Publications by authors named "Majid Khazaei"

201 Publications

The Potential Association between the Risk of Post-Surgical Adhesion and the Activated Local Angiotensin II Type 1 Receptors: Need for Novel Treatment Strategies.

Gastrointest Tumors 2021 Jun 31;8(3):107-114. Epub 2021 Mar 31.

Cancer Research Center, Shahrekord University of Medical Sciences, Shahrekord, Iran.

Background: Post-surgical adhesion bands (PSABs) are a common complication after abdominal or pelvic surgeries for different reasons like cancer treatment. Despite improvements in surgical techniques and the administration of drugs or the use of physical barriers, there has only been limited improvement in the frequency of postoperative adhesions. Complications of PSAB are pain, infertility, intestinal obstruction, and increased mortality. The most important molecular mechanisms for the development of PSAB are inflammatory response, oxidative stress, and overexpression of pro-fibrotic molecules such as transforming growth factor β. However, questions remain about the pathogenesis of this problem, for example, the causes for individual differences or why certain tissue sites are more prone to post-surgical adhesions.

Summary: Addressing the pathological causes of PSAB, the potential role of local angiotensin II/angiotensin II type 1 receptors (AngII/AT1R), may help to prevent this problem.

Key Message: The objective of this article was to explore the role of the AngII/AT1R axis potential to induce PSAB and the therapeutic potential of angiotensin receptor blockers in the prevention and treatment of PSAB.
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http://dx.doi.org/10.1159/000514614DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8280452PMC
June 2021

Metformin inhibits polyphosphate-induced hyper-permeability and inflammation.

Int Immunopharmacol 2021 Oct 13;99:107937. Epub 2021 Jul 13.

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

Circulating inflammatory factor inorganic polyphosphate (polyP) released from activated platelets could enhance factor XII and bradykinin resulted in increased capillary leakage and vascular permeability. PolyP induce inflammatory responses through mTOR pathway in endothelial cells, which is being reported in several diseases including atherosclerosis, thrombosis, sepsis, and cancer. Systems and molecular biology approaches were used to explore the regulatory role of the AMPK activator, metformin, on polyP-induced hyper-permeability in different organs in three different models of polyP-induced hyper-permeability including local, systemic short- and systemic long-term approaches in murine models. Our results showed that polyP disrupts endothelial barrier integrity in skin, liver, kidney, brain, heart, and lung in all three study models and metformin abrogates the disruptive effect of polyP. We also showed that activation of AMPK signaling pathway, regulation of oxidant/anti-oxidant balance, as well as decrease in inflammatory cell infiltration constitute a set of molecular mechanisms through which metformin elicits it's protective responses against polyP-induced hyper-permeability. These results support the clinical values of AMPK activators including the FDA-approved metformin in attenuating vascular damage in polyP-associated inflammatory diseases.
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http://dx.doi.org/10.1016/j.intimp.2021.107937DOI Listing
October 2021

Rigosertib elicits potent anti-tumor responses in colorectal cancer by inhibiting Ras signaling pathway.

Cell Signal 2021 Sep 29;85:110069. Epub 2021 Jun 29.

Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran; Metabolic Syndrome Research Center, Mashhad University of Medical Science, Mashhad, Iran. Electronic address:

Background: The therapeutic potency of Rigosertib (RGS) in the treatment of the myelodysplastic syndrome has been investigated previously, but little is known about its mechanisms of action.

Methods: The present study integrates systems and molecular biology approaches to investigate the mechanisms of the anti-tumor effects of RGS, either alone or in combination with 5-FU in cellular and animal models of colorectal cancer (CRC).

Results: The effects of RGS were more pronounced in dedifferentiated CRC cell types, compared to cell types that were epithelial-like. RGS inhibited cell proliferation and cell cycle progression in a cell-type specific manner, and that was dependent on the presence of mutations in KRAS, or its down-stream effectors. RGS increased both early and late apoptosis, by regulating the expression of p53, BAX and MDM2 in tumor model. We also found that RGS induced cell senescence in tumor tissues by increasing ROS generation, and impairing oxidant/anti-oxidant balance. RGS also inhibited angiogenesis and metastatic behavior of CRC cells, by regulating the expression of CD31, E-cadherin, and matrix metalloproteinases-2 and 9.

Conclusion: Our findings support the therapeutic potential of this potent RAS signaling inhibitor either alone or in combination with standard regimens for the management of patients with CRC.
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http://dx.doi.org/10.1016/j.cellsig.2021.110069DOI Listing
September 2021

Therapeutic potential of active components of saffron in post-surgical adhesion band formation.

J Tradit Complement Med 2021 Jul 20;11(4):328-335. Epub 2021 Jan 20.

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

Background: Abdominal adhesions are common and often develop after abdominal surgery. There are currently no useful targeted pharmacotherapies for adhesive disease. Saffron and its active constituents, Crocin and Crocetin, are wildly used in traditional medicine for alleviating the severity of inflammatory or malignant disease.

Purpose: The aim of this study was to investigate the therapeutic potential of the pharmacological active component of saffron in attenuating the formation of post-operative adhesion bands using different administration methods in a murine model.

Material Method: saffron extract (100 mg/kg), Crocin (100 mg/kg), and Crocetin (100 mg/kg) were administered intraperitoneally and by gavage in various groups of male Wistar rat post-surgery. Also three groups were first treated intra-peritoneally by saffron extract, Crocin, and Crocetin (100 mg/kg) for 10 days and then had surgery. At the end of the experiments, animals sacrificed for biological assessment.

Result: A hydro-alcoholic extract of saffron and crocin but not crocetin potently reduced the adhesion band frequency in treatment and pre-treatment groups in the mice given intra-peritoneal (i.p) injections. Following the saffron or crocin administration, histological evaluation and quantitative analysis represented less inflammatory cell infiltration and less collagen composition, compared to control group. Moreover, the oxidative stress was significantly reduced in treatment groups.

