Effects of Rosmarinic Acid on Methotrexate-induced Nephrotoxicity and Hepatotoxicity in Wistar Rats.

INTRODUCTION: Methotrexate (MTX), used in the treatment of cancerous patients, causes toxicity in the different organs of the body. This study of rosmarinic acid (RA) is as an antioxidant on nephrotoxicity and hepatotoxicity induced by MTX. METHODS: Rats (n = 32) were divided into four groups: sham; MTX; 100 mg\kg RA + MTX; 200 mg/kg RA + MTX. The amount of MTX was 20 mg/kg. 24 hours after injection of the last dose of MTX, the blood samples and kidneys and liver of rats were studied. The aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), urea, serum creatinine were assessed. Tissue antioxidant enzymes and malondialdehyde (MDA) levels were measured. The liver and kidney tissues were histopathologically examined. RESULTS: MTX significantly increased the urea, creatinine, ALT, AST, ALP levels, and renal MDA and significantly decreased renal catalase (CAT), hepatic glutathione (GSH), and hepatic CAT activity. MTX induced necrosis, leukocyte infiltration, eosinophilic casts, glomerular damage in kidney tissue and necrosis, degeneration and cellular vacuolization in liver tissues. RA at 100 mg/kg caused a significant decrease in ALT and AST and at two doses significantly decreased urea, renal MDA, and liver MDA. RA at 200 mg/kg significantly increased the renal CAT and liver GSH. RA in two doses significantly decreased necrosis and Leukocyte infiltration. RA caused a significant decrease in degeneration and cellular vacuolization in liver tissues. CONCLUSIONS: RA with its antioxidant and anti-inflammatory characteristics decreased the MTX induced nephrotoxicity and hepatotoxicity.

Lung cancer cells and their sensitivity/resistance to cisplatin chemotherapy: Role of microRNAs and upstream mediators.

Cisplatin (CP) is a well-known chemotherapeutic agent with excellent clinical effects. The anti-tumor activity of CP has been demonstrated in different cancers such as breast, cervical, reproductive, lung, brain, and prostate cancers. However, resistance of cancer cells to CP chemotherapy has led to its failure in eradication of cancer cells, and subsequent death of patients with cancer. Fortunately, much effort has been put to identify molecular pathways and mechanisms involved in CP resistance/sensitivity. It seems that microRNAs (miRs) are promising candidates in mediating CP resistance/sensitivity, since they participate in different biological aspects of cells such as proliferation, migration, angiogenesis, and differentiation. In this review, we focus on miRs and their regulation in CP chemotherapy of lung cancer, as the most malignant tumor worldwide. Oncogenic miRs trigger CP resistance in lung cancer cells via targeting various pathways such as Wnt/ß-catenin, Rab6, CASP2, PTEN, and Apaf-1. In contrast, onco-suppressor miRs inhibit oncogene pathways such as STAT3 to suppress CP resistance. These topics are discussed to determine the role of miRs in CP resistance/sensitivity. We also describe the upstream modulators of miRs such as lncRNAs, circRNAs, NF-κB, SOX2 and TRIM65 and their association with CP resistance/sensitivity in lung cancer cells. Finally, the effect of anti-tumor plant-derived natural compounds on miR expression during CP sensitivity of lung cancer cells is discussed.

C-Myc Signaling Pathway in Treatment and Prevention of Brain Tumors.

Brain tumors are responsible for high morbidity and mortality worldwide. Several factors such as the presence of blood-brain barrier (BBB), sensitive location in the brain, and unique biological features challenge the treatment of brain tumors. The conventional drugs are no longer effective in the treatment of brain tumors, and scientists are trying to find novel therapeutics for brain tumors. In this way, identification of molecular pathways can facilitate finding an effective treatment. c-Myc is an oncogene signaling pathway capable of regulation of biological processes such as apoptotic cell death, proliferation, survival, differentiation, and so on. These pleiotropic effects of c-Myc have resulted in much fascination with its role in different cancers, particularly brain tumors. In the present review, we aim to demonstrate the upstream and down-stream mediators of c-Myc in brain tumors such as glioma, glioblastoma, astrocytoma, and medulloblastoma. The capacity of c-Myc as a prognostic factor in brain tumors will be investigated. Our goal is to define an axis in which the c-Myc signaling pathway plays a crucial role and to provide direction for therapeutic targeting in these signaling networks in brain tumors.

