have mostly focused on the significant non-coding RNAs regulators of the PI3K/AKT/mTOR pathway and their contribution to the development or inhibition of CRC and their potential as diagnostic or therapeutic targets in CRC treatment.
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http://dx.doi.org/10.1007/s11033-021-06458-yDOI Listing
May 2021

The Effect of SP/NK1R on the Expression and Activity of Catalase and Superoxide Dismutase in Glioblastoma Cancer Cells.

Biochem Res Int 2021 21;2021:6620708. Epub 2021 Apr 21.

Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.

Introduction: Glioblastoma is the most malignant brain tumor with different therapeutic protocols, including surgery, radiotherapy, and chemotherapy. Substance P (SP), a peptide released by sensory nerves, increases cellular excitability by activating the neurokinin-1 receptor (NK1R) in several human tumor cells. Aprepitant is a potent and long-lasting NK1R antagonist, considered a new agent for inhibiting proliferation and induction of apoptosis in malignant cells. This study aimed to evaluate the effects of the SP/NK1R system on the expression and activity of catalase and superoxide dismutase (SOD) in the glioblastoma U87 cancer cell line.

Methods: Cytotoxicity was measured by the resazurin test, 24 hours after treatment, with increasing aprepitant concentrations. The production of reactive oxygen species (ROS) was also measured 24 hours after treatment with SP and aprepitant. Enzymes activity of catalase and SOD was measured using the corresponding assay kits. Real-time PCR also measured their expression.

Results: Aprepitant significantly reduced the viability of U87 cells in a concentration-dependent manner. ROS production was significantly reduced, and the activity of catalase and SOD increased after treatment with aprepitant. The expression of catalase and SOD enzymes also increased significantly in the presence of aprepitant.

Conclusion: The present study showed that aprepitant inhibited SP's oxidizing effects via inducing the antioxidant effects of catalase and SOD in the U87 cell line. Therefore, this drug might be introduced as a potential candidate for controlling glioblastoma cancer in animal models and clinical trials.
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http://dx.doi.org/10.1155/2021/6620708DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8084669PMC
April 2021

Evaluation of Antioxidant Capacity and Cotinine Levels of Saliva in Male Smokers and Non-smokers.

Addict Health 2020 Oct;12(4):244-250

Department of Biostatistics, School of Dentistry, Mashhad University of Medical Sciences, Mashhad, Iran.

Background: The cigarette compounds are associated with the increase in the incidence of oral cancer and precancerous lesions. Salivary antioxidant system plays an important role in anti-carcinogenic capacity of saliva. Cotinine, a nicotine metabolite, has a longer half-life in comparison with nicotine and is a suitable marker for exposure to cigarette smoke. This study aims to measure total antioxidant capacity (TAC) and cotinine level in saliva of smokers and non-smokers and compare salivary cotinine level and TAC in each group.

Methods: In this cross-sectional study, 32 smokers and 34 non-smokers were recruited by consecutive sampling from Department of Oral Medicine, School of Dentistry, Mashhad University of Medical Sciences, Mashhad, Iran. Salivary cotinine and TAC concentrations were determined using the enzyme-linked immunosorbent assay (ELISA) technique. For data analysis, correlation tests of Spearman, Mann-Whitney U, and independent samples t-test were used.

Findings: A significant difference was observed between the two groups in the mean cotinine level and in the mean TAC (P = 0.015, P = 0.027, respectively). TAC showed a weak negative correlation with the cotinine level, but the difference was not significant (P = 0.651).

Conclusion: Antioxidants are of great importance to smokers because antioxidants are able to scavenge free radicals found in cigarette smoke. According to the results of present study, the salivary TAC in smokers was lower than that of non-smokers, and the salivary cotinine level in smokers was higher than non-smokers. Therefore, smoking endangers the oral cavity health by reducing the salivary TAC. Further studies with a higher sample size and other factors affecting the salivary TAC are needed for definitive comment.
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http://dx.doi.org/10.22122/ahj.v12i4.278DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7878005PMC
October 2020

MicroRNA Regulation of Androgen Receptor in Castration-Resistant Prostate Cancer: Premises, Promises, and Potentials.

Curr Mol Pharmacol 2021 10;14(4):559-569

Bioinformatics Research Group, Mashhad University of Medical Sciences, Mashhad,, Iran.

