PD-1/PD-L1 pathway: Basic biology and role in cancer immunotherapy

Over the course of past few years, cancer immunotherapy has been accompanied with promising results. However, preliminary investigations with respect to immunotherapy concentrated mostly on targeting the immune checkpoints, nowadays, emerge as the most efficient strategy to raise beneficial antitumor immune responses. Programmed cell death protein 1 (PD-1) plays an important role in subsiding immune responses and promoting self-tolerance through suppressing the activity of T cells and promoting differentiation of regulatory T cells. PD-1 is considered as an immune checkpoint and protects against autoimmune responses through both induction of apoptosis in antigen-specific T cells and inhibiting apoptosis in regulatory T cells. Several clinical trials exerting PD-1 monoclonal antibodies as well as other immune-checkpoint blockades have had prosperous outcomes and opened new horizons in tumor immunotherapy. Nonetheless, a bulk of patients have failed to respond to these newly emerging immune-based approach and the survival rate was not satisfying. Additional strategies, especially combination therapies, has been initiated and been further promising. Attempts to identify novel and well-suited predictive biomarkers are also sensed. In this review, the promotion of cancer immunotherapy targeting PD-1 immunoinhibitory pathway is discussed.     

Major depressive disorder diagnosis based on effective connectivity in EEG signals: a convolutional neural network and long short-term memory approach

Deep learning techniques have recently made considerable advances in the field of artificial intelligence. These methodologies can assist psychologists in early diagnosis of mental disorders and preventing severe trauma. Major Depression Disorder (MDD) is a common and serious medical condition whose exact manifestations are not fully understood. So, early discovery of MDD patients helps to cure or limit the adverse effects. Electroencephalogram (EEG) is prominently used to study brain diseases such as MDD due to having high temporal resolution information, and being a noninvasive, inexpensive and portable method. This paper has proposed an EEG-based deep learning framework that automatically discriminates MDD patients from healthy controls. First, the relationships among EEG channels in the form of effective brain connectivity analysis are extracted by Generalized Partial Directed Coherence (GPDC) and Direct directed transfer function (dDTF) methods. A novel combination of sixteen connectivity methods (GPDC and dDTF in eight frequency bands) was used to construct an image for each individual. Finally, the constructed images of EEG signals are applied to the five different deep learning architectures. The first and second algorithms were based on one and two-dimensional convolutional neural network (1DCNN–2DCNN). The third method is based on long short-term memory (LSTM) model, while the fourth and fifth algorithms utilized a combination of CNN with LSTM model namely, 1DCNN-LSTM and 2DCNN-LSTM. The proposed deep learning architectures automatically learn patterns in the constructed image of the EEG signals. The efficiency of the proposed algorithms is evaluated on resting state EEG data obtained from 30 healthy subjects and 34 MDD patients. The experiments show that the 1DCNN-LSTM applied on constructed image of effective connectivity achieves best results with accuracy of 99.24% due to specific architecture which captures the presence of spatial and temporal relations in the brain connectivity. The proposed method as a diagnostic tool is able to help clinicians for diagnosing the MDD patients for early diagnosis and treatment.     

In silico identification of novel lncRNAs with a potential role in diagnosis of gastric cancer

Abstract

Gastric cancer (GC) is the second leading cause of cancer-related deaths in the world. Due to the shortage of adequate symptoms in the early stages, it is diagnosed when the tumor has spread to distant organs. Early recognition of GC enhances the chance of successful treatment. Molecular mechanisms of GC are still poorly understood. LncRNAs are emerging as new players in cancer in both oncogene and tumor suppressor roles. High-throughput technologies such as RNA-Seq, have revealed thousands of lncRNAs which are dysregulated in GC. In this study, we retrieved lncRNAs obtained by High-throughput technologies from OncoLnc database. Consequently, retrieved lncRNAs were compared in literature-based databases including PubMed. As a result, two lists, including experimentally validated lncRNAs and predicted lncRNAs were provided. We found 43 predicted lncRNAs that had not been experimentally validated in GC, so far. Further Bioinformatics analyses were performed to obtain the expression profile of predicted lncRNAs in tumor and normal tissues. Also, the roles and targets of predicted lncRNAs in GC were identified by related databases. Finally, using the GEPIA database was reviewed the significant relationship of predicted lncRNAs with the survival of GC patients. By recognizing the lncRNAs involved in initiation and progression of GC, they may be considered as potential biomarkers in the GC early diagnosis or targeted treatment and lead to novel therapeutic strategies.

Communicated by Ramaswamy H. Sarma     

Molecular mechanisms by which aerobic exercise induces insulin sensitivity

Insulin resistance is a key feature of Type 2 diabetes and an important therapeutic target to address glycemic control to prevent diabetic complications. Lifestyle advice is the first step in the ADA/EASD consensus guidelines followed by metformin therapy. Aerobic exercise (AE) can increase insulin sensitivity by several molecular pathways including upregulation of insulin transporters in the cellular membrane of insulin-dependent cells. In addition, AE improves insulin sensitivity by amelioration of the pathophysiologic pathways involved in insulin resistance such as the reduction of adipokines, inflammatory and oxidative stress responses, and improvement of insulin signal transduction via different molecular pathways. This review details the molecular pathways by which AE induces beneficial effects on insulin resistance     

Chitosan-based delivery systems for curcumin: A review of pharmacodynamic and pharmacokinetic aspects

Effective drug delivery is one of the most important issues associated with the administration of therapeutic agents that have low oral bioavailability. Curcumin is an active ingredient in the turmeric plant, which has low oral bioavailability due to its poor aqueous solubility. One strategy that has been considered for enhancing the aqueous solubility, and, thus, its oral bioavailability, is the use of chitosan as a carrier for curcumin. Chitosan is a biodegradable and biocompatible polymer that is relatively water-soluble. Therefore, various studies have sought to improve the aqueous solubility of chitosan. The use of different pharmaceutical excipients and formulation strategies has the potential to improve aqueous solubility, formulation processing, and the overall delivery of hydrophobic drugs. This review focuses on various methods utilized for chitosan-based delivery of curcumin.     

