Publications by authors named "Amirhossein Sahebkar"

1,113 Publications

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The clinical use of curcumin on neurological disorders: An updated systematic review of clinical trials.

Phytother Res 2021 Sep 15. Epub 2021 Sep 15.

Food Security Research Center, Isfahan University of Medical Sciences, Isfahan, Iran.

Neuroprotective effects of curcumin have been shown in previous studies. This updated systematic review of clinical trials aimed to investigate the effect of curcumin on neurological disorders. Databases including PubMed, Scopus, Web of Science, and Google Scholar were systematically searched to identify clinical trials investigating the effects of curcumin/turmeric supplements alone, or in combination with other ingredients, on neurological diseases. Nineteen studies comprising 1,130 patients met the inclusion criteria. Generally, intervention and study outcomes were heterogeneous. In most of the studies, curcumin had a favorable effect on oxidative stress and inflammation. However, with the exception of AD, curcumin supplementation either alone, or in combination with other ingredients, had beneficial effects on clinical outcomes for the other aforementioned neurodegenerative diseases. For example, the frequency, severity, and duration of migraine attacks, scores on the revised ALS functional rating scale, and the occurrence of motor complications in PD were all significantly improved with curcumin supplementation either alone or in combination with other ingredients. However, in three studies, several adverse side effects (mostly gastrointestinal in nature) were reported. Curcumin supplementation may have favorable effects on inflammatory status and clinical outcomes of patients with neurological disease, although the results were not consistent.
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http://dx.doi.org/10.1002/ptr.7273DOI Listing
September 2021

The Effects of Statin Dose, Lipophilicity, and Combination of Statins plus Ezetimibe on Circulating Oxidized Low-Density Lipoprotein Levels: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Mediators Inflamm 2021 4;2021:9661752. Epub 2021 Sep 4.

Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.

Background: Elevated plasma low-density lipoprotein cholesterol (LDL-C) is the main risk factor for atherosclerotic cardiovascular disease (ASCVD). Statins are the drugs of choice for decreasing LDL-C and are used for the prevention and management of ASCVD. Guidelines recommend that subjects with high and very high ASCVD risk should be treated with high-intensity statins or a combination of high-intensity statins and ezetimibe. The lipophilicity or hydrophilicity (solubility) of statins is considered to be important for at least some of their LDL-C lowering independent pleiotropic effects. Oxidative modification of LDL (ox-LDL) is considered to be the most important atherogenic modification of LDL and is supposed to play a crucial role in atherogenesis and ASCVD outcomes.

Objective: The aim of this systematic review and meta-analysis was to find out what are the effects of statin intensity, lipophilicity, and combination of statins plus ezetimibe on ox-LDL.

Methods: PubMed, Scopus, Embase, and Web of Science were searched from inception to February 5, 2021, for randomized controlled trials (RCTs). Two independent and blinded authors evaluated eligibility by screening the titles and abstracts of the studies. Risk of bias in the studies included in this meta-analysis was evaluated according to the Cochrane instructions. Meta-analysis was performed using Comprehensive Meta-Analysis (CMA) V2 software. Evaluation of funnel plot, Begg's rank correlation, and Egger's weighted regression tests were used to assess the presence of publication bias.

Results: Among the 1427 published studies identified by a systematic databases search, 20 RCTs were finally included in the systematic review and meta-analysis. A total of 1874 patients are included in this meta-analysis. This meta-analysis suggests that high-intensity statin treatment is associated with a significant decrease in circulating concentrations of ox-LDL when compared with low-to-moderate treatment (SMD: -0.675, 95% CI: -0.994, -0.357, < 0.001; : 55.93%). There was no difference concerning ox-LDL concentration between treatments with hydrophilic and lipophilic statins (SMD: -0.129, 95% CI: -0.330, -0.071, = 0.206; : 45.3%), but there was a significant reduction in circulating concentrations of ox-LDL associated with statin plus ezetimibe combination therapy when compared with statin monotherapy (SMD: -0.220, 95% CI: -0.369, -0.071, = 0.004; : 0%).

Conclusion: High-dose statin or combination of statins with ezetmibe reduces plasma ox-LDL in comparison low-to-moderate intensity statin therapy alone. Statin lipophilicity is not associated with reduction in ox-LDL plasma concentrations.
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http://dx.doi.org/10.1155/2021/9661752DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8437664PMC
September 2021

Effect of atorvastatin on delirium status of patients in the intensive care unit: a randomized controlled trial.

Arch Med Sci 2021 12;17(5):1423-1428. Epub 2019 Nov 12.

Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.

Introduction: Delirium is one of the most prevalent complications in intensive care unit (ICU) patients, which is related to worse clinical outcomes including a longer ICU stay, longer duration of mechanical ventilation, higher mortality rates and increased risk of cognitive impairment. Observational studies have suggested that statins might have a positive effect on delirium status of hospitalized patients. To date, there has been no trial assessing the effect of atorvastatin on delirium status in critically ill patients. Thus, the aim of the current study was to determine the efficacy of atorvastatin on delirium status of patients in the ICU.

Methods: In this randomized, double-blind and controlled trial, a total of 90 patients in the general ICU who had delirium for at least 2 days were randomly divided into atorvastatin (40 mg/day) ( = 40) and control ( = 50) groups. Delirium status of the patients was determined twice a day at 10:00 a.m. and 18:00 p.m. using the Richmond Agitation-Sedation Scale (RASS).

Results: Administration 40 mg/day of atorvastatin significantly reduced the mean RASS score and increased delirium-free days at both morning and afternoon time points compared to the control group ( < 0.05).

