Assessment of Hemoglobin A1c Management and Prescription Cost Due to Polypharmacy Among Patients With Diabetes in Iran Based on the STEPS Iran 2016 Survey and a Prescription Database: A Multi-level, Cross-sectional National Study.

BACKGROUND: Diabetes frequently results in the need for multiple medication therapies, known as 'Polypharmacy'. This situation can incur significant costs and increase the likelihood of medication errors. This study evaluated the prescriptions of patients with diabetes regarding polypharmacy to assess its effect on the control of hemoglobin A1c (HbA1c) levels and prescription costs. METHODS: A cross-sectional national study was conducted based on data from linking the Iranians Health Insurance Service prescriptions in 2015 and 2016 with the STEPS 2016 survey in Iran. The association of the individual and sociodemographic factors, as well as polypharmacy, as independent variables, with control of HbA1c levels and the cost of the prescriptions were assessed among diabetic patients using logistic and linear regression, respectively. RESULTS: Among 205 patients using anti-diabetic medications, 47.8% experienced polypharmacy. The HbA1c of 74 patients (36.1%) was equal to or less than 7, indicating controlled diabetes. HbA1c control showed no significant association with gender. However, prescription costs were notably lower in females (ß=0.559 [0.324‒0.964], P=0.036). No significant correlation was found between the area of residence and prescription costs, but HbA1c was significantly more controlled in urban areas (OR=2.667 [1.132‒6.282], P=0.025). Prescription costs were significantly lower in patients without polypharmacy (ß=0.211, [0.106‒0.423], P<0.001), though there was no significant association between polypharmacy and HbA1c levels. CONCLUSION: Our results demonstrated that diabetics with polypharmacy paid significantly more for their prescriptions without experiencing a positive effect on the control of HbA1c levels.

MMP inhibition as a novel strategy for extracellular matrix preservation during whole liver decellularization.

As the only reliable treatment option for end-stage liver diseases, conventional liver transplantation confronts major supply limitations. Accordingly, the decellularization of discarded livers to produce bioscaffolds that support recellularization with progenitor/stem cells has emerged as a promising translational medicine approach. The success of this approach will substantially be determined by the extent of extracellular matrix (ECM) preservation during the decellularization process. Here, we assumed that the matrix metalloproteinase (MMP) inhibition could reduce the ECM damage during the whole liver decellularization of an animal model using a perfusion-based system. We demonstrated that the application of doxycycline as an MMP inhibitor led to significantly higher preservation of collagen, glycosaminoglycans, and hepatic growth factor (HGF) contents, as well as mechanical and structural features, including tensile strength, fiber integrity, and porosity. Notably, produced bioscaffolds were biocompatible and efficiently supported cell viability and proliferation in vitro. We also indicated that produced bioscaffolds efficiently supported HepG2 cell function upon seeding onto liver ECM discs using albumin and urea assay. Additionally, MMP inhibitor pretreated decellularized livers were more durable in contact with collagenase digestion compared to control bioscaffolds in vitro. Using zymography, we confirmed the underlying mechanism that results in these promising effects is through the inhibition of MMP2 and MMP9. Overall, we demonstrated a novel method based on MMP inhibition to ameliorate the ECM structure and composition preservation during liver decellularization as a critical step in fabricating transplantable bioengineered livers.

The Cross-Talks Among Bone Morphogenetic Protein (BMP) Signaling and Other Prominent Pathways Involved in Neural Differentiation.

