Milad Moloudizargari

Garlic (Allium sativum L. family Liliaceae) is well known in Iran and its leaves, flowers, and cloves have been used in traditional medicine for a long time. Research in recent decades has shown widespread pharmacological effects of A. sativum and its organosulfur compounds especially Allicin. Studies carried out on the chemical composition of the plant show that the most important constituents of this plant are organosulfur compounds such as allicin, diallyl disulphide, S-allylcysteine, and diallyl trisulfide. Allicin represents one of the most studied among these naturally occurring compounds. In addition to A. sativum, these compounds are also present in A. hirtifolium (shallot) and have been used to treat various diseases. This article reviews the pharmacological effects and traditional uses of A. sativum, A. hirtifolium, and their active constituents to show whether or not they can be further used as potential natural sources for the development of novel drugs. For this purpose...

Background and objectives: Alternative medicine is widely used to replace a variety of commonly prescribed synthetic drugs in order to achieve a state of substantial efficacy with considerably less adverse effects. The present work has focused on the comparative evaluation of the analgesic efficacy of five members of Lamiaceae family to prioritize their potentials to be used herein. Methods: Two common models of pain studies including the hot-plate and tail-flick tests were used to compare the analgesic properties of Thymus vulgaris, Mentha piperita, Rosmarinus officinalis, Satureja hortensis, and Mentha pulegium essential oils (EOs) at two doses of 0.5 and 1 cc per animal. Results: Significant increase in the response times of both tests were recorded compared to the control group following the administration of the EOs with the order of potency T. vulgaris 1 mL > T. vulgaris (0.5 mL) > M. piperita (1 mL) > M. piperita (0.5 mL) > R. officinalis (1 mL) > R. officinali...

Objective(s): Garlic (Allium sativum L. family Liliaceae) is well known in Iran and its leaves, flowers, and cloves have been used in traditional medicine for a long time. Research in recent decades has shown widespread pharmacological effects of A. sativum and its organosulfur compounds especially Allicin. Studies carried out on the chemical composition of the plant show that the most important constituents of this plant are organosulfur compounds such as allicin, diallyl disulphide, S-allylcysteine, and diallyl trisulfide. Allicin represents one of the most studied among these naturally occurring compounds. In addition to A. sativum, these compounds are also present in A. hirtifolium (shallot) and have been used to treat various diseases. This article reviews the pharmacological effects and traditional uses of A. sativum, A. hirtifolium, and their active constituents to show whether or not they can be further used as potential natural sources for the development of novel drugs. Ma...

The biological functions of melatonin range beyond the regulation of circadian rhythms. With regard to cancer, melatonin's potential to suppress cancer initiation, progression, angiogenesis and metastasis as well as sensitizing malignant cells to conventional chemo- and radiotherapy are among its most interesting effects. The targets at which melatonin initiates its anti-cancer effects are in common with those of a majority of existing anti-cancer agents, giving rise to the notion that this molecule is a pleiotropic agent sharing many features with other antineoplastic drugs in terms of their mechanisms of action. Among these common mechanisms of action are the regulation of several major intracellular pathways including mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinase (ERK) and protein kinase B (AKT/PKB) signaling. The important mediators affected by melatonin include cyclins, nuclear factor-κB (NF-κB), heat shock proteins (HSPs) and c-Myc, all of which can serve as potential targets for cancer drugs. Melatonin also exerts some of its anti-cancer effects via inducing epigenetic modifications, DNA damage and mitochondrial disruption in malignant cells. The regulation of these mediators by melatonin mitigates tumor growth and invasiveness via modulating their downstream responsive genes, housekeeping enzymes, telomerase reverse transcriptase, apoptotic gene expression, angiogenic factors and structural proteins involved in metastasis. Increasing our knowledge on how melatonin affects its target sites will help find ways of exploiting the beneficial effects of this ubiquitously-acting molecule in cancer therapy. Acknowledging this, here we reviewed the most studied target pathways attributed to the anti-cancer effects of melatonin, highlighting its therapeutic potential.

