Mostafa Mostafazadeh

Tabriz University of Medical Sciences

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Sanya Haiaty

Tabriz University of Medical Sciences

Heibatollah Sadeghi

Yasuj University of Medical Sciences

Reza Rahbarghazi‬

Tabriz University of Medical Sciences

Hossein Sadeghi

Yasuj University of Medical Sciences

Mohammad Nouri

Tabriz University of Medical Sciences

Ahad Bazmani

Tabriz University of Medical Sciences

Vahid Zarezade

Ahvaz Jundishapur University of Medical Sciences

Saba Nikanfar

UCLouvain

Fouad Mehraban

University of Tehran

Houman Kahroba

Maastricht University

Cooperative Institutions

Tabriz University of Medical Sciences

University of Tabriz

Yasuj University of Medical Sciences

Tehran University of Medical Sciences

Biotechnology Research Center

Kermanshah University of Medical Sciences

Shiraz University of Medical Sciences

Islamic Azad University, Tehran

Urmia University

Ferdowsi University of Mashhad

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Vandetanib alters the tumoricidal capacity of human breast cancer stem cells via inhibiting vasculogenic capacity

Bioimpacts (2022)

Sanya Haiaty Mohammad‐Reza Rashidi Maryam Akbarzadeh Ahad Bazmany Mostafa Mostafazadeh

The inhibition of vascularization into tumor stroma as well as dynamic cell growth is the center of attention. Here, we aimed to examine the role of vandetanib on angiogenesis capacity of breast cancer stem cell (CSCs).MDA-MB-231 cells were exposed to different doses of vandetanib and survival rate was monitored. Stimulatory effects of vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), and epidermal growth factor (EGF) were evaluated in vandetanib-treated MDA-MB-231 cells. In vitro tubulogenesis capacity was studied on the Matrigel surface. The synergistic effects of vandetanib on cell survival were also assessed after PI3K and/or Wnt3a inhibition. Vascular endothelial (VE)-cadherin, matrix metalloproteinase-2 (MMP-2), -9, Wnt3a, and p-Akt/Akt ratio were measured using western blotting.Vandetanib reduced survival rate in a dose-dependent manner (P<0.05). Proliferative effects associated with VEGF, FGF, and EGF were blunted in these cells pre-exposed to vandetanib (P<0.05). The microcirculation pattern's triple-negative breast cancer (TNBC) was suppressed by 1, 5 µM of vandetanib (P<0.05). Hence 1, 5 µM of vandetanib potentially decreased the population of CD24- cells. 1 and 5 µM of vandetanib inhibited cell proliferation by blocking PI3K and Wnt3a pathways and decreased the p-Akt/Akt ratio, Wnta3 protein levels (P<0.05). 1 and 5 µM vandetanib combined with PI3K inhibitor diminished metastatic markers including, MMP-2, and MMP-9. The concurrent treatment (PI3K, inhibitor+ 1, 5 µM vandetanib) also considerably reduced epithelial-mesenchymal transition (EMT) markers such as VE-cadherin (P<0.05).Vandetanib suppressed vasculogenic mimicry (VM) networking through blunting stemness properties, coincided with suppression of VE-cadherin in CSCs.

Vandetanib

Matrigel

10.34172/bi.2022.24208

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Citations (1)

Effect of ethanolic extract of Stachys pilifera Benth on subacute experimental models of inflammation and some underlying mechanisms

Research in Pharmaceutical Sciences (2021)

Vahid Zarezade Hossein Sadeghi Esmaeel Panahi Kokhdan Jafar Nikbakht Mehdi Molavi