Conclusion: These findings suggest that a hydro-alcoholic extract of saffron or its active compound, crocin, is a potentially novel therapeutic strategy for the prevention of adhesions formation and might be used as beneficial anti-inflammatory or anti-fibrosis agents in clinical trials.

Taxonomy: Abdominal surgeries/post-surgical adhesions.
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http://dx.doi.org/10.1016/j.jtcme.2021.01.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8240116PMC
July 2021

The Therapeutic Potential of Targeting the Angiotensin Pathway as a Novel Therapeutic Approach to Ameliorating Post-Surgical Adhesions.

Curr Pharm Des 2021 Jun 25. Epub 2021 Jun 25.

Metabolic Syndrome Research Centre, Mashhad University of Medical Sciences, Mashhad, Iran.

Background: Post-surgical adhesion is a common complication after abdominal or pelvic surgeries. Despite improvements in surgical techniques or the application of physical barriers, little improvements have been achieved. It causes bowel obstruction, pelvic pain, and infertility in women and has an adverse effect on the quality of life. Renin-Angiotensin System (RAS) is traditionally considered as a blood pressure regulator. However, recent studies also indicate that the RAS plays a vital role in other processes, including oxidative stress, fibrosis, proliferation, inflammation, and the wound healing process. Angiotensin II (Ang II) is the main upstream effector of the RAS that can bind to the AT1 receptor (ATIR). A growing body of evidence has revealed that targeting Angiotensin-Converting Enzyme Inhibitors (ACEIs), Angiotensin II type 1 Receptor Blockers (ARBs), and Direct Renin Inhibitors (DRIs) can prevent post-surgical adhesions. Here we provide an overview of the therapeutic effect of RAS antagonists for adhesion.

Methods: PubMed, EMBASE, and the Cochrane library were reviewed to identify potential agents targeting the RAS system as a potential approach for post-surgical adhesion.

Results: Available evidence suggests the involvement of the RAS signaling pathway in inflammation, proliferation, and fibrosis pathways as well as in post-surgical adhesions. Several FDA-approved drugs are being used for targeting the RAS system. Some of them are being tested in different models to reduce fibrosis and improve adhesion after surgery, including Telmisartan, valsartan, and enalapril.

Conclusion: Identification of the pathological causes of post-surgical adhesion and the potential role of targeting Renin-Angiotensin System may help prevent this problem. Based on the pathological function of RAS signaling after surgeries, the administration of ARBs may be considered as a novel and efficient approach to prevent postsurgical adhesions. Pre-clinical and clinical studies should be carried out to have better information on the clinical significance of this therapy against post-surgical adhesion formation.
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http://dx.doi.org/10.2174/1381612827666210625153011DOI Listing
June 2021

Determination of flood probability and prioritization of sub-watersheds: A comparison of game theory to machine learning.

J Environ Manage 2021 Oct 18;295:113040. Epub 2021 Jun 18.

Department of Forests, Rangelands, and Watershed Management Engineering, Kohgiluyeh & Boyer Ahmad Agricultural and Natural Resources Research and Education Center, AREEO, Yasouj, Iran; Department of Geography, Texas State University, San Marcos, TX, 78666, United States.

Floods often significantly impact human lives, properties, and activities. Prioritizing areas in a region for mitigation based on flood probability is essential for reducing losses. In this study, two game theory (GT) algorithms - Borda and Condorcet - were used to determine the areas in the Tajan watershed, Iran that were most likely to flood, and two machine learning models - random forest (RF), and artificial neural network (ANN) - were used to model flood probability (the probability of flooding). Twelve independent variables (slope, aspect, elevation, topographic position index (TPI), topographic wetness index (TWI), terrain ruggedness index (TRI), land use, soil, lithology, rainfall, drainage density, and distance to river) and 263 locations of flooding were used to model and prepare flood-probability maps. The RF model was more accurate (AUC = 0.949) than the ANN model (AUC = 0.888). Frequency ratio (FR) was calculated for all factors to determine which had the most influence on flood probability. The values of twelve factors that affect flood probability were estimated for each sub-watershed. Then, game-theory algorithms were used to prioritize sub-watersheds in terms of flood probability. A pairwise comparison matrix revealed that the sub-watersheds most likely to flood. The Condorcet algorithm selected sub-watersheds 1, 2, 4, 5, and 11 and the Borda algorithm selected sub-watersheds 2, 4, 5, 20 and 11. Both models predicted that most of the watershed has very low flood probability and a very small portion has a high probability for flooding. The quantitative analysis and characterization of the watersheds from the perspective of flood hazard can support decision making, planning, and investment in mitigation measures.
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http://dx.doi.org/10.1016/j.jenvman.2021.113040DOI Listing
October 2021

Inhibition of angiotensin II type 1 receptor by candesartan reduces tumor growth and ameliorates fibrosis in colorectal cancer.

EXCLI J 2021 7;20:863-878. Epub 2021 May 7.

Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.

Colorectal cancer (CRC) is an important cause of cancer-related mortality. Aberrant activation of the renin-angiotensin system (RAS) is reported to be associated with poor clinical outcomes in patients with CRC. This study was designed to explore the anti-tumor effects of the angiotensin receptor blocker Candesartan either alone or in combination with 5-FU in and models of CRC. The cytotoxic effects of Candesartan were assessed using the MTT assay in two colorectal cancer cell lines (CT-26 and SW-480). To investigate the potential regulatory role of Candesartan on tumor growth, apoptosis, and migration, the expression levels of Cyclin D1, Survivin, MMP3, MMP9, and E-cadherin mRNAs were evaluated. The oxidant/antioxidant balance was also examined by determining the levels of MDA, thiols, SOD, and CAT. We used a xenograft model of colon cancer to investigate the effects of Candesartan alone, or in combination with 5-FU, on tumor growth following histological staining (Hematoxylin & Eosin and Masson trichrome staining) and biochemical studies as well as gene expression analyses by RT-PCR and western blotting. Candesartan suppressed tumor cell proliferation and migration by modulating Cyclin D1, MMP3/9, and E-cadherin. Treatment with Candesartan either alone, or in combination with 5-FU decreased tumor size in the mouse model, and also increased the level of oxidative markers MDA and reduced CAT, SOD, and thiols. Histological evaluation showed that Candesartan increased tumor necrosis, reduced tumor density and attenuated collagen deposition reducing tumor fibrosis in tumor xenograft. Candesartan, an inhibitor of the RAS, when used in combination with 5-FU reduced tumor growth by inhibiting fibrosis and inducing ROS production, supporting further clinical studies on this therapeutic approach for treatment of CRC.
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http://dx.doi.org/10.17179/excli2021-3421DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8192880PMC
May 2021

Anticancer activity of Helicobacter pylori ribosomal protein (HPRP) with iRGD in treatment of colon cancer.