Hematological malignancies are classified as a heterogeneous category of cancers with various degrees of incidence and prognosis and different etiologies. Due to their aggressive essence they should be diagnosed as early as possible to improve prognosis, treatment outcome and survival. Bases on the limitations of previously identified biomarkers in terms of sensitivity, specificity and predictability, it is necessary to develop new diagnostic tools and biomarkers for the early diagnosis of hematological malignancies. Exosomes are nanovesicles secreted by almost all cell types in both physiological and pathological conditions. They play major roles in intercellular communication and are recently being considered as disease biomarkers. These nanovesicles carry proteins, lipids and nucleic acids like microRNAs (miRNAs). miRNAs are small noncoding RNAs, which act as translational suppressors via regulating protein-coding genes. The aberrant expression of miRNAs has been shown in various conditions including hematological malignancies. Moreover, it is now known that tumor cells secrete higher amounts of exosomes compared to normal cells. The idea of using exosomal miRNAs in serum as biomarkers is based on their surprisingly high stability and specificity. In the present paper, we reviewed and recommended exosomal miRNA panels including (miR-150, miR-155 and miR-1246), (miR-17-5p, miR-20a-5p, miR-16-5p and miR-5a-5p), (miR-18a, Let-7b) and (miR192-5p, miR21-5p, miR320b and Let-7d), for their potential to be used as non-invasive biomarkers in different hematological malignancies such as multiple myeloma, leukemia, and lymphoma.

BACKGROUND Despite the advances in the treatment of multiple myeloma (MM), complete remission is usually challenging. The interactions between tumor and host cells, in which exosomes (EXs) play critical roles, have been shown to be among the major deteriorative tumor-promoting factors herein. Therefore, any endeavor to beneficially target these EX-mediated interactions could be of high importance. OBJECTIVES a) To investigate the effects of myeloma EXs on natural killer (NK) cell functions. b) To check whether treatment of myeloma cells with eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA), two polyunsaturated omega-3 fatty acids with known anti-cancer effects, can modify myeloma EXs in terms of their effects on natural killer functions. METHODS L363 cells were treated with either EPA or DHA or left untreated and the released EXs (designated as E-EX, D-EX and C-EX, respectively) were used to treat NK cells for functional studies. RESULTS Myeloma EXs (C-EXs) significantly reduced NK cytotoxicity against K562 cells (P ≤ 0.05), while the cytotoxicity suppression was significantly lower (P ≤ 0.05) in the (E-EX)- and (D-EX)-treated NK cells compared to the (C-EX)-treated cells. The expression of the activating NK receptor NKG2D and NK degranulation, after treatment with the EXs, were both altered following the same pattern. However, C-EXs could increase IFN-γ production in NK cells (P < 0.01), which was not significantly affected by EPA/DHA treatment. This indicates a dual effect of myeloma EXs on NK cells functions. CONCLUSION Our observations showed that myeloma EXs have both suppressive and stimulatory effects on different NK functions. Treatment of myeloma cells with EPA/DHA can reduce the suppressive effects of myeloma EXs while maintaining their stimulatory effects. These findings, together with the previous findings on the anti-cancer effects of EPA/DHA, provide stronger evidence for the repositioning of the currently existing EPA/DHA supplements to be used in the treatment of MM as an adjuvant treatment. EXs released from L363 (myeloma) cells in their steady state increase IFN-γ production of NK cells, while reduce their cytotoxicity against the K562 cell line (right blue trace). EXs from L363 cells pre-treated with either EPA or DHA are weaker stimulators of IFN-γ production. These EXs also increase NK cytotoxicity and NKG2D expression (left brown trace) compared to the EXs obtained from untreated L363 cells. Based on these findings, myeloma EXs have both suppressive and stimulatory effects on different NK functions depending on the properties of their cells of origin, which can be exploited in the treatment of myeloma.

Mesenchymal stem cells (MSCs) are mesenchymal precursors of various origins, with well‐known immunomodulatory effects. Natural killer (NK) cells, the major cells of the innate immune system, are critical for the antitumor and antiviral defenses; however, in certain cases, they may be the main culprits in the pathogenesis of some NK‐related conditions such as autoimmunities and hematological malignancies. On the other hand, these cells seem to be the major responders in beneficial phenomena like graft versus leukemia. Substantial data suggest that MSCs can variably affect NK cells and can be affected by these cells. Accordingly, acquiring a profound understanding of the crosstalk between MSCs and NK cells and the involved mechanisms seems to be a necessity to develop therapeutic approaches based on such interactions. Therefore, in this study, we made a thorough review of the existing literature on the interactions between MSCs and NK cells with a focus on the underlying mechanisms. The current knowledge herein suggests that MSCs possess a great potential to be used as tools for therapeutic targeting of NK cells in disease context and that preconditioning of MSCs, as well as their genetic manipulation before administration, may provide a wider variety of options in terms of eliciting more specific and desirable therapeutic outcomes. Nevertheless, our knowledge regarding the effects of MSCs on NK cells is still in its infancy, and further studies with well‐defined conditions are warranted herein.