This study was designed to evaluate the anti-inflammatory activities of S. pilifera (HESP) in two sub-acute models of inflammation and clarified some possible mechanisms.Colorimetric methods were used to determine total phenol and flavonoid contents. Carrageenan or formalin-induced rat paw edema (seven days) and multiple application TPA-induced ear edema in mice (9 days) were used. The concentration of IL-1 and TNF-α were measured in the inflamed paw, as well as MDA levels in the serum and liver. Histopathological studies and in vitro anti-inflammatory effects of the extract were also studied using heat-or hypotonicity-induced hemolysis in RBC humans.Total phenol and flavonoid contents of HESP were 101.35 ± 2.96 mg GAE/g extract and 660.79 ± 10.06 mg RE g extract, respectively. Oral (100 and 200 mg/kg) and topical application (5 mg/ear) of HESP significantly inhibited formalin-induced paw edema and multiple TPA-induced ear edema. The extract also significantly decreased the serum and liver levels of MDA in the carrageenan and formalin tests. The elevated levels of TNF-α and IL-1β in the carrageenan-injected paw were not affected by HESP. The extract (50-800 μg/mL) inhibited heat-or hypotonicity-induced hemolysis. Histopathological examination of the inflamed tissues revealed that HESP inhibited congestion and leukocyte infiltration.The findings confirmed the potent anti-inflammatory effects of S. pilifera in two sub-acute inflammation models and suggested that these properties were not related to IL-1 and TNF-α, but could be attributed to inhibition of lipid peroxidation, membrane stabilization, and inhibition of leukocyte penetration.

Carrageenan

Phenol red

Infiltration (HVAC)

10.4103/1735-5362.323918

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Citations (3)

In vivoanti-inflammatory properties of aerial parts ofNasturtium officinale

Pharmaceutical Biology (2013)

Heibatollah Sadeghi Mostafa Mostafazadeh Hossein Sadeghi Moslem Naderian Mehrzad Jafari Barmak

Context: Nasturtium officinale R. Br. (watercress) has long been used in Iranian folk medicine to treat hypertension, hyperglycemia, and renal colic. Moreover, anticancer, antioxidant, and hepatoprotective properties of N. officinale have been reported.

Watercress

Folk medicine

10.3109/13880209.2013.821138

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Citations (60)

Anti-inﬂammatory Activity of Stachys Pilifera Benth

Iranian Red Crescent Medical Journal (2014)

Heibatollah Sadeghi Vahid Zarezade Hossein Sadeghi Mehdi Akbartabar Toori Mehrzad Jafari Barmak

Stachys pilifera Benth has long been used to treat infectious diseases as well as respiratory and rheumatoid disorders in Iranian folk medicine. Antioxidants, antitumor, and antimicrobial properties of the plant have been reported.This experimental study was designed to evaluate systemic and topical anti-inflammatory effects of the hydro-alcoholic extract from aerial parts of Stachys pilifera (HESP).Anti-inflammatory effects of HESP was studied in four well-known animal models of inflammation, including carrageenan- or formalin-induced paw edema in rat (thirteen groups, 6 rats per each group), and 12-O-tetradecanoylphorbol-13-acetate (TPA)- or xylene-induced ear edema in mouse (ten groups, 6 mice per each group). The rats received HESP (50-400 mg/ kg) orally 45 minutes before the subplantar injection of carrageenan or formalin. In TPA or xylene tests, HESP (1, 2.5, and 5 mg/ear) was applied topically simultaneous with these phlogistic agents on the ear mice. Finally, pathological examination of the inflamed tissues (paw and ear) was carried out.Acute toxicity study of the extract showed that no rats were killed at 5000 mg/kg (LD50 > 5000 mg/kg). The extract (100 and 200 mg/ kg) significantly suppressed carrageenan-induced paw edema 1, 2, 3, and 4 hours after carrageenan challenge in comparison with the control group (P < 0.001). The HESP (100 and 200 mg/kg) also produced a considerable antiedematogenic effect in the formalin test over a period of 24 hours (P < 0.01). Furthermore, topical administration of the HESP (1, 2.5, and 5 mg/ear) inhibited TPA- and xylene-induced ear edema in comparison with the control group (P < 0.001). The pathological analysis of the paws and ears revealed that HESP was capable of reducing tissue destruction, cellular inﬁltration, and subcutaneous edema induced by the indicated phlogistic agents.The present data confirmed systemic and topical anti-inflammatory effects of Stachys pilifera which is comparable to indomethacin.