Prostate cancer (PCa) is the second most prevalent cancer and the fifth leading cause of cancer-related deaths among men. Androgen deprivation therapy (ADT) is the most frequently used therapeutic strategy in PCa; however, the development of resistance to ADT, known as castration- resistant prostate cancer (CRPC), continues to be a major obstacle against the successful treatment of PCa. The abnormal activation of the androgen receptor (AR) signaling pathway has been found as one of the main contributing factors to the development of resistance in CRPC. Therefore, AR regulatory strategies are urgently required to combat resistance. Recently, microRNAs (miRNAs) have been found as major AR regulatory factors affecting ADT resistance. MiRNAs can target AR itself, AR-related genes, AR splice variants, AR-related signaling pathways as well as cancer stem cells (CSCs), and play critical roles in regulating ADT resistance. Due to their capability to affect various genes and signaling pathways, miRNAs are now being studied for their potential role as a new therapeutic target in CRPC. It has been recommended that combination therapies, including miRNAs and existing drugs, can synergistically decrease castration resistance. miRNAs also have prognostic values for ADT, and their expression profiling in CRPC patients before therapeutic scheduling may enable the physician to diagnose patients who are ADT-resistant. Overall, extant evidence obviously supports the predictive and therapeutic potential of miRNAs in CRPC patients. This review summarizes the available information about the microRNA-mediated AR controlling mechanisms involved in ADT resistance.
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http://dx.doi.org/10.2174/1874467213666201223121850DOI Listing
October 2021

Effects of hydroalcoholic extract on the lipid and antioxidant profile in high fat diet-induced hepatic steatosis in rats.

Drug Chem Toxicol 2021 Jan 17;44(1):75-83. Epub 2018 Dec 17.

Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.

Oxidative stress is related to increased fat deposition in the liver, known as hepatic steatosis. The present study is an evaluation of the anti-oxidative and antihyperlipidemic effects of the hydroalcoholic extract of (HARE) in rats on a high-fat diet (HFD). Twenty male Wistar rats were divided into four groups: control, HFD, HFD + HARE 50 mg/kg/day, and HFD + HARE 250 mg/kg/day for 12 weeks. Animals were weighed weekly and treated with the HARE extract for 12 weeks by gavage. Subsequently, the histopathological changes, oxidative markers, and lipid profile were evaluated. Statistical analysis was performed using the one-way analysis of variance (ANOVA) for multiple comparisons. First, the active ingredients of the extract were determined by HPLC. Then, the levels in the serum lipid profile (TG, cholesterol, HDL, and LDL) in rats fed with the HFD + HARE were analyzed where a significant reduction was observed. The HFD proved to increase the activity of the liver enzymes, the serum lipid levels, and the malondialdehyde (MDA) level. The ferric-reducing antioxidant activity power (FRAP), catalase (CAT), and superoxide dismutase (SOD) catalytic activity were reduced in the liver homogenate of HFD rats compared to the controls. Additionally, the aforementioned liver enzymes activities were reduced in response to HARE. Evaluation of oxidative stress determined a reduction in the MDA level while a raised FRAP was confirmed. In accordance with the present results, histopathological observations have also demonstrated that HARE ameliorated grade-1 hepatic steatosis induced by HFD. Taken together, the findings of this study introduce HARE as a future potential therapeutic agent in treating hepatic steatosis and reducing oxidative damages of an HFD in the liver.
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http://dx.doi.org/10.1080/01480545.2018.1533024DOI Listing
January 2021

Assessment of salivary thioredoxin levels in oral lichen planus and oral squamous cell carcinoma.

Clin Exp Dent Res 2020 Dec 1. Epub 2020 Dec 1.

Social Determinants of Health Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.

Objective: Oral lichen planus (OLP) is a chronic mucocutaneous inflammatory disease, which is considered as a potentially malignant condition and could transformed into oral squamous cell carcinoma (OSCC). Squamous cell carcinmoma is the most common oral cancer. This study aimed to compare salivary thioredoxin levels as an antioxidant protein among patients with OSSC, OLP and healthy subjects.

Materials And Methods: Twenty-eight patients with OLP, 20 patients with OSCC and 40 healthy people enrolled in this observational study. Saliva samples were collected from all subjects and salivary thioredoxin levels were evaluated by Elisa test. The data were recorded in the check lists and analyzed using SPSS (ver.17).