Toward Regulatory Effects of Curcumin on Transforming Growth Factor-Beta Across Different Diseases: A Review.

Immune response, proliferation, migration and angiogenesis are juts a few of cellular events that are regulated by transforming growth factor-ß (TGF-ß) in cells. A number of studies have documented that TGF-ß undergoes abnormal expression in different diseases, e.g., diabetes, cancer, fibrosis, asthma, arthritis, among others. This has led to great fascination into this signaling pathway and developing agents with modulatory impact on TGF-ß. Curcumin, a natural-based compound, is obtained from rhizome and roots of turmeric plant. It has a number of pharmacological activities including antioxidant, anti-inflammatory, anti-tumor, anti-diabetes and so on. Noteworthy, it has been demonstrated that curcumin affects different molecular signaling pathways such as Wnt/ß-catenin, Nrf2, AMPK, mitogen-activated protein kinase and so on. In the present review, we evaluate the potential of curcumin in regulation of TGF-ß signaling pathway to corelate it with therapeutic impacts of curcumin. By modulation of TGF-ß (both upregulation and down-regulation), curcumin ameliorates fibrosis, neurological disorders, liver disease, diabetes and asthma. Besides, curcumin targets TGF-ß signaling pathway which is capable of suppressing proliferation of tumor cells and invading cancer cells.

Broad-Spectrum Preclinical Antitumor Activity of Chrysin: Current Trends and Future Perspectives.

Pharmacological profile of phytochemicals has attracted much attention to their use in disease therapy. Since cancer is a major problem for public health with high mortality and morbidity worldwide, experiments have focused on revealing the anti-tumor activity of natural products. Flavonoids comprise a large family of natural products with different categories. Chrysin is a hydroxylated flavonoid belonging to the flavone category. Chrysin has demonstrated great potential in treating different disorders, due to possessing biological and therapeutic activities, such as antioxidant, anti-inflammatory, hepatoprotective, neuroprotective, etc. Over recent years, the anti-tumor activity of chrysin has been investigated, and in the present review, we provide a mechanistic discussion of the inhibitory effect of chrysin on proliferation and invasion of different cancer cells. Molecular pathways, such as Notch1, microRNAs, signal transducer and activator of transcription 3 (STAT3), nuclear factor-kappaB (NF-κB), PI3K/Akt, MAPK, etc., as targets of chrysin are discussed. The efficiency of chrysin in promoting anti-tumor activity of chemotherapeutic agents and suppressing drug resistance is described. Moreover, poor bioavailability, as one of the drawbacks of chrysin, is improved using various nanocarriers, such as micelles, polymeric nanoparticles, etc. This updated review will provide a direction for further studies in evaluating the anti-tumor activity of chrysin.

A review of medications used to control and improve the signs and symptoms of COVID-19 patients.

In December 2019, an unprecedented outbreak of pneumonia associated with a novel coronavirus disease 2019 (COVID-19) emerged in Wuhan City, Hubei province, China. The virus that caused the disease was officially named by the World Health Organization (WHO) as the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). According to the high transmission rate of SARS-CoV-2, it became a global pandemic and public health emergency within few months. Since SARS-CoV-2 is genetically 80% homologous with the SARS-CoVs family, it is hypothesized that medications developed for the treatment of SARS-CoVs may be useful in the control and management of SARS-CoV-2. In this regard, some medication being tested in clinical trials and in vitro studies include anti-viral RNA polymerase inhibitors, HIV-protease inhibitors, anti-inflammatory agents, angiotensin converting enzyme type 2 (ACE 2) blockers, and some other novel medications. In this communication, we reviewed the general characteristics of medications, medical usage, mechanism of action, as well as SARS-CoV-2 related trials.