J Cancer Res Clin Oncol 2021 Oct 12;147(10):2851-2865. Epub 2021 Jun 12.

Antimicrobial Resistance Research Center, Bu-Ali Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran.

Purpose: As the conventional therapeutic approaches were not completely successful in the treatment of colon cancer, there is still a need for finding the most efficient therapeutic agents. Here we investigated the anticancer activity of HPRP-A1 that was derived from the N-terminal region of Helicobacter pylori ribosomal protein L1 (RpL1) alone or in combination with tumor-homing peptide iRGD and 5-Fluorouracil (5FU) on colon cancer cell lines (CT26 and HT29) and isograft models of colon cancer.

Method: We assessed the tumor growth inhibitory activity of HPRP-A1 with or without iRGD and 5FU on colon cancer in vitro and in vivo. In the in vitro part, we investigate the effect of HPRP-A1 alone and in combination with iRGD/5FU.

Results: Our results demonstrated that co-administration of HPRP-A1 with iRGD increased the apoptosis, while these two peptides in combination with 5FU increased the intracellular level of p53 that upregulate the pro-apoptotic gene BAX and downregulate the anti-apoptotic gene BCL2. HPRP-A1 blocks the cell cycle progression in G0/G1. Co-administration of two peptides significantly reduced the size and weight of the tumors, while the group that received 5FU in combination with the peptides increased the necrotic and decrease the fibrotic area significantly in the tumor tissues, which also disrupt the oxidant/antioxidant balance.

Conclusions: Our results indicated that HPRP-A1 could be considered an effective agent toward colon cancer in vitro and in vivo with the ability to enhance the effects of conventional chemotherapy agent 5FU.
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http://dx.doi.org/10.1007/s00432-021-03683-7DOI Listing
October 2021

High Diagnostic and Prognostic Value of miRNAs Compared with the Carcinoembryonic Antigen as a Traditional Tumor Marker.

Anticancer Agents Med Chem 2021 Jun 7. Epub 2021 Jun 7.

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

A significant challenge in cancer detection and treatment is early diagnosis and accurate prognosis of the disease that enables effective therapies and interventions to improve the patient's condition. Up to now, many parts of research have tended to focus on the carcinoembryonic antigen (CEA) to detect cancers and estimate the survival rates of patients with multiple cancer types, including colorectal, breast, non-small cell lung, and pancreas cancer. Limited sensitivity and specificity of this traditional tumor marker make it an inappropriate biomarker to diagnose cancer, especially in the early stages, while several lines of research have introduced miRNAs as reliable indicators of tumor initiation, development, and therapy response. Indeed, miRNAs have unique properties that provide considerable benefits, such as discriminating benign diseases from malignancies, prediction of cancer possibility and progress, checking sensitivity to treatment, and initial detection of tumors. This review summarizes the relationships between miRNAs and CEA, the diagnostic significance of CEA in combination with miRNAs, and the distinct advantages of miRNAs over CEA as tumor biomarkers. Advancement in our current understanding of miRNAs is essential to discover new and effective biomarkers for diagnostic, prognostic, and therapeutic goals of cancer patients.
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http://dx.doi.org/10.2174/1871520621666210608094908DOI Listing
June 2021

The Therapeutic Potential of Targeting Autophagy in The Treatment of Cancer.

Curr Cancer Drug Targets 2021 Jun 1. Epub 2021 Jun 1.

Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.

Autophagy is a mechanism by which unwanted cellular components are degraded through a pathway that involves the lysosomes and contributes to several pathological conditions such as cancer. Gastrointestinal cancers affect the digestive organs from the esophagus to the anus and are among the most commonly diagnosed cancers globally. The modulation of autophagy using pharmacologic agents potentially offers a great potential for cancer therapy. In this review, some commonly used compounds, together with their molecular target and the mechanism through which they stimulate or block the autophagy pathway as well as their therapeutic benefit in treating patients with gastrointestinal cancers, are summarized.
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http://dx.doi.org/10.2174/1568009621666210601113144DOI Listing
June 2021

Delivery of oxaliplatin to colorectal cancer cells by folate-targeted UiO-66-NH.

Toxicol Appl Pharmacol 2021 07 13;423:115573. Epub 2021 May 13.

Department of Medical Physiology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran; Metabolic syndrome Research center, Mashhad University of Medical Sciences, Mashhad, Iran. Electronic address:

