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

Introduction: 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). Methods: 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. Results: 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). Conclusion: Vandetanib suppressed vasculogenic mimicry (VM) networking through blunting stemness properties, coincided with suppression of VE-cadherin in CSCs.

Saffron as a promising therapy for diabetes and Alzheimer's disease: mechanistic insights.

The prevalence of both Alzheimer's disease (AD) and diabetes mellitus is increasing with the societies' aging and has become an essential social concern worldwide. Accumulation of amyloid plaques and neurofibrillary tangles (NFTs) of tau proteins in the brain are hallmarks of AD. Diabetes is an underlying risk factor for AD. Insulin resistance has been proposed to be involved in amyloid-beta (Aß) aggregation in the brain. It seems that diabetic conditions can result in AD pathology by setting off a cascade of processes, including inflammation, mitochondrial dysfunction, and ROS and advanced glycation end products (AGEs) synthesis. Due to the several side effects of chemical drugs and their high cost, using herbal medicine has recently attracted attention for the treatment of diabetes and AD. Saffron and its active ingredients have been used for its anti-inflammatory, anti-oxidant, anti-diabetic, and anti-AD properties. Therefore, in the present review paper, we take account of the clinical, in vivo and in vitro evidence regarding the anti-diabetic and anti-AD effects of saffron and discuss the preventive or postponing properties of saffron or its components on AD development via its anti-diabetic effects.

The effects of selenium supplementation on inflammatory markers in critically ill patients.

Abstract: Low serum selenium (Se) levels have been shown in critical illness, which is associated with poor clinical outcomes and a higher mortality rate. Se plays an important role in inflammation and oxidative stress. Since the overproduction of inflammatory cytokines and increased oxidative stress is a major component of critical illnesses, its supplementation has been demonstrated to have promising effects on critically ill patients. This study aims to review the evidence regarding the effects of Se supplementation on inflammatory and oxidative markers in critically ill patients. The literature review highlights alterations of inflammatory markers, including procalcitonin, leukocyte count, albumin, prealbumin, C-reactive protein (CRP), inflammatory cytokines, and cholesterol following Se supplementation in critically ill patients. Besides, the antioxidant properties of Se due to its presence in the structure of several selenoenzymes have been reported. Article highlights: Low serum Se level have been shown in critical illness, which is associated with poor clinical outcome and higher mortality rate.Se plays an important role in inflammation and oxidative stress.Se supplementation can have promising effects by alterations of inflammatory markers and its antioxidant properties for critically ill patients.

Oncostatin M and its receptor in women with polycystic ovary syndrome and association with assisted reproductive technology outcomes.

The role of adipokines in ovarian-related disorders such as polycystic ovary syndrome (PCOS) has been reported. However, the involvement of Oncostatin M (OSM), a recently identified adipokine, in ovarian function is unknown. Therefore, we investigated the association of the OSM signaling pathway with ovarian functions and PCOS pathogenesis. This case-control study enrolled 30 PCOS and 30 healthy women who underwent the intracytoplasmic sperm injection procedure. OSM and OSM receptor (OSMR) levels were evaluated in the follicular fluid (FF). Moreover, the expression of insulin receptor substrates (IRS1 and IRS2), OSM, OSMR, suppressor of cytokine signaling 3 (SOCS3), and androgen receptor (AR) genes were analyzed in the isolated cumulus cells (CCs). For the in-vitro experiment, the effect of recombinant OSM on the expression of related genes in isolated CCs was analyzed. Follicular concentrations of OSM and OSMR were significantly lower in PCOS (123.91±48.58 pg/ml and 0.93±0.35 ng/ml, respectively) compared to control women (283.53 ± 96.62 pg/ml and 1.45 ± 0.18 ng/ml, respectively; p < 0.001) and were positively correlated with the oocyte maturation (r = 0.611 and r = 0.611, respectively) and fertilization (r = 0.592 and r = 0.627, respectively) rates in the PCOS group. Furthermore, the SOCS3 expression was upregulated about eight times in PCOS patients compared to the controls (p < 0.05). The treatment of cells with recombinant OSM significantly increased SOCS3, OSMR, IRS-1, and -2 expression and decreased AR expression. The decreased levels of OSM and its receptor in PCOS patients, possibly mediated by SOCS3, could negatively affect oocyte maturation and fertilization rates.

N1-Methylnicotinamide: Is it Time to Consider it as a Dietary Supplement for Athletes?