Results: Thioredoxin levels of healthy controls were insignificantly higher than OLP and SCC patients (p = 0.135). There was a statistically remarkable indirect relationship between thioredoxin levels and severity of the lesions determined by Thongprasom criteria among OLP patients. The thioredoxin concentration was significantly higher in the keratotic OLP. Among the OSCC patients, the highest levels of thioredoxin were found among patients aged more than 65 years. Salivary thioredoxin levels based on other variables were not significantly different between the studied groups.

Conclusion: In this study, there was not any significant difference between salivary thioredoxin levels in the OLP and OSCC patients, though it was unremarkable higher in the healthy group compared to the patients; therefore, the role of thioredoxin in the cellular oxidation-reduction status could be suggested; however, further studies are recommended.
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http://dx.doi.org/10.1002/cre2.364DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8404483PMC
December 2020

Protective effects of propolis on hepatic steatosis and fibrosis among patients with nonalcoholic fatty liver disease (NAFLD) evaluated by real-time two-dimensional shear wave elastography: A randomized clinical trial.

Phytother Res 2021 Mar 9;35(3):1669-1679. Epub 2020 Nov 9.

Department of Nutrition, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease, while no drugs have been approved for its treatment. The pieces of evidence indicate that propolis as a novel anti-inflammatory agent might be a promising candidate to treat NAFLD. We aimed to evaluate the efficacy of propolis on hepatic steatosis and fibrosis in patients with NAFLD. This randomized clinical trial was conducted on 54 patients with NAFLD. Patients were randomly assigned to receive propolis tablets at a dose of 250 mg twice daily for 4 months or placebo. The improvement in hepatic steatosis and fibrosis was evaluated using two-dimensional shear wave elastography. Improvement in the hepatic steatosis was significantly higher in the propolis group than the placebo group, even after adjustment for baseline value and changes in weight, energy intake, and physical activity (odds ratio [OR]: 5.67; 95% confidence intervals [CI]: 1.41-22.8; p = .014). A significant reduction was observed on the liver stiffness in the propolis group (-0.65 ± 0.56 kPa; p = .001), whereas it increased in the placebo group (0.27 ± 0.59 kPa; p = .037). Also, the intake of propolis significantly decreased high-sensitivity C-reactive protein (hs-CRP) levels compared with the placebo group (-0.371; 95%CI: -0.582 to -0.16 mg/L; p = .01). Changes in serum levels of fasting blood sugar, alanine aminotransferase, aspartate aminotransferase, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, cholesterol, and triglyceride did not differ significantly between the two groups (p > .05). There was no significant improvement in insulin resistance in both groups (p > .05). Propolis seems to have protective effects on hepatic steatosis and fibrosis and to reduce the serum levels of hs-CRP in patients with NAFLD.
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http://dx.doi.org/10.1002/ptr.6937DOI Listing
March 2021

Protective effects of BiP inducer X (BIX) against diabetic cardiomyopathy in rats.

Can J Physiol Pharmacol 2021 Jun 23;99(6):644-653. Epub 2020 Oct 23.

Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.

Diabetic cardiomyopathy (DC) is associated with impaired endoplasmic reticulum (ER) function, development of ER stress, and induction of cardiac cell apoptosis. Preventive effects of BiP inducer X (BIX) were investigated against DC characteristic changes in a type 2 diabetes rat model. To establish diabetes, a high-fat diet and a single dose of streptozotocin were administered. Then, animals were assigned into the following groups: control, BIX, diabetic animals monitored for one, two, and three weeks. Diabetic rats were treated with BIX for one, two, and three weeks. Expressions of various ER stress and apoptotic markers were assessed by immunoblotting method. CHOP gene expression was assessed by Real-time PCR. Tissue expression of BiP was evaluated by immunohistochemistry method. Hematoxylin and eosin and Masson's trichrome staining were performed to assess histological changes in the left ventricle. Cardiac cell apoptosis was examined using TUNEL assay. BIX administration suppressed the activation of the ER stress markers and cleavage of procaspase-3 in the diabetic rats. Likewise, tissue expression of BiP protein was increased, while CHOP mRNA levels were decreased. These results were accompanied by reducing cardiac fibrosis and myocardial cell apoptosis suggesting protective effects of BIX against the development of DC by decreasing cardiomyocyte apoptosis and fibrosis.
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http://dx.doi.org/10.1139/cjpp-2020-0419DOI Listing
June 2021

A Study on Association Between Protein Carbonyl and Anti-cyclic Citrullinated Peptide Antibody in Rheumatoid Arthritis: Introducing a New Supplementary Biomarker.