Oxaliplatin is being used in different malignancies and several side effects are reported for patients taking Oxaliplatin, including peripheral neuropathy, nausea and vomiting, diarrhea, mouth sores, low blood counts, fatigue, loss of appetite, etc. Here we have developed a targeted anticancer drug delivery system based on folate-conjugated amine-functionalized UiO-66 for the delivery of oxaliplatin (OX). UiO-66-NH (U) and UiO-66-NH-FA(FU) were pre-functionalized by the incorporation of folic acid (FA) into the structure via coordination of the carboxylate group of FA. The FTIR spectra of drug-loaded U and FU showed the presence of new carboxylic and aliphatic groups of OX and FA. Powder X-ray diffraction (PXRD) patterns were matched accordingly with the reference pattern and FESEM results showed semi-spherical particles (115-128 nm). The evaluated amounts of OX in U and FU were calculated 304.5 and 293 mg/g respectively. The initial burst release of OX was 15.7% per hour for U(OX) and 10.8% per hour for FU(OX). The final release plateau gives 62.9% and 52.3% for U(OX) and FU(OX). To evaluate the application of the prepared delivery platform, they were tested on colorectal cancer cells (CT-26) via MTT assay, cell migration assay, and spheroid model. IC values obtained from MTT assay were 21.38, 95.50, and 18.20 μg/mL for OX, U(OX), and FU(OX), respectively. After three days of treatment, the CT26 spheroids at two doses of 500 and 50 μg/mL of U(OX) and FU(OX) showed volume reduction. Moreover, the oxidative behavior of the prepared systems within the cell was assessed by total thiol, malondialdehyde, and superoxide dismutase activity. The results showed that FU(OX) had higher efficacy in preventing the growth of CT-26 spheroid, and was more effective than oxaliplation in cell migration inhibition, and induced higher oxidative stress and apoptosis.
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http://dx.doi.org/10.1016/j.taap.2021.115573DOI Listing
July 2021

When metal-organic framework mediated smart drug delivery meets gastrointestinal cancers.

J Mater Chem B 2021 05;9(19):3967-3982

Department of Chemistry, Faculty of Science, Ferdowsi University of Mashhad, Mashhad 9177948974, Iran.

Cancers of the gastrointestinal tract constitute one of the most common cancer types worldwide and a ∼58% increase in the global number of cases has been estimated by IARC for the next twenty years. Recent advances in drug delivery technologies have attracted scientific interest for developing and utilizing efficient therapeutic systems. The present review focuses on the use of nanoscale MOFs (Nano-MOFs) as carriers for drug delivery and imaging purposes. In pursuit of significant improvements to current gastrointestinal cancer chemotherapy regimens, systems that allow multiple concomitant therapeutic options (polytherapy) and controlled release are highly desirable. In this sense, MOF-based nanotherapeutics represent a significant step towards achieving this goal. Here, the current state-of-the-art of interdisciplinary research and novel developments into MOF-based gastrointestinal cancer therapy are highlighted and reviewed.
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http://dx.doi.org/10.1039/d1tb00155hDOI Listing
May 2021

Inhibition of transforming growth factor-beta by Tranilast reduces tumor growth and ameliorates fibrosis in colorectal cancer.

EXCLI J 2021 9;20:601-613. Epub 2021 Mar 9.

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

Transforming Growth Factor-beta (TGF-β) is dysregulated in colorectal cancer and there is growing evidence that it is associated with a poor prognosis and chemo-resistance in several malignances, including CRC. In this study we have explored the therapeutic potential of targeting TGF-β using Tranilast in colon cancer. The anti-proliferative activity of Tranilast was evaluated in 2- and 3-dimensional cells. We used a xenograft model of colon cancer to investigate the activity of Tranilast alone or in combination with 5-FU on tumor growth using histological staining and biochemical studies, as well as gene expression analyses using RT-PCR and Western blotting. Tranilast alone or in combination with 5-FU inhibited tumor growth and was associated with a reduction of TGF-β expression and CD31 positive endothelial cells. Histological evaluation showed that Tranilast increased tumor necrosis and reduced tumor density and angiogenesis. Tranilast increased MDA and ROS production. It was also found that Tranilast reduced total thiol concentration and reduced SOD and catalase activity. Tranilast plus 5-FU was also found to attenuate collagen deposition, reducing tumor fibrosis in tumor xenografts. Our results show that Tranilast, a TGF inhibitor, in combination with 5-FU reduces tumor growth by inhibiting fibrosis and inducting ROS, thus supporting this therapeutic approach in CRC treatment.
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http://dx.doi.org/10.17179/excli2020-2932DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8056055PMC
March 2021

Angiotensin receptor blocker Losartan inhibits tumor growth of colorectal cancer.

EXCLI J 2021 1;20:506-521. Epub 2021 Mar 1.

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

The renin-angiotensin system (RAS) is up-regulated in patients with colorectal cancer (CRC) and is reported to be associated with poor prognosis and chemo-resistance. Here we explored the therapeutic potential of targeting RAS in CRC using Losartan, an angiotensin receptor blocker. An integrative-systems biology approach was used to explore a proteome-level dataset of a gene signature that is modulated by Losartan. The anti-proliferative activity of Losartan was evaluated using 2- and 3-dimensional cell culture models. A xenograft model of colon cancer was used to investigate tumor growth with Losartan alone and in combination with 5-FU followed by histological staining (Hematoxylin & Eosin and Masson trichrome staining), biochemical analyses, gene expression analyses by RT-PCR, western blot/IHC, or MMP Gelatin Zymography studies. Effects on cell cycle and cell death were assessed by flow cytometry. Losartan inhibited cell growth and suppressed cell cycle progression, causing an increase in CRC cells in the G1 phase. Losartan significantly reduced tumor growth and enhanced tumor cell necrosis. An impact on the inflammatory response, including up-regulation of pro-inflammatory cytokines and chemokines in CRC cells are potential mechanisms that could partially explain Losartan's anti-proliferative effects. Moreover, metastasis and angiogenesis were reduced in Losartan-treated mice as observed by inhibited matrix metalloproteinase-2 and -9 activities and decreased tumor vasculature. These data demonstrate the therapeutic potential of combining chemotherapeutic regimens with Losartan to synergistically enhance its activity and target the renin-angiotensin system as a new approach in colorectal cancer treatment.
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http://dx.doi.org/10.17179/excli2020-3083DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8056058PMC
March 2021

Cerium oxide nanoparticles acts as a novel therapeutic agent for ulcerative colitis through anti-oxidative mechanism.

Life Sci 2021 Aug 20;278:119500. Epub 2021 Apr 20.

