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BACKGROUND/OBJECTIVES: Endothelial dysfunction, which can be manifested by loss of nitric oxide bioavailability, is an increasingly recognized cause of cardiovascular diseases. Previous studies showed that diets affect endothelial function and modify cardiovascular risks. This study aimed to assess the effects of Ramadan fasting, as a diet intervention, on endothelial function. SUBJECTS/METHODS: The study population consisted of 21 male patients (mean age: 52[+ or -]9 years) with cardiovascular risks (coronary artery disease, cerebrovascular or peripheral arterial diseases). The biochemical variables in serum of patients were measured 2 days before and after Ramadan fasting. The levels of asymmetric dimethylarginine (ADMA) and vascular endothelial growth factor (VEGF) were evaluated using the enzyme-linked immunosorbent assay. Nitric oxide (NO) and Malondialdehyde (MDA) levels were measured by the Griess and thiobarbituric acid reaction substances assay, respectively. RESULTS: NO levels in patients after Ramadan fasting were significantly higher compared with the baseline value (85.1 [+ or -]11.54 vs 75.8 [+ or -]10.7 [micro]mol/l) (P < 0.05). Post-Ramadan levels of ADMA decreased significantly in comparison with pre-Ramadan levels (802.6 [+ or -] 60.9 vs 837.6 [+ or -] 51.0 nmol/l) (P < 0.05). In addition, the levels of VEGF and MDA changed during Ramadan fasting, but these changes were not statistically significant (228.1 [+ or -] 27.1 vs 222.7 [+ or -] 22.9 pg/ml and 3.2 [+ or -]0.7 vs 3.6 [+ or -]1.1 [micro]mol/l, respectively). CONCLUSIONS: Ramadan fasting may have beneficial effects on endothelial function and can modulate cardiovascular risks. Further studies are needed to confirm the clinical significance of Ramadan fasting on cardiovascular health. doi:10.1038/ejcn.2014.61;published online 23 April 2014, INTRODUCTION Ramadan is a lunar month during which Muslims are prescribed fasting for moral and spiritual reasons. As more than one billion people worldwide believe in Islam, it is estimated [...]

Inflammation during pregnancy may occur due to various factors. This condition, in which maternal immune system activation occurs, can affect fetal brain development and be related to neurodevelopmental diseases. MIA interacts with the fetus's brain development through maternal antibodies, cytokines, chemokines, and microglial cells. Antibodies are associated with the development of the nervous system by two mechanisms: direct binding to brain inflammatory factors and binding to brain antigens. Cytokines and chemokines have an active presence in inflammatory processes. Additionally, glial cells, defenders of the nervous system, play an essential role in synaptic modulation and neurogenesis. Maternal infections during pregnancy are the most critical factors related to MIA; however, several studies show the relation between these infections and neurodevelopmental diseases. Infection with specific viruses, such as Zika, cytomegalovirus, influenza A, and SARS-CoV-2, has revealed effects on neurodevelopment and the onset of diseases such as schizophrenia and autism. We review the relationship between maternal infections during pregnancy and their impact on neurodevelopmental processes., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Long-term exposure to ionizing radiation (IR) can cause dire health consequences even less than the dose limits. Previous biomonitoring studies have focused more on complete blood counts (CBCs), with non-coherent results. In this study, we aimed to investigate the association between exposure to IR and cytokine interleukin-6 (IL-6) along with hematological parameters in Tabriz megacity's radiation workers. In this hospital-based study, blood samples were taken from 33 radiation workers (exposed group) and 34 non-radiation workers (control group) in 4 hospitals. Absorbed radiation dose was measured by a personal film badge dosimeter in radiation workers. The studied biomarkers and all of the selected covariates were measured and analyzed using adjusted multiple linear regression models. The exposed doses for all radiation workers were under the dose limits (overall mean = 1.18 mSv/year). However, there was a significant association between exposure to ionizing radiation and IL-6 (49.78 vs 36.17; t = 2.4; p = 0.02) and eosinophils (0.17 vs 0.14; t = 2.02; p = 0.049). The difference between the mean of the other biomarkers in radiation workers was not statistically significant compared to the control group. This study demonstrated that long-term exposure to ionizing radiation, even under the dose limits, is related to a significantly increased level of some blood biomarkers (Il-6 and eosinophil) that, in turn, can cause subsequent health effects such as cancer., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Bone is an alive and dynamic organ that is well-differentiated and originated from mesenchymal tissues. Bone undergoes continuous remodeling during the lifetime of an individual. Although knowledge regarding bones and their disorders has been constantly growing, much attention has been devoted to effective treatments that can be used, both from materials and medical performance points of view. Polymers derived from natural sources, for example polysaccharides, are generally biocompatible and are therefore considered excellent candidates for various biomedical applications. This review outlines the development of chitosan-based biomaterials for the treatment of bone disorders including bone fracture, osteoporosis, osteoarthritis, arthritis rheumatoid, and osteosarcoma. Different examples of chitosan-based formulations in the form of gels, micro/nanoparticles, and films are discussed herein. The work also reviews recent patents and important developments related to the use of chitosan in the treatment of bone disorders. Although most of the cited research was accomplished before reaching the clinical application level, this manuscript summarizes the latest achievements within chitosan-based biomaterials used for the treatment of bone disorders and provides perspectives for future scientific activities., (Copyright © 2022. Published by Elsevier B.V.)