The bone morphogenetic proteins (BMPs) are a group of potent morphogens which are critical for the patterning, development, and function of the central nervous system. The appropriate function of the BMP pathway depends on its interaction with other signaling pathways involved in neural differentiation, leading to synergistic or antagonistic effects and ultimately favorable biological outcomes. These opposite or cooperative effects are observed when BMP interacts with fibroblast growth factor (FGF), cytokines, Notch, Sonic Hedgehog (Shh), and Wnt pathways to regulate the impact of BMP-induced signaling in neural differentiation. Herein, we review the cross-talk between BMP signaling and the prominent signaling pathways involved in neural differentiation, emphasizing the underlying basic molecular mechanisms regarding the process of neural differentiation. Knowing these cross-talks can help us to develop new approaches in regenerative medicine and stem cell based therapy. Recently, cell therapy has received significant attention as a promising treatment for traumatic or neurodegenerative diseases. Therefore, it is important to know the signaling pathways involved in stem cell differentiation toward neural cells. Our better insight into the cross-talk of signaling pathways during neural development would improve neural differentiation within in vitro tissue engineering approaches and pre-clinical practices and develop futuristic therapeutic strategies for patients with neurological disease.

Pre-clinical safety and therapeutic efficacy of a plant-based alkaloid in a human colon cancer xenograft model.

A high-throughput drug screen revealed that veratridine (VTD), a natural plant alkaloid, induces expression of the anti-cancer protein UBXN2A in colon cancer cells. UBXN2A suppresses mortalin, a heat shock protein, with dominant roles in cancer development including epithelial-mesenchymal transition (EMT), cancer cell stemness, drug resistance, and apoptosis. VTD-dependent expression of UBXN2A leads to the deactivation of mortalin in colon cancer cells, making VTD a potential targeted therapy in malignant tumors with high levels of mortalin. VTD was used clinically for the treatment of hypertension in decades past. However, the discovery of newer antihypertensive drugs and concerns over potential neuro- and cardiotoxicity ended the use of VTD for this purpose. The current study aims to determine the safety and efficacy of VTD at doses sufficient to induce UBXN2A expression in a mouse model. A set of flow-cytometry experiments confirmed that VTD induces both early and late apoptosis in a dose-dependent manner. In vivo intraperitoneal (IP) administration of VTD at 0.1 mg/kg every other day (QOD) for 4 weeks effectively induced expression of UBXN2A in the small and large intestines of mice. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) assays on tissues collected from VTD-treated animals demonstrated VTD concentrations in the low pg/mg range. To address concerns regarding neuro- and cardiotoxicity, a comprehensive set of behavioral and cardiovascular assessments performed on C57BL/6NHsd mice revealed that VTD generates no detectable neurotoxicity or cardiotoxicity in animals receiving 0.1 mg/kg VTD QOD for 30 days. Finally, mouse xenograft experiments in athymic nude mice showed that VTD can suppress tumor growth. The main causes for the failure of experimental oncologic drug candidates are lack of sufficient safety and efficacy. The results achieved in this study support the potential utility of VTD as a safe and efficacious anti-cancer molecule.

Human placenta-derived amniotic epithelial cells as a new therapeutic hope for COVID-19-associated acute respiratory distress syndrome (ARDS) and systemic inflammation.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19), has become in the spotlight regarding the serious early and late complications, including acute respiratory distress syndrome (ARDS), systemic inflammation, multi-organ failure and death. Although many preventive and therapeutic approaches have been suggested for ameliorating complications of COVID-19, emerging new resistant viral variants has called the efficacy of current therapeutic approaches into question. Besides, recent reports on the late and chronic complications of COVID-19, including organ fibrosis, emphasize a need for a multi-aspect therapeutic method that could control various COVID-19 consequences. Human amniotic epithelial cells (hAECs), a group of placenta-derived amniotic membrane resident stem cells, possess considerable therapeutic features that bring them up as a proposed therapeutic option for COVID-19. These cells display immunomodulatory effects in different organs that could reduce the adverse consequences of immune system hyper-reaction against SARS-CoV-2. Besides, hAECs would participate in alveolar fluid clearance, renin-angiotensin-aldosterone system regulation, and regeneration of damaged organs. hAECs could also prevent thrombotic events, which is a serious complication of COVID-19. This review focuses on the proposed early and late therapeutic mechanisms of hAECs and their exosomes to the injured organs. It also discusses the possible application of preconditioned and genetically modified hAECs as well as their promising role as a drug delivery system in COVID-19. Moreover, the recent advances in the pre-clinical and clinical application of hAECs and their exosomes as an optimistic therapeutic hope in COVID-19 have been reviewed.