Exercise is considered to be a "medicine" due to its modulatory roles in metabolic disorders, such as diabetes and obesity. The intensity and duration of exercise determine the mechanism of energy production by various tissues of the body, especially by muscles, in which the requirement for adenosine triphosphate (ATP) increases by as much as 100-fold. Naturally, athletes try to improve their exercise performance by dietary supplementation with, e.g., vitamins, metabolites, and amino acids. MNAM, as a vitamin B3 metabolite, reduces serum levels and liver contents of triglycerides and cholesterol, and induces lipolysis. It stimulates gluconeogenesis and prohibits liver cholesterol and fatty acid synthesis through the expression of sirtuin1 (SIRT1). It seems that MNAM is not responsible for the actions of NNMT in the adipose tissues as MNAM inhibits the activity of NNMT in the adipose tissue and acts as an inhibitor of its activity.NNMT-MNAM axis is more activated in the muscles of individuals undergoing the high-volume-low-intensity exercise and caloric restriction. Therefore, MNAM could be an important myokine during exercise and fasting where it provides the required energy for muscles through the induction of lipolysis and gluconeogenesis in the liver and adipose tissues, respectively. Increased levels of MNAM in exercise and fasting led us to propose that the consumption of MNAM during training, especially endurance training, could boost exercise capacity and improve performance. Therefore, in this review, we shed light on the potential of MNAM as a dietary supplement in sports medicine.

Role of adipokines in embryo implantation.

Embryo implantation is a complex process in which multiple molecules acting together under strict regulation. Studies showed the production of various adipokines and their receptors in the embryo and uterus, where they can influence the maternal-fetal transmission of metabolites and embryo implantation. Therefore, these cytokines have opened a novel area of study in the field of embryo-maternal crosstalk during early pregnancy. In this respect, the involvement of adipokines has been widely reported in the regulation of both physiological and pathological aspects of the implantation process. However, the information about the role of some recently identified adipokines is limited. This review aims to highlight the role of various adipokines in embryo-maternal interactions, endometrial receptivity, and embryo implantation, as well as the underlying molecular mechanisms.

microRNAs in the pathogenesis of non-obstructive azoospermia: the underlying mechanisms and therapeutic potentials.

miRNAs are involved in different biological processes, including proliferation, differentiation, and apoptosis. Interestingly, 38% of the X chromosome-linked miRNAs are testis-specific and have crucial roles in regulating the renewal and cell cycle of spermatogonial stem cells. Previous studies demonstrated that abnormal expression of spermatogenesis-related miRNAs could lead to nonobstructive azoospermia (NOA). Moreover, differential miRNAs expression in seminal plasma of NOA patients has been reported compared to normozoospermic men. However, the role of miRNAs in NOA pathogenesis and the underlying mechanisms have not been comprehensively studied. Therefore, the aim of this review is to mechanistically describe the role of miRNAs in the pathogenesis of NOA and discuss the possibility of using the miRNAs as therapeutic targets.Abbreviations: AMO: anti-miRNA antisense oligonucleotide; AZF: azoospermia factor region; CDK: cyclin-dependent kinase; DAZ: deleted in azoospermia; ESCs: embryonic stem cells; FSH: follicle-stimulating hormone; ICSI: intracytoplasmic sperm injection; JAK/STAT: Janus kinase/signal transducers and activators of transcription; miRNA: micro-RNA; MLH1: Human mutL homolog l; NF-κB: Nuclear factor-kappa B; NOA: nonobstructive azoospermia; OA: obstructive azoospermia; PGCs: primordial germ cells; PI3K/AKT: Phosphatidylinositol 3-kinase/protein kinase B; Rb: retinoblastoma tumor suppressor; ROS: Reactive Oxygen Species; SCOS: Sertoli cell-only syndrome; SIRT: sirtuin; SNPs: single nucleotide polymorphisms; SSCs: spermatogonial stem cells; TESE: testicular sperm extraction; TGF-ß: transforming growth factor-beta.

Omics in Seminal Plasma: An Effective Strategy for Predicting Sperm Retrieval Outcome in Non-obstructive Azoospermia.

Non-obstructive azoospermia (NOA) is a severe form of male factor infertility resulting from the impairment of sperm production. Surgical sperm retrieval followed by intracytoplasmic sperm injection (ICSI) is the only alternative for NOA patients to have their own genetic children. Nevertheless, due to an approximately 50% chance of success, harvesting sperm from these patients remains challenging. Thus, discovering noninvasive biomarkers, which are able to reliably predict the probability of sperm acquisition, not only can eliminate the risk of surgery but also can lower the costs of NOA diagnosis and treatment. Seminal plasma is the non-cellular and liquid portion of the ejaculate that consists of the secretions originating from testes and male accessory glands. In past years, a wide range of biomolecules including DNAs, RNAs, proteins, and metabolic intermediates have been identified by omics techniques in human seminal plasma. The current review aimed to briefly describe genomic, transcriptomic, proteomic, and metabolomic profiles of human seminal plasma in an attempt to introduce potential candidate noninvasive biomarkers for sperm-retrieval success in men with NOA.