For the first time, nitrogen, sulfur, phosphorus, and boron-doped carbon dots (N, S, P, B-codoped CDs) were synthesized through a hydrothermal reaction. The produced CDs were utilized to develop an optical sensor to determine methotrexate (MTX) in cell lysates and patients' plasma samples. Basically, in the presence of MTX, the fluorescence emission of the CD-based probe was quenched. Under optimum conditions, a good proportional relationship was obtained between the quenched fluorescence signal and MTX concentrations from 74.9 ng/mL to 99.9 µg/mL with a limit of detection of 74.9 ng/mL. The developed nanoprobe provided a wide linear range and high accuracy and was successfully utilized in the routine therapeutic drug monitoring of MTX in plasma samples. The obtained results proposed the developed nanoprobe for the on-time and specific detection of MTX in blood samples. As another application, N, S, P, B-codoped CDs were utilized for bioimaging MCF-7 cancer cells and could be proposed as efficient bioimaging agents for tumor cells., Competing Interests: Conflict of Interests: Jafar Soleymani reports grants from Urmia University of Medical Sciences, Urmia, Iran during the conduct of the study., (Copyright © 2022, Author(s).)

Coagulopathy is a frequently reported finding in the pathology of coronavirus disease 2019 (COVID-19); however, the molecular mechanism, the involved coagulation factors, and the role of regulatory proteins in homeostasis are not fully investigated. We explored the dynamic changes of nine coagulation tests in patients and controls to propose a molecular mechanism for COVID-19-associated coagulopathy. Coagulation tests including prothrombin time (PT), partial thromboplastin time (PTT), fibrinogen (FIB), lupus anticoagulant (LAC), proteins C and S, antithrombin III (ATIII), D-dimer, and fibrin degradation products (FDPs) were performed on plasma collected from 105 individuals (35 critical patients, 35 severe patients, and 35 healthy controls). There was a statically significant difference when the results of the critical (CRT) and/or severe (SVR) group for the following tests were compared to the control (CRL) group: PT CRT (15.014) and PT SVR (13.846) (PT CRL  = 13.383, p  < 0.001), PTT CRT (42.923) and PTT SVR (37.8) (PTT CRL  = 36.494, p  < 0.001), LAC CRT (49.414) and LAC SVR (47.046) (LAC CRL  = 40.763, p  < 0.001), FIB CRT (537.66) and FIB SVR (480.29) (FIB CRL  = 283.57, p  < 0.001), ProC CRT (85.57%) and ProC SVR (99.34%) (ProC CRL  = 94.31%, p  = 0.04), ProS CRT (62.91%) and ProS SVR (65.06%) (ProS CRL  = 75.03%, p  < 0.001), D-dimer ( p  < 0.0001, χ 2  = 34.812), and FDP ( p  < 0.002, χ 2  = 15.205). No significant association was found in the ATIII results in groups (ATIII CRT  = 95.71% and ATIII SVR  = 99.63%; ATIII CRL -values) have significance in the prognosis of patients. Disruptions in homeostasis in protein C (and S), VIII/VIIIa and V/Va axes, probably play a role in COVID-19-associated coagulopathy.p  = 0.321). D-dimer, FIB, PT, PTT, LAC, protein S, FDP, and protein C (ordered according to p -values) have significance in the prognosis of patients. Disruptions in homeostasis in protein C (and S), VIII/VIIIa and V/Va axes, probably play a role in COVID-19-associated coagulopathy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Elieh Ali Komi, Rahimi, Asghari, Jafari, Rasouli, Mohebalizadeh, Abbasi, Nejadrahim, Rezazadeh and Shafiei-Irannejad.)

Memantine is a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist that was initially indicated for the treatment of moderate to severe Alzheimer's disease. It is now also considered for a variety of other pathologies in which activation of NMDA receptors apparently contributes to the pathogenesis and progression of disease. In addition to the central nervous system (CNS), NMDA receptors can be found in non-neuronal cells and tissues that recently have become an interesting research focus. Some studies have shown that glutamate signaling plays a role in cell transformation and cancer progression. In addition, these receptors may play a role in cardiovascular disorders. In this review, we focus on the most recent findings for memantine with respect to its pharmacological effects in a range of diseases, including inflammatory disorders, cardiovascular diseases, cancer, neuropathy, as well as retinopathy., (Copyright © 2021 Elsevier B.V. All rights reserved.)

There have been many efforts to synthesize advanced materials that are capable of real-time specific recognition of a molecular target, and allow the quantification of a variety of biomolecules. Scaffold materials have a porous structure, with a high surface area and their intrinsic nanocavities can accommodate cells and macromolecules. The three-dimensional structure (3D) of scaffolds serves not only as a fibrous structure for cell adhesion and growth in tissue engineering, but can also provide the controlled release of drugs and other molecules for biomedical applications. There has been a limited number of reports on the use of scaffold materials in biomedical sensing applications. This review highlights the potential of scaffold materials in the improvement of sensing platforms and summarizes the progress in the application of novel scaffold-based materials as sensor, and discusses their advantages and limitations. Furthermore, the influence of the scaffold materials on the monitoring of infectious diseases such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and bacterial infections, was reviewed., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: MRH declares the following potential conflicts of interest. Scientific Advisory Boards: Transdermal Cap Inc, Cleveland, OH; BeWell Global Inc, Wan Chai, Hong Kong; Hologenix Inc. Santa Monica, CA; LumiThera Inc, Poulsbo, WA; Vielight, Toronto, Canada; Bright Photomedicine, Sao Paulo, Brazil; Quantum Dynamics LLC, Cambridge, MA; Global Photon Inc, Bee Cave, TX; Medical Coherence, Boston MA; NeuroThera, Newark DE; JOOVV Inc, Minneapolis-St. Paul MN; AIRx Medical, Pleasanton CA; FIR Industries, Inc. Ramsey, NJ; UVLRx Therapeutics, Oldsmar, FL; Ultralux UV Inc, Lansing MI; Illumiheal & Petthera, Shoreline, WA; MB Lasertherapy, Houston, TX; ARRC LED, San Clemente, CA; Varuna Biomedical Corp. Incline Village, NV; Niraxx Light Therapeutics, Inc, Boston, MA. Consulting; Lexington Int, Boca Raton, FL; USHIO Corp, Japan; Merck KGaA, Darmstadt, Germany; Philips Electronics Nederland B.V. Eindhoven, Netherlands; Johnson & Johnson Inc, Philadelphia, PA; Sanofi-Aventis Deutschland GmbH, Frankfurt am Main, Germany. Stockholdings: Global Photon Inc, Bee Cave, TX; Mitonix, Newark, DE. The other authors report no potential conflicts of interest., (© 2021 Elsevier B.V. All rights reserved.)