Conclusions: Administration of atorvastatin had a significant positive effect on delirium status in patients admitted to the ICU.
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http://dx.doi.org/10.5114/aoms.2019.89330DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8425261PMC
November 2019

Statins as anti-pyroptotic agents.

Arch Med Sci 2021 9;17(5):1414-1417. Epub 2021 Aug 9.

Applied Biomedical Research Centre, Mashhad University of Medical Sciences, Mashhad, Iran.

Introduction: Pyroptosis is a regulated form of cell death, which is often a consequence of the activation of inflammatory caspases.

Methods: Appropriate inflammatory responses and the induction of pyroptosis enhance the clearance of pathogens and increase innate immunity.

Results: However, excessive pyroptosis contributes to a hyperinflammatory response and aggravates tissue damage, thereby causing inflammatory diseases. There have been recent reports on the modulation of pyroptosis by statins, which may explain part of the pleiotropic actions of these drugs in inflammatory diseases and cancer.

Conclusions: Herein, the extant evidence for the potential value of statins in targeting pyroptosis in various diseases is reviewed.
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http://dx.doi.org/10.5114/aoms/141155DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8425236PMC
August 2021

PCSK9 immunization using nanoliposomes: preventive efficacy against hypercholesterolemia and atherosclerosis.

Arch Med Sci 2021 18;17(5):1365-1377. Epub 2021 Mar 18.

Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.

Introduction: The aim of the study was to study a nanoliposomal anti-PCSK9 vaccine as a novel approach for cholesterol lowering via PCSK9 inhibition.

Material And Methods: An immunogenic peptide construct termed immunogenic fused PCSK9-tetanus (IFPT) was displayed on the surface of liposome nanoparticles (L-IFPT) and mixed into alum adjuvant (L-IFPTA+). The manufactured vaccine formulations IFPT, L-IFPT, L-IFPTA+, IFPTA+, and free nanoliposomes were subcutaneously injected four times with bi-weekly intervals in C57BL/6 mice on a severe atherogenic protocol.

Results: Among the formulations, L-IFPTA+ vaccine was found to elicit the highest IgG response against PCSK9 peptide. The induced PCSK9 antibodies inhibited PCSK9-LDLR interaction through binding to PCSK9 in vaccinated mice. Liver low-density lipoprotein receptor (LDLR) protein was increased in vaccinated mice. L-IFPTA+, L-IFPT and IFPTA+ vaccines reduced total cholesterol by up to -38.13 ±3.8% ( = 0.006), -23 ±4.1% ( = 0.027) and -19.12 ±3% ( = 0.038), and low-density lipoprotein cholesterol (LDL-C) by up to -57 ±7.7% ( = 0.0003), -41.67 ±4.2% ( = 0.03) and -36.11 ±5% ( = 0.02) in hypercholesterolemic mice, respectively, versus control mice after 8 weeks. Long-term assessment indicated that the vaccine formulations could stimulate a long-lasting humoral immune response against PCSK9 peptide, which was associated with a marked reduction of total cholesterol in L-IFPTA+, L-IFPT and IFPTA+ vaccine groups by up to -82.5 ±7.3% ( = 0.002), -70.54 ±6.2% ( = 0.013) and -72.02 ±8.7% ( = 0.004), respectively, and LDL-C by up to -88.14 ±5.6% ( = 0.002), -55.92 ±8.3% ( = 0.003) and 54.81 ±9.3% ( = 0.003), respectively, versus the pre-vaccination time point adjusted to the control group. Anti-inflammatory Th2 cells and IL-4 cytokine were considerably increased in splenocytes of vaccinated mice.

Conclusions: L-IFPTA+ vaccine can induce long-lasting, functional and safe PCSK9-specific antibodies in hypercholesterolemic C57BL/6 mice, providing a long-term protective impact on dyslipidemia and atherosclerosis.
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http://dx.doi.org/10.5114/aoms/133885DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8425258PMC
March 2021

Anti-proliferative potential of fluorinated curcumin analogues: experimental and computational analysis and review of the literature.

Curr Med Chem 2021 Sep 10. Epub 2021 Sep 10.

Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad. Iran.

Background: Curcuminoids, flavoring, and coloring agents in food have potent antioxidant, anti-tumor activity, and anti-inflammatory effects. However, they are rapidly metabolized to lesser active metabolites. Therefore, various studies have been conducted to synthesize new and stable curcumin analogues with enhanced therapeutic activity.

Methods: Fluorinated curcumin compounds (2a-2f) were synthesized by Knoevenagel condensation between fluorobenzaldehydes (1a-1f) with curcumin. Fluorinated demethoxycurcumin (3a) was synthesized by condensation between demethoxycurcumin and 3,4-difluorobenzaldehyde (1f). The structures of these compounds were confirmed by FT-IR, 1H-NMR, 13C-NMR, 19FNMR, and mass spectroscopy. Antiproliferative activities of these synthetic compounds were evaluated against breast cancer cells (4T1), melanoma cancer cells (B16F10), and normal cell lines (NIH 3T3) using MTT assay. The interaction of curcumin, 2f and 3a with several proteins (1HCL, 2ZOQ, 3D94, 5EW3, 4WA9, 1XKK, 6CCY) was investigated. The structural preservation of the epidermal growth factor receptor (EGFR) was investigated by molecular dynamics simulation.

Results: The spectroscopic data obtained confirmed the proposed structure of fluorinated analogues. The results showed that compounds 2f and 3a inhibited cancer cells proliferation significantly more than other compounds. Compounds 2f and 3a showed the highest affinity and lowest binding energy with EGFR. The binding energies were -7.8, -10, and -9.8 kcal/mol for curcumin, 2f and 3a with EGFR, respectively. The molecular docking results demonstrated that compounds 2f and 3a were firmly bound in a complex with EGFR via the formation of a hydrogen bond.

