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- Volume 29, Issue 1, 2023
Current Pharmaceutical Design - Volume 29, Issue 1, 2023
Volume 29, Issue 1, 2023
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Advancements in Hepatocellular Carcinoma: Potential Preclinical Drugs and their Future
Authors: Noor-ul-Huda Butt and Sultan N. BaytasHepatocellular carcinoma (HCC) is one of the foremost causes of tumor-affiliated demises globally. The HCC treatment has undergone numerous developments in terms of both drug and non-drug treatments. The United States Food and Drug Administration (FDA) has authorized the usage of a variety of drugs for the treatment of HCC in recent years, involving multi-kinase inhibitors (lenvatinib, regorafenib, ramucirumab, and cabozantinib), immune checkpoint inhibitors (ICIs) (pembrolizumab and nivolumab), and combination therapies like atezolizumab along with bevacizumab. There are currently over a thousand ongoing clinical and preclinical studies for novel HCC drugs, which portrays a competent setting in the field. This review discusses the i. FDA-approved HCC drugs, their molecular targets, safety profiles, and potential disadvantages; ii. The intrial agents/drugs, their molecular targets, and possible benefits compared to alternatives, and iii. The current and future status of potential preclinical drugs with novel therapeutic targets for HCC. Consequently, existing drug treatments and novel strategies with their balanced consumption could ensure a promising future for a universal remedy of HCC in the near future.
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Nanoparticle and Stem Cell Combination Therapy for the Management of Stroke
Authors: Mehdi Farhoudi, Saeed Sadigh-Eteghad, Afsaneh Farjami and Sara SalatinStroke is currently one of the primary causes of morbidity and mortality worldwide. Unfortunately, the available treatments for stroke are still extremely limited. Indeed, stem cell (SC) therapy is a new option for the treatment of stroke that could significantly expand the therapeutic time window of stroke. Some proposed mechanisms for stroke-based SC therapy are the incorporation of SCs into the host brain to replace dead or damaged cells/tissues. Moreover, acute cell delivery can inhibit apoptosis and decrease lesion size, providing immunomudolatory and neuroprotection effects. However, several major SC problems related to SCs such as homing, viability, uncontrolled differentiation, and possible immune response, have limited SC therapy. A combination of SC therapy with nanoparticles (NPs) can be a solution to address these challenges. NPs have received considerable attention in regulating and controlling the behavior of SCs because of their unique physicochemical properties. By reviewing the pathophysiology of stroke and the therapeutic benefits of SCs and NPs, we hypothesize that combined therapy will offer a promising future in the field of stroke management. In this work, we discuss recent literature in SC research combined with NP-based strategies that may have a synergistic outcome after stroke incidence.
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Effects of Coffee Supplementation on Homocysteine and Leptin Levels: A Systematic Review and Meta-analysis of Clinical Trials
Authors: Luis E. Simental-Mendía, Mario Simental-Mendía and Mayela Ríos-MierBackground: It has been reported that the consumption of antioxidant foods and beverages may benefit the development of cardiovascular risk factors. However, the impact of coffee consumption on some of these factors, such as homocysteine and leptin is controversial. Some clinical trials have suggested that coffee administration increases plasma total homocysteine levels, while others have found no significant changes in leptin concentrations. Objective: This study aimed to assess the effects of coffee supplementation on homocysteine and leptin concentrations in a meta-analysis of clinical trials. Methods: PubMed, Web of Science, Scopus, ClinicalTrials.gov, and Google Scholar databases were searched from inception to September 29, 2021. A fixed-effects model and the generic inverse variance weighting method were used for meta-analysis. Results: The meta-analysis demonstrated that coffee administration significantly increases homocysteine levels (WMD: 0.55 μmol/L, 95% CI: 0.17, 0.93, p = 0.005, I2 = 0%) but has no significant changes in leptin concentrations (WMD: 1.34 ng/mL, 95% CI: -0.78, 3.45, p = 0.21, I2 = 0%). Additionally, the sensitivity analysis was robust for both homocysteine and leptin levels. Conclusion: The results of the present meta-analysis revealed that coffee supplementation raises serum homocysteine concentrations but has no effect on circulating leptin levels.
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Insulin Signaling Pathway Model in Adipocyte Cells
Authors: Monir Sheibani, Farhang Jalali-Farahani, Reza Zarghami and Sima SadraiBackground: Worldwide, type 2 diabetes mellitus (T2DM) is one of the most pervasive and fastgrowing disorders, bringing long-term adverse effects. T2DM arises from pancreatic β-cells deficiency to produce enough insulin or when the body cannot effectively use the insulin produced by such cells. Accordingly, early diagnosis will decrease the long-term effects and high-healthcare costs of diabetes. Objective: The objective is developing an integrated mathematical model of the insulin signaling network based on Brännmark's model, which can simulate the signaling events more comprehensively with the added key components. Methods: In this study, a thorough mathematical model of the insulin signaling network was developed by expanding the previously validated model and incorporating the glycogen synthesis module. Parameters (69 parameters) of the integrated model were evaluated by a genetic algorithm by fitting the model predictions to eighty percent of experimental data from the literature. Twenty percent of the experimental data were used to evaluate the final optimized model. Results: The time-response curves indicate that the GS phosphorylation reaches its maximum in response to 10-7 M insulin after 4 min, while the maximum phosphorylated GSK3 is attained within ~50 min. The doseresponse curves for the GSP and GSK3 of the insulin signaling intermediaries in response to the increased concentration of insulin, after 10 min, in the input from 0-100 nM exhibits a decreasing trend, whereas an increasing trend was observed for the GS and GSK3P. The GSK and GS phosphorylation sensitivity was enhanced by increasing the initial insulin concentration level from 0.001 to 100 nM. However, the sensitivity of GSK3 to insulin concentration changes (from 0.001 to 100 nM) was 3-fold higher than GS sensitivity. Conclusion: Considerably, the trends of all signaling components simulated by the expanded model shows high compatibility with experimental data (R2 ≥ 0.9), which approves the accuracy of the proposed model. The proposed mathematical model can be used in many biological systems and combined with the whole-body model of the blood glucose regulation system for a better understanding of the causes and potential treatment of type 2 diabetes. Although, this model is not a complete description of insulin signaling, yet it can make profound contributions to improvements regarding other important components and signaling branches such as epidermal growth factor (EGF) signaling, as well as signaling in other cell types in the model structure of future works.