A novel strategy was developed for the detection of methotrexate (MTX) via the quenching effect of MTX on the fluorescence intensity of terbium-doped dendritic silica particles (Tb@KCC-1). The fluorescence intensity of Tb@KCC-1 can be effectively quenched by MTX at 546 nm under an excitation wavelength of 233 nm. The quenched fluorescence is proportional to the amount of MTX in both plasma and exhaled breath condensate (EBC) samples. Under the optimal conditions, the linear dynamic ranges of the developed method were 44 nM to 2.2 μM for EBC, 44 nM to 0.22 μM and 0.22-2.2 μM for plasma samples. The limit of detection (LOD) and limit of quantification (LOQ) in both plasma and EBC media are 35 and 116 nM, respectively. The developed method has the benefits of fast analysis time, simple approach, high specificity, and sensitivity for the detection of MTX in both media. This nanoprobe has been successfully utilized for the quantification of MTX in patients' plasma and spiked EBC samples, proving the applicability of the nanoprobe for MTX detection in real samples.

A wide variety of species, such as different ions, reactive oxygen species, and biomolecules play critical roles in many cell functions. These species are responsible for a range of cellular functions such as signaling, and disturbed levels could be involved in many diseases, such as diabetes, cancer, neurodegeneration etc. Thus, sensitive and specific detection methods for these biomarkers could be helpful for early disease detection and mechanistic investigations. New ultrasensitive sensors for detection of markers within living cells are a growing field of research. The present review provides updates in live cell-based biosensing, which have been published within the last decade. These sensors are mainly based on carbon, gold and other metals, and their physicochemical advantages and limitations are discussed. Advanced materials can be incorporated into probes for the detection of various analytes in living cells. The sensitivity is strongly influenced by the intrinsic properties of the nanomaterials as well their shape and size. The mechanisms of action and future challenges in the developments of new methods for live cell based biosensing are discussed., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Immunotherapy-based cancer treatment has revolutionized the era of cancer patients recuperation and it has brought a strong hope to treatment of some types of cancers. Metformin, a widely used antidiabetic drug, which has intensely been studied for its anticancer effects, is believed to have positive influences on immune responses against tumor cells. Metformin can affect metabolic pathways within cells mainly through activation of AMPK. Metabolic restriction of tumor microenvironment on effector immune cells is one of the important strategies favoring tumor cells to escape from immunogenic cell death. The metabolism of T cells has an axial role in shaping and supporting immune responses and may have an important role in anticancer immunity, suggesting that the functionality and durability of tumor-specific T cells need sufficient energy and nutrients. Energy biogenesis of tumor-specific cytotoxic T cells has become an interesting field of study and it is suggested that activation and maintenance of effector T cell responses in tumor microenvironment may occur by metabolic reprogramming of T cells. AMPK has been noticed as the main intracellular energy sensor and mitochondrial biogenesis key regulator which can control and regulate metabolic reprogramming in immune cells and increase antitumor immunity. Metabolic reprogramming of T cells to overcome metabolic restriction in tumor microenvironment, maiming effector T cell responses against tumor cells, has been noticed by several studies. Here we represent metformin, an AMPK activator, as a new candidate drug for metabolic reprogramming of tumor-specific T cells to increase the efficacy and accountability of cancer immunotherapy., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Despite the prominent progress in understanding cancer immunosurveillance mechanisms, there are some types of problems which have been identified to hinder effective and successful immunotherapy of cancers. Such problems have been ascribed to the tumor abilities in the creation of a tolerant milieu that can impair immune responses against cancer cells. In the present study, we represent possible approaches for metabolic reprogramming of T cells in cancer immunotherapy to overcome tumor metabolic impositions on immune responses against cancer cells. Metabolic suppression of effector immune cells in tumor milieu is one of the important strategies recruited by tumor cells to escape from immunogenic cell death. We have investigated the metabolic reprogramming of T cells as a method and a possible new target for cancer immunotherapy. Synergic effects of PPAR ligands in immunotherapy of cancers on the metabolic reprogramming of T cells have been noticed by several studies as a new target of cancer immunotherapy. The current wealth of data like this promises a future scenario which the consideration of metabolic restriction in the tumor microenvironment and administration of therapeutic agents such as PPAR ligands to overcome metabolic restrictions on T cells (refreshing their functionality) may be effective and enhance the accountability and efficacy of cancer immunotherapy., (Copyright © 2020. Published by Elsevier B.V.)