Conclusion: In summary, we found that fluorinated demethoxycurcumin and fluorinated curcumin induces cancer cell death and binds to EGFR with high affinity.
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http://dx.doi.org/10.2174/0929867328666210910141316DOI Listing
September 2021

A comprehensive review on the lipid and pleiotropic effects of pitavastatin.

Prog Lipid Res 2021 Sep 9:101127. Epub 2021 Sep 9.

Department of Preventive Cardiology and Lipidology, Medical University of Lodz (MUL), Lodz, Poland; Cardiovascular Research Centre, University of Zielona Gora, Zielona-Gora, Poland. Electronic address:

The 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, or statins, are administered as first line therapy for hypercholesterolemia, both in primary and secondary prevention. There is a growing body of evidence showing that beyond their lipid-lowering effect, statins have a number of additional beneficial properties. Pitavastatin is a unique lipophilic statin with a strong effect on lowering plasma total cholesterol and triacylglycerol. It has been reported to have pleiotropic effects such as decreasing inflammation and oxidative stress, regulating angiogenesis and osteogenesis, improving endothelial function and arterial stiffness, and reducing tumor progression. Based on the available studies considering the risk of statin-associated muscle symptoms it seems to be also the safest statin. The unique lipid and non-lipid effects of pitavastatin make this molecule a particularly interesting option for the management of different human diseases. In this review, we first summarized the lipid effects of pitavastatin and then strive to unravel the diverse pleiotropic effects of this molecule.
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http://dx.doi.org/10.1016/j.plipres.2021.101127DOI Listing
September 2021

Impact of PCSK9 Immunization on Glycemic Indices in Diabetic Rats.

J Diabetes Res 2021 30;2021:4757170. Epub 2021 Aug 30.

Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.

Methods: To prepare the anti-PCSK9 vaccine, a peptide construct called Immunogenic Fused PCSK9-Tetanus (IFPT) was linked to the surface of nanoliposome carriers. Healthy rats received four subcutaneous injections of the vaccine at biweekly intervals. Two weeks after the last vaccination, anti-PCSK9 antibody titers, PCSK9 targeting, and inhibition of PCSK9-low-density lipoprotein receptor (LDLR) interaction were evaluated. After verification of antibody generation, the immunized rats were intraperitoneally treated with a single dose (45 mg/kg) of streptozotocin (STZ) to induce diabetes mellitus. The levels of fasting blood glucose (FBG) were measured, and the oral glucose tolerance test (OGTT) as well as the insulin tolerance test (ITT) were carried out to assess glycemic status. At the end of the study, the total cholesterol, low-density lipoprotein cholesterol (LDL-C), triglyceride, and high-density lipoprotein cholesterol concentrations were assayed. Histopathology examination of the liver and pancreas was also performed using the hematoxylin-eosin staining method.

Results: The prepared nanoliposomal vaccine could strongly induce anti-PCSK9 antibodies in the vaccinated rats. Within one week following the STZ injection, the FBG level was lower in the vaccinated group vs. diabetic control group (49% (-171.7 ± 35 mg/dL, < 0.001)). In the OGTT, the injected rats showed improved glucose tolerance as reflected by the reduction of blood glucose levels over 180 min, compared with the diabetic controls. Moreover, the ITT demonstrated that, after the insulin injection, blood glucose concentration declined by 49.3% in the vaccinated group vs. diabetic control group. Expectedly, the vaccinated rats exhibited lower (-26.65%, = 0.03) plasma LDL-C levels compared with the diabetic controls. Histopathology examination of pancreas tissue demonstrated that the pancreatic islets of the vaccinated rats had a slight decline in the population of -cells and few -cells. Normal liver histology was also observed in the vaccinated rats.

Conclusion: PCSK9 inhibition through the liposomal IFPT vaccine can improve the glucose and insulin tolerance impairments as well as the lipid profile in diabetes.
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http://dx.doi.org/10.1155/2021/4757170DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8423580PMC
August 2021

Implications for the role of lipopolysaccharide in the development of atherosclerosis.

Trends Cardiovasc Med 2021 Sep 5. Epub 2021 Sep 5.

Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; School of Medicine, The University of Western Australia, Perth, Australia; School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran. Electronic address:

Mounting scientific evidence over decades has established that atherosclerosis is a chronic inflammatory disorder. Among the potentially critical sources of vascular inflammation during atherosclerosis are the components of pathogenic bacteria, especially lipopolysaccharide (LPS). Toll-like receptor (TLR)-4, expressed on different inflammatory cells involved with the recognition of bacterial LPS, has been recognized to have mutations that are prevalent in a number of ethnic groups. Such mutations have been associated with a decreased risk of atherosclerosis. In addition, epidemiological investigations have proposed that LPS confers a risk factor for the development of atherosclerosis. Gram-negative bacteria are the major source of LPS in an individual's serum, which may be generated during subclinical infections. The major cell receptors on inflammatory cells involved in the pathogenesis of atherosclerosis, like macrophages, monocytes, and dendritic cells (DCs), are CD14, MD-2, and LPS binding protein (LBP). These receptors have been blamed for the development of atherosclerosis through dysregulated activation following LPS recognition. Lipoproteins may also play a role in modulating the LPS-induced inflammatory events during atherosclerosis development. In this review article, we attempt to clarify the role of LPS in the initiation and progression of atherosclerotic lesion development.
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http://dx.doi.org/10.1016/j.tcm.2021.08.015DOI Listing
September 2021

The Effect of Statins on C-Reactive Protein in Stroke Patients: A Systematic Review of Clinical Trials.