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Design, Synthesis, Molecular Docking, Dynamics and in vitro Evaluation of Novel 2-substituted-1-hydroxyethane-1, 1-bis(phosphonic acid) Derivatives as Human Farnesyl Pyrophosphate Synthase Inhibitors with Expected Anticancer Activity
Authors: Mohammed A. Khedr, Reem I. Al-Wabli, Maha S. Almutairi and Wafaa A. ZagharyBackground: Nitrogenous bisphosphonates (NBPs) are the major class of drugs that are used to treat osteoporosis. Recently, bisphosphonates (BPs) were reported to have an anticancer effect. These agents feature a high affinity that enables them to bind strongly to the human farnesyl pyrophosphate synthase enzyme. The correlation between this affinity and their anticancer effect was confirmed. Objective: To date, the use of an oxygen atom as an isosteric replacement for the electronegative nitrogen atom in NBPs has not been reported, and its ability to retain the linker length and bisphosphonate pharmacophore remains unknown. The main aim of this work was to design some isosteric bisphosphonate analogs with oxygen atoms and evaluation of their binding affinity and anticancer activity. Methods: The binding mode and stability of the designed compounds were achieved using human farnesyl pyrophosphate synthase (HFPPS) by docking and dynamic simulations. The compounds were synthesized, characterized, and screened for their anticancer activity against the breast cancer MCF-7 cell line and lung cancer A-549 cell line. The inhibitory activity of the tested compounds against HFPPS was evaluated. Results: The compounds under investigation showed potential anticancer activity against the lung cell line with IC50 values of 41.7, 47.4, and 34.8 μg/ml in comparison to that of Risedronic acid (115 μg/ml). However, they do not exhibit potential activity against the breast cancer cell line. Conclusion: Compounds VII and VIII showed in vitro inhibition of human farnesyl pyrophosphate synthase with IC50 values of 82.2 and 98.8 μg/ml, respectively. Further optimization may be required in the future.
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Use of Novel m6A Regulator-mediated Methylation Modification Patterns in Distinct Tumor Microenvironment Profiles to Identify and Predict Glioma Prognosis and Progression, T-cell Dysfunction, and Clinical Response to ICI Immunotherapy
Authors: Binghao Zhao, Zhongtian Xiang, Bo Wu, Xiang Zhang, Nan Feng, Yiping Wei and Wenxiong ZhangBackground: The specific functions of RNA N6-methyladenosine (m6A) modifications in the glioma tumor microenvironment (TME) and glioma patient prognosis and treatment have not been determined to date. Objective: The objective of the study was to determine the role of m6A modifications in glioma TME. Methods: Nonnegative matrix factorization (NMF) methods were used to determine m6A clusters and m6A gene signatures based on 21 genes relating to m6A modifications. TME characteristics for each m6A cluster and m6A gene signature were quantified by established m6A score. The utility of m6A score was validated in immunotherapy and other antiangiogenic treatment cohorts. Results: Three m6A clusters were identified among 3,395 glioma samples, and they were linked to different biological activities and clinical outcomes. The m6A clusters were highly consistent with immune profiles known as immune-inflamed, immune-excluded, and immune-desert phenotypes. Clusters within individual tumors could predict glioma inflammation, molecular subtypes, TME stromal activity, genetic variation, alternative splicing, and prognosis. As for the m6A score and m6A gene signature, patients with low m6A scores exhibited an increased tumor mutation burden, immune activity, neoantigen load, and prolonged survival. A low m6A score indicated the potential for a low level of T-cell dysfunction, a considerably better treatment response, and durable clinical benefits from immunotherapy, bevacizumab and regorafenib. Conclusion: Glioma m6A clusters and gene signatures have distinctive TME features. The m6A gene signature may guide prognostic assessments and promote the use of effective strategies.
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Volumes & issues
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Volume 31 (2025)
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Volume (2025)
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Volume 30 (2024)
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Volume 29 (2023)
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Volume 28 (2022)
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Volume 27 (2021)
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Volume 26 (2020)
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Volume 25 (2019)
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Volume 24 (2018)
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Volume 23 (2017)
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Volume 22 (2016)
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Volume 21 (2015)
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Volume 20 (2014)
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Volume 19 (2013)
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Volume 18 (2012)
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Volume 17 (2011)
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Volume 16 (2010)
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Volume 15 (2009)
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Volume 14 (2008)
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Volume 13 (2007)
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Volume 12 (2006)
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Volume 11 (2005)
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Volume 10 (2004)
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Volume 9 (2003)
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Volume 8 (2002)
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Volume 7 (2001)
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Volume 6 (2000)
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