Carrageenan

10.5812/ircmj.19259

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Blockage of Wnt/β-catenin Signaling Pathway in Colorectal Cancer Resistant Cells by Nitazoxanide Effects on Peptidylarginine Deiminases Expression

Asian Pacific Journal of Cancer Prevention (2022)

Mohsen Hemmati-Dinarvand Shahnaz Kheirandish Ali Khodadadian Mostafa Mostafazadeh Atefeh Seghatoleslam

Background: Multidrug resistance (MDR) is a major cause of unsuccessful cancer treatment in which drugs are not effective. Therefore, it is necessary to identify the critical mechanisms of the development of MDR and target those with novel compounds. Accordingly, the current study is the first to investigate the combination effect and molecular mechanism of nitazoxanide (NTZ) and oxaliplatin (OXP) on LS174T/OXP-resistant cells. Methods: The effect of NTZ on OXP cytotoxicity in LS174T and LS174T/OXP cell lines was evaluated by MTT assay. Changes in expression levels of MDR1, MRP1, CTNNB1, peptidylarginine deiminase (PAD)2, and PAD4 genes and proteins were evaluated by RT-qPCR and western blotting methods, respectively. Lastly, the apoptosis assay was performed by flow cytometer. Results: OXP resistant and sensitive cells were identified based on the IC50 values (11567 nM vs. 1745 nM, p<0.05 for 24 h treatment; and 5161 nM vs. 882 nM, p<0.05 for 48 h incubation). The combination of NTZ and OXP for 48 h led to a reduction in IC50 values in resistant cells (2154 nM, p<0.05). The effect of NTZ plus OXP significantly decreased the expression of MDR1 (p<0.001), MRP1 (p<0.05), and CTNNB1 (p<0.001), while PAD2 and PAD4 expression was significantly increased (p<0.001). This combination therapy enhanced the percentage of the sub-G1 population (apoptosed) compared to other groups. Conclusion: The results showed that NTZ leads to notable upregulation of PAD2 and PAD4, which can disrupt the Wnt/β-catenin signaling pathway and reverse the MDR by reducing MDR1 and MRP1 expression.

Nitazoxanide

MTT assay

10.31557/apjcp.2022.23.9.3215

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Thymoquinone inhibited vasculogenic capacity and promoted mesenchymal-epithelial transition of human breast cancer stem cells

BMC Complementary Medicine and Therapies (2021)

Sanya Haiaty Mohammad‐Reza Rashidi Maryam Akbarzadeh Ahad Bazmani Mostafa Mostafazadeh

Vasculogenic mimicry (VM) is characterized by the formation of tubular structure inside the tumor stroma. It has been shown that a small fraction of cancer cells, namely cancer stem cells (CSCs), could stimulate the development of vascular units in the tumor niche, leading to enhanced metastasis to the remote sites. This study aimed to study the inhibitory effect of phytocompound, Thymoquinone (TQ), on human breast MDA-MB-231 cell line via monitoring Wnt/PI3K signaling pathway.MDA-MB-231 CSCs were incubated with different concentrations of TQ for 48 h. The viability of CSCs was determined using the MTT assay. The combination of TQ and PI3K and Wnt3a inhibitors was examined in CSCs. By using the Matrigel assay, we measured the tubulogenesis capacity. The percent of CD24- CSCs and Rhodamine 123 efflux capacity was studied using flow cytometry analysis. Protein levels of Akt, p-Akt, Wnt3a, vascular endothelial-cadherin (VE-cadherin), and matrix metalloproteinases-2 and -9 (MMP-2 and -9) were detected by western blotting.TQ decreased the viability of CSCs in a dose-dependent manner. The combination of TQ with PI3K and Wnt3a inhibitors reduced significantly the survival rate compared to the control group (p < 0.05). TQ could blunt the stimulatory effect of vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), fibroblast growth factor (FGF) on CSCs (p < 0.05). The vasculogenic capacity of CSCs was reduced after being-exposed to TQ (p < 0.05). Western blotting revealed the decrease of CSCs metastasis by suppressing MMP-2 and -9. The protein level of VE-cadherin was also diminished in TQ-treated CSCs as compared to the control cell (p < 0.05), indicating inhibition of mesenchymal-endothelial transition (MendT). TQ could suppress Wnt3a and PI3K, which coincided with the reduction of the p-Akt/Akt ratio. TQ had the potential to decrease the number of CD24- CSCs and Rhodamine 123 efflux capacity after 48 h.TQ could alter the vasculogenic capacity and mesenchymal-epithelial transition of human breast CSCs in vitro. Thus TQ together with anti-angiogenic therapies may be a novel therapeutic agent in the suppression of VM in breast cancer.