Indian J Clin Biochem 2020 Jul 5;35(3):347-352. Epub 2019 Mar 5.

Surgical Oncology Research Centre, Mashhad University of Medical Sciences, Mashhad, Iran.

Redox state and immune mechanisms are two major factors implicated in rheumatoid arthritis (RA). Regarding some limitations of anti-cyclic citrullinated peptide (anti-CCP) antibody in RA diagnosis, recruiting another strong marker of oxidative stress could lead to more definitive diagnosis. To evaluate the potential of protein carbonyl content as a supplementary biomarker for RA. Eighty patients with RA attending the Research Center from 2015 to 2016 were recruited in this study. Smoker and alcoholic subjects, or those with any other systemic illness were excluded from the study. Demographic information and clinical data were collected. Numbers of swollen and tender joints were determined and RA disease activity was assessed. Serum samples were used for assessing protein carbonyl level, platelet count, and anti-CCP antibody values. Statistical analyses for significant differences were performed according to parametric (Student test) and nonparametric (Mann-Whitney test) tests. The correlation was determined by Pearson coefficient. There was a significant correlation between protein carbonyl levels and anti-CCP antibodies in active RA ( value = 0.01), but not in remission phase ( value = 0.28). A significant positive correlation was observed between protein carbonyl levels and platelets count in active RA ( value = 0.001), but not in remission phase ( value = 0.85). Protein carbonyl could be considered as a future cost-effective supplementary biomarker, alongside anti-CCP antibody, in active RA diagnosis as it showed a significant positive correlation with anti-CCP antibody and platelet, two major mediators in the disease pathogenesis.
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http://dx.doi.org/10.1007/s12291-019-00823-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7326851PMC
July 2020

Application of Molecular Docking for the Development of Improved HIV-1 Reverse Transcriptase Inhibitors.

Curr Comput Aided Drug Des 2021 ;17(4):538-549

Bioinformatics Research Group, Mashhad University of Medical Sciences, Mashhad, Iran.

Introduction: Inhibition of the reverse transcriptase (RT) enzyme of the human immunodeficiency virus (HIV) by low molecular weight inhibitors is still an active area of research. Here, protein-ligand interactions and possible binding modes of novel compounds with the HIV-1 RT binding pocket (the wild-type as well as Y181C and K103N mutants) were obtained and discussed.

Methods: A molecular fragment-based approach using FDA-approved drugs were followed to design novel chemical derivatives using delavirdine, efavirenz, etravirine and rilpivirine as the scaffolds. The drug-likeliness of the derivatives was evaluated using Swiss-ADME. The parent molecule and derivatives were then docked into the binding pocket of related crystal structures (PDB ID: 4G1Q, 1IKW, 1KLM and 3MEC). Genetic Optimization for Ligand Docking (GOLD) Suite 5.2.2 software was used for docking and the results analyzed in the Discovery Studio Visualizer 4. A derivative was chosen for further analysis, if it passed drug-likeliness and the docked energy was more favorable than that of its parent molecule. Out of the fifty-seven derivatives, forty-eight failed in drug-likeness screening by Swiss-ADME or at the docking stage.

Results: The final results showed that the selected compounds had higher predicted binding affinities than their parent scaffolds in both wild-type and the mutants. Binding energy improvement was higher for the structures designed based on second-generation NNRTIs (etravirine and rilpivirine) than the first-generation NNRTIs (delavirdine and efavirenz). For example, while the docked energy for rilpivirine was -51 KJ/mol, it was improved for its derivatives RPV01 and RPV15 up to - 58.3 and -54.5 KJ/mol, respectively.

Conclusion: In this study, we have identified and proposed some novel molecules with improved binding capacity for HIV RT using a fragment-based approach.
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http://dx.doi.org/10.2174/1573409916666200628103359DOI Listing
January 2022

Genotypic and phenotypic characterization of Mycobacterium tuberculosis resistance against fluoroquinolones in the northeast of Iran.

BMC Infect Dis 2020 Jun 1;20(1):390. Epub 2020 Jun 1.