Cancer and SOX proteins: New insight into their role in ovarian cancer progression/inhibition.

Transcription factors are potential targets in disease therapy, particularly in cancer. This is due to the fact that transcription factors regulate a variety of cellular events, and their modulation has opened a new window in cancer therapy. Sex-determining region Y (SRY)-related high-mobility group (HMG) box (SOX) proteins are potential transcription factors that are involved in developmental processes such as embryogenesis. It has been reported that abnormal expression of SOX proteins is associated with development of different cancers, particularly ovarian cancer (OC). In the present review, our aim is to provide a mechanistic review of involvement of SOX members in OC. SOX members may suppress and/or promote aggressiveness and proliferation of OC cells. Clinical studies have also confirmed the potential of transcription factors as diagnostic and prognostic factors in OC. Notably, studies have demonstrated the relationship between SOX members and other molecular pathways such as ST6Ga1-I, PI3K, ERK and so on, leading to more complexity. Furthermore, SOX members can be affected by upstream mediators such as microRNAs, long non-coding RNAs, and so on. It is worth mentioning that the expression of each member of SOX proteins is corelated with different stages of OC. Furthermore, their expression determines the response of OC cells to chemotherapy. These topics are discussed in this review to shed some light on role of SOX transcription factors in OC.

PTEN, a Barrier for Proliferation and Metastasis of Gastric Cancer Cells: From Molecular Pathways to Targeting and Regulation.

Cancer is one of the life-threatening disorders that, in spite of excellent advances in medicine and technology, there is no effective cure for. Surgery, chemotherapy, and radiotherapy are extensively applied in cancer therapy, but their efficacy in eradication of cancer cells, suppressing metastasis, and improving overall survival of patients is low. This is due to uncontrolled proliferation of cancer cells and their high migratory ability. Finding molecular pathways involved in malignant behavior of cancer cells can pave the road to effective cancer therapy. In the present review, we focus on phosphatase and tensin homolog (PTEN) signaling as a tumor-suppressor molecular pathway in gastric cancer (GC). PTEN inhibits the PI3K/Akt pathway from interfering with the migration and growth of GC cells. Its activation leads to better survival of patients with GC. Different upstream mediators of PTEN in GC have been identified that can regulate PTEN in suppressing growth and invasion of GC cells, such as microRNAs, long non-coding RNAs, and circular RNAs. It seems that antitumor agents enhance the expression of PTEN in overcoming GC. This review focuses on aforementioned topics to provide a new insight into involvement of PTEN and its downstream and upstream mediators in GC. This will direct further studies for evaluation of novel signaling networks and their targeting for suppressing GC progression.

MicroRNAs and Their Influence on the ZEB Family: Mechanistic Aspects and Therapeutic Applications in Cancer Therapy.

Molecular signaling pathways involved in cancer have been intensively studied due to their crucial role in cancer cell growth and dissemination. Among them, zinc finger E-box binding homeobox-1 (ZEB1) and -2 (ZEB2) are molecules that play vital roles in signaling pathways to ensure the survival of tumor cells, particularly through enhancing cell proliferation, promoting cell migration and invasion, and triggering drug resistance. Importantly, ZEB proteins are regulated by microRNAs (miRs). In this review, we demonstrate the impact that miRs have on cancer therapy, through their targeting of ZEB proteins. MiRs are able to act as onco-suppressor factors and inhibit the malignancy of tumor cells through ZEB1/2 down-regulation. This can lead to an inhibition of epithelial-mesenchymal transition (EMT) mechanism, therefore reducing metastasis. Additionally, miRs are able to inhibit ZEB1/2-mediated drug resistance and immunosuppression. Additionally, we explore the upstream modulators of miRs such as long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs), as these regulators can influence the inhibitory effect of miRs on ZEB proteins and cancer progression.

Curcumin in cancer therapy: A novel adjunct for combination chemotherapy with paclitaxel and alleviation of its adverse effects.