Mediators Inflamm 2021 27;2021:7104934. Epub 2021 Aug 27.

Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.

Background: Statins reportedly have anti-inflammatory effects aside from their lipid-lowering impact. We investigated the effects of statin therapy on the level of C-reactive protein (CRP) or highly sensitive CRP (hs-CRP), a liver-derived marker of systemic inflammation, among stroke patients.

Methods: An online search was performed in Scopus, PubMed/MEDLINE, ISI Web of Science, and Google Scholar up to November 2020 to recognize clinical trials investigating the effects of statins on the CRP level in stroke patients.

Results: Overall, nine studies (11 treatment arms) with 1659 participants met the inclusion criteria. Six out of 9 studies (8 out of 11 arms) were categorized as studies with a high-quality methodological approach using the Cochrane Collaboration's tool. Data from 5 treatment arms indicated a significant decrease in CRP concentration, and in one treatment arm, CRP concentration did not suggest any considerable alteration following statin therapy. Moreover, two treatment arms showed a significant reduction in hs-CRP concentration and three treatment arms revealed no significant alteration in hs-CRP concentration following statin therapy. Generally, results were heterogeneous and independent of the type of statin, statin dose, treatment duration, and changes in plasma low-density lipoprotein cholesterol concentration.

Conclusion: The results suggest that statin therapy could reduce and, therefore, could be considered in these patients as potential anti-inflammatory agents.
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http://dx.doi.org/10.1155/2021/7104934DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8418548PMC
August 2021

3D-QSAR-Based Pharmacophore Modeling, Virtual Screening, and Molecular Docking Studies for Identification of Tubulin Inhibitors with Potential Anticancer Activity.

Biomed Res Int 2021 24;2021:6480804. Epub 2021 Aug 24.

Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.

In this study, we aimed to develop a pharmacophore-based three-dimensional quantitative structure activity relationship (3D-QSAR) for a set including sixty-two cytotoxic quinolines (1-62) as anticancer agents with tubulin inhibitory activity. A total of 279 pharmacophore hypotheses were generated based on the survival score to build QSAR models. A six-point pharmacophore model (AAARRR.1061) was identified as the best model which consisted of three hydrogen bond acceptors (A) and three aromatic ring (R) features. The model showed a high correlation coefficient ( = 0.865), cross-validation coefficient ( = 0.718), and value (72.3). The best pharmacophore model was then validated by the Y-Randomization test and ROC-AUC analysis. The generated 3D contour maps were used to reveal the structure activity relationship of the compounds. The IBScreen database was screened against AAARRR.1061, and after calculating ADMET properties, 10 compounds were selected for further docking study. Molecular docking analysis showed that compound STOCK2S-23597 with the highest docking score (-10.948 kcal/mol) had hydrophobic interactions and can form four hydrogen bonds with active site residues.
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http://dx.doi.org/10.1155/2021/6480804DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8410400PMC
August 2021

Impact of Curcumin on Hepatic Low-Density Lipoprotein Uptake.

Methods Mol Biol 2022 ;2343:395-400

Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.

Elevated levels of plasma low-density lipoprotein cholesterol (LDL-C) are causally related to atherosclerotic cardiovascular disease. Enhancing the removal of LDL particles from the plasma, mainly by the liver, is the most efficient strategy for reducing LDL-C and the ensuing atherosclerosis. In this context, polyphenolic compounds like curcumin have generated interest owing to their lipid-modifying capacity. The promising effect of curcumin has been studied in attenuating atherosclerosis (in experimental models), and correcting dyslipidemia (in clinical studies). The underlying mechanisms of the effects of curcumin are relatively unknown, and the impact of curcumin on hepatic LDL uptake warrants further investigations. Here, we present a protocol to assess the effects of curcumin on LDL uptake in hepatocytes.
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http://dx.doi.org/10.1007/978-1-0716-1558-4_29DOI Listing
January 2022

Protocol for Testing the Potential Antioxidant Effects of Curcuminoids on Patients with Type 2 Diabetes Mellitus.

Methods Mol Biol 2022 ;2343:371-379

Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.

Oxidative stress has a key role in the pathogenesis of type 2 diabetes mellitus. Alternative therapy with antioxidants has been tested as a potential approach to curb the effects of this disorder. Here, we present a protocol to set up a randomized double-blind placebo-controlled trial to assess the impact of treatment with a mixture of curcuminoids on a number of physiological and molecular biomarker measures with the main focus on determining the total antioxidant capacity.
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http://dx.doi.org/10.1007/978-1-0716-1558-4_27DOI Listing
January 2022

Analysis of Cytotoxic Effects of Zerumbone in Malignant Glioblastoma Cells.

Methods Mol Biol 2022 ;2343:361-369

Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.

Glioblastoma multiforme (GBM) is an aggressive tumor in the central nervous system with a poor prognosis. Currently, the main interventions include surgery, chemotherapy, and radiotherapy. Recently, several natural products have been reported as potentially effective and safer treatment options. Here, we studied the effects of zerumbone, a sesquiterpene compound derived from Zingiber zerumbet Smith rhizomes, on human GBM U-87 MG cells in vitro. To meet this purpose, we used a cytotoxicity assay, as well as a quantitative polymerase chain reaction of apoptosis-related genes and western blot analysis of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), a transcription factor that controls the production of cytokines and molecules involved in cell survival.
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http://dx.doi.org/10.1007/978-1-0716-1558-4_26DOI Listing
January 2022

Testing the Anti-inflammatory Effects of Curcuminoids in Patients with Colorectal Cancer.