Vasculogenic mimicry

Matrigel

Viability assay

10.1186/s12906-021-03246-w

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Citations (24)

Hepatoprotective activity of aerial parts of Otostegia persica against carbon tetrachloride-induced liver damage in rats.

PubMed (2015)

Mehdi Akbartabar Toori Behzad Joodi Heibatollah Sadeghi Hossein Sadeghi Mehrzad Jafari Barmak

To evaluate the hepatoprotective properties of Otostegia persica (O. persica) ethanol extract on carbon tetrachloride-induced liver damage in rats.Fifty adult male Wistar rats were randomly divided into five groups. Group I served as normal control and was given only olive oil intraperitoneally (i.p.). Group II, III, IV, and V were administered CCl4 mixed with olive oil 1:1 (1 ml/kg) i.p., twice a week for 8 weeks. Group II was maintained as CCl4-intoxicated control (hepatotoxic group). Group III, IV, and V received O. persica extract at a dose of 40, 80, and 120 mg/kg for 8 weeks every 48 h orally, respectively. Biochemical parameters including aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP), total bilirubin (TB), albumin (ALB), total protein (TP), and lipid peroxidation marker (Malonaldialdehyde, (MDA) were determined in serum. After 8 weeks, animals were sacrificed, livers dissected out, and evaluated for histomorphological changes.The administration of CCl4 increased AST, ALT, ALP, TB, and MDA in serum but it decreased TP , and ALB compared with normal control. Treatment with O. persica extract at three doses resulted in decreased enzyme markers, bilirubin levels, and lipid peroxidation marker (MDA) and increased TP and ALB compared with CCl4 group. The results of pathological study also support the hepatoprotective effects which were observed at doses of 80 and 120 mg/kg.The results of the present study indicate that ethanol extract of O. persica may have hepatoprotective effect which is probably due to its antioxidant property.

Aspartate transaminase

CCL4

Transaminase

Source

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Citations (25)

In vitro exosomal transfer of Nrf2 led to the oxaliplatin resistance in human colorectal cancer LS174T cells

Cell Biochemistry and Function (2022)

Mostafa Mostafazadeh Houman Kahroba Sanya Haiaty Abbas Pirpour Tazekand Nasser Samadi

Chemotherapy resistance is a serious pitfall in the treatment of colon cancers (CCs). Previous studies have found that exosomes (Exo) play a pivotal role in tumor drug resistance via the transfer of proteins and genetic materials to the acceptor cells. To date, the mechanisms orchestrating Exo-derived resistance in cancer cells have been the center of attention. Herein, we aimed to evaluate the role of exosomal nuclear factor erythroid 2-related factor 2 (Nrf2) on oxaliplatin (1-OHP) resistance in human colorectal cancer LS174T cells in vitro. To this end, exosomal-Nrf2-mediated 1-OHP resistance was examined using different assays. Exo was isolated from resistant LS174T cells (LS174T/R) and added to the culture medium of sensitive LS174T cells (LS174T/S). According to our data, LS174T/S cells successfully adsorbed PKH26-Exo driven from LS174T/R cells. Western blotting showed an increased Nrf2 level in Exo isolated from LS174T/R cells compared to LS174T/S cell-derived Exo (p < .05). The incubation of LS174T/S cells with LS174T/R-derived Exo increased half-maximal inhibitory concentration values in response to treatment with 1-OHP (p < .05). Besides this, the apoptotic changes were diminished in LS174T/S cells after incubation with LS174T/R-derived Exo. Of note, the exposure of LS174T/S cells to LS174T/R cell-derived Exo increased the expression of Nrf2 and P-glycoprotein (P-gp) compared to the nontreated LS174T/S cells (p < .05). In line with these changes, lower intracellular Rhodamin 123 content was detected in Exo-treated cells compared to the nontreated LS174T/S cells. Exo increased migration and clonogenic capacity of LS174T/S cells after incubation with Exo-derived from resistant cells. Of note, inhibition of Nrf2 with a specific blocker, brusatol, blunted these effects. Taken together, Exo-mediated transfer of Nrf2 is involved in the development of oxaliplatin resistance in CC cells by upregulating P-gp.