Department of Physiology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran; Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran. Electronic address:

Background: Cerium (IV) oxide (CeO) exhibit anti-inflammatory activity via scavenge free radicals and decreasing the oxygen species (ROS) production. Here we aimed to exhibit the therapeutic effect of this nanoparticle in experimental colitis models.

Methods: Cerium oxide nanoparticles (CeONPs) were synthesized via using UiO-66 as a precursor. We used dextran sodium sulfate (DSS) to induce colitis in experimental models to investigate the anti-inflammatory effect of CeONPs. Colitis models are divided into four groups to receive the treatment, including control, colitis, cerium oxide, and sulfasalazine. We evaluated the therapeutic effects of CeONPs for the increased colitis clinical symptoms and attenuated the histological damage to colon tissue in colitis.

Result: This nanoparticle was significantly able to reduce the clinical symptoms of colitis. Moreover, CeONPs can enhance the disease activity index such as body lose weight, diarrhea, rectal bleeding, colon length, and spleen weight. Moreover, CeONPs showed a significant reduction in the histological characteristics of the colitis models.

Conclusion: These results suggest that CeONPs can be considered as promising therapeutic agents in treating the ulcerative colitis.
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http://dx.doi.org/10.1016/j.lfs.2021.119500DOI Listing
August 2021

Therapeutic effect of an anti-tuberculosis agent, isoniazid, and its nano-isoform in ulcerative colitis.

Int Immunopharmacol 2021 Jul 1;96:107577. Epub 2021 Apr 1.

Antimicrobial Resistance Research Center, Bu-Ali Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Department of Microbiology and Virology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran. Electronic address:

Background: Isoniazid (INH) is well known as a first-line anti-tuberculosis, while some studies demonstrate that it has anti-inflammatory activity via a different mechanism such as inhibitionthe production of IL-1, ROS, activation of PPARγ expression, inhibition of the transcriptional regulatory activity of NF-κB and AP-1. The aim of this study, investigate the anti-inflammatory effect of INH and INH combined with Sulfasalazine-loaded nanoparticles (NPs) in the ulcerative colitis mouse model.

Methods: To investigate the anti-inflammatory effect of INH and NPs in the ulcerative colitis mice model, we evaluated the effect of INH clinical symptoms and colonic mucosal histology in colitis.

Result: The present study demonstrates that combination therapy of INH with sulfasalazine as well as NPs reduces the symptom of ulcerative colitis and improved disease activity index include body lose weight, diarrhea, rectal bleeding, colonic length, spleen weight, and colon histopathological score in DSS-induced colitis mice model.

Conclusion: Our results suggest that the nanoforms of INH with sulfasalazine enhances the therapeutic effect of the drugs in the treatment of ulcerative colitis.
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http://dx.doi.org/10.1016/j.intimp.2021.107577DOI Listing
July 2021

The Clinical Application of Circulating Tumor Cells and DNAs as Prognostic and Predictive Biomarkers in Gastrointestinal Cancer.

Curr Cancer Drug Targets 2021 Mar 10. Epub 2021 Mar 10.

Metabolic syndrome Research center, Mashhad University of Medical Sciences, Mashhad. Iran.

Gastrointestinal (GI) cancer is one of the most common cancers globally. Genetic and epigenetic mechanisms are involved in its pathogenesis. The conventional methods for diagnosis and screening for GI cancers are often invasive and have other limitations. In the era of personalized medicine, a novel non-invasive approach called liquid biopsy has been introduced for the detection and management of GI cancers, which focuses on the analysis of circulating tumor cells (CTCs) and circulating cell-free tumor DNA (ctDNA). Several studies have shown that this new approach allows for an improved understanding of GI tumor biology and will lead to an improvement in clinical management. The aim of the current review is to explore the clinical applications of CTCs and ctDNA in patients with GI cancer.
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http://dx.doi.org/10.2174/1568009621666210311090531DOI Listing
March 2021

A mini review on the pathogenesis, diagnosis and treatment options for COVID-19.

Infect Disord Drug Targets 2021 Mar 1. Epub 2021 Mar 1.

Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad. Iran.

Coronavirus disease 2019 (COVID-19) is a serious viral disease caused by SARS-CoV-2, associated with a high morbidity and mortality, and represents the greatest public health crisis worldwide. Despite recent efforts for developing novel antiviral agents, no specific drugs are approved for management and treatment of COVID-19. The immune responses to viral infection followed by cytokine storm and acute respiratory distress syndrome are serious issues that may cause death in patients with severe COVID-19. Therefore, developing a novel therapeutic strategy for management of COVID-19 is urgently needed to control the virus spread and improving patient survival rate and clinical outcomes. In this mini review, we summarize the symptoms, pathogenesis and therapeutic approaches that are currently being used to managing the spread of SARS-CoV-2.
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http://dx.doi.org/10.2174/1871526521666210301142223DOI Listing
March 2021

Programmed cell death 1 as prognostic marker and therapeutic target in upper gastrointestinal cancers.

Pathol Res Pract 2021 Apr 18;220:153390. Epub 2021 Feb 18.

Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran; Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran. Electronic address:

Gastrointestinal (GIs) cancers are among the most common causes of cancer related death, and hence the importance for the identification of novel prognostic/predictive biomarkers for detection of patients at an early stage, and for using these to identify novel targeted therapies to improve the efficacy of existing chemotherapeutic regimens. Programmed cell death 1 has been reported as a potential target in several malignancies, and targeting agents are being developed, some already approved by FDA, such as: pembrolizumab, Atezolizumab, Nivolumab. Pembrolizumab that have been approved for the treatment of metastatic non-small cell lung cancer. Here we provide an overview of the mechanism of action PD-1/PD-L1, prognostic value and current progress in clinical trials using PD-1/PD-L1 inhibitors, and the resistant mechanisms at underlie the inhibitory effect of these agents in the treatment of gastrointestinal cancers.
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http://dx.doi.org/10.1016/j.prp.2021.153390DOI Listing
April 2021

The beneficial effect of combination therapy with sulfasalazine and valsartan in the treatment of ulcerative colitis.

