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Mitochondrion Jul 2021Metabolic reprogramming and mitochondrial dysfunction are central elements in a broad variety of physiological and pathological processes. While cell culture established... (Review)
Review
Metabolic reprogramming and mitochondrial dysfunction are central elements in a broad variety of physiological and pathological processes. While cell culture established itself as a versatile technique for the elaboration of physiology and disease, studying metabolism using standard cell culture protocols is profoundly interfered by the Crabtree effect. This phenomenon refers to the adaptation of cultured cells to a glycolytic phenotype, away from oxidative phosphorylation in glucose-containing medium, and questions the applicability of cell culture in certain fields of research. In this systematic review we aim to provide a comprehensive overview and critical appraisal of strategies reported to circumvent the Crabtree effect.
Topics: Cell Culture Techniques; Culture Media; Glucose; Glycolysis; Humans; Mitochondria; Mitochondrial Dynamics; Oxidative Phosphorylation
PubMed: 33812964
DOI: 10.1016/j.mito.2021.03.014 -
Clinical Epigenetics Jul 2023To systematically evaluate the efficacy and safety of FDA-approved isocitrate dehydrogenase (IDH) inhibitors in the treatment of IDH-mutated acute myeloid leukemia (AML). (Meta-Analysis)
Meta-Analysis Review
OBJECTIVE
To systematically evaluate the efficacy and safety of FDA-approved isocitrate dehydrogenase (IDH) inhibitors in the treatment of IDH-mutated acute myeloid leukemia (AML).
METHODS
We used R software to conduct a meta-analysis of prospective clinical trials of IDH inhibitors in the treatment of IDH-mutated AML published in PubMed, Embase, Clinical Trials, Cochrane Library and Web of Science from inception to November 15th, 2022.
RESULTS
A total of 1109 IDH-mutated AML patients from 10 articles (11 cohorts) were included in our meta-analysis. The CR rate, ORR rate, 2-year survival (OS) rate and 2-year event-free survival (EFS) rate of newly diagnosed IDH-mutated AML (715 patients) were 47%, 65%, 45% and 29%, respectively. The CR rate, ORR rate, 2-year OS rate, median OS and median EFS of relapsed or refractory (R/R) IDH-mutated AML (394 patients) were 21%, 40%, 15%, 8.21 months and 4.73 months, respectively. Gastrointestinal adverse events were the most frequently occurring all-grade adverse events and hematologic adverse events were the most frequently occurring ≥ grade 3 adverse events.
CONCLUSION
IDH inhibitor is a promising treatment for R/R AML patients with IDH mutations. For patients with newly diagnosed IDH-mutated AML, IDH inhibitors may not be optimal therapeutic agents due to low CR rates. The safety of IDH inhibitors is controllable, but physicians should always pay attention to and manage the differentiation syndrome adverse events caused by IDH inhibitors. The above conclusions need more large samples and high-quality RCTs in the future to verify.
Topics: Humans; Prospective Studies; DNA Methylation; Leukemia, Myeloid, Acute; Enzyme Inhibitors; Mutation
PubMed: 37434249
DOI: 10.1186/s13148-023-01529-2 -
International Journal of Molecular... Dec 2022The pathophysiology of allergic rhinitis (AR), one of the most common diseases in the world, is still not sufficiently understood. Extracellular vesicles (EVs), which... (Review)
Review
The pathophysiology of allergic rhinitis (AR), one of the most common diseases in the world, is still not sufficiently understood. Extracellular vesicles (EVs), which are secreted by host and bacteria cells and take part in near and distant intracellular communication, can provide information about AR. Recently, attention has been drawn to the potential use of EVs as biomarkers, vaccines, or transporters for drug delivery. In this review, we present an up-to-date literature overview on EVs in AR to reveal their potential clinical significance in this condition. A comprehensive and systematic literature search was conducted following PRISMA statement guidelines for original, completed articles, available in English concerning EVs and AR. For this purpose, PubMed/MEDLINE, Scopus, Web of Science, and Cochrane, were searched up until 10 Novenmber 2022. From 275 records, 18 articles were included for analysis. The risk of bias was assessed for all studies as low or moderate risk of overall bias using the Office and Health Assessment and Translation Risk of Bias Rating Tool for Human and Animal Studies. We presented the role of exosomes in the pathophysiology of AR and highlighted the possibility of using exosomes as biomarkers and treatment in this disease.
Topics: Animals; Humans; Rhinitis, Allergic; Extracellular Vesicles; Exosomes; Biomarkers; Biological Transport
PubMed: 36613810
DOI: 10.3390/ijms24010367 -
Advanced Drug Delivery Reviews 2020Microneedles (MNs) have been used to deliver drugs for over two decades. These platforms have been proven to increase transdermal drug delivery efficiency dramatically...