Antimicrobial Resistance Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.

Background: Fluoroquinolones are broad-spectrum antibiotics that are recommended, and increasingly important, for the treatment of multidrug-resistant tuberculosis (MDR-TB). Resistance to fluoroquinolones is caused by mutations in the Quinolone Resistance Determining Region (QRDR) of gyrA and gyrB genes of Mycobacterium tuberculosis. In this study, we characterized the phenotypic and genotypic resistance to fluoroquinolones for the first time in northeast Iran.

Methods: A total of 123 Mycobacterium tuberculosis isolates, including 111 clinical and 12 collected multidrug-resistant isolates were studied. Also, 19 WHO quality control strains were included in the study. The phenotypic susceptibility was determined by the proportion method on Löwenstein-Jensen medium. The molecular cause of resistance to the fluoroquinolone drugs ofloxacin and levofloxacin was investigated by sequencing of the QRDR region of the gyrA and gyrB genes.

Results: Among 123 isolates, six (4.8%) were fluoroquinolone-resistant according to phenotypic methods, and genotypically three of them had a mutation at codon 94 of the gyrA gene (Asp→ Gly) which was earlier reported to cause resistance. All three remaining phenotypically resistant isolates had a nucleotide change in codon 95. No mutations were found in the gyrB gene. Five of the 19 WHO quality control strains, were phenotypically fluoroquinolone-resistant, four of them were genotypically resistant with mutations at codon 90, 91 of the gyrA gene and one resistant strain had no detected mutation.

Conclusions: Mutation at codon 94 of the gyrA gene, was the main cause of fluoroquinolone resistance among M. tuberculosis isolates in our region. In 3/6 fluoroquinolone-resistant isolates, no mutations were found in either gyrA or gyrB. Therefore, it can be concluded that various other factors may lead to fluoroquinolone resistance, such as active efflux pumps, decreased cell wall permeability, and drug inactivation.
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http://dx.doi.org/10.1186/s12879-020-05112-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268510PMC
June 2020

Substance P accelerates the progression of human esophageal squamous cell carcinoma via MMP-2, MMP-9, VEGF-A, and VEGFR1 overexpression.

Mol Biol Rep 2020 Jun 20;47(6):4263-4272. Epub 2020 May 20.

Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.

Tachykinins such as Substance P (SP) are a group of neuropeptides that are involved in cancer development. Neurokinin-1 receptor (NK-1R) is the main tachykinin receptor mediating the effects of SP, which is overexpressed in human esophageal squamous cell carcinoma (ESCC) and other malignant tissues. However, the effects of SP/NK-1R system on the migration of esophageal cancer cells and angiogenesis is not clear yet. This study seeks to obtain data to address these research gaps. In order to assess the effects of the FDA-approved aprepitant drug, a commercially available NK-1R antagonist, on the viability of KYSE-30 ESCC cells, resazurin assay was performed. The influence of SP/NK-1R system on the migration potential of these cells was examined using scratch assay. The effects of this system on the expression levels of metastatic factors were also examined by RT-PCR and western blot analyses. The half-maximal inhibitory concentration (IC) value for KYSE-30 cells treated with aprepitant found to be 29.88 μM. Treatment with SP significantly promoted KYSE-30 esophageal cancer cell migration, and aprepitant blocked this effect. In addition, SP significantly induced the expression of matrix metalloproteinase-2 (MMP-2), MMP-9, vascular endothelial growth factor-A (VEGF-A), and VEGF receptor1 (VEGFR1) in the cells, whereas aprepitant inhibited the up-regulation effects caused by SP. SP plays important roles in the development of human esophageal squamous cell carcinoma by promoting cancer cell invasion and enhancing the expression of factors involved in cellular migration and angiogenesis, which can be blocked by the NK-1R antagonist, aprepitant.
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http://dx.doi.org/10.1007/s11033-020-05532-1DOI Listing
June 2020

Evaluation of serum level of substance P and tissue distribution of NK-1 receptor in colorectal cancer.

Mol Biol Rep 2020 May 10;47(5):3469-3474. Epub 2020 Apr 10.

Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.