Methods Mol Biol 2022 ;2343:319-330

Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.

Colorectal cancer is the third most common cancer and accounts for the second highest number of cancer-related deaths worldwide. Natural products such as the turmeric-derived curcuminoids are known to have protective effects against several kinds of cancers by acting as antioxidant and anti-inflammatory agents. Here, we present a protocol for assessing the effects of curcuminoids on serum cytokine profiles in a double-blind placebo-controlled trial of patients with stage 3 colorectal cancer undergoing chemotherapy. The protocol could also be applied to other cancer types.
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http://dx.doi.org/10.1007/978-1-0716-1558-4_23DOI Listing
January 2022

Measuring the Effects of Berberine on Serum Prooxidant-Antioxidant Balance in Metabolic Syndrome.

Methods Mol Biol 2022 ;2343:309-318

Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.

Disturbances in the prooxidant-antioxidant balance can occur in metabolic syndrome. Here, we present a protocol for the setup of a clinical trial of metabolic syndrome patients treated with berberine, a dietary phytochemical of the Berberis vulgaris plant, or placebo. The main aim is to obtain a quick and real-time assessment on the overall redox state based on measurement of the prooxidant-antioxidant balance.
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http://dx.doi.org/10.1007/978-1-0716-1558-4_22DOI Listing
January 2022

Testing the Effect of Curcumin on Proliferative Capacity of Colorectal Cancer Cells.

Methods Mol Biol 2022 ;2343:287-298

Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.

This chapter presents a protocol for studying the effects of curcumin in a colorectal cell line and a mouse model of colitis-associated colon carcinogenesis. The protocol using the CT26 cell line incorporates cell proliferation, migration, invasion, spheroid formation, cell cycle, polymerase chain reaction (PCR), and western blot analyses. For the mouse model, this involved a macroscopic and histological examination of the colon and assays for oxidative damage markers.
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http://dx.doi.org/10.1007/978-1-0716-1558-4_20DOI Listing
January 2022

Effect of resveratrol on C-reactive protein: An updated meta-analysis of randomized controlled trials.

Phytother Res 2021 Sep 2. Epub 2021 Sep 2.

Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.

We conducted a meta-analysis on the available randomized clinical trials (RCTs) to assess the role of resveratrol in lowering C-reactive protein (CRP) and high-sensitivity CRP (hs-CRP) levels, as markers of inflammation, in various inflammatory disorders. Literature search through Medline/PubMed, Scopus, ISI Web of Science, and Cochrane Library yielded 35 RCTs (24 studies for hs-CRP and 11 studies for CRP). Pooled results revealed that resveratrol supplementation significantly reduced the hs-CRP (MWD = -0.40 mg/L; 95% CI: -0.70 to -0.09 mg/L; p = .01) and CRP (MWD = -0.31 mg/L; 95% CI: -0.47 to -0.15 mg/L; p < .001) levels in serum. Subgroup analysis revealed that resveratrol in group with ≥10 weeks significantly reduces hs-CRP levels (MWD = -0.48 mg/L; 95% CI: -0.92 to -0.04 mg/L; p = .03) and CRP (WMD = -0.47 mg/L, 95% CI = -0.69 to -0.25, p < .001). A dose of ≥500 mg/day supplementation improves the levels of CRP, but not hs-CRP. This meta-analysis demonstrates that resveratrol consumption is effective in lowering the levels of CRP and hs-CRP in inflammatory conditions, especially if supplementation takes place for ≥10 weeks with ≥500 mg/day.
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http://dx.doi.org/10.1002/ptr.7262DOI Listing
September 2021

Renoprotective Effects of Incretin-Based Therapy in Diabetes Mellitus.

Biomed Res Int 2021 21;2021:8163153. Epub 2021 Aug 21.

Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.

Glucagon-like peptide-1 (GLP-1) receptor agonists are recently discovered antidiabetic drugs with potent hypoglycemic effects. Among different mechanisms of activity, these compounds were shown to reduce blood glucose by suppression of glucagon secretion and stimulation of glucose-dependent insulin secretion. These antidiabetic agents have a minor risk of hypoglycemia and have been suggested as a second-line therapy to be added to metformin treatment to further optimize glycemic control in diabetes. More recently, scientific evidence suggests that GLP-1 receptor agonists may particularly afford protection from diabetic nephropathy through modulation of the molecular pathways involved in renal impairment and so improve renal function. This additional benefit adds further weight for these compounds to become promising drugs not only for glycemic control but also to prevent diabetic complications. In this review, we have updated evidence on the beneficial effects of GLP-1 receptor agonists on diabetic nephropathy and detailed the underlying pathophysiological mechanisms.
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http://dx.doi.org/10.1155/2021/8163153DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8405289PMC
August 2021

Lipoprotein(a): Knowns, unknowns and uncertainties.

Pharmacol Res 2021 Aug 24;173:105812. Epub 2021 Aug 24.