The history, properties, and characteristics of para-sulfonato-calixarenes are described. On the one hand, the inherent antibacterial and antifungal properties against microorganisms, and on the other hand non-toxicity of these supramolecules toward human organs are analyzed. The resulting biocompatibility of para-sulfonato-calixarenes makes them potential candidates for diverse life sciences and pharmaceutical applications without significant side effects. The interactions with different drugs, the capability of drug encapsulation, delivery, and release, the formation of host-quest assemblies and inclusion complexation between para-sulfonato-calixarenes and drugs were also investigated in detail. Besides, their function in cancer treatment and their toxicity against different cancer cell lines were fully reviewed and summarized. Afterward, the capability of these macrocyclic compounds for biosensing of organic compounds, peptides and enzymes activity was highlighted. In this review, we also take a brief look at recent reports on the applications of para-sulfonato-calixarenes in fluorescence imaging and their usage as highly stable and bright probes for in vivo and in vitro imaging and sensing., Competing Interests: Declaration of competing interest The authors report no conflicts of interest., (Copyright © 2020. Published by Elsevier Masson SAS.)

Wound healing is a dynamic and complex process which affects the quality of life in patients and annually causes high costs for the health system, worldwide. Polymers from natural origins such as polysaccharides have gained particular interest between researchers for wound dressing applications due to their abundance in nature, biocompatibility with human tissues, and ideal physicochemical properties. Aside from their supportive effect in wound care, polysaccharides and their derivatives can actively contribute to the healing process. Silver nanoparticles are widely used noble metal nanoparticles incorporated in wound dressings due to their low toxicity for human cells, naturally availability, and strong antimicrobial effects. In the present study, we will review the most frequently used polysaccharides in wound dressing procedure with silver or silver nanoparticles accommodated. The methods of synthesis, physicochemical properties, healing efficiencies, toxicity against human tissues, antibacterial and antifungal effects of each material will also be discussed., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Ovarian cancer is considered as one of the most lethal gynecological cancers, and cisplatin-based therapy has an important role as the first-line option for chemotherapy. Resistance to chemotherapy is the main obstacle against successful cancer chemotherapy with cisplatin. Therefore, identifying potent compositions and molecules with fewer side-effects is a big challenge to overcome cisplatin resistance. In this study, we investigated the possible mechanism and potency of sanguinarine, a plant-derived alkaloid, in human cisplatin-resistant ovarian cancer (A2780/R) cells. The effect of sanguinarine on cytotoxicity of cisplatin was determined by MTT assay. Apoptosis-inducing effect of sanguinarine alone and in combination with cisplatin was evaluated by annexin V/PI assay and DAPI staining. Intracellular glutathione (GSH) content was quantitated using GSH assay kit after treatment with sanguinarine. Results indicated that sanguinarine enhances the sensitivity of A2780/R cells to cisplatin. Apoptosis-inducing effect of cisplatin was also enhanced when combined with sanguinarine. Furthermore, sanguinarine reduced intracellular GSH content in a dose-dependent but not time-dependent manner. These findings suggest that sanguinarine could reverse cisplatin resistance in A2780/R cells through GSH reduction. Therefore, sanguinarine can be used as one of the potent adjuvants for ovarian cancer chemotherapy., (© 2019 John Wiley & Sons A/S.)

The prevalence of diabetes mellitus is increasing all over the world and it is apparent that treatment of diabetic complications has the same importance as primary diabetes treatment and glycemic control. Diabetic complications occur as a result of prolonged hyperglycemia and its consequences, such as advanced glycation end products and reactive oxygen species. Impairment of lipid profile is also contributed to worsening diabetic complications. Therefore, it seems that the application of lipid-lowering agents may have positive effects on reversing diabetic complications besides glycemic control. Statins, a group of lipid-lowering compounds, have been shown to exert antioxidant, immunomodulatory, anti-inflammatory, and antiproliferative properties beyond their lipid-lowering effects. Furthermore, they have been reported to improve diabetic complications with different pathways. In this review, we will discuss the clinical importance, molecular biology of the most important microvascular/macrovascular diabetic complications, possible application of statins and their mechanism of action in retarding these complications., (© 2019 Wiley Periodicals, Inc.)

Overcoming multidrug resistance (MDR) is a final goal of various recent studies, in which combination of different compounds and conventional chemotherapeutics results in circumventing MDR and hence cancer progression. Therefore, we aimed to investigate the effects of peroxisome proliferator-activated receptors (PPARs)-γ on MDR in doxorubicin-resistant human myelogenous leukemia cells. The effect of doxorubicin on cell viability following treatment with ciglitazone was measured using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. The activity of P-glycoprotein (P-gp), as one of the membrane transporters, was determined by the rhodamine 123 (Rho 123) assay. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and Western blot were used for the measurement of P-gp, and tensin homolog deleted on chromosome ten (PTEN) expression at mRNA and protein, respectively. For evaluation of doxorubicin (DOX)-induced apoptosis by annexin V/PI staining was used. Ciglitazone significantly increases the cytotoxic effects of DOX. In addition, ciglitazone considerably decreased the expression levels and activity of P-gp in DOX-resistant K562 cells. Furthermore, upon the ciglitazone treatment, PTEN expression could be increased in K562/DOX cells in a PPARγ-dependent manner. Moreover, ciglitazone significantly enhanced DOX-induced apoptosis in K562/DOX cells. The combination treatment of K562/DOX leukemia cancer cells with doxorubicin and ciglitazone might be an effective strategy in inducing apoptosis and reversing developed MDR, and more importantly decreasing the adverse side effects of these agents., (© 2019 Wiley Periodicals, Inc.)

