Curcumin and its derivatives in cancer therapy: Potentiating antitumor activity of cisplatin and reducing side effects.

Curcumin is a phytochemical isolated from Curcuma longa with potent tumor-suppressor activity, which has shown significant efficacy in pre-clinical and clinical studies. Curcumin stimulates cell death, triggers cycle arrest, and suppresses oncogenic pathways, thereby suppressing cancer progression. Cisplatin (CP) stimulates DNA damage and apoptosis in cancer chemotherapy. However, CP has adverse effects on several organs of the body, and drug resistance is frequently observed. The purpose of the present review is to show the function of curcumin in decreasing CP's adverse impacts and improving its antitumor activity. Curcumin administration reduces ROS levels to prevent apoptosis in normal cells. Furthermore, curcumin can inhibit inflammation via down-regulation of NF-κB to maintain the normal function of organs. Curcumin and its nanoformulations can reduce the hepatoxicity, neurotoxicity, renal toxicity, ototoxicity, and cardiotoxicity caused by CP. Notably, curcumin potentiates CP cytotoxicity via mediating cell death and cycle arrest. Besides, curcumin suppresses the STAT3 and NF-ĸB as tumor-promoting pathways, to enhance CP sensitivity and prevent drug resistance. The targeted delivery of curcumin and CP to tumor cells can be mediated nanostructures. In addition, curcumin derivatives are also able to reduce CP-mediated side effects, and increase CP cytotoxicity against various cancer types.

Expression of selected long non-coding RNAs in gastric cancer cells treated with coumarin: Possible mechanisms for anti-cancer activity.

Long non-coding RNAs (lncRNAs) can be utilized as prognostic indicators of gastric cancer since they can affect several cancer-related processes. Coumarin is a natural product with some useful anti-cancer properties. Here, we measured the expression of selected lncRNAs (RuPAR, SNHG6, CASC11, and their targets, miR-340-5p, p21, E-cadherin, and CDK1) in AGS gastric cancer cells treated with coumarin. MTT test has been utilized for assessing the AGS cells' cell viability after exposure to coumarin. The expression of the lncRNAs (RuPAR, SNHG6, and CASC11) and miR-340-5p was evaluated via qRT-PCR. Western blot analysis has been utilized to determine changes in p21, E-cadherin, and CDK1 expression. Coumarin decreased AGS viability in a dose-dependent manner. The coumarin treated cells had lower levels of the mRNAs known to be targets of lncRNAs SNHG6 and CASC11 compared to control. Additionally, the coumarin group had increased levels of lncRNA RuPAR expression when compared with the control group. Some lncRNA targets, including p21, E-cadherin, and CDK1, showed lower expression in the coumarin group compared to the control by Western blotting. Coumarin could be a promising pharmacological candidate to be included in gastric cancer treatment regimens because it modulates lncRNAs and their targets.

Emerging insights into keratin 7 roles in tumor progression and metastasis of cancers.

Keratin 7 (KRT7), also known as cytokeratin-7 (CK-7) or K7, constitutes the principal constituent of the intermediate filament cytoskeleton and is primarily expressed in the simple epithelia lining the cavities of the internal organs, glandular ducts, and blood vessels. Various pathological conditions, including cancer, have been linked to the abnormal expression of KRT7. KRT7 overexpression promotes tumor progression and metastasis in different human cancers, although the mechanisms of these processes caused by KRT7 have yet to be established. Studies have indicated that the suppression of KRT7 leads to rapid regression of tumors, highlighting the potential of KRT7 as a novel candidate for therapeutic interventions. This review aims to delineate the various roles played by KRT7 in the progression and metastasis of different human malignancies and to investigate its prognostic significance in cancer treatment. Finally, the differential diagnosis of cancers based on the KRT7 is emphasized.

Overcoming doxorubicin resistance in cancer: siRNA-loaded nanoarchitectures for cancer gene therapy.