10.1002/cbf.3703

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Citations (19)

Short‐chain fatty acids profile in patients with SARS‐CoV‐2: A case‐control study

Health Science Reports (2023)

Edris Nabizadeh Mohammad Yousef Memar Hamed Hamishehkar Hadi Ghanbari Hiva Kadkhoda

Abstract Background and Aims SARS‐CoV‐2, as a new pandemic disease, affected the world. Short‐chain fatty acids (SCFAs) such as acetic, propionic, and butyric acids are the main metabolites of human gut microbiota. The positive effects of SCFAs have been shown in infections caused by respiratory syncytial virus, adenovirus, influenza, and rhinovirus. Therefore, this study aimed to evaluate the concentration of SCFAs in patients with SARS‐CoV‐2 compared with the healthy group. Methods This research was designed based on a case and control study. Twenty healthy individuals as the control group and 20 persons admitted to the hospital with a positive test of coronavirus disease (COVID‐19) real‐time polymerase chain reaction were included in the study as the patient group from September 2021 to October 2021, in Tabriz, Iran. Stool specimens were collected from volunteers, and analysis of SCFAs was carried out by a high‐performance liquid chromatography system. Results The amount of acetic acid in the healthy group was 67.88 ± 23.09 μmol/g, while in the group of patients with COVID‐19 was 37.04 ± 13.29 μmol/g. Therefore, the concentration of acetic acid in the patient group was significantly ( p < 0.001) lower than in the healthy group. Propionic and butyric acid were present in a higher amount in the control group compared with the case group; however, this value was not statistically significant ( p > 0.05). Conclusion This study showed that the concentration of acetic acid as the metabolite caused by gut microbiota is significantly disturbed in patients with COVID‐19. Therefore, therapeutic interventions based on gut microbiota metabolites in future research may be effective against COVID‐19.

Rhinovirus

Coronavirus

10.1002/hsr2.1411

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Citations (4)

Preptin and Myostatin Independently Increase in Pre-Diabetics and Patients of Type 2 Diabetes Mellitus

ACTA MEDICA IRANICA (2019)

Saeed Nazari Soltan Ahmad Sajjad Nourollahi Manouchehr Nakhjavani Mehran Khojastehfard Mostafa Mostafazadeh

Abstract- The relation between serum preptin, myostatin, insulin, and also homeostatic model assessmentinsulin resistance were examined in pre-diabetes persons and newly diagnosed patients with overt type 2 diabetes mellitus. A total of 84 subjects were included in the study and assigned into three groups: normoglycemic participants (group 1=27), pre-diabetes (group 2=30), and T2DM (group 3=29). Serum insulin, preptin, and myostatin levels were measured with immunoradiometric assay (IRMA), enzyme-linked immunosorbent assay (ELISA), and chemiluminescent immunoassay (CLIA), respectively. Patients with T2DM had higher levels of preptin compared to normoglycemic (461.25±53.90 vs. 407.54±54.78, P<0.001). Furthermore, these patients had elevated levels of myostatin compared with controls (2710.60±559.09 vs. 2246.37±416.40, P<0.001). Preptin and myostatin both positively correlated with serum insulin (r=0.369, P=0.01, and r=0.309, P=0.04, respectively). However, no significant association was found between serum preptin and myostatin levels. Stepwise multiple regression analysis showed that insulin was affected more by preptin, with only a trivial contribution from myostatin. Serum preptin and myostatin levels increase in prediabetic subjects and even further in type 2 diabetic patients. The correlation between preptin and insulin evolves when pre-diabetes or overt type 2 diabetes develops. Moreover, serum myostatin increases in association with insulin and not HOMA-IR in diabetic conditions.

Myostatin

10.18502/acta.v57i3.1818

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Citations (2)