Wound care is crucial for controlling infections of the injured area. Regarding this, wound dressings with antimicrobial activities are useful to minimize the microbial infections of the wounds. Herein, a series of quaternized chitosan nanocomposite films blended with silver nanoparticles were fabricated with high potential for wound dressing applications. After characterization of the prepared films by Fourier-transform infrared spectroscopy (FTIR), X-Ray diffraction (XRD), scanning electron microscopy (SEM), energy-dispersive X-ray spectroscopy (EDX), and element mapping analysis (MAP). Other parameters such as swelling ratio, blood clotting activity, and biocompatibility of the films were also investigated. Besides, the antibacterial and antifungal activities of prepared samples were examined against Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa, Candida albicans, and a multi drug resistance Pseudomonas aeruginosa as a drug resistance bacterium strain. Interestingly, the designed quaternized chitosan film (even without silver nanoparticles) showed high antimicrobial activity against all tested microbial strains which is probably due to the presence of imidazolium moiety in the film matrix. Furthermore, all nanocomposites showed a potent antimicrobial activity. Generally, the results of cell proliferation and attachment with MTT assay and DAPI staining on HFFF cells, have proved the cytocompatibility nature of the nanocomposite films. These results indicate that the developed bioactive quaternized chitosan nanocomposite films can be considered as biomaterial for wound dressing applications., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Despite the major progresses in comprehending the mechanisms of tumor immunosurveillance and the role of innate and adaptive immune systems in recent years, there are still a number of obstacles hindering successful and effective immunotherapy of cancer. Such obstacles have been mainly attributed to the ability of tumors in creating a tolerant microenvironment and exploiting a plethora of immunosuppressive factors that counter effective immune responses against tumor cells. Here we represent a new insight into probable links between immune system disability with metabolism and chronic psychological stress which is beyond the other strategies recruited by tumors to thwart tumor immunosurveillance. In addition, we underscore the prominent role of improper innate immune responses as one of the underlying causes of either pro-tumorigenic capability or tumor immunosurveillance failure. However the insufficiency of stimulatory factors in immune responses is a major fact leading to tumor survival, metabolic suppression of immune cells in tumor microenvironment, as well as the negative influences of chronic stress and depression in cancer patients are important parameters amplifying disability of immune responses which have mostly been underestimated in cancer immunotherapy. Stress-related catecholamines are suggested as immunosuppressive factors. In addition, tumor cells have distinct metabolic pathways and secrete various metabolites in the tumor microenvironment which may inhibit T cells activity. We believe that simultaneous control of metabolic and psychological negative influences on the tumor immunosurveillance, along with addressing the weak aspects of innate and adaptive immune responses in cancer immunotherapy may result in more successful treatment of tumors., (Copyright © 2019 European Federation of Immunological Societies. Published by Elsevier B.V. All rights reserved.)

Clustered regularly interspaced short palindromic repeats/CRISPR-associated nuclease 9 (CRISPR-Cas9) is an RNA-guided gene editing tool which offers several advantageous characteristics in comparison with the conventional methods (e.g., zinc finger nucleases and transcription activator-like effector nucleases) such as cost-effectiveness, flexibility, and being easy-to-use. Despite some limitations such as efficient delivery and safety, CRISPR-Cas9 is still the most convenient tool for gene editing purposes. Due to the potential capability of the CRISPR-Cas9 system in genome editing and correction of casual mutations, it can be considered as a possible therapeutic system in the treatment of disorders associated with the genome mutations and in particular cancer treatment. In this review, we will discuss CRISPR-Cas-based gene editing along with its classifications and mechanism of action. Furthermore, the therapeutic application of the CRISPR-Cas9 system in mutational disorders, delivery systems, as well as its advantages and limitations with a special emphasis on cancer treatment will be discussed., (© 2019 Wiley Periodicals, Inc.)

Cancer is the leading cause of death all over the world and chemotherapy is an important approach to fight cancer, however, there are many obstacles against successful cancer chemotherapy such as development of multidrug resistance, poor solubility of chemotherapeutic agents and adverse side effects to healthy tissues. An important strategy to overcome these obstacles, is the use of nanotechnology. In recent years, natural polymers such as cellulose and its nanoform structure, nanocrystalline cellulose (NCC), have attracted the interest of researchers in the field of nanotechnology and specially drug delivery systems, due to biocompatibility and biodegradability of NCC. Cellulose is the most abundant natural biopolymer and changes to NCC by several chemical and mechanical methods. In this review, we mainly focus on the methods for production of NCC, physicochemical properties and medical applications of NCC (e.g. regenerative medicine, replacement of vascular grafts, tissue engineering, anti-bacterial/anti-viral applications, diagnosis and biosensing) with a special emphasize on drug delivery systems., (Copyright © 2019. Published by Elsevier B.V.)