Gene therapy can be used as a cancer therapy by affecting signaling networks participating in the aggressive behavior of tumors. Small interfering RNA (siRNA) is a genetic tool employed for gene silencing. The siRNA molecules have a length of 21-22 nucleotides, and are synthetic, short non-coding RNAs. The siRNA molecule should be loaded into the RISC complex to carry out its function to degrade mRNA and reduce protein expression. By targeting oncogenic pathways, siRNA can also promote chemosensitivity and reduce resistance. Doxorubicin (DOX) is an anthracycline family member capable of triggering cell cycle arrest via binding to topoisomerase II and inhibiting DNA replication. The present review focuses on the design of siRNA for increasing DOX sensitivity and overcoming resistance. Molecular pathways such as STAT3, Notch1, Mcl-1 and Nrf2 can be down-regulated by siRNA to promote DOX sensitivity. Furthermore, siRNA can be used to suppress the activity of P-glycoprotein as a cell membrane transporter of drugs, leading to enhanced accumulation of DOX. The co-delivery of DOX and siRNA both incorporated into nanoparticles can increase the intracellular accumulation in cancer cells, and protect siRNA against degradation by enzymes. Furthermore, the circulation time of DOX is lengthened to boost cytotoxicity against cancer cells. The surface modification of nanocarriers with ligands such as RGD or folate increases their selectivity towards cancer cells. Moreover, smart nanostructures, including pH-, redox- and light-responsive are optimized for siRNA and DOX delivery and tumor treatment.

Quercetin improved histological structure and upregulated adiponectin and adiponectin receptors in the placenta of rats with gestational diabetes mellitus.

INTRODUCTION: Gestational diabetes mellitus (GDM) is a metabolic syndrome among pregnant mothers that increases the risk of developing growth disorders in the fetus and the placenta. Adiponectin is an adipokine, which plays a central role in the regulation of glucose and lipid metabolism, energy homeostasis, and insulin resistance in various tissues. Quercetin is a natural flavonoid with beneficial effects in the diabetic animal model, but data related to its effect on histological change and adiponectin system in the placenta of GDM are limited. In the current study, some histological changes and expression of adiponectin and its two receptors in the placenta of rats with GDM were investigated. METHODS: This study was carried out on placentas from the rodent model. To induce GDM, female rats were treated with a single dose of STZ. Placenta tissue was harvested and stained by PAS method. Protein and mRNA levels of adiponectin and its two receptors were assessed by immunohistochemistry and Real time PCR analysis, respectively. RESULTS: The results showed the increased number of glycogen cells and thickness of the labyrinth interhemal membrane (LIM) in the embryonic part of the placenta in diabetic rats, while the use of quercetin significantly prevented their increase in diabetic rats. Treatment of the diabetic group with quercetin caused significantly increased adiponectin expression and decreased its receptors.The immunohistochemical study revealed the expression of AdipoR2 in the cytoplasm of syncytiotrophoblast and cytotrophoblast cells. DISCUSSION: The results indicated that quercetin in pregnant diabetic rats could attenuate the histological abnormalities and improved adiponectin system dysregulation in the placenta.

Non-Coding RNAs and Brain Tumors: Insights Into Their Roles in Apoptosis.

A major terrifying ailment afflicting the humans throughout the world is brain tumor, which causes a lot of mortality among pediatric and adult solid tumors. Several major barriers to the treatment and diagnosis of the brain tumors are the specific micro-environmental and cell-intrinsic features of neural tissues. Absence of the nutrients and hypoxia trigger the cells' mortality in the core of the tumors of humans' brains: however, type of the cells' mortality, including apoptosis or necrosis, has been not found obviously. Current studies have emphasized the non-coding RNAs (ncRNAs) since their crucial impacts on carcinogenesis have been discovered. Several investigations suggest the essential contribution of such molecules in the development of brain tumors and the respective roles in apoptosis. Herein, we summarize the apoptosis-related non-coding RNAs in brain tumors.

Artemisia Species as a New Candidate for Diabetes Therapy: A Comprehensive Review.