Colorectal cancer (CRC) is known as the most common form of malignancies in the world and its occurrence is annually increasing. Due to the relatively high death rates in patients, finding better diagnostic and prognostic factors are required. Substance P (SP) belongs to the tachykinin family that acts as an immunomodulator by binding to the neurokinin-1 receptor (NK1R). The interaction of SP with NK1R might be involved in tumor cell proliferation, angiogenesis, and migration. Hence, this study was aimed to evaluate the serum SP level and tissue distribution of NK1Rs in CRC. Also, we assessed the relationship between tissue distribution of NK1R and some different tumor characteristics, including tumor size, and lymph node status. Recruiting 38 patients primarily diagnosed with CRC, the tissue distribution of NK1R was immunohistochemically evaluated in tumor tissues and their adjacent normal tissue. The serum level of SP was measured using an ELISA method in both cases and healthy control group. The SP value was significantly increased in the serum of patients in comparison with the healthy group (p = 0.001). Tumor tissues expressed a higher number of NK1R than adjacent normal tissues (p = 0.01) considering both the percentage of stained cells and intensity of staining. However, there was not any statistically significant relevance between NK1R distribution and tumor characteristics. The SP/NK1R system is involved in tumorigenesis of CRC, and might be suggested as a potent prognostic or diagnostic factor, or a new target in the treatment of CRC.
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http://dx.doi.org/10.1007/s11033-020-05432-4DOI Listing
May 2020

New insight into the role of substance P/neurokinin-1 receptor system in breast cancer progression and its crosstalk with microRNAs.

Clin Genet 2020 10 20;98(4):322-330. Epub 2020 Apr 20.

Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.

The neuropeptide substance P (SP) triggers a variety of tumor-promoting signaling pathways through the activation of neurokinin-1receptor (NK1R), a class of neurokinin G protein-coupled receptors superfamily. Recent researches in our and other laboratories have shown the overexpression of both SP and NK1R in breast cancer (BC) patients. SP/NK1R signaling is strongly implicated in the pathogenesis of BC through affecting cell proliferation, migration, metastasis, angiogenesis, and resistance. Therefore, SP/NK1R signaling responses must be rigorously regulated; otherwise, they would contribute to a more aggressive BC phenotype. Recently, microRNAs (miRNAs) as a specific class of epigenetic regulators have been shown to regulate NK1R and thus, controlling SP/NK1R signaling responses in BC. This review summarizes the current knowledge of the role of SP/NK1R signaling and its therapeutic potentials in BC. We also provide an overview regarding the effects of miRNA-mediated NK1R regulatory mechanisms in controlling BC tumorigenesis to gain a clearer view and thus better management of cancer.
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http://dx.doi.org/10.1111/cge.13750DOI Listing
October 2020

Evaluation of Serum Substance P Level in Chronic Urticaria and Correlation with Disease Severity.

Iran J Allergy Asthma Immunol 2020 Feb 1;19(1):18-26. Epub 2020 Feb 1.

Department of Immunology, Immunology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.

Substance P (SP) is a neurotransmitter emitted from neurons that plays a role in the pathogenesis of itching conditions including chronic urticarial (CU). The present research aims to investigate the serum level of S.P among CU patients and compare them with healthy subjects and explore how it correlates with the severity of urticaria. The present research was conducted on 87 CU patients who visited the allergy clinic of Ghaem Hospital, Mashhad, Iran from October 2017 to June 2018. Besides, 86 healthy subjects were recruited as the control group. Background information of patient was collected including age, sex, duration of the disease and the co-occurrence of angioedema. S.P serum level was measured in two groups by ELISA method. In the patients group, the autologous serum skin test (ASST) was performed along with the urticaria evaluation questionnaire include Urticaria Activity Score 7 (UAS7), Urticaria Control Test (UCT) and Chronic Urticaria Quality of Life (CU-Q2OL). Among the patients, the SP serum level showed to be about two times higher than the healthy subjects (p˂0.001). SP showed to be increased as patients' age grew (p=0.010). In patients with a positive ASST, SP level was higher (p=0.012). No correlation was found between SP and the presence of angioedema among patients. There was no correlation between the SP serum level and the scores obtained from urticaria evaluation questionnaires. SP among CU patients was higher than healthy subjects. SP was also higher among female, older and positive ASST patients. The SP value was not correlated with the severity of urticaria, angioedema. In conclusion, Using SP antagonist drugs could be a potential treatment for chronic urticaria.
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http://dx.doi.org/10.18502/ijaai.v19i1.2414DOI Listing
February 2020
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