Purpose: Chemotherapy as an important tool for cancer treatment faces many obstacles such as multidrug resistance and adverse toxic effects on healthy tissues. Drug delivery systems have opened a new window to overcome these problems., Methods: A polyelectrolyte carboxymethyl cellulose polymer as a magnetic nanocarrier was synthesized for enhancing delivery and uptake of doxorubicin in MCF7 breast cancer cells and decreasing the adverse toxic effects to healthy tissues., Results: The physicochemical properties of developed nanocarrier showed that it can be used in drug delivery purposes. The efficiency of the delivery system was assessed by loading and release studies. Besides, biological assays including protein-particle interaction, hemolysis assay, cytotoxicity study, cellular uptake, and apoptosis analysis were performed. All results persuaded us to investigate the cytotoxic effects of nanocarrier in an animal model by determining the biochemical parameters attributed to organ injuries, and hematoxylin and eosin (H&E) staining for histopathological manifestations. We observed that the nanocarrier has no toxic effect on healthy tissues, while, it is capable of reducing the toxic side effects of doxorubicin by more cellular internalization., Conclusion: Chemical characterizations and biological studies confirmed that developed nanocarrier with permanent cationic groups of imidazolium and anionic carboxylic acid groups is an effective candidate for anticancer drug delivery.

Colorectal cancer (CRC) is one of the most common cancers worldwide, and it is considered the fourth most common cause of life-threatening cancers. Diabetes mellitus, especially type 2 diabetes, is an independent risk factor for CRC, due to shared risk factors like physical inactivity and obesity. Thiazolidinediones (TZDs) are among the most common medications for type 2 diabetes mellitus. Recent investigations have suggested a correlation between TZD usage (in a time-dependent manner) and reduced risk of CRC such that a longer period of TZDs treatment can lead to higher protection against CRC. TZDs have antitumor effects in a wide variety of in vitro and in vivo cancer models through different mechanisms such as the impacts on cell cycle, apoptosis, cell differentiation, and angiogenesis. These effects can be mediated via both peroxisome proliferator-activated receptors γ (PPARγ)-dependent and PPARγ-independent pathways. Due to the protective effects of TZDs in cancer prevention and treatment, they can be considered potent adjuvants in cancer treatment. In the current review, we discuss the effects of TZDs on prevention and treatment of cancers, with special emphasis on CRC and the association of TZD administration with metabolic regulation of T cells in defense against tumor cells.

The prevalence of diabetes mellitus especially type 2 diabetes mellitus is increasing all over the world. In addition to cardiomyopathy and nephropathy, diabetics are at higher risk of mortality and morbidity due to greater risk of bone fractures and skeletal abnormalities. Patients with diabetes mellitus have lower bone quality in comparison to their non-diabetic counterparts mainly because of hyperglycemia, toxic effects of advanced glycosylation end-products (AGEs) on bone tissue, and impaired bone microvascular system. AGEs may also contribute to the development of osteoarthritis further to osteoporosis. Therefore, glycemic control in diabetic patients is vital for bone health. Metformin, a widely used antidiabetic drug, has been shown to improve bone quality and decrease the risk of fractures in patients with diabetes in addition to glycemic control and improving insulin sensitivity. AMP activated protein kinase (AMPK), the key molecule in metformin antidiabetic mechanism of action, is also effective in signaling pathways involved in bone physiology. This review, discusses the molecules linking diabetes and bone turnover, role of AMPK in bone metabolism, and the effect of metformin as an activator of AMPK on bone disorders and malignancies., (Copyright © 2018 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

A possible approach for clinical cancer treatment is combination chemotherapy. To address this issue, many anticancer agents have been used simultaneously to achieve synergistic effects with the different mechanism of actions, however, their toxic side effects are still a big challenge. In this study, a smart, biocompatible, magnetic nanocarrier composed of multi-branched ionic liquid-chitosan grafted mPEG was designed and used for targeted multidrug delivery of DOX and MTX as model anticancer agents to MCF7 breast cancer cells. The results of hemolysis assay on human red blood cells and cytotoxicity studies indicated that blank nanocarrier has no significant hemolytic and cytotoxic effects in MCF7 cells as observed in the results of MTT assay, however, drugs-loaded nanocarrier could decrease the viability of MCF7 cells in a dose-dependent manner. To further simulate the interaction of nanocarrier with plasma proteins, the SDS-PAGE assay was performed after the nanocarrier was incubated with human plasma and the results indicated that a series of proteins were attached to the surface of nanocarrier leading protein-particle corona complex. This complex gives a stealth property as well as increasing cellular uptake process due to the presence of proteins acting as ligands for receptors in the surface of cancer cells that are suitable for drug delivery systems. The efficiency of dual-drug delivery was also confirmed by cellular uptake and DAPI staining. All these results persuade us, this nanocarrier is suitable for use in further animal studies in future investigations., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

The study was aimed at investigating the synergistic inhibitory effect of unique combinational regimen of nanocapsulated Metformin (Met) and Curcumin (Cur) against T47D breast cancer cells. For this purpose, Met and Cur were co-encapsulated in PEGylated PLGA nanoparticles (NPs) and evaluated for their therapeutic efficacy. The morphology and dynamic light scattering (DLS) analyses were carried out to optimize the nanoformulations. Drug release study was performed using dialysis method and then the cytotoxic and inhibitory effect of individual and combined drugs on expression level of hTERT in T47D breast cell line were evaluated using MTT assay and qPCR, respectively. The results showed that free drugs and formulations exhibited a dose-dependent cytotoxicity against T47D cells and especially, Met-Cur-PLGA/PEG NPs had more synergistic antiproliferative effect and significantly arrested the growth of cancer cells than the other groups (p < .05). Real-time PCR results revealed that Cur, Met and combination of Met-Cur in free and encapsulated forms inhibited hTERT gene expression. It was found that Met-Cur-PLGA/PEG NPs in relative to free combination could further decline hTERT expression in all concentration (p < .05). Taken together, our study demonstrated that Met-Cur-PLGA/PEG NPs based combinational therapy holds promising potential towards the treatment of breast cancer.