The current era of cancer research has been continuously advancing upon identifying novel aspects of tumorigenesis and the principal mechanisms behind the unleashed proliferation, invasion, drug resistance and immortality of cancer cells in hopes of exploiting these findings to achieve a more effective treatment for cancer. In pursuit of this goal, the identification of the first components of an extremely important regulatory pathway in Drosophila melanogaster that largely determines cell fate during the developmental stages, ended up in the discovery of the highly sophisticated Hippo signaling cascade. Soon after, it was revealed that deregulation of the components of this pathway either via mutations or through epigenetic alterations can be observed in a vast variety of tumors and these alterations greatly contribute to the neoplastic transformation of cells, their survival, growth and resistance to therapy. As more hidden aspects of this pathway such as its widespread entanglement with other major cellular signaling pathways are continuously being uncovered, many researchers have sought over the past decade to find ways of therapeutic interventions targeting the major components of the Hippo cascade. To date, various approaches such as the use of exogenous targeting miRNAs and different molecular inhibitors have been recruited herein, among which naturally occurring compounds have shown a great promise. On such a basis, in the present work we review the current understanding of Hippo pathway and the most recent evidence on targeting its components using natural plant-derived phytochemicals.

Poly-unsaturated fatty acids (PUFAs) have been shown to have cytotoxic effects in both solid and non-solid tumors. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are among the most studied PUFAs. The aim of the present study was to evaluate the cytotoxic effects of these two fatty acids (FAs) in the peripheral blood mononuclear cells (PBMCs) obtained from untreated patients (new cases) with confirmed symptomatic multiple myeloma (MM). Our results showed that EPA at the concentration of 100 μM and DHA at 50 and 100 μM induce potent apoptotic effects in the PBMCs of MM patients (P < 0.05) as evidenced by Annexin V and propidium iodide (PI) staining, while they have little or no effects on the PBMCs isolated from healthy donors (P > 0.05). The observed effects were concentration- and time-dependent and 72 h treatment with DHA at a concentration of 100 μM had the strongest effect (P < 0.01). CD138 + cells isolated from MM patients showed great sensitivity to EPA/DHA. EPA- and DHA-induced apoptosis was significantly inhibited by the pan-caspase inhibitor (Z-VAD-FMK), indicating that cell death was at least partly dependent on caspase activation. The results of the present study showed that EPA and DHA have selective toxicities for malignant human plasma cells from MM patients, but not for mononuclear cells of healthy donors. These results warrant further studies with larger study populations to investigate the usefulness of PUFAs as a promising adjunctive therapy in the treatment of MM.

Multiple myeloma (MM), one of the most prevalent hematological malignancies, accounts for approximately 10% of all blood cancers. In spite of the recent advancements in MM therapy, this malignancy of terminally differentiated plasma cells (PCs) continues to remain a hard-to-cure disease due to the emergence of drug resistance and frequent relapses. It is now well-established that the tumor-supportive involvement of the bone marrow microenvironment (BMM) including the cellular and non-cellular elements are the major causes behind treatment failures of MM as well as its main complications such as osteolytic bone loss. Exosomes (EXs) are membranous structures that carry signaling molecules and have recently received a great deal of attention as important mediators of inter-cellular communication in health and disease. EXs involve in the growth and drug resistance of many tumors via delivering their rich contents of bioactive molecules including miRNAs, growth factors, cytokines, signaling molecules, etc. With regard to MM, many studies have reported that EXs are among the main culprits playing key roles in the vicious network within the BMM of these patients. The main producers of EXs that largely contribute to MM pathogenesis are bone marrow stromal cells (BMSCs) as well as MM cells themselves. These cell types produce large amounts of EXs that affect a variety of target cells including natural killer (NK) cells, osteoclasts (OCs) and osteoblasts (OBs) to the advantage of tumor survival and progression. These EXs contain a different profile of proteins and miRNAs from that of EXs obtained from their counterparts in healthy individuals. MM patients exhibit distinguishable elevations in some of their contents such as miR-21, miR-146a, let-7b and miR-18a, while some molecules like miR-15a are markedly downregulated in EXs of MM patients compared to healthy individuals. These findings make EXs desirable biomarkers for early prediction of disease progression and drug resistance in the context of MM. On the other hand, due to the tumor-supportive role of EXs, targeting these structures in parallel to the conventional therapeutic regimens may be a promising approach to a successful anti-MM therapy. In the present work, an extensive review of the literature has been carried out to highlight the recent advances in the field.

