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Öğe Advances in understanding the role of P-gp in doxorubicin resistance: molecular pathways, therapeutic strategies, and prospects(Elsevier, 2022) Mirzaei, Sepideh; Gholami, Mohammad Hossein; Hashemi, Farid; Zabolian, Amirhossein; Zarrabi, AliP-glycoprotein (P-gp) is a drug efflux transporter that triggers doxorubicin (DOX) resistance. In this review, we highlight the molecular avenues regulating P-gp, such as Nrf2, HIF-1?, miRNAs, and long noncoding (lnc)RNAs, to reveal their participation in DOX resistance. These antitumor compounds and genetic tools synergistically reduce P-gp expression. Furthermore, ATP depletion impairs P-gp activity to enhance the antitumor activity of DOX. Nanoarchitectures, including liposomes, micelles, polymeric nanoparticles (NPs), and solid lipid nanocarriers, have been developed for the co-delivery of DOX with anticancer compounds and genes enhancing DOX cytotoxicity. Surface modification of nanocarriers, for instance with hyaluronic acid (HA), can promote selectivity toward cancer cells. We discuss these aspects with a focus on P-gp expression and activity. © 2021 The Author(s)Öğe Cervical cancer progression is regulated by SOX transcription factors: Revealing signaling networks and therapeutic strategies(Elsevier Science, 2021) Paskeh, Mahshid Deldar Abad; Mirzaei, Sepideh; Gholami, Mohammad Hossein; Zarrabi, Ali; Zabolian, Amirhossein; Hashemi, Mehrdad; Hushmandi, KiavashCervical cancer is the fourth common gynecologic cancer and is considered as second leading cause of death among women. Various strategies are applied in treatment of cervical cancer including radiotherapy, chemotherapy and surgery. However, cervical cancer cells demonstrate aggressive behavior in advanced phases, requiring novel strategies in their elimination. On the other hand, SOX proteins are transcription factors capable of regulating different molecular pathways and their expression varies during embryogenesis, disease development and carcinogenesis. In the present review, our aim is to reveal role of SOX transcription factors in cervical cancer. SOX transcription factors play like a double-edged sword in cancer. For instance, SOX9 possesses both tumor-suppressor and tumor-promoting role in cervical cancer. Therefore, exact role of each SOX members in cervical cancer has been discussed to direct further experiments for revealing other functions. SOX proteins can regulate proliferation and metastasis of cervical cancer cells. Furthermore, response of cervical cancer cells to chemotherapy and radiotherapy is tightly regulated by SOX transcription factors. Different downstream targets of SOX proteins such as Wnt signaling, EMT and Hedgehog have been identified. Besides, upstream mediators such as microRNAs, lncRNAs and circRNAs can regulate SOX expression in cervical cancer. In addition to pre-clinical studies, role of SOX transcription factors as prognostic and diagnostic tools in cervical cancer has been shown.Öğe Correction: The long and short non-coding RNAs modulating EZH2 signaling in cancer (Journal of Hematology & Oncology, (2022), 15, 1, (18), 10.1186/s13045-022-01235-1)(BioMed Central Ltd, 2022) Mirzaei, Sepideh; Gholami, Mohammad Hossein; Hushmandi, Kiavash; Hashemi, Farid; Zabolian, Amirhossein; Canadas, Israel; Zarrabi, Ali; Nabavi, Noushin; Aref, Amir Reza; Crea, Francesco; Wang, Yuzhuo; Ashrafizadeh, Milad; Kumar, Alan PremThe original article [1] contained an error in co-author, Farid Hashemi’s name which has since been corrected. © 2022, The Author(s).Öğe Exosome-mediated miR-200a delivery into TGF-?-treated AGS cells abolished epithelial-mesenchymal transition with normalization of ZEB1, vimentin and Snail1 expression(Academic Press Inc Elsevier Science, 2023) Mirzaei, Sepideh; Gholami, Mohammad Hossein; Aghdaei, Hamid Asadzadeh; Hashemi, Mehrdad; Parivar, Kazem; Karamian, Amin; Zarrabi, AliExosomes are small extracellular vesicles that can be derived from human cells such as mesenchymal stem cells (MSCs). The size of exosomes is at nano-scale range and owing to their biocompatibility and other characteristics, they have been promising candidates for delivery of bioactive compounds and genetic materials in disease therapy, especially cancer therapy. Gastric cancer (GC) is a leading cause of death among patients and this malignant disease affects gastrointestinal tract that its invasiveness and abnormal migration mediate