School of Medicine, University of Western Australia, Perth, Australia; Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran. Electronic address:

Over the last 10 years, there have been advances on several aspects of lipoprotein(a) which are reviewed in the present article. Since the standard immunoassays for measuring lipoprotein(a) are not fully apo(a) isoform-insensitive, the application of an LC-MS/MS method for assaying molar concentrations of lipoprotein(a) has been advocated. Genome wide association, epidemiological, and clinical studies have established high lipoprotein(a) as a causal risk factor for atherosclerotic cardiovascular diseases (ASCVD). However, the relative importance of molar concentration, apo(a) isoform size or variants within the LPA gene is still controversial. Lipoprotein(a)-raising single nucleotide polymorphisms has not been shown to add on value in predicting ASCVD beyond lipoprotein(a) concentrations. Although hyperlipoproteinemia(a) represents an important confounder in the diagnosis of familial hypercholesterolemia (FH), it enhances the risk of ASCVD in these patients. Thus, identification of new cases of hyperlipoproteinemia(a) during cascade testing can increase the identification of high-risk individuals. However, it remains unclear whether FH itself increases lipoprotein(a). The ASCVD risk associated with lipoprotein(a) seems to follow a linear gradient across the distribution, regardless of racial subgroups and other risk factors. The inverse association with the risk of developing type 2 diabetes needs consideration as effective lipoprotein(a) lowering therapies are progressing towards the market. Considering that Mendelian randomization analyses have identified the degree of lipoprotein(a)-lowering that is required to achieve ASCVD benefit, the findings of the ongoing outcome trial with pelacarsen will clarify whether dramatically lowering lipoprotein(a) levels can reduce the risk of ASCVD.
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http://dx.doi.org/10.1016/j.phrs.2021.105812DOI Listing
August 2021

PLGA-Based Curcumin Delivery System: An Interesting Therapeutic Approach in Treatment of Alzheimer's Disease.

Curr Neuropharmacol 2021 Aug 22. Epub 2021 Aug 22.

Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad. Iran.

Progressive degeneration and dysfunction of the nervous system because of oxidative stress, aggregations of misfolded proteins, and neuroinflammation are the key pathological features of neurodegenerative diseases. Alzheimer's disease is a chronic neurodegenerative disorder driven by uncontrolled extracellular deposition of β-amyloid (Aβ) in the amyloid plaques and intracellular accumulation of hyperphosphorylated tau protein. Curcumin is a hydrophobic polyphenol with noticeable neuroprotective and anti-inflammatory effects that can cross the blood-brain barrier. Therefore, it is widely studied for the alleviation of inflammatory and neurological disorders. However, the clinical application of curcumin is limited due to its low aqueous solubility and bioavailability. Recently, nano-based curcumin delivery systems are developed to overcome these limitations effectively. This review article discusses the effects and potential mechanisms of curcumin-loaded PLGA nanoparticles in Alzheimer's disease.
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http://dx.doi.org/10.2174/1570159X19666210823103020DOI Listing
August 2021

A Novel Splice Site Variant in the LDLRAP1 Gene Causes Familial Hypercholesterolemia

Iran Biomed J 2021 09 15;25(5):374-9. Epub 2021 May 15.

International UNESCO Center for Health-Related Basic Sciences and Human Nutrition, Department of Nutrition, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.

Background: familial hypercholesterolemia (FH), a hereditary disorder, is caused by pathogenic variants in the LDLR, APOB, and PCSK9 genes. This study has assessed genetic variants in a family, clinically diagnosed with FH.

Methods: A family was recruited from MASHAD study in Iran with possible FH based on the Simon Broom criteria. The DNA sample of an affected individual (proband) was analyzed using whole exome sequencing, followed by bioinformatics and segregation analyses.

Results: A novel splice site variant (c.345-2A>G) was detected in the LDLRAP1 gene, which was segregated in all affected family members. Moreover, HMGCR rs3846662 g.23092A>G was found to be homozygous (G/G) in the proband, probably leading to reduced response to simvastatin and pravastatin.

Conclusion: LDLRAP1 c.345-2A>G could alter the phosphotyrosine-binding domain, which acts as an important part of biological pathways related to lipid metabolism.
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http://dx.doi.org/10.52547/ibj.25.5.374DOI Listing
September 2021

Bortezomib: a proteasome inhibitor for the treatment of autoimmune diseases.

Inflammopharmacology 2021 Aug 23. Epub 2021 Aug 23.

Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.

Autoimmune diseases (ADs) are conditions in which the immune system cannot distinguish self from non-self and, as a result, tissue injury occurs primarily due to the action of various inflammatory mediators. Different immunosuppressive agents are used for the treatment of patients with ADs, but some clinical cases develop resistance to currently available therapies. The proteasome inhibitor bortezomib (BTZ) is an approved agent for first-line therapy of people with multiple myeloma. BTZ has been shown to improve the symptoms of different ADs in animal models and ameliorated symptoms in patients with systemic lupus erythematous, rheumatoid arthritis, myasthenia gravis, neuromyelitis optica spectrum disorder, Chronic inflammatory demyelinating polyneuropathy, and autoimmune hematologic diseases that were nonresponsive to conventional therapies. Proteasome inhibition provides a potent strategy for treating ADs. BTZ represents a proteasome inhibitor that can potentially be used to treat AD patients resistant to conventional therapies.
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http://dx.doi.org/10.1007/s10787-021-00863-2DOI Listing
August 2021

Negatively-charged liposome nanoparticles can prevent dyslipidemia and atherosclerosis progression in the rabbit model.

Curr Vasc Pharmacol 2021 Aug 20. Epub 2021 Aug 20.

Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad. Iran.

Background And Aim: Negatively charged nanoliposomes have a strong attraction towards plasma lipoprotein particles and can thereby regulate lipid metabolism. Here, the impact of such nanoliposomes on dyslipidaemia and progression of atherosclerosis was investigated in a rabbit model.