Therapeutic properties of stem cell-derived exosomes in ischemic heart disease.

Ischemic heart disease is the most prominent cause of death worldwide. Current treatment options have shown limited success in preventing morbidity and mortality and the need for alternative therapeutic options is evident. Accumulating evidence points to the rising role of stem cell-derived exosomes as potential sources for treatment of ischemic heart disease. Exosomes are nano-scale (50-150 nm), membrane-bound extracellular vesicles that contain a variety of proteins, nucleic acids, lipids, and metabolites and can be released from almost every cell type in the body, including but not restricted to cardiac cells, immune cells, and stem cells. In this review exosomes derived from stem cells which may have potential application in ischemic heart disease are classified based on their source: mesenchymal, adipose, cardiac, and circulating endothelial progenitor stem cells. Alterations in exosome cargo, for instance through regulation of certain miRNAs, may regulate the cross-talk among cardiac cells and usually result in enhanced cardioprotective properties through various signaling mechanisms, leading to enhancement of angiogenesis, prevention of apoptosis and reducing fibrosis. However, many critical challenges remain in translation of exosomes-assisted therapies such as lack of a unified method for exosome isolation and characterization, finding the optimal cell culture conditions, proper route of administration, targeted delivery of exosomes to cardiac tissue, and difficulties with production and storage of exosomes in large numbers.

Doxorubicin-Induced Cardiotoxicity: An Overview on Pre-clinical Therapeutic Approaches.

Doxorubicin is an effective chemotherapeutic agent prescribed to treat solid tumors (e.g., ovary, breast, and gastrointestinal cancers). This anti-cancer drug has various side effects, such as allergic reactions, cardiac damage, hair loss, bone marrow suppression, vomiting, and bladder irritation. The most dangerous side effect of doxorubicin is cardiomyopathy, leading to congestive heart failure. The exact mechanisms of doxorubicin-induced cardiotoxicity remain incompletely understood. Alteration in myocardial structure and functional cardiac disorders is provoked by doxorubicin administration; subsequently, cardiomyopathy and congestive heart failure can occur. Congestive heart failure due to doxorubicin is associated with mortality and morbidity. Probably, doxorubicin-induced cardiotoxicity starts from myocardial cell injury and is followed by left ventricular dysfunction. Many factors and multiple pathways are responsible for the creation of doxorubicin-induced cardiotoxicity. Inflammatory cytokines, oxidative stress pathways, mitochondrial damage, intracellular Ca2+ overload, iron-free radical production, DNA, and myocyte membrane injuries have critical roles in the pathophysiology of doxorubicin-induced cardiotoxicity. Unfortunately, there are currently a few medications for the treatment of doxorubicin-induced cardiotoxicity in clinical settings. Extensive basic and clinical researches have been carried out to discover preventive treatments. This review briefly discusses the basic and experimental approaches for treating or preventing doxorubicin-mediated cardiotoxicity based on its pathophysiological mechanisms.

Related Fluoxetine and Methylprednisolone Changes of TNF-α and IL-6 Expression in The Hypothyroidism Rat Model of Spinal Cord Injury.