Purpose: P-glycoprotein (P-gp) mediated multidrug resistance (MDR) has been recognized as the main obstacle against successful cancer treatment. To address this problem, co-encapsulated doxorubicin (DOX) and metformin (Met) in a biodegradable polymer composed of poly(lactide-co-glycolide) (PLGA) and D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) was prepared. We reported in our previous study that Met inhibits P-gp in DOX resistant breast cancer (MCF-7/DOX) cells. TPGS is a bioactive compound which has also been shown to inhibit P-gp, further to its pharmaceutical advantages., Methods: The DOX/Met loaded PLGA-TPGS nanoparticles (NPs) were prepared by double emulsion method and characterized for their surface morphology, size and size distribution, and encapsulation efficiencies of drugs in NPs., Results: All NPs were found to be spherical-shaped with the size distribution below 100 nm and encapsulation efficiencies were 42.26 ± 2.14% for DOX and 7.04 ± 0.52% for Met. Dual drug loaded NPs showed higher cytotoxicity and apoptosis in MCF-7/DOX cells in comparison to corresponding free drugs. The higher cytotoxicity of dual drug loaded NPs was attributed to the enhanced intracellular drug accumulation due to enhanced cellular uptake and reduced drug efflux which was obtained by combined effects of Met and TPGS in reducing cellular ATP content and inhibiting P-gp., Conclusion: Simultaneous delivery of DOX and Met via PLGA-TPGS NPs would be a promising approach to overcome MDR in breast cancer chemotherapy.

Introduction: p53R2 is a p53-inducible protein that contributes to DNA repair by providing dNTPs in response to DNA damage. The roles of p53R2 in cancer cells and malignancies still remain controversial. Herein, we examined the effects of p53R2 silencing on HepG2 human hepatocellular carcinoma (HHC) cell line (wild-type p53) viability, apoptosis and cell cycle arrest in the presence and absence of doxorubicin., Methods: Cell transfection was performed using a liposomal approach. Gene silencing was determined by quantitative real-time PCR and western blot analysis. To evaluate the cell growth rate after transfection, trypan blue dye exclusion assay was employed. The cytotoxicity of the doxorubicin and p53R2 siRNA as single agents or in combination against HepG2 cell was analyzed by MTT assay and the drug combination effects was evaluated by calculating the combination index. The effects of treatments on different stages of cell cycle were analyzed by flow cytometry using propidium iodide (PI) and induction of apoptosis was assessed using DNA-histone ELISA., Results: We found that silencing of p53R2 alone had a strong effect on growth inhibition and spontaneous apoptosis in HepG2 cells. p53R2 siRNA synergistically enhanced the cytotoxic effect of doxorubicin. Furthermore, when used in combination with doxorubicin (0.4μM), a significant increase in the rate of apoptosis was observed (P<0.05). Moreover, cell cycle at S and G2/M phases progressed at a lower rate after p53R2 combination treatment compared with doxorubicin mono-therapy., Conclusion: These findings suggest that siRNA-mediated silencing of p53R2 has great potential as a therapeutic tool and adjuvant in chemotherapy., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Resistance against chemotherapy is still a major problem in successful cancer treatment in the clinic. Therefore, identifying new compounds with lower side-effects and higher efficacy is an important approach to overcome multidrug resistance (MDR). Here, we investigated the activity and possible mechanism of the antidiabetic drug, metformin, in human doxorubicin (DOX)-resistant breast cancer (MCF-7/DOX) cells. The effect of metformin on the cytotoxicity of DOX was evaluated by MTT assay. The P-gp mRNA/protein expression levels following treatment with metformin were determined using real-time polymerase chain reaction and Western blot analysis, respectively. Intracellular rhodamine 123 accumulation assay was performed to evaluate the P-gp function. Cellular ATP content was determined using ATP assay kit. The effect of metformin on DOX-induced apoptosis was evaluated by annexin V/FITC assay. Exposure to metformin considerably enhanced the cytotoxicity of DOX. Metformin had no substantial effect on P-gp expression, while the activity of P-gp and intracellular ATP content decreased with metformin treatment in a dose-dependent manner. Furthermore, metformin significantly increased the DOX-induced apoptosis. These results indicate that metformin could reverse MDR in breast cancer cells by reducing P-gp activity. Therefore, metformin can be suggested as a potent adjuvant in breast cancer chemotherapy., (© 2017 John Wiley & Sons A/S.)

Globally at 2014, it was estimated that there was 347 million people with diabetes in which 90 percent of them were diagnosed with type 2 diabetes mellitus (T2DM). Although the association between diabetes mellitus and cancer risk was found about 100 years ago, the issue is not still clear. Many studies especially cohort and case-control studies have suggested a higher risk of cancer in patients with diabetes mainly in those with type 2 diabetes. Insulin concentration is high in these patients, and due to its mitogenic effects, it may be a possible hypotheses for higher risk of cancer in diabetic patients. Therefore, antidiabetic drugs, which are involved in insulin secretion and sensitivity, may have beneficial effects in cancer treatment. Several groups of drugs with different mechanisms of action, mostly prescribed orally, are used for the treatment of type 2 diabetes mellitus including, insulin sensitizers (thiazolidinediones), insulin secretagogues (sulfonylureas), and biguanides. In this review, the possible effects of antidiabetic drugs (biguanides, thiazolidinediones, and sulfonylureas) and some of their mechanisms for overcoming cancer will be discussed., (© 2017 John Wiley & Sons A/S.)