Methods: Two sets of negatively-charged nanoliposome formulations including [hydrogenated soy phosphatidylcholine (HSPC)/1,2-distearoyl-sn-glycero-3- phosphoglycerol (DSPG)] and [1,2-Dimyristoyl-sn-glycero-3-phosphorylcholine (DMPC)/1,2-Dimyristoyl-sn-glycero-3-phosphorylcholine (DMPG)/Cholesterol] were evaluated. Rabbits fed a high-cholesterol diet were randomly divided into 3 groups (n=5/group) intravenously administrated with HSPC/DSPG formulation (DSPG group; 100 mmol/kg), DMPC/DMPG formulation (DMPG group; 100 mmol/kg), or the normal saline (control group; 0.9% NaCl) over a 4-week period. The atherosclerotic lesions of the aortic arch wall were studied using haematoxylin and eosin staining.

Results: Both DSPG and DMPG nanoliposome formulations showed a nano-sized range in diameter with a negatively-charged surface and a polydispersity index of <0.1. After 4 weeks administration, the nanoliposome formulations decreased triglycerides (-62±3% [DSPG group] and -58±2% [DMPG group]), total cholesterol (-58±9% [DSPG group] and -37±5% [DMPG group]), and low-density lipoprotein cholesterol (-64±6% [DSPG group] and -53±10% [DMPG group]) levels, and increased high-density lipoprotein cholesterol (+67±28% [DSPG group] and +35±19% [DMPG group]) levels compared with the controls. The nanoliposomes showed a significant decrease in the severity of atherosclerotic lesions: mean values of the intima to media ratio in DMPG (0.96±0.1 fold) and DSPG (0.54±0.02 fold) groups were found to be significantly lower than that in the control (1.2±0.2 fold) group (p<0.05).

Conclusion: Anionic nanoliposomes containing [HSPC/DSPG] and [DMPC/DMPG] correct dyslipidaemia and inhibit the progression of atherosclerosis.
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http://dx.doi.org/10.2174/1570161119666210820115150DOI Listing
August 2021

Antidiabetic drugs and oxidized low-density lipoprotein: A review of anti-atherosclerotic mechanisms.

Pharmacol Res 2021 Aug 14;172:105819. Epub 2021 Aug 14.

Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; School of Medicine, The University of Western Asutralia, Perth, Australia; School of Pharmacy, Mashhad University of Medical Sciences, Mashhad 9177948567, Iran. Electronic address:

Cardiovascular disease is one of the leading causes of mortality globally. Atherosclerosis is an important step towards different types of cardiovascular disease. The role of oxidized low-density lipoprotein (oxLDL) in the initiation and progression of atherosclerosis has been thoroughly investigated in recent years. Moreover, clinical trials have established that diabetic patients are at a greater risk of developing atherosclerotic plaques. Hence, we aimed to review the clinical and experimental impacts of various classes of antidiabetic drugs on the circulating levels of oxLDL. Metformin, pioglitazone, and dipeptidyl peptidase-4 inhibitors were clinically associated with a suppressive effect on oxLDL in patients with impaired glucose tolerance. However, there is an insufficient number of studies that have clinically evaluated the relationship between oxLDL and newer agents such as agonists of glucagon-like peptide 1 receptor or inhibitors of sodium-glucose transport protein 2. Next, we attempted to explore the multitude of mechanisms that antidiabetic agents exert to counter the undesirable effects of oxLDL in macrophages, endothelial cells, and vascular smooth muscle cells. In general, antidiabetic drugs decrease the uptake of oxLDL by vascular cells and reduce subsequent inflammatory signaling, which prevents macrophage adhesion and infiltration. Moreover, these agents suppress the oxLDL-induced transformation of macrophages into foam cells by either inhibiting oxLDL entrance, or by facilitating its efflux. Thus, the anti-inflammatory, anti-oxidant, and anti-apoptotic properties of antidiabetic agents abrogate changes induced by oxLDL, which can be extremely beneficial in controlling atherosclerosis in diabetic patients.
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http://dx.doi.org/10.1016/j.phrs.2021.105819DOI Listing
August 2021

Targeting interleukin-β by plant-derived natural products: Implications for the treatment of atherosclerotic cardiovascular disease.

Phytother Res 2021 Aug 12. Epub 2021 Aug 12.

Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.

Inflammation is the main contributing factor to atheroma formation in atherosclerosis. Interleukin-1 beta (IL-1β) is an inflammatory mediator found in endothelial cells and resident leukocytes. Canakinumab is a selective monoclonal antibody against IL-1β which attenuates inflammation and concurrently precipitates fatal infections and sepsis. Natural products derived from medicinal plants, herbal remedy and functional foods are widely used nowadays. Experimental and clinical trial evidence supports that some natural products such as curcumin, resveratrol, and quercetin have potential effects on IL-1β suppression. In this review, we tried to document findings that used medicinal plants and plant-based natural products for treating atherosclerosis and its related diseases through the suppression of IL-1β.
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http://dx.doi.org/10.1002/ptr.7194DOI Listing
August 2021

Prevalence of vitamin D deficiency and its prognostic impact on patients hospitalized with COVID-19.

Nutrition 2021 Jul 1;91-92:111408. Epub 2021 Jul 1.

Unit of Internal Medicine, Department of Medicine and Surgery, University of Perugia, Perugia, Italy.

Objectives: Although hypovitaminosis D appears to be highly prevalent in patients with coronavirus disease 2019 (COVID-19), its impact on their prognosis remains unclear.

Methods: In this study, serum 25-hydroxyvitamin D (Vit-D) level was measured in 200 patients hospitalized with COVID-19. The association between Vit-D and the composite endpoint of intensive care unit (ICU) admission/in-hospital death was explored using univariable and multivariable analyses. Also, serum Vit-D level in patients with COVID-19 was compared with that in age- and sex-balanced COVID-19-negative controls (i.e., 50 inpatients with sepsis).