poor prognosis of patients. Metastasis is an increasing challenge in GC and microRNAs (miRNAs) are potential reg-ulators of metastasis and related molecular pathways, especially epithelial-to-mesenchymal transition (EMT). In the present study, our aim was to explore role of exosomes in miR-200a delivery for suppressing EMT-mediated GC metastasis. Exosomes were isolated from MSCs via size exclusion chromatography. The synthetic miR-200a mimics were transfected into exosomes via electroporation. AGS cell line exposed to TGF-beta for EMT induction and then, these cells cultured with miR-200a-loaded exosomes. The transwell assays performed to evaluate GC migration and expression levels of ZEB1, Snail1 and vimentin measured. Exosomes demonstrated loading effi-ciency of 5.92 +/- 4.6%. The TGF-beta treatment transformed AGS cells into fibroblast-like cells expressing two stemness markers, CD44 (45.28%) and CD133 (50.79%) and stimulated EMT. Exosomes induced a 14.89-fold increase in miR-200a expression in AGS cells. Mechanistically, miR-200a enhances E-cadherin levels (P < 0.01), while it decreases expression levels of beta-catenin (P < 0.05), vimentin (P < 0.01), ZEB1 (P < 0.0001) and Snail1 (P < 0.01), leading to EMT inhibition in GC cells. This pre-clinical experiment introduces a new strategy for miR-200a delivery that is of importance for preventing migration and invasion of GC cells.Öğe EZH2 as a new therapeutic target in brain tumors: Molecular landscape, therapeutic targeting and future prospects(Elsevier, 2022) Paskeh, Mahshid Deldar Abad; Mehrabi, Atefeh; Gholami, Mohammad Hossein; Zabolian, Amirhossein; Ranjbar, Ehsan; Zarrabi, AliBrain tumors are responsible for high mortality and morbidity worldwide. The brain tumor treatment depends on identification of molecular pathways involved in progression and malignancy. Enhancer of zeste homolog 2 (EZH2) has obtained much attention in recent years in field of cancer therapy due to its aberrant expression and capacity in modulating expression of genes by binding to their promoter and affecting methylation status. The present review focuses on EZH2 signaling in brain tumors including glioma, glioblastoma, astrocytoma, ependymomas, medulloblastoma and brain rhabdoid tumors. EZH2 signaling mainly participates in increasing proliferation and invasion of cancer cells. However, in medulloblastoma, EZH2 demonstrates tumor-suppressor activity. Furthermore, EZH2 can regulate response of brain tumors to chemotherapy and radiotherapy. Various molecular pathways can function as upstream mediators of EZH2 in brain tumors including lncRNAs and miRNAs. Owing to its enzymatic activity, EZH2 can bind to promoter of target genes to induce methylation and affects their expression. EZH2 can be considered as an independent prognostic factor in brain tumors that its upregulation provides undesirable prognosis. Both anti-tumor agents and gene therapies such as siRNA have been developed for targeting EZH2 in cancer therapy.Öğe The long and short non-coding RNAs modulating EZH2 signaling in cancer(2022) Mirzaei, Sepideh; Gholami, Mohammad Hossein; Hushmandi, Kiavash; Hshemi, Farid; Zabolian, Amirhossein; Canadas, Israel; Zarrabi, Ali; Nabavi, Noushin; Aref, Amir Reza; Crea, Francesco; Wang, Yuzhuo; Ashrafizadeh, Milad; Kumar, Alan PremNon-coding RNAs (ncRNAs) are a large family of RNA molecules with no capability in encoding proteins. However, they participate in developmental and biological processes and their abnormal expression affects cancer progression. These RNA molecules can function as upstream mediators of different signaling pathways and enhancer of zeste homolog 2 (EZH2) is among them. Briefly, EZH2 belongs to PRCs family and can exert functional roles in cells due to its methyltransferase activity. EZH2 affects gene expression via inducing H3K27me3. In the present review, our aim is to provide a mechanistic discussion of ncRNAs role in regulating EZH2 expression in different cancers. MiRNAs can dually induce/inhibit EZH2 in cancer cells to affect downstream targets such as Wnt, STAT3 and EMT. Furthermore, miRNAs can regulate therapy response of cancer cells via affecting EZH2 signaling. It is noteworthy that EZH2 can reduce miRNA expression by binding to promoter and exerting its methyltransferase activity. Small-interfering RNA (siRNA) and short-hairpin RNA (shRNA) are synthetic, short ncRNAs capable of reducing EZH2 expression and suppressing cancer progression. LncRNAs mainly regulate EZH2 expression via targeting miRNAs. Furthermore, lncRNAs induce EZH2 by modulating miRNA expression. Circular RNAs (CircRNAs), like lncRNAs, affect EZH2 expression via targeting miRNAs. These areas are discussed in the present review with a focus on molecular pathways leading to clinical translation.