Dealing with cancer is of importance due to enhanced incidence rate of this life-threatening disorder. Chemotherapy is an ideal candidate in overcoming and eradication of cancer. To date, various chemotherapeutic agents have been applied in cancer therapy and paclitaxel (PTX) is one of them. PTX is a key member of taxane family with potential anti-tumor activity against different cancers. Notably, PTX has demonstrated excellent proficiency in elimination of cancer in clinical trials. This chemotherapeutic agent is isolated from Taxus brevifolia, and is a tricyclic diterpenoid. However, resistance of cancer cells into PTX chemotherapy has endangered its efficacy. Besides, administration of PTX is associated with a number of side effects such as neurotoxicity, hepatotoxicity, cardiotoxicity and so on, demanding novel strategies in obviating PTX issues. Curcumin is a pharmacological compound with diverse therapeutic effects including anti-tumor, anti-oxidant, anti-inflammatory, anti-diabetic and so on. In the current review, we demonstrate that curcumin, a naturally occurring nutraceutical compound is able to enhance anti-tumor activity of PTX against different cancers. Besides, curcumin administration reduces adverse effects of PTX due to its excellent pharmacological activities. These topics are discussed with an emphasis on molecular pathways to provide direction for further studies in revealing other signaling networks.

PD-1/PD-L1 axis regulation in cancer therapy: The role of long non-coding RNAs and microRNAs.

Cancer immunotherapy is a growing field nowadays. Among different molecular pathways, PD-1/PD-L1 signaling pathway plays a significant role in the regulation of immune responses. It has been reported that stimulation of PD-1/PD-L1 axis is correlated with T cell exhaustion, T cell apoptosis, and their reduced capability in proliferation. PD-1/PD-L1 axis provides a condition for immune evasion of cancer cells and interferes with anti-tumor immunity. Much attention has been directed towards targeting PD-1/PD-L1 axis in cancer immunotherapy. It seems that identification of upstream modulators of this axis can broaden our understanding to develop novel anti-tumor drugs for cancer immunotherapy. MicroRNAs (miRs) and long non-coding RNAs (lncRNAs) are key subcategories of non-coding RNAs, since they can regulate various biological processes by targeting different molecular pathways. In this review, we demonstrate that onco-suppressor miRs and lncRNAs inhibit PD-1/PD-L1 axis to provide anti-tumor immunity and in this way, other molecular pathways such as STAT, ZEB, PI3K/Akt and so on may be targeted. In contrast, oncogene miRs and lncRNAs induce PD-1/PD-L1 axis. Identification of miR/PD-1 and lncRNA/PD-1 signaling pathways can help us in finding an effective drug for cancer immunotherapy, and can direct us towards genetic manipulation of the aforementioned pathways.

Nobiletin in Cancer Therapy: How This Plant Derived-Natural Compound Targets Various Oncogene and Onco-Suppressor Pathways.

Cancer therapy is a growing field, and annually, a high number of research is performed to develop novel antitumor drugs. Attempts to find new antitumor drugs continue, since cancer cells are able to acquire resistance to conventional drugs. Natural chemicals can be considered as promising candidates in the field of cancer therapy due to their multiple-targeting capability. The nobiletin (NOB) is a ubiquitous flavone isolated from Citrus fruits. The NOB has a variety of pharmacological activities, such as antidiabetes, antioxidant, anti-inflammatory, hepatoprotective, and neuroprotective. Among them, the antitumor activity of NOB has been under attention over recent years. In this review, we comprehensively describe the efficacy of NOB in cancer therapy. NOB induces apoptosis and cell cycle arrest in cancer cells. It can suppress migration and invasion of cancer cells via the inhibition of epithelial-to-mesenchymal transition (EMT) and EMT-related factors such as TGF-ß, ZEB, Slug, and Snail. Besides, NOB inhibits oncogene factors such as STAT3, NF-κB, Akt, PI3K, Wnt, and so on. Noteworthy, onco-suppressor factors such as microRNA-7 and -200b undergo upregulation by NOB in cancer therapy. These onco-suppressor and oncogene pathways and mechanisms are discussed in this review.