EXCLI J 2021 5;20:236-247. Epub 2021 Feb 5.

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

Inflammatory bowel disease (IBD) is defined by the chronic inflammation of the digestive tract. Ulcerative colitis is one of the most prevalent chronic IBDs. The increase in the mucosal expression of angiotensin II (AT-II) in colitis suggests a possible role of AT-II in colitis-associated inflammation. Here, we examined the potential therapeutic effects of combination therapy regarding valsartan (Val), as an AT-II receptor blocker, with sulfasalazine (SSZ) in a murine colitis model. DSS induced colitis was initiated by the administration of dextran sodium sulfate (DSS) in male C57BL/6 mice for 1 week. Val (160 mg/kg/day, gavage) was given on the third day and continued for seven days. SSZ (100 mg/kg/day) was used as reference drug and also used in combination in one group (Val; 160 mg/kg/day and/or SSZ; 100 mg/kg/day). Colonic mucosal inflammation was evaluated clinically, biochemically, and histologically. The disease activity index in DSS-treated mice, including weight loss, stool consistency, and rectal bleeding, were significantly lower in the group of mice receiving the combination of valsartan and sulfasalazine compared to the DSS-treated group. Valsartan and sulfasalazine treatment was associated with a lower reduction in colon length, diminished colon weight, and high sensitivity C-reactive protein level in mice with DSS-induced colitis. Valsartan and sulfasalazine also reduced markers of oxidative stress after DSS administration. Our findings demonstrate the anti-inflammatory and anti-fibrotic activities of a combination therapy with sulfasalazine and valsartan in experimentally induced colitis, indicating its value as a potential therapeutic option for the treatment of colitis.
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http://dx.doi.org/10.17179/excli2021-3370DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7898046PMC
February 2021

The therapeutic potential of renin-angiotensin system inhibitors in the treatment of pancreatic cancer.

Life Sci 2021 Apr 3;270:119118. Epub 2021 Feb 3.

Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran; Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran. Electronic address:

Pancreatic cancer is among the most lethal malignancies with poor prognosis and patients become chemoresistant to current therapies, supporting further investigations to identify new therapeutic regimens in the treatment of this condition. Preclinical and clinical studies now appear to support the role of the renin-angiotensin system (RAS) in the regulation of tumor growth, angiogenesis, and metastasis in different malignancies including pancreatic cancer. These studies suggest that RAS blockers; Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs); could have anti-carcinogenic effects and improve clinical outcomes in the management of pancreatic cancer. Here we provided an overview of ACE inhibitors and ARBs as a potential therapeutic option in the treatment of pancreatic cancer.
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http://dx.doi.org/10.1016/j.lfs.2021.119118DOI Listing
April 2021

MicroRNAs as potential investigative and predictive biomarkers in colorectal cancer.

Cell Signal 2021 04 30;80:109910. Epub 2020 Dec 30.

Bioinformatics Research Group, Mashhad University of Medical Sciences, Mashhad, Iran; Department of Medical Biotechnology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran. Electronic address:

Colorectal cancer (CRC) is a noticeable reason of cancer-associated deaths with a high incidence and mortality rate. Countless effort have been put into the improving clinical management of CRC patients including more effective tools and a wide variety of biomarkers for diagnostic, prognostic or predictive purposes. In recent years, dysregulated miRNAs have been emerged as highly sensitive and specific markers to manage CRC in an effective way. They can play key roles in carcinogenesis as potential oncogenes, tumor suppressors or regulators of cancer network. Therefore, miRNAs may serve as molecular tools that can be quantified and used in diagnostic and prognostic approaches. Growing evidence also suggests that forced expression of tumor suppressor miRNAs or inhibiting the oncogene ones, can be used as a novel treatment strategy. In this review, we focus on the clinical applications of miRNAs as promising biomarkers of early cancer detection, prognosis and treatment.
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http://dx.doi.org/10.1016/j.cellsig.2020.109910DOI Listing
April 2021

Ginger (Zingiber Officinale Roscoe) Extract Protects the Heart Against Inflammation and Fibrosis in Diabetic Rats.

Can J Diabetes 2021 Apr 2;45(3):220-227. Epub 2020 Sep 2.

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

Background: Fibrosis and inflammation in the heart of patients with diabetes mellitus alongside increased production of free radicals and collagen are together known as diabetic cardiomyopathy. Ginger rhizome has antidiabetic, antioxidant and anti-inflammatory effects. Thus, we investigated the effect of ginger extract on diabetes-induced cardiomyopathy in streptozotocin-induced diabetic rats.

Methods: Animals were divided into 7 groups: control; diabetic; diabetic treated with different doses of ginger extract of 100, 200 and 400 mg/kg; metformin (200 mg/kg); and metformin-valsartan (200 and 30 mg/kg, respectively). Serum levels of glucose, aspartate aminotransferase, lactate dehydrogenase and creatine kinase-muscle/brain were measured. Fibrosis and inflammation were determined by histologic assessment. Gene expression of transforming growth factor (TGF)-β1, TGF-β3 and angiotensin II type 1 receptor was evaluated by real-time polymerase chain reaction in heart tissue.

Results: Serum glucose level in all treated groups, except for the ginger extract 100-mg/kg group, was significantly lower than in the diabetic group. Serum levels of aspartate aminotransferase, lactate dehydrogenase and creatine kinase-muscle/brain were significantly reduced in all treated groups compared with the diabetic group. In the study of fibrosis, collagen amount in the heart tissue of all treated groups, except the ginger extract 100-mg/kg group, was significantly lower than in the diabetic group. Inflammatory cell infiltrates were decreased, and disarrangement was improved in cardiac tissues of all treated groups compared with the diabetic group. Expression of angiotensin II type 1 receptor and TGF-β1 and TGF-β3 genes in all treated groups downregulated compared with the diabetic group.