Therapeutic potency of pharmacological adenosine receptors agonist/antagonist on cancer cell apoptosis in tumor microenvironment,current status,and perspectives

The hypoxic niche of tumor leads to a tremendous increase in the extracellular adenosine concentration through alteration of adenosine metabolism in the tumor microenvironment (TME). This consequently affects cancer progression, local immune responses, and apoptosis of tumor cells. Regulatory effect of adenosine on apoptosis in TME depends on the cancer cell type, pharmacological characteristics of adenosine receptor subtypes, and the adenosine concentration in the tumor niche. Exploiting specific pharmacological adenosine receptor agonist and antagonist inducing apoptosis in cancer cells can be considered as a proper procedure to control cancer progression. This review summarizes the regulatory role of adenosine in cancer cell apoptosis for a better understanding, and hence better management of the disease.     

Antidiabetic potential of saffron and its active constituents

The prevalence of diabetes mellitus is growing rapidly worldwide. This metabolic disorder affects many physiological pathways and is a key underlying cause of a multitude of debilitating complications. There is, therefore, a critical need for effective diabetes management. Although many synthetic therapeutic glucose-lowering agents have been developed to control glucose homeostasis, they may have unfavorable side effects or limited efficacy. Herbal-based hypoglycemic agents present an adjunct treatment option to mitigate insulin resistance, improve glycemic control and reduce the required dose of standard antidiabetic medications. Saffron (Crocus sativus L.), whilst widely used as a food additive, is a natural product with insulin-sensitizing and hypoglycemic effects. Saffron contains several bioactive β carotenes, which exert their pharmacological effects in various tissues without any obvious side effects. In this study, we discuss how saffron and its major components exert their hypoglycemic effects by induction of insulin sensitivity, improving insulin signaling and preventing β-cell failure, all mechanisms combining to achieve better glycemic control.     

Mechanisms of apoptosis modulation by curcumin: Implications for cancer therapy

Cancer incidences are growing and cause millions of deaths worldwide. Cancer therapy is one of the most important challenges in medicine. Improving therapeutic outcomes from cancer therapy is necessary for increasing patients’ survival and quality of life. Adjuvant therapy using various types of antibodies or immunomodulatory agents has suggested modulating tumor response. Resistance to apoptosis is the main reason for radioresistance and chemoresistance of most of the cancers, and also one of the pivotal targets for improving cancer therapy is the modulation of apoptosis signaling pathways. Apoptosis can be induced by intrinsic or extrinsic pathways via stimulation of several targets, such as membrane receptors of tumor necrosis factor-α and transforming growth factor-β, and also mitochondria. Curcumin is a naturally derived agent that induces apoptosis in a variety of different tumor cell lines. Curcumin also activates redox reactions within cells inducing reactive oxygen species (ROS) production that leads to the upregulation of apoptosis receptors on the tumor cell membrane. Curcumin can also upregulate the expression and activity of p53 that inhibits tumor cell proliferation and increases apoptosis. Furthermore, curcumin has a potent inhibitory effect on the activity of NF-κB and COX-2, which are involved in the overexpression of antiapoptosis genes such as Bcl-2. It can also attenuate the regulation of antiapoptosis PI3K signaling and increase the expression of MAPKs to induce endogenous production of ROS. In this paper, we aimed to review the molecular mechanisms of curcumin-induced apoptosis in cancer cells. This action of curcumin could be applicable for use as an adjuvant in combination with other modalities of cancer therapy including radiotherapy and chemotherapy.     

Mechanisms of statin-induced new-onset diabetes

Statins, with their lipid-lowering properties, are a first-line therapy for the prevention of cardiovascular diseases. Recent evidence, however, suggests that statins can increase the risk of new-onset diabetes (NOD). The molecular mechanisms of statin-induced NOD are not precisely known, although some pathophysiologic mechanisms have been suggested. Specific to the beta cell, these mechanisms include alterations in insulin secretion, changes in ion channels, modulation of signaling pathways, and inflammation/oxidative stress. Outwith the beta cell, other suggested mechanisms involve adipocytes, including alterations in adipocyte differentiation and modulation of leptin and adiponectin, and genetic and epigenetic mechanisms, including alterations in microRNA. The evidence supporting these and other mechanisms will be discussed. Greater understanding of the underlying mechanisms linking the onset of diabetes to statin therapy is essential and clinically relevant, as it may enable novel preventative or therapeutic approaches to be instituted and guide the production of a new generation of statins lacking this side effect.     

Protective effects of plant-derived natural products on renal complications

Diabetic nephropathy is the leading cause of renal failure worldwide. This debilitating disorder has several underlying pathophysiologic mechanisms, and therefore a variety of pharmacologic agents have been developed to prevent or treat diabetic nephropathy; however, synthetic drugs may possess unfavorable side effects. In response to this, the global use of herbal-based pharmacologic agents is increasing among diabetic patients. Numerous studies have reported therapeutic benefits of herbal-based compounds against diabetes-induced renal dysfunction. These agents can prevent renal dysfunction and improve renal function by blocking or suppressing deleterious pathways such as oxidative stress, inflammation, apoptosis, necrosis, and nitric oxide deprivation that lead to vascular injuries. In the current study, we have reviewed the beneficial properties of the most common herbal agents used in renal complications and diabetic nephropathy.