Hormonal markers as noninvasive predictors of sperm retrieval in non-obstructive azoospermia.

Non-obstructive azoospermia (NOA) is one of the leading causes of male factor infertility, which results from impaired spermatogenesis. Currently, the sole feasible therapeutic option for men with NOA to father their biologic children is sperm retrieval by testicular sperm extraction (TESE) approaches followed by an intracytoplasmic sperm injection program. Nevertheless, the rate of sperm retrieval from NOA men following TESE has remained as low as 50%, leading to a significant number of unsuccessful TESE operations. Given that TESE is associated with multiple side effects, the prediction of TESE outcome preoperatively can abolish unnecessary operations and thereby prevent NOA patients from sustaining adverse side effects. As the process of spermatogenesis is under the regulation of hormones, the hormonal profile of serum and/or seminal plasma may contain useful information about spermatogenesis status and can potentially predict the chance of sperm retrieval from NOA patients. A large body of literature is available on the predictive capability of different serum and seminal plasma hormones such as FSH, LH, testosterone, inhibin B, AMH, estradiol, prolactin, and leptin in a stand-alone basis or combinational fashion with respect to the TESE outcome. The present review aimed to evaluate the potential of these hormonal markers as noninvasive predictors of sperm retrieval in men with NOA.

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

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Role of adipokines in the ovarian function: Oogenesis and steroidogenesis.

Adipokines are mainly produced by adipose tissue; however, their expression has been reported in other organs including female reproductive tissues. Therefore, adipokines have opened new avenues of research in female fertility. In this regard, studies reported different roles for certain adipokines in ovarian function, although the role of other recently identified adipokines is still controversial. It seems that adipokines are essential for normal ovarian function and their abnormal levels could be associated with ovarian-related disorders. The objective of this study is to review the available information regarding the role of adipokines in ovarian functions including follicular development, oogenesis and steroidogenesis and also their involvement in ovary-related disorders.

Epididymosomes: the black box of Darwin's pangenesis?

Darwin, in the pangenesis theory, imagined particles, named as 'gemmules', which are released from all ('pan') cells of the body. By cell-cell communication and also circulation through the body, they finally reach the germ cells to participate in the generation ('genesis') of the new individual. It has been shown that circulatory exosomes are affected by environmental stressors and they can reach the parental germ cells. Therefore, in the mirror of his theory, circulatory exosomes could interact with epididymosomes: epididymis-derived exosomes which have a wide spectrum of variation in content and size, are very sensitive to environmental stressors, and may be involved in translating external information to the germ cells. The protein and RNA cargo would be transferred by epididymosomes to sperm during sperm maturation, which would be then delivered to the embryo at fertilization and inherited by offspring. Therefore, in this study, we will briefly discuss Darwin's pangenesis theory and its possible relation with epididymosomes. We believed that epididymosomes could be considered as an attractive candidate for the storage of RNA contents, changing the epigenome of the next generations, and allowing the reappearance acquired characteristics of ancestors. Therefore, epididymosomes, as a black box of Darwin's pangenesis, may unravel parental life history and also disclose the historical events that affect the life of offspring.

N1-Methylnicotinamide: An Anti-Ovarian Aging Hormetin?

Ovarian aging occurs due to the reduction of the quality and quantity of the oocytes, and is regulated by mitochondrial survival and apoptotic signals. Reactive Oxygen Species (ROS) are one of those signals considered detrimental to cellular homeostasis. Nowadays, ROS are regarded as a regulatory factor at low levels as it induces the stress resistance which in turn increases the longevity. It is believed that the main mechanism for the life-promoting role of the ROS mediated by the 5' Adenosine Monophosphate-activated Protein Kinase (AMPK). N1-Methylnicotinamide (MNAM) is well known for its anti-diabetic, anti-thrombotic, and anti-inflammatory activity. Aldehyde oxidase 1 (AOX1) is a detoxifying enzyme, which metabolizes the MNAM and produces two metabolites including N1-methyl-2-pyridone-5- carboxamide (2py) and N1-methyl-4-pyridone-3-carboxamide (4py). The activity of AOX1 enhances the production of ROS and improves the longevity. It has been reported that the MNAM could postpone the aging through the induction of low-level stress. It has been documented that the production of MNAM is significantly higher in the cumulus cells of the patients with Polycystic Ovary Syndrome (PCOS) and its administration on the rat model of PCOS has been shown to alleviate the hyperandrogenism and successfully activate the ovarian AMPK. Therefore, it can be hypothesized that the anti-ovarian aging effects of the MNAM are possibly based on the activation of AMPK through transient elevation of the ROS.