AIMS Senescence is a state ensuing aging to eliminate age-associated damage with an irreversible cell-cycle arrest mechanism, which is historically believed to be one of the tumor responses to therapy. Doxorubicin as an anti-cancer drug has been used in cancer treatment for a long time. Liposomal doxorubicin (Ldox) is a liposomal formulation of doxorubicin, which increases the doxorubicin permanency. The aim of this study was to examine the toxicity of these two formulations by comparing them in terms of their ability to induce cellular senescence. MAIN METHODS The study groups included a control group, three DOX (0.75, 0.5, 0.1 mg/kg/BW) and three Ldox groups (0.1, 0.05, 0.025 mg/kg/BW). Heart tissues were studied regarding oxidative stress assessment, mitochondrial function, inflammatory markers and biochemical and histopathological evaluation. Real-Time PCR was used for P53 and SA β-gal expression. KEY FINDINGS Based on the results, the highest doses of Dox and Ldox (0.75 and 0.1 mg/kg/BW respectively) significantly increased the level of inflammatory markers and according to other factors especially p53 and SA β-gal expression, both were able to induce senescence but the changes in Ldox were less tangible than the Dox.

Melatonin is a ubiquitous indole amine that plays a fundamental role in the regulation of the biological rhythm. Disrupted circadian rhythm alters the expression of clock genes and deregulates oncogenes, which finally promote tumor development and progression. An evidence supporting this notion is the higher risk of developing malignancies among night shift workers. Circadian secretion of the pineal hormone also synchronizes the immune system via a reciprocal association that exists between the immune system and melatonin. Immune cells are capable of melatonin biosynthesis in addition to the expression of its receptors. Melatonin induces big changes in different immune cell proportions, enhances their viability and improves immune cell metabolism in the tumor microenvironment. These effects might be directly mediated by melatonin receptors or indirectly through alterations in hormonal and cytokine release. Moreover, melatonin induces apoptosis in tumor cells via the intrinsic and extrinsic pathways of apoptosis, while it protectsthe immune cells. In general, melatonin has a profound impact on immune cell trafficking, cytokine production and apoptosis induction in malignant cells. On such a basis, using melatonin and resynchronization of sleep cycle may have potential implications in immune function enhancement against malignancies, which will be the focus of the present paper.

Graphical abstract Figure. No caption available. &NA; The reciprocal interactions of cancer cells with their microenvironment constitute an inevitable aspect of tumor development, progression and response to treatment in all cancers. Such bilateral transactions also serve as the key scenario underlying the development of drug resistance in many cases finally determining the fate of the disease and survival. In this view, a class of extracellular vesicles (EV) known as exosomes (EX) have been shown in the past few years to be important mediators of local and remote cell‐to‐cell contact changing the activity of their target cells by introducing their content of proteins, non‐coding RNAs, and membrane‐associated small molecules. In addition to the direct targeting of cancer cells, which has been routinely undertaken by different means to date, parallel attempts to change the signaling network governed by tumor‐derived exosomes (TDE) may offer a promising potential to be utilized in cancer therapy. TDE drive diverse functions in the body, most of which have been shown to act to the advantage of tumor progression; however, there are also several studies that report the good aspects of TDE the interruption of which may result in undesirable outcomes. In the present paper, we made an effort to address this important issue by reviewing the very recent literature on different aspects of EX biogenesis and regulation and the various bodily effects of TDE which have been uncovered to date. Moreover, we have reviewed the possible interventions that can be made in TDE release as an important stage of EX biogenesis. Finally, keeping a criticizing view, the advantages and disadvantages of such interventions have been discussed and the future prospect in the field has been outlined.