OBJECTIVE: Spinal cord injury (SCI) is a serious clinical condition that leads to disability. Following primary injury, proinflammatory cytokines play an important role in the subsequent secondary events. The thyroid hormone (TH) is known as the modulator of inflammatory cytokines and acts as a neuroprotective agent. Methylprednisolone (MP) is used for the early treatment of SCI. Fluoxetine (FLX), also is known as a selective serotonin reuptake inhibitor (SSRI), has therapeutic potential in neurological disorders. The aim of the present study was to investigate the combined effects of MP and FLX on SCI in the rat hypothyroidism (hypo) model. MATERIALS AND METHODS: In this experimental study, 48 male Wistar rats with hypothyroidism were randomly divided into 6 groups (n=8/group): control (Hypo), Hypo+Surgical sham, Hypo+SCI, Hypo+SCI+MP, Hypo+SCI+FLX, and Hypo+SCI+MP+FLX. SCI was created using an aneurysm clip and Hypothyroidism was induced by 6-Propyl-2-thiouracil (PTU) at a dose of 10 mg/kg/day administered intraperitoneally. Following SCI induction, rats received MP and FLX treatments via separate intraperitoneal injections at a dose of 30 and 10 mg/kg/day respectively on the surgery day and FLX continued daily for 3 weeks. The expression levels of tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) were quantified by Real-time polymerase chain reaction (PCR) and Western blotting. Myelination and glutathione (GSH) levels were analyzed by Luxol Fast Blue (LFB) staining and ELISA respectively. RESULTS: Following combined MP and FLX treatments, the expression levels of TNF-α and IL-6 significantly decreased and GSH level considerably increased in the trial animals. CONCLUSION: Our results show the neuroprotective effects of MP and FLX with better results in Hypo+SCI+MP+FLX group. Further study is required to identify the mechanisms involved.

Recent Advances on Drug-Loaded Mesenchymal Stem Cells With Anti-neoplastic Agents for Targeted Treatment of Cancer.

Mesenchymal stem cells (MSCs), as an undifferentiated group of adult multipotent cells, have remarkable antitumor features that bring them up as a novel choice to treat cancers. MSCs are capable of altering the behavior of cells in the tumor microenvironment, inducing an anti-inflammatory effect in tumor cells, inhibiting tumor angiogenesis, and preventing metastasis. Besides, MSCs can induce apoptosis and inhibit the proliferation of tumor cells. The ability of MSCs to be loaded with chemotherapeutic drugs and release them in the site of primary and metastatic neoplasms makes them a preferable choice as targeted drug delivery procedure. Targeted drug delivery minimizes unexpected side effects of chemotherapeutic drugs and improves clinical outcomes. This review focuses on recent advances on innate antineoplastic features of MSCs and the effect of chemotherapeutic drugs on viability, proliferation, and the regenerative capacity of various kinds of MSCs. It also discusses the efficacy and mechanisms of drug loading and releasing procedures along with in vivo and in vitro preclinical outcomes of antineoplastic effects of primed MSCs for clinical prospection.

Ascorbic Acid interaction with analgesic effect of morphine and tramadol in mice.

BACKGROUND: Combining different analgesic drugs for improvement of drug efficacy is a recommended strategy intended to achieve the optimal therapeutic effects. OBJECTIVES: The purpose of the present study was to assess the nature of the interaction between ascorbic acid and two analgesic drugs, morphine and tramadol. MATERIALS AND METHODS: The analgesic activity was assessed by the acetic acid writhing test in male Naval Medical Research Institute (NMRI) mice. The results were obtained using four to six animals in each group. All the drugs were injected intraperitoneally. The effective doses (ED) that produced 20%, 50%, and 65% antinociception (ED20, ED50 and ED65) were calculated from the dose-response curve of each drug alone as well as co-administration of ascorbic acid and tramadol or morphine. The interaction index was calculated as experimental ED/theoretical ED. For each drug combination, ED50, ED20 and ED65 were determined by linear regression analysis of the dose-response curve, and they were compared to theoretical ED50, ED20 and ED65 using t-test. RESULTS: The antinociceptive effects of all drugs were dose-dependent (ED50was 206.1 mg/kg for ascorbic acid, 8.33 mg/kg for tramadol, and 0.79 mg/kg for morphine). The interaction index demonstrated additive effects at ED50 and ED65 for co-administration of ascorbic acid and tramadol or morphine. However, at ED20, combination of ascorbic acid and tramadol or morphine showed synergic effects. The interaction index values of the combinations demonstrated the potency ratio of ascorbic acid/morphine to be lower than ascorbic acid/tramadol. CONCLUSIONS: This study demonstrated the results of interactions between ascorbic acid and tramadol or morphine. The results showed that the interaction effects on antinociception may be synergistic or additive, depending on the level of effect.