Conclusions: Treatment by ginger extract reduced myocardial fibrosis and inflammation in the course of diabetic cardiomyopathy, possibly through regulation of the expression of genes involved in the SMAD/TGF-β pathway.
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http://dx.doi.org/10.1016/j.jcjd.2020.08.102DOI Listing
April 2021

Cardiovascular Effect of Cuneiform Nucleus During Hemorrhagic Hypotension.

Basic Clin Neurosci 2020 May-Jun;11(3):251-259. Epub 2020 May 1.

Neurogenic Inflammation Research Centre, Mashhad University of Medical Sciences, Mashhad, Iran.

Introduction: The underlying mechanism responsible for the cardiovascular response to Hemorrhage (HEM) is still unknown; however, several brain areas, such as the Cuneiform nucleus (CnF) have shown to be involved. In this study, the cardiovascular effect of the CnF during HEM was evaluated.

Methods: The animals were divided into the following groups: 1. Vehicle; 2. HEM; 3. Cobalt chloride (CoCl); 4. CoCl+saline; and 5. CoCl+HEM. Catheterization of the left and right femoral artery was performed to record blood pressure and blood withdrawal, respectively. Saline and CoCl were microinjected into the CnF nucleus, and then blood withdrawal was done for HEM induction. Cardiovascular regulation throughout the experiments was recorded and changes (Δ) in the Systolic Blood Pressure (SBP), Mean Arterial Pressure (MAP) and Heart Rate (HR) were calculated over time and compared with those treated with saline and HEM, using repeated-measures ANOVA.

Results: HEM significantly reduced ΔSBP and ΔMAP and augmented ΔHR than the vehicle group. CoCl did not significantly affect basic ΔSBP, ΔMAP, and ΔHR compared with the vehicle group. However, injection of CoCl into the CnF before HEM (CoCl+HEM group) significantly decreased ΔSBP, ΔMAP, and tachycardia, induced by HEM.

Conclusion: Our results indicated that blockade of the CnF by CoCl significantly reduced the hypotension and tachycardia, induced by HEM indicating the involvement of CnF in cardiovascular regulation during HEM.
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http://dx.doi.org/10.32598/bcn.11.2.84.4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7502186PMC
May 2020

Clinical Association between Phospho-AKT Expression with Clinicopathological Characteristics of Gastrointestinal Cancer Patients: A Meta-Analysis.

Crit Rev Eukaryot Gene Expr 2020 ;30(4):299-309

Department of Medical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran; Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.

Deregulation of AKT (protein kinase B) is frequently observed in human malignancies including gastrointestinal (GI) cancers. Here we have reviewed the association between AKT phosphorylation (activation) and clinical and pathological characteristics of patients with GI cancer. Articles in the EMBASE, PubMed, Cochrane Library, and Web of Science databases were searched up to July 2018. Eighteen studies comprising 1,698 patients with 5 different cancer types were included in the meta-analysis. In the pooled analysis, AKT phosphorylation was positively correlated with tumor size (r = 0.14, 95% CI: 0.06-0.22; P < 0.001), tumor grade (r = 0.08, 95% CI: 0.02-0.14; P < 0.009), tumor stage (r = 0.19, 95% CI: 0.13-0.24; P < 0.001), lymph node status (r = 0.18, 95% CI: 0.09-0.25; P < 0.001) and the presence of distant metastasis (r = 0.14, 95% CI: 0.06-0.22; P < 0.001) in the patients with GI cancer. These findings support the potential clinical value of AKT as a prognostic marker and therapeutic target in patients with GI carcinomas.
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http://dx.doi.org/10.1615/CritRevEukaryotGeneExpr.2020028658DOI Listing
July 2021

The effect of aerobic, resistance, and combined training on PPAR-α, SIRT1 gene expression, and insulin resistance in high-fat diet-induced NAFLD male rats.

Physiol Behav 2020 12 2;227:113149. Epub 2020 Sep 2.

Department of Physiology, School of Medicine, Mashhad University of Medical Sciences, Mashhad 91779-48564, Iran.

Background: Insulin resistance (IR) is known as the most important cause of Non-alcoholic Fatty Liver Disease (NAFLD), which is accompanied by a decline in gene expression of hepatic's peroxisomes Proliferator-Activated Receptors-alpha (PPAR-α) and Sirtuin-1 (SIRT1). This study aimed to investigate the effect of eight weeks of aerobic, resistance, and combined training on hepatic PPAR-α and SIRT1 expression, IR, serum Alanine aminotransferase (ALT), and aspartate aminotransferase (AST) in rats of NAFLD induced by high-fat diet (HFD).

Methods: A total of 37 male NAFLD rats induced 12 weeks of HFD were randomly divided into 4 groups: control, aerobic, resistance, and combined training. All groups continued the HFD until the end of the study. The training groups carried out exercise training with moderate intensity by 8 weeks of running on a treadmill and climbing a ladder for 5 sessions/week. At the end of the trainings, PPAR-α and SIRT1 expressions were examined via qPCR technique in the liver tissue.

Results: The 3 types of trainings controlled the weight gain caused by HFD and showed a significant decrease in serum ALT (P<0.05). Post-hoc test results indicated a significant reduction in AST and IR between the control group and HFD+AT, as well as the control group and HFD+RT (P<0.05). Despite a notable increase in hepatic PPAR-α and SIRT1 expression, it was not statistically significant (P ≥ 0.05).

Conclusion: Doing any aerobic, resistance, and combined training for 8 weeks can control body weight, improve IR, decrease ALT; nevertheless, resistance training is more effective in improving NAFLD.
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http://dx.doi.org/10.1016/j.physbeh.2020.113149DOI Listing
December 2020

p28 Bacterial Peptide, as an Anticancer Agent.

Front Oncol 2020 6;10:1303. Epub 2020 Aug 6.

Antimicrobial Resistance Research Center, Bu-Ali Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran.