Nontuberculous mycobacteria (NTM) are categorized as one of the large and diverse groups of environmental organisms which are abundant in water and soil.  NTM cause a variety of diseases in humans that mainly affect the lung. A predisposition to pulmonary NTM is evident in patients with parenchymal structural diseases including bronchiectasis, emphysema, tuberculosis (TB), cystic fibrosis (CF), rheumatologic lung diseases and other chronic diseases with pulmonary manifestations. Lung infections are not the only consequences of being infected by NTM as they can also infect skin and soft tissue and may also cause lymphadenitis (predominantly in young children) and disseminated disease in human immunodeficiency virus (HIV)-infected patients or those with severely compromised immune system. NTM are also found in many subjects without any known risk factors.  Although the recent advances in imaging and microbiologic techniques including gene sequencing have provided a better view of the ...

Adipose tissue-derived mesenchymal stromal cells (AT-MSCs), widely known as multipotent progenitors, release several cytokines that support cell survival and repair. There are in vitro and in vivo studies reporting the regenerative role of AT-MSCs possibly mediated by their protective effects on functional islet cells as well as their capacity to differentiate into insulin-producing cells (IPCs). On such a basis, our goal in the present study was to use three different models including direct and indirect co-cultures and islet-derived conditioned medium (CM) to differentiate AT-MSCs into IPCs and to illuminate the molecular mechanisms of the beneficial impact of AT-MSCs on pancreatic islet functionality. Furthermore, we combined in vitro co-culture of islets and AT-MSCs with in vivo assessment of islet graft function to assess whether co-transplantation of islets with AT-MSCs can reduce marginal mass required for successful islet transplantation and prolong graft function in a diabetic rat model. Our findings demonstrated that AT-MSCs are suitable for creating a microenvironment favorable for the repair and longevity of the pancreas β cells through the improvement of islet survival and maintenance of cell morphology and insulin secretion due to their potent properties in differentiation. Most importantly, hybrid transplantation of islets with AT-MSCs significantly promoted survival, engraftment and insulin-producing function of the graft and reduced the islet mass required for reversal of diabetes. This strategy might be of therapeutic potential solving the problem of donor islet material loss that currently limits the application of allogeneic islet transplantation as a more widespread therapy for type 1 diabetes.

Thanks to the comments of Zamani and HassanianMoghaddam (2017), the importance of aluminum phosphide (AlP) poisoning and the lacking data on its clinical management has been once again subjected to debate. To date, no efficient and specific therapy has been proposed to cope with AlP poisoning in humans and all the current therapeutic measures are limited to symptom-based supportive therapies (Asghari et al. 2017c). The reason is presumably the scant available data on the precise mechanisms underlying the toxicity of AlP, encouraging more research to be carried out in this field. The inhibition of cytochrome oxidase, however, has been proposed to be the most important mechanism giving rise to the clinical manifestations during AlP poisoning (Asghari et al. 2017a, d; Baghaei et al. 2016). A reliable clinical treatment protocol needs to be evaluated in various pre-clinical and clinical studies or at least in one valid clinical trial to be accepted for use in routine clinical practice, a necessity that seems to be absent in the protocol addressed in the comment by Zamani and Hassanian-Moghaddam (2017). To reach a consensus regarding the efficacy of a clinical protocol for the management of any medical condition (in this case AlP poisoning), all the AlP-poisoned patients referred to a clinical toxicology ward or the emergency service of a health care center must be evaluated based on their received dose of AlP to be able to discriminate between the patients who ingested amounts equal to LD100 and those who might have been exposed to lower doses. As explained in our previous response (Asghari et al. 2017b), the importance of this issue becomes obvious in case one would postulate in mind that the response to treatment in the protocol mentioned by Zamani and Hassanian-Moghaddam might have been basically due to lower-ingested doses of AlP which is not enough to cause death in the patients. On the other hand, the clinical success of the recommended protocol has not been supported by any literature with an adequate number of participants which adds to its ambiguities. Even with the assumption that the protocol has had all the criteria mentioned above, there still exist a few questions that come to mind whose mentioning in the present comment may be worthwhile: Based on the comments of Zamani and HassanianMoghaddam, the administration of glucose, insulin, and potassium increases survival after AlP poisoning up to 20% by improving cellular carbohydrate metabolism, increasing the contractile force, and reversal of acidosis. Previous studies show that AlP ingestion induces apoptosis and depletes ATP reserves of cells by inhibiting the electron transfer chain (Baghaei et al. 2016; Solgi et al. 2015). Under such conditions, any increase in the contractility of the heart causes more rapid energy consumption, increased ATP depletion and apoptosis of cells. Necrosis of heart tissue, atrioventricular fibrillation, and cardiac arrhythmias are among other consequences of AlP poisoning (Anand et al. 2012; Soltaninejad et al. 2012). Keeping in mind all the mentioned mechanistic outcomes of AlP ingestion and noting that survival of patients following exposure to lethal doses of AlP can be only achieved by targeting and reversing at least one of the key mechanisms involved in AlP toxicity, the question that arises is that which of these mechanisms have been targeted by the recommended protocol? Addressing this question may explain the benefits of using such a protocol as a specific AlP-targeting therapy rather * Mohammad Abdollahi Mohammad@TUMS.Ac.Ir; Mohammad.Abdollahi@UToronto.Ca