Diabetes mellitus (DM) is a chronic disease and a threatening problem for world health. Allopathic medications are not efficient enough in controlling DM and its complications. Therefore, much attention has been directed towards the traditional medicine system. Plant derived-natural compounds with medicinal properties play an essential role in DM management and treatment. Artemisia is a varied and widespread genus of the family Asteraceae, which has more than 500 species with beneficial economic and therapeutic significance. Electronic databases such as Science Direct, Scopus, Pubmed, Web of Science, medRixv, and Wiley were used to search scientific literature. In folklore medicine, Artemisia species have been widely utilized for diabetes management. Molecular investigations have revealed that the NF-κB suppression, Notch 1 inhibition, cell cycle stop at S+G2/M-phase, enhanced Bax protein concentrations, mitochondrial membrane potential attenuation, activation of p53 and caspase, Bcl-2 regulation, and ROS formation are crucial mechanisms that could be targeted via various Artemisia species. Anti-diabetic effects of single or multiple doses of alcoholic and aqueous extracts of Artemisia species are due to the presence of bioactive compounds, and they are completely efficient in lowering levels of blood glucose in experimental examinations. In spite of the available anti-diabetic drugs, therapeutic agents obtained from the mentioned plants have been used for the treatment of this disease and its complications with less adverse impacts. Taken together, multiple lines of evidence indicated that Artemisia species could be introduced as a potential therapeutic candidate in the treatment and management of diabetes.

Pre-clinical investigation of STAT3 pathway in bladder cancer: Paving the way for clinical translation.

Effective cancer therapy requires identification of signaling networks and investigating their potential role in proliferation and invasion of cancer cells. Among molecular pathways, signal transducer and activator of transcription 3 (STAT3) has been of importance due to its involvement in promoting proliferation, and invasion of cancer cells, and mediating chemoresistance. In the present review, our aim is to reveal role of STAT3 pathway in bladder cancer (BC), as one of the leading causes of death worldwide. In respect to its tumor-promoting role, STAT3 is able to enhance the growth of BC cells via inhibiting apoptosis and cell cycle arrest. STAT3 also contributes to metastasis of BC cells via upregulating of MMP-2 and MMP-9 as well as genes in the EMT pathway. BC cells obtain chemoresistance via STAT3 overexpression and its inhibition paves the way for increasing efficacy of chemotherapy. Different molecular pathways such as KMT1A, EZH2, DAB2IP and non-coding RNAs including microRNAs and long non-coding RNAs can function as upstream mediators of STAT3 that are discussed in this review article.

Small interfering RNA (siRNA) to target genes and molecular pathways in glioblastoma therapy: Current status with an emphasis on delivery systems.

Glioblastoma multiforme (GBM) is one of the worst brain tumors arising from glial cells, causing many deaths annually. Surgery, chemotherapy, radiotherapy and immunotherapy are used for GBM treatment. However, GBM is still an incurable disease, and new approaches are required for its successful treatment. Because mutations and amplifications occurring in several genes are responsible for the progression and aggressive behavior of GBM cells, genetic approaches are of great importance in its treatment. Small interfering RNA (siRNA) is a new emerging tool to silence the genes responsible for disease progression, particularly cancer. SiRNA can be used for GBM treatment by down-regulating genes such as VEGF, STAT3, ELTD1 or EGFR. Furthermore, the use of siRNA can promote the chemosensitivity of GBM cells. However, the efficiency of siRNA in GBM is limited via its degradation by enzymes, and its off-targeting effects. SiRNA-loaded carriers, especially nanovehicles that are ligand-functionalized by CXCR4 or angiopep-2, can be used for the protection and targeted delivery of siRNA. Nanostructures can provide a platform for co-delivery of siRNA plus anti-tumor drugs as another benefit. The prepared nanovehicles should be stable and biocompatible in order to be tested in human studies.

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.