Multidrug resistance in tumor cells is still a big challenge in cancer treatment. Therefore, identification ofsafe and effective multidrug resistance-reversing compounds with minimal side effects is an important approach in cancer treatment. Here, we investigated the role and potential mechanisms of peroxisome proliferator-activated receptor γ in doxorubicin-resistant human myelogenous leukemia (K562/DOX) cells. The effect of doxorubicin on cell viability following treatment with balaglitazone, a peroxisome proliferator-activated receptor γ agonist, was evaluated using trypan blue and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays. Rhodamine123 assay was used to determine the activity of two common drug efflux membrane transporters P-glycoprotein and multidrug resistance protein-1. P-glycoprotein, multidrug resistance protein-1, and phosphatase and tensin homolog deleted on chromosome 10 messenger RNA/protein expression levels were measured by quantitative reverse transcription polymerase chain reaction and western blot analyses. Annexin V/fluorescein isothiocyanate assay was also employed to investigate apoptosis. We showed that balaglitazone considerably enhanced the cytotoxicity of doxorubicin. Balaglitazone also significantly downregulated P-glycoprotein expression and activity in K562/DOX cells and reduced multidrug resistance through elevation of intracellular doxorubicin in cells. Furthermore, upon balaglitazone treatment, phosphatase and tensin homolog deleted on chromosome 10 expression could be restored in K562/DOX cells in a peroxisome proliferator-activated receptor γ-dependent manner. We concluded that peroxisome proliferator-activated receptor γ agonist, balaglitazone, could reverse multidrug resistance by inducing phosphatase and tensin homolog deleted on chromosome 10 and peroxisome proliferator-activated receptor/ phosphatase and tensin homolog deleted on chromosome 10 signaling pathway. These findings suggest that targeting peroxisome proliferator-activated receptor γ might serve as an effective approach for circumventing multidrug resistance in chemotherapy of cancerous patients.

Peroxisome proliferator-activated receptor gamma (PPARγ) plays key roles in regulating cellular differentiation, proliferation and apoptosis pathways. As such, they are considered promising targets for anticancer drug development, especially for breast cancer, multiple myeloma and hematologic malignancies. Chronic myeloid leukemia (CML) is a myeloproliferative disorder arising from an oncogenic Bcr-Abl tyrosine kinase. Inhibitors of this oncogene by small molecules such as imatinib are effective only in 75% of the patient's population. One of the potential strategies to overcome this resistance is to devise combination therapy protocols with other therapeutic agents including PPAR ligands. Since PPAR ligands are potentially interesting in different hematologic malignancies, this article will review the potential of PPAR ligands for use in CML treatment.

Imatinib therapy remains the gold standard for treatment of chronic myeloid leukemia; however, the acquired resistance to this therapeutic agent in patients has urged the scientists to devise modalities for overcoming this chemoresistance. For this purpose, initially therapeutic agents with higher tyrosine kinase activity were introduced, which had the potential for inhibiting even mutant forms of Bcr-Abl. Furthermore, coupling imatinib with peroxisome proliferator-activated receptor ligands also showed beneficial effects in chronic myeloid leukemia cell proliferation. These combination protocols inhibited cell growth and induced apoptosis as well as differentiation in chronic myeloid leukemia cell lines. In addition, peroxisome proliferator-activated receptors ligands increased imatinib uptake by upregulating the expression of human organic cation transporter 1. Taken together, peroxisome proliferator-activated receptors ligands are currently being considered as novel promising therapeutic candidates for chronic myeloid leukemia treatment, because they can synergistically enhance the efficacy of imatinib. In this article, we reviewed the potential of peroxisome proliferator-activated receptors ligands for use in chronic myeloid leukemia treatment. The mechanism of action of these therapeutics modalities are also presented in detail., (© 2016 John Wiley & Sons A/S.)

P-glycoprotein (P-gp)-mediated multidrug resistance (MDR) in tumor cells is still a main obstacle for the chemotherapeutic treatment of cancers. Therefore, identification of safe and effective MDR reversing compounds with minimal adverse side effects is an important approach in the cancer treatment. Studies show that peroxisome proliferator-activated receptor (PPARs) ligands can inhibit cell growth in many cancers. Here, we investigated the effect of different PPAR agonists include fenofibrate, troglitazone and aleglitazar on doxorubicin-resistant human myelogenous leukemia (K562/DOX) cells. The effects of doxorubicin (DOX) following treatment with PPAR agonists on cell viability were evaluated using MTT assay and the reversal fold (RF) values. Rhodamine123 (Rh123) assays were used to determine P-gp functioning. P-gp mRNA/protein expression was measured by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and western blot analysis after incubation with troglitazone and aleglitazar. Our results showed that troglitazone and aleglitazar significantly enhanced the cytotoxicity of DOX and decreased the RF values in K562/DOX cells, however, no such results were found for fenofibrate. Troglitazone and aleglitazar significantly down regulated P-gp expression in K562/DOX cells; in addition, the present study revealed that aleglitazar elevated intracellular accumulation of Rh123in K562/DOX cells as short-term effects, which also contribute to the reversal of MDR. These findings show that troglitazone and especially aleglitazar exhibited potent effects in the reversal of P-gp-mediated MDR, suggesting that these compounds may be effective for combination therapy strategies and circumventing MDR in K562/DOX cells to other conventional chemotherapeutic drugs.