Our knowledge regarding the implications of melatonin in the therapy of numerous medical conditions, including cancer is constantly expanding. Melatonin can variably affect cancer pathology via targeting several key aspects of any neoplastic condition, including the very onset of carcinogenesis as well as tumor growth, differentiation, and dissemination. Numerous studies have examined the effects of melatonin in the context of various cancers reporting the enhanced efficacy of chemo/radiotherapy in combination with this compound. Reduced sensitivity and also resistance of cancer cells to antineoplastic agents are common events which might arise as a result of genomic instability of the malignant cells. Genetic mutations provide numerous mechanisms for these cells to resist cytotoxic therapies. Melatonin, due to its pleitropic effects, is able to correct these alterations in favour of sensitization to antineoplastic agents as evident by increased response to treatment via modulating ...

Omega-3 polyunsaturated fatty acids (PUFAs) have well established anti-cancer properties. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are among this biologically active family of macromolecules for which various anti-cancer effects have been explained. These PUFAs have a high safety profile and can induce apoptosis and inhibit growth of cancer cells bothand, following a partially selective manner. They also increase the efficacy of chemotherapeutic agents by increasing the sensitivity of different cell lines to specific anti-neoplastic drugs. Various mechanisms have been proposed for the anti-cancer effects of these omega-3 PUFAs; however, the exact mechanisms still remain unknown. While numerous studies have investigated the effects of DHA and EPA on solid tumors and the responsible mechanisms, there is no consensus regarding the effects and mechanisms of action of these two FAs in hematological malignancies. Here, we performed a systematic review of the beneficial e...

Melatonin, a pineal indolamine, participates in different body functions and is shown to possess diverse biological activities such as anti-tumor action. Angiogenesis inhibition is one of the mechanisms by which melatonin exerts its oncostatic effects. Increased angiogenesis is a major feature of tumor progression, thus angiogenesis inhibition is a critical step in cancer therapy. Melatonin employs a variety of mechanisms to target nutrients and oxygen supply to cancer cells. At the transcriptional level, hypoxia induced factor-1α (HIF-1α) and the genes under its control, such as vascular endothelial growth factor (VEGF) are the main targets of melatonin for inhibition of angiogenesis. Melatonin prevents translocation of HIF-1α into the nucleus thereby hindering VEGF expression and also prevents the formation of HIF-1α, phospho-STAT3 and CBP/p300 complex which is involved in the expression of angiogenesis-related genes. Angiostatic properties of melatonin could be also due to its ab...

Autophagy is a major regulatory cellular mechanism which gives the cell an ability to cope with some of the destructive events that normally occur within a metabolically living cell. This is done by maintaining the cellular homeostasis, clearance of damaged organelles and proteins and recycling necessary molecules like amino acids and fatty acids. There is a wide array of factors that influence autophagy in the state of health and disease. Disruption of these mechanisms may not only give rise to several autophagy-related disease, but also it can occur as the result of intracellular changes induced during disease pathogenesis causing exacerbation of the disease. Our knowledge is increasing regarding the role of autophagy and its mechanisms in the pathogenesis of various neurodegenerative diseases such as multiple sclerosis, Parkinson's disease, Alzheimer's disease, Huntington's disease and Amyotrophic lateral sclerosis. Indeed, getting to know about the pathways of autophagy and its regulation can provide the basis for designing therapeutic interventions. In the present paper, we review the pathways of autophagy, its regulation and the possible autophagy-targeting interventions for the treatment of neurodegenerative disorders.