Cancer remains a major cause of morbidity and mortality irrespective of the type of conventional chemotherapy. Therefore, there is an urgent need for new and effective anticancer therapeutic agents. Bacterial proteins and their derivative peptides appear as a promising approach for cancer treatment. Several, including an amphipathic, α-helical, 28-amino acid peptide derived from azurin, a 128-amino acid copper-containing redox protein secreted from , show clinical promise in the treatment of adult and pediatric solid tumors. The peptide, p28, is a post-translational, multi-target anticancer agent that preferentially enters a wide variety of solid tumor cells. Mechanistically, after entry, p28 has two major avenues of action. It binds to both wild-type and mutant p53 protein, inhibiting constitutional morphogenic protein 1 (Cop1)-mediated ubiquitination and proteasomal degradation of p53. This results in increased levels of p53, which induce cell-cycle arrest at G2/M and an eventual apoptosis that results in tumor cell shrinkage and death. In addition, p28 also preferentially enters nascent endothelial cells and decreases the phosphorylation of FAK and Akt inhibiting endothelial cell motility and migration. Here, we review the current basic and clinical evidence suggesting the potential of p28 as a cancer therapeutic peptide.
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http://dx.doi.org/10.3389/fonc.2020.01303DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7424061PMC
August 2020

Angiotensin-Converting Enzyme Inhibitor Captopril: Does it Improve Renal Function in Lipopolysaccharide-induced Inflammation Model in Rats.

Saudi J Kidney Dis Transpl 2020 Jul-Aug;31(4):727-738

Neurogenic Inflammation Research Center; Department of Physiology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.

Renin-angiotensin system as an important regulator of renal function has also a major role in inflammation. In the present study, the effects of captopril on renal dysfunction, renal cytokine levels, and renal tissue oxidative damage were investigated in lipopolysaccharide (LPS)-induced inflammation model in rats. Treatment of five groups of the rats was carried out as follows: (1) saline as a control, (2) LPS 1 mg/kg, and (3-5) 10, 50, or 100 mg/kg captopril 30 min, respectively, before LPS. The treatments were given for 12 days. Finally, the animals were deeply anesthetized, the blood samples were obtained, and the renal tissues were removed and kept for biochemical measurements. Administration of LPS increased serum blood urea nitrogen and creatinine (P < 0.001). Pretreatment with all doses of captopril decreased these parameters (P < 0.001). LPS also increased interleukin-6 (IL-6), malondialdehyde, and nitric oxide metabolites in the renal tissues (P<0.05 - P < 0.001), which was prevented by captopril (P < 0.05 - P < 0.001). The total thiol concentration and superoxide dismutase and catalase activities in the kidney of the LPS group were lower than the control (P < 0.001), while they were enhanced when the animals were cotreated by captopril (P <0.01 - P < 0.001). The results of the present study showed that captopril improved renal function and attenuated tissue oxidative stress in LPS-induced inflammation model in rats.
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http://dx.doi.org/10.4103/1319-2442.292306DOI Listing
July 2021

Involvement of the 5-HT receptor of the cuneiform nucleus in the regulation of cardiovascular responses during normal and hemorrhagic conditions.

Iran J Basic Med Sci 2020 Jul;23(7):858-864

Neurogenic Inflammation Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.

Objectives: The 5-hydroxytryptamine1A (5-HT) receptor is one of the serotonin receptors in the brain, which regulates cardiovascular responses, especially in hemorrhage. Presence of this receptor in the cuneiform nucleus (CnF) has been shown. The present study evaluates the cardiovascular effect of this receptor of the CnF in normal and hypotensive hemorrhagic rats.

Materials And Methods: Agonist (8-OH-DPAT) and antagonist (WAY-100635) of 5-HT microinjected into the CnF in basal and hemorrhagic conditions and cardiovascular responses were evaluated. Hemorrhage induced by blood withdrawal from the femoral artery and 2 min after that drugs microinjected. Time course and peak changes (∆) of the mean arterial pressure (MAP), systolic blood pressure (SBP) and heart rate (∆HR) were obtained and compared to the control and hemorrhage groups.

Results: In basal condition, 8-OH-DPAT significantly decreased ∆SBP, ∆MAP and ∆HR compared to the control (0.05-0.01), while way-100635 did not have a significant effect. Hypotension and tachycardia induced by hemorrhage ameliorated by agonist (0.05-0.01), while antagonist deteriorated hypotension (0.05) but attenuated tachycardia (0.01).

Conclusion: This study shows that 5-HT receptor of the CnF involves in regulation of the cardiovascular responses. However, this effect in basal and hemorrhage conditions is different.
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http://dx.doi.org/10.22038/ijbms.2020.40453.9579DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7395185PMC
July 2020

The Prognostic Value of Small Noncoding microRNA-21 Expression in the Survival of Cancer Patients: A Meta-Analysis.

Crit Rev Eukaryot Gene Expr 2020 ;30(3):207-221

Department of Medical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran; Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.

microRNA-21 (miR-21) is a small noncoding RNA that regulates gene expression in different types of human malignancies. The potential prognostic value of miR-21 in cancer progression is controversial. This meta-analysis includes 76 studies of 10,213 cancer patients to test miR-21 prognostic value in various human cancers. We obtain hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) for overall survival (OS) to assess association strength. In the pooled analysis, high miR-21 expression is associated with poor OS, with a combined HR of 1.59 (95% CI, 1.49-1.70; p < 0.001; random-effects model). Furthermore, subgroup analysis demonstrates that high miR-21 expression is related to shorter OS in patients with digestive system cancers (HR = 1.02; 95% CI, 1.002 to 1.04; p = 0.026), respiratory system cancers (HR = 1.93; 95% CI, 1.48 to 2.51; p < 0.001), and breast cancer (HR = 2.20; 95% CI, 1.78 to 2.73; p = 0.001). These results indicate that miR-21 may be a clinically useful prognostic biomarker for cancer progression.
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http://dx.doi.org/10.1615/CritRevEukaryotGeneExpr.2020028719DOI Listing
July 2021
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