Results: Serum Vit-D level was comparable between patients with COVID-19 and COVID-19-negative inpatients with sepsis (P = 0.397). No significant differences were found in serum Vit-D level according to COVID-19 severity at the time of hospital admission (P = 0.299). Incidence rates of the composite endpoint of ICU admission/in-hospital death did not differ significantly between patients with either Vit-D deficiency (i.e., Vit-D <20 ng/mL) or severe Vit-D deficiency (i.e., Vit-D <12 ng/mL) and those without (31% vs 35% with P = 0.649, and 34% vs 30% with P = 0.593, respectively). Vit-D level and status (i.e., Vit-D deficiency and severe Vit-D deficiency) were not prospectively associated with the risk of the composite endpoint of ICU admission/in-hospital death (P > 0.05 for all Cox regression models).

Conclusions: Regardless of the potential usefulness of Vit-D measurement to guide appropriate supplementation, Vit-D does not appear to provide helpful information for the stratification of in-hospital prognosis in patients with COVID-19.
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http://dx.doi.org/10.1016/j.nut.2021.111408DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8247197PMC
July 2021

Ginger: A complementary approach for management of cardiovascular diseases.

Biofactors 2021 Aug 13. Epub 2021 Aug 13.

Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.

Cardiovascular disease (CVD) is a leading cause of morbidity and mortality worldwide. Inflammation and oxidative stress play critical roles in progression of various types of CVD. Broad pharmacological properties of ginger (the rhizome of Zingiber officinale) and its bioactive components have been reported, suggesting that they can be a therapeutic choice for clinical use. Consistent with its rich phenolic content, the anti-inflammatory and antioxidant properties of ginger have been confirmed in many studies. Ginger modifies many cellular processes and in particular was shown to have potent inhibitory effects against nuclear factor kappa B (NF-κB); signal transducer and activator of transcription; NOD-, LRR-, and pyrin domain-containing proteins; toll-like receptors; mitogen-activated protein kinase; and mammalian target of rapamycin signaling pathways. Ginger also blocks pro-inflammatory cytokines and the activation of the immune system. Ginger suppresses the activity of oxidative molecules such as reactive oxygen species, inducible nitric oxide synthase, superoxide dismutase, glutathione, heme oxygenase, and GSH-Px. In this report, we summarize the biochemical pathologies underpinning a variety of CVDs and the effects of ginger and its bioactive components, including 6-shogaol, 6-gingerol, and 10-dehydrogingerdione. The properties of ginger and its phenolic components, mechanism of action, biological functions, side effects, and methods for enhanced cell delivery are also discussed. Together with preclinical and clinical studies, the positive biological effects of ginger and its bioactive components in CVD support the undertaking of further in vivo and especially clinical studies.
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http://dx.doi.org/10.1002/biof.1777DOI Listing
August 2021

Recent advances in lung cancer therapy based on nanomaterials: a review.

Curr Med Chem 2021 Aug 10. Epub 2021 Aug 10.

Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad 9177948564, Iran.

Lung cancer is one of the commonest cancers with a significant mortality rate for both genders, particularly in men. Lung cancer is recognized as one of the leading cause of death worldwide, which threatens the lives of over 1.6 million people every day.. Although cancer is the leading cause of death in industrialized countries, conventional anticancer medications are unlikely to increase patients' life expectancy and quality of life significantly. In recent years, there are significant advances in the development and application of nanotechnology in cancer treatment. The superiority of nanostructured approaches is that they act more selectively than traditional agents. This progress led to the development of a novel field of cancer treatment known as nanomedicine. Various formulations based on nanocarriers, including lipids, polymers, liposomes, nanoparticles and dendrimers have opened new horizons in lung cancer therapy. The application and expansion of nano-agents lead to an exciting and challenging research era in pharmaceutical science, especially for the delivery of emerging anti-cancer agents. The objective of this review is to discuss the recent advances in three types of nanoparticle formulations for lung cancer treatments modalities including liposomes, polymeric micelles, and dendrimers for efficient drug delivery. Afterward, we have summarized the promising clinical data on nanomaterials based therapeutic apperoches in ongoing clinical studies.
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http://dx.doi.org/10.2174/0929867328666210810160901DOI Listing
August 2021

Implications on the Therapeutic Potential of Statins Modulation of Autophagy.

Oxid Med Cell Longev 2021 30;2021:9599608. Epub 2021 Jul 30.

Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.

Statins, which are functionally known as 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) inhibitors, are lipid-lowering compounds widely prescribed in patients with cardiovascular diseases (CVD). Several biological and therapeutic functions have been attributed to statins, including neuroprotection, antioxidation, anti-inflammation, and anticancer effects. Pharmacological characteristics of statins have been attributed to their involvement in the modulation of several cellular signaling pathways. Over the past few years, the therapeutic role of statins has partially been attributed to the induction of autophagy, which is critical in maintaining cellular homeostasis and accounts for the removal of unfavorable cells or specific organelles within cells. Dysregulated mechanisms of the autophagy pathway have been attributed to the etiopathogenesis of various disorders, including neurodegenerative disorders, malignancies, infections, and even aging. Autophagy functions as a double-edged sword during tumor metastasis. On the one hand, it plays a role in inhibiting metastasis through restricting necrosis of tumor cells, suppressing the infiltration of the inflammatory cell to the tumor niche, and generating the release of mediators that induce potent immune responses against tumor cells. On the other hand, autophagy has also been associated with promoting tumor metastasis. Several anticancer medications which are aimed at inducing autophagy in the tumor cells are related to statins. This review article discusses the implications of statins in the induction of autophagy and, hence, the treatment of various disorders.
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http://dx.doi.org/10.1155/2021/9599608DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8349293PMC
July 2021
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