Gastric cancer (GC) is a predominant malignancy with a high mortality rate affecting a large population worldwide. The etiology of GC is multifactorial spanning from various genetic determinants to different environmental causes. Current tretaments of GC are not efficient enough and require improvements to minimize the adverse effects. Melatonin, a naturally occurring compound with known potent inhibitory effects on cancer cells is one of the major candidates which can be recruited herein. Here we reviewed the articles conducted on the therapeutic effects of melatonin in gastric cancer in various models. The results are classified according to different aspects of cancer pathogenesis and the molecular mechanisms by which melatonin exerts its effects. Melatonin could be used to combat GC exploiting its effects on multiple aspects of its pathogenesis, including formation of cancer cells, tumor growth andangiogenesis, differentiation and metastasis as well as enhancing the anti-tumor i...

Aluminum phosphide (AlP), one of the most commonly used pesticides worldwide, has been the leading cause of self-poisoning mortalities among many Asian countries. The heart is the main organ affected in AlP poisoning. Melatonin has been previously shown to be beneficial in reversing toxic changes in the heart. The present study reveals evidence on the probable protective effects of melatonin on AlP-induced cardiotoxicity in rats. The study groups included a control (almond oil only), ethanol 5% (solvent), sole melatonin (50 mg/kg), AlP (16.7 mg/kg), and 4 AlP + melatonin groups which received 20, 30, 40 and 50 mg/kg of melatonin by intraperitoneal injections following AlP treatment. An electronic cardiovascular monitoring device was used to record the electrocardiographic (ECG) parameters. Heart tissues were studied in terms of oxidative stress biomarkers, mitochondrial complexes activities, ADP/ATP ratio and apoptosis. Abnormal ECG records as well as declined heart rate and blood p...

Having considered current reports concerning plagiarisms taking place in the global science community, the authors decided to address the principal reasons, which lead to these illegalities. In recent years, misconduct in research, such as plagiarism, fabrication, falsification, guest author, ghost author, self-citation, etc. have been increasing significantly in scientific papers, proving a lack of commitment to publication ethics among some authors...

Abstract Objective To investigate the healing effects of two herbal preparations. Methods For this purpose, 106 wistar rats were divided into 9 groups including a control, eucerine, phenytoin, Urtica dioica ( U. dioica ) (2%), U. dioica (5%), Sambucus ebulus ( S. ebulus ) (2%), S. ebulus (5%), combination (2%), and combination (5%) groups. The control group remained untreated, the eucerin and phenytoin groups were considered as the negative and positive controls respectively, and the remaining groups received different concentrations of the ointments. Full thickness wounds were made. The healing process of the wounds was investigated on day 7, 14 and 21 of the experiment. Several factors including the number of fibroblasts, new vessel formation (angiogenesis), thickness of the granulomatous tissues (GT), and the overlying epithelium were analyzed. Results Among the studied groups, all of the treatment groups were significantly different from the control, eucerin, and phenytoin groups in a positive manner with regard to all studied factors ( P  ≤ 0.05). However, the best results were observed with the S. ebulus (2%) and the combination 2% groups ( P  ≤ 0.05). Conclusions Topical ointments prepared from the extracts of U. dioica and S. ebulus and their combination possess strong wound healing properties. It is postulated that a synergistic effect may exist between the two extracts since the combination 2% showed better results than the sole extracts.

Cyclophosphamide (CP) is an alkylating antineoplastic agent with known toxicity to the male reproductive system. Areas covered: This review summarizes the known mechanisms by which CP exerts its toxic effects on the male reproductive system and the methods utilized to prevent such effects so that it could be further investigated and applied in clinical use. Keywords including ['Cyclophosphamide' AND 'male reproductive' OR' sperm toxicity' OR 'spermatotoxicity' OR 'infertility] were searched through Google Scholar, PubMed and Scopus databases based on PRISMA guidelines. After removing duplicates and irrelevant data, 76 papers were reviewed concerning the outcomes of treatment of male mice, rats, and humans with CP and the effects of co-administration of various natural and synthetic compounds on male reproductive system. Expert opinion: CP exerts its effect mainly by inducing oxidative stress and changing gene expression in spermatocytes variably d...