Öğe Molecular landscape of LncRNAs in prostate cancer: A focus on pathways and therapeutic targets for intervention(PMC, 2022) Mirzaei, Sepideh; Abad Paskeh, Mahshid Deldar; Okina, Elena; Gholami, Mohammad Hossein; Hushmandi, Kiavash; Hashemi, Mehrdad; Kalu , Azuma; Zarrabi, Ali; Nabav, Noushin; Rabiee, Navid; Sharifi, Esmaeel; Karimi-Maleh, Hassan; Ashrafizadeh, Milad; Kumar, Alan Prem; Wang, YuzhuoBackground: One of the most malignant tumors in men is prostate cancer that is still incurable due to its heterog? enous and progressive natures. Genetic and epigenetic changes play signifcant roles in its development. The RNA molecules with more than 200 nucleotides in length are known as lncRNAs and these epigenetic factors do not encode protein. They regulate gene expression at transcriptional, post-transcriptional and epigenetic levels. LncRNAs play vital biological functions in cells and in pathological events, hence their expression undergoes dysregulation. Aim of review: The role of epigenetic alterations in prostate cancer development are emphasized here. Therefore, lncRNAs were chosen for this purpose and their expression level and interaction with other signaling networks in prostate cancer progression were examined. Key scientifc concepts of review: The aberrant expression of lncRNAs in prostate cancer has been well-docu? mented and progression rate of tumor cells are regulated via afecting STAT3, NF-?B, Wnt, PI3K/Akt and PTEN, among other molecular pathways. Furthermore, lncRNAs regulate radio-resistance and chemo-resistance features of prostate tumor cells. Overexpression of tumor-promoting lncRNAs such as HOXD-AS1 and CCAT1 can result in drug resistance. Besides, lncRNAs can induce immune evasion of prostate cancer via upregulating PD-1. Pharmacological compounds such as quercetin and curcumin have been applied for targeting lncRNAs. Furthermore, siRNA tool can reduce expression of lncRNAs thereby suppressing prostate cancer progression. Prognosis and diagnosis of prostate tumor at clinical course can be evaluated by lncRNAs. The expression level of exosomal lncRNAs such as lncRNA-p21 can be investigated in serum of prostate cancer patients as a reliable biomarkerÖğe Resveratrol Augments Doxorubicin and Cisplatin Chemotherapy: A Novel Therapeutic Strategy(Bentham Science Publ Ltd, 2023) Mirzaei, Sepideh; Gholami, Mohammad Hossein; Zabolian, Amirhossein; Saleki, Hossein; Bagherian, Morteza; Torabi, Seyed Mohammadreza; Sharifzadeh, Seyed OmidBackground The treatment of cancer is a current challenge for public health, causing high rates of morbidity and mortality worldwide. Doxorubicin (DOX) and cisplatin (CP) are two well-known chemotherapeutic agents approved by the Food and Drug Administration to treat cancer patients. However, there are two problems associated with DOX and CP: drug resistance and adverse impact. Resveratrol (Res) belongs to the stilbene class and possesses various health-promoting effects, such as antioxidant, anti-inflammatory, anticancer, hepatoprotective, and neuroprotective effects. Objective The present review aims to give special attention to the therapeutic impacts of Res in potentiating DOX and CP's antitumor activities and reducing their side effects. Methods PubMed, Science Direct, and Google Scholar were used to search articles for the current manuscripts. Results Co-administration of Res can prevent chemoresistance and potentiate the induction of apoptosis and cell cycle arrest in cancer cells. Res can enhance the sensitivity of cancer cells to DOX and CP chemotherapy by inhibiting the migration and metastasis of cancer cells. Simultaneously, Res, due to its therapeutic actions ameliorates the adverse impacts of DOX and CP on normal cells and organs, including the liver, kidney, brain, and testes. As Res suffers from poor bioavailability, nanoformulations have been developed with promising results to improve its antitumor activity and protective effects. Conclusion Based on preclinical studies, it is obvious that Res is a promising adjsuvant for CP and DOX chemotherapy, and its benefits can be utilized in the clinical course.