Effect of Aloe vera on the expression of nerve factors, p75 and TrkA receptors in the hippocampus of diabetic rats / Efecto del Aloe vera sobre la expresión de factores de crecimiento nervioso, Receptores p75 y TrkA en el hipocampo de ratas diabéticas

SUMMARY: Diabetes mellitus can lead to structural disorders in the brain. One of the most common complications of diabetes, diabetic neuropathy is associated with central nervous system disorders. Aloe vera has anti-diabetic, antioxidant, and neuroprotective effects. This study was designed to evaluate the effects of Aloe vera gel on the hippocampus changes as well as the expression of nerve growth factor and receptors TrkA and P75 in the hippocampus of streptozotocin (STZ)-induced diabetic rats. 25 male Wistar rats were randomly divided into 5 groups including: control (normal saline), diabetic (normal saline), Aloe vera gel (400 mg/kg/day; gavage), diabetic + Aloe vera gel (400 mg/kg/day; gavage) and diabetic + insulin NPH (10 IU/kg/day; subcutaneous). Experimental diabetes was induced by streptozotocin injection (60 mg/kg; intraperitoneal). All groups treated for 8 weeks. At the end of treatment course, the rat brains were removed for measuring the expression of nerve growth factor, p75 and TrkA receptors were evaluated in the hippocampus. Diabetes induction after 8 weeks caused NGF and P75 expression levels in the diabetic group than other groups significantly increased (p<0.05). The TrkA receptor expression in the diabetic group compared with the control had a significant reduction (p<0.05). On the other hand in the diabetic group receiving Aloe vera gel expression of NGF and P75 expression levels compared to the diabetic group was significantly reduced (p<0.05) and the TrkA receptor expression compared with the diabetic group had a significant increase (p<0.05). The results showed that oral administration of Aloe vera gel in diabetic rats ameliorates diabetes-induced hyperglycemia. On the other hand, Aloe vera gel cause modulation of the expression of NGF neurotrophic factor via increased expression of TrkA receptor-specific and non-specific receptor down-regulation of P75 in the hippocampus of STZ-induced diabetic rats.

RESUMEN: La diabetes mellitus puede provocar trastornos estructurales en el cerebro. Es una de las complicaciones más comunes de la diabetes y la neuropatía diabética y está relacionada con trastornos del sistema nervioso central. El Aloe vera tiene efectos antidiabéticos, antioxidantes y neuroprotectores. Este estudio fue diseñado para evaluar los efectos del gel de Aloe vera en los cambios del hipocampo, así como la expresión del factor de crecimiento nervioso y los receptores TrkA y P75 en el hipocampo de ratas diabéticas inducidas por estreptozotocina (STZ). Se dividieron al azar 25 ratas Wistar macho en 5 grupos de: control (solución salina normal), diabéticos (solución salina normal), gel de Aloe vera (400 mg / kg / día; sonda), diabéticos + gel de Aloe vera (400 mg / kg / día; sonda) y diabéticos + insulina NPH (10 UI / kg / día; subcutánea). La diabetes experimental fue inducida por inyección de estreptozotocina (60 mg / kg; intraperitoneal). Todos los grupos fueron tratados durante 8 semanas. Al final del tratamiento, se extrajeron los cerebros de las ratas para medir la expresión del factor de crecimiento nervioso y se evaluaron los receptores p75 y TrkA en el hipocampo. La inducción de diabetes después de 8 semanas provocó que los niveles de expresión de NGF y P75 en el grupo de diabéticos aumentaran significativamente en comparación con otros grupos (p <0,05). La expresión del receptor TrkA en el grupo diabético comparado con el control tuvo una reducción significativa (p <0,05). Por otro lado, el grupo de ratas diabéticas que recibieron la expresión en gel de Aloe vera de NGF y los niveles de expresión de P75 en comparación con el grupo de ratas diabéticas se redujo significativamente (p <0,05) y la expresión del receptor de TrkA en comparación con el grupo de ratas diabéticas tuvo un aumento significativo (p <0,05). Los resultados mostraron que la administración oral de gel de Aloe vera en ratas diabéticas mejora la hiperglucemia inducida por la diabetes. Por otro lado, el gel de Aloe vera causa modulación de la expresión del factor neurotrófico NGF a través del aumento de la expresión de receptor TrkA específico y no específico y regulación negativa del receptor de P75 en el hipocampo de ratas diabéticas inducidas por STZ.