Pesticides are among the most important chemicals used in agriculture sector. However, their extensive use has polluted the environment and increased human vulnerability to various chronic diseases. Pesticide exposure causes genetic and epigenetic modifications, endocrine disruption, mitochondrial dysfunction and oxidative stress. This review is based on the literature studies currently reported on pesticide-induced toxicity and the protective role of melatonin. Scientific databases such as PubMed, Scopus and Web of Science were searched using keywords 'pesticide' and 'melatonin' up to January 2016. Full length articles related to animal and human exposure were retrieved. A total number of 181 records were obtained, and after excluding the duplicates, 97 papers were further screened on the basis of relevance to the topic. Melatonin as a broad-spectrum antioxidant is able to penetrate cellular compartments specifically the mitochondria. It is a potent free radical sca...

Introduction: The aim of this study was the evaluation of the synergistic effect of sub-MIC doses of Phosphomycin with β-Chloro-L-alanine against urinary tract isolates of E. coli. Materials and methods: A total of 40 isolates were collected from urine specimens submitted to the clinical diagnostic Laboratories in Urmia, Iran. The amounts of MIC and MBC for Phosphomycin, β-Chloro-L-alanine or a mixture of 0.5 mM β-Chloro-L-alanine with sub-MIC doses of Phosphomycin were determined and three groups were compared. Results: Of 40 E. coli isolates, 12. 5% were susceptible to all investigated concentrations of phosphomycin and 2. 5% were resistant. The mean MIC value for phosphomycin in the other E. coli isolates was determined as 25. 7± 35. 5 μg/ mL. All of the bacterial isolates were resistant to all investigated concentrations of β-Chloro-L-alanine. Application of β-Chloro-L-alanine and phosphomycin combination decreased the MIC and MBC values in 22. 5% of the isolates. Discussion and...

We present a novel hypothesis on the effect of topical administration of NO in form of tri-nitroglycerin (TNG) on the healing process of diabetic ulcers. Since all of the multiple causes of these ulcers such as diabetic peripheral neuropathy and vascular complications ultimately end up in vasoconstriction and impairment of blood supply to the site of ulcers and because almost all of the prescribed drugs regarding diabetic ulcers only concern reduction of the pain and prevention of the ulcers from further aggravation and not improvement of the nature of the ulcers, it seems to be necessary to think of a more effective way of treatment to improve the ulcers. NO is an indigenous vasodilator that increases blood supply to ulcers, thus accelerating their amelioration. It has been shown in previous studies that not only the production of NO in diabetic patients is decreased, but also the sensitivity of the cells of such patients to NO is significantly declined. Administration of TNG may i...

Background: Cynodon dactylon is a traditional medicinal plant which has been widely used by traditional rural healers for the treatment of cardiovascular disease. Our aim in preparing this study was to evaluate the probable effects of this plant on angiogenesis in rats. Methods: For this purpose, 25 male rats were divided into 5 groups each in which 5 rats were placed. The first group was considered as the control group and in the second group inflammation was induced using and air pouch method. The three remaining groups orally received 100, 200 and 400 mg/kg of Cynodon dactylon aqueous extract, respectively. At the end of the experimental period the jugular vein of each animal was cannulated and 2 cc of carmine red was injected. Specimens of the granulation tissues and skin were collected and studied for angiogenesis. Results: Angiogenesis was significantly enhanced in all treatment groups in comparison to the control group. The best effect was observed at a dosage of 400 mg/kg. C...

Diabetes mellitus is one of the main problems of the health care systems of all societies. A vast number of diabetic patients suffer from diabetic foot ulcers (DFUs) some of which may lead to the amputation of the organ(s). Nitric oxide (NO) is an indigenous gas that is produced at various sites in the body and has been shown to possess important roles in wound healing. Previous studies have shown that not only is the production of NO decreased in diabetic patients but also the sensitivity of the cells of such patients to NO is dramatically reduced. Nitroglycerine (isosorbide dinitrate) can be employed as an effective donor of NO to diabetic wounds. On such a basis, we suggest a novel hypothesis that delivery of compensatory amounts of NO to the ulcers by the administration of topical nitroglycerine enhances blood flow and biochemical activity of the ulcers and thus promotes wound healing.