An evaluation on potential anti-inflammatory effects of ß-lapachone.

Inflammation plays a significant role in the pathogenesis of chronic diseases. Inflammatory diseases such as bacterial diseases, Alzheimer's disease, rheumatoid arthritis, multiple sclerosis, and so on, impose huge costs on the health systems. On the other hand, some side effects have been reported for the classic drugs used to treat these diseases. Plants phytochemicals have revealed important prospects in the handling and controlling of human diseases. ß-lapachone, is a derivative of the naturally occurring element lapachol, from Tabebuia avellanedae and its anti-inflammatory effects have been reported in several reports. This review summarized the evidence from cell and animal studies supporting the anti-inflammatory role of ß-lapachone and discussed its potential mechanisms.

Effects of bacteria on male fertility: Spermatogenesis and sperm function.

Bacterial infection can negatively affect different parts of the male genital tract and subsequently cause impaired spermatogenesis and male fertility. However, most of the previous studies have focused on the infected organs of the male genital tract and there are not many studies that investigated the direct effect of bacteria on sperm and their mechanism of action. Interestingly, bacteria can induce different damages on sperm cells such as DNA fragmentation, cell membrane peroxidation, and acrosome impairment. Such negative effects can be mediated by bacteria-secreted toxins and metabolites or by direct attachment of bacteria on the sperm cells and subsequent activation of signaling pathways related to oxidative stress, apoptosis, and inflammation. These bacteria-induced changes can impair semen parameters and subsequently cause infertility. Given the significant destructive effect of some bacteria on sperm function and male fertility, in this study, we reviewed the impact of male urogenital bacteria on spermatogenesis and sperm functions as well as the underlying mechanisms by which the bacteria can damage sperm.

Cytotoxic effect of 2, 5-dimethyl-celecoxib as a structural analog of celecoxib on human colorectal cancer (HT-29) cell line.

Dimethyl-celecoxib (DMC), a close derivative of celecoxib (CXB) with a low COX-2 inhibitory function, exhibits significant anti-neoplastic properties. In this study, we have investigated the effect of CXB and DMC on the human HT-29 cell line. The cellular viability, caspase-3 activity, and VEGF, NF-κB, and COX-2 genes expressions were assessed respectively with MTT, colorimetric, and real-time RT-PCR methods. DMC, a close analogue of CXB, was more potent in inhibiting the growth of cells (IC50: 23.45 µM at 24 hr) than CXB (IC50: 30.41 µM at 24 hr). Both CXB and DMC caused a significant difference in caspase-3 activity compared to the control group. DMC significantly decreased the NF-κB expression. Down-regulation of the COX-2 mRNA expression in the celecoxib-treated group was significant compared with that in the DMC-treated group. Alterations in the mRNA expression of VEGF were not significant between the groups. Owing to the more potent growth inhibitory effects of DMC compared to that of celecoxib, it may be important to conduct research on the anticancer application of this compound, which can reduce the side effects relating to COX2 inhibition.

Imatinib and its combination with 2,5-dimethyl-celecoxibinduces apoptosis of human HT-29 colorectal cancer cells.

Mono-targeting by imatinib as a main antitumor agent does not always accomplish complete cancer suppression. 2,5-dimethyl-celecoxib (DMC) is a close structural analog of the selective cyclooxygenase-2 (COX-2) inhibitor, celecoxib, that lacks COX-2 inhibitory function. In this study, we aimed to show the apoptotic effects of imatinib in combination with DMC in human HT-29 colorectal cancer (CRC) cells. HT-29 CRC cells were treated with IC50 dose of imatinib (6.60 µM), DMC (23.45 µM), and their combination (half dose of IC50) for 24 h. The caspase-3 activity was estimated with colorimetric kit. The caspase-3 gene expression was evaluated by real-time PCR method. There was a significant up-regulation in caspase-3 enzyme activity and caspase-3 expression by imatinib and its half dose combination with DMC as compared to control. As a summary, the results of this study strongly suggest that half dose combination of imatinib with DMC induced apoptosis as potent as full dose imatinib in human HT-29 CRC cells, while minimizing undesired side effects related to imatinib mono-therapy. This study also pointed towards possible caspase-dependent actions of imatinib and DMC.