Microneedles (MNs) have been used to deliver drugs for over two decades. These platforms have been proven to increase transdermal drug delivery efficiency dramatically by penetrating restrictive tissue barriers in a minimally invasive manner. While much of the early development of MNs focused on transdermal drug delivery, this technology can be applied to a variety of other non-transdermal biomedical applications. Several variations, such as multi-layer or hollow MNs, have been developed to cater to the needs of specific applications. The heterogeneity in the design of MNs has demanded similar variety in their fabrication methods; the most common methods include micromolding and drawing lithography. Numerous materials have been explored for MN fabrication which range from biocompatible ceramics and metals to natural and synthetic biodegradable polymers. Recent advances in MN engineering have diversified MNs to include unique shapes, materials, and mechanical properties that can be tailored for organ-specific applications. In this review, we discuss the design and creation of modern MNs that aim to surpass the biological barriers of non-transdermal drug delivery in ocular, vascular, oral, and mucosal tissue.
Topics: Administration, Topical; Biological Transport; Drug Delivery Systems; Equipment Design; Humans; Microinjections; Microtechnology; Polymers; Prostheses and Implants
PubMed: 31837356
DOI: 10.1016/j.addr.2019.11.010 -
Systematic Reviews Jul 2023The purpose of this systematic review is to collect, appraise, and synthesize existing evidence from systematic reviews and meta-analyses (SRs/MAs) on the effectiveness...
OBJECTIVE
The purpose of this systematic review is to collect, appraise, and synthesize existing evidence from systematic reviews and meta-analyses (SRs/MAs) on the effectiveness of tolvaptan for water retention in heart failure.
METHODS
A comprehensive literature search was performed on PubMed, EMBASE, web of science, Cochrane reviews for SRs/Mas published between the databases' establishment to November 17, 2021. All the records were managed with Endnote 20. Standardized forms were used to extract data. Revman 5.3 was used to make forest plots to show the characteristics of outcomes. The methodological and evidence quality were respectively evaluated by AMSTAR-2 (A MeaSurement Tool to Assess systematic Reviews 2) and GRADE (Grading of Recommendation of Assessment, Development, and Evaluation) system.
RESULTS
A total of 9 SRs/Mas between 2015 to 2020 met inclusion criteria. Serum sodium concentration and urine output were considered as primary outcomes and body weight change and all-cause mortality as second outcomes. Through conducting forest plots, it appeared that tolvaptan brought more positive effect than conventional therapies. It was pessimistic when it comes to the quality of the 9 studies. all the 9 articles were rated as low-quality because AMSTAR 2 evaluation showed that they each had at least one critical item (items 2, 4, 7, 9, 11, 13 and 15) defect. Besides, every article had a few non-critical item defects too. The result of GRADE assessment was not optimistic, so the overall quality of the evidences was low as well.
CONCLUSION
Tolvaptan can be recommended for water retention in HF patients, but more evidence is needed.
Topics: Humans; Tolvaptan; Water-Electrolyte Balance; Heart Failure; Databases, Factual; Water
PubMed: 37516894
DOI: 10.1186/s13643-023-02293-3 -
Journal of Controlled Release :... Dec 2020For the past two decades, biomimetic high-density lipoproteins (b-HDL) have been used for various drug delivery applications. The b-HDL mimic the endogenous HDL, and... (Meta-Analysis)
Meta-Analysis Review
For the past two decades, biomimetic high-density lipoproteins (b-HDL) have been used for various drug delivery applications. The b-HDL mimic the endogenous HDL, and therefore possess many attractive features for drug delivery, including high biocompatibility, biodegradability, and ability to transport and deliver their cargo (e.g. drugs and/or imaging agents) to specific cells and tissues that are recognized by HDL. The b-HDL designs reported in the literature often differ in size, shape, composition, and type of incorporated cargo. However, there exists only limited insight into how the b-HDL design dictates their biodistribution. To fill this gap, we conducted a comprehensive systematic literature search of biodistribution studies using various designs of apolipoprotein A-I (apoA-I)-based b-HDL (i.e. b-HDL with apoA-I, apoA-I mutants, or apoA-I mimicking peptides). We carefully screened 679 papers (search hits) for b-HDL biodistribution studies in mice, and ended up with 24 relevant biodistribution profiles that we compared according to b-HDL design. We show similarities between b-HDL biodistribution studies irrespectively of the b-HDL design, whereas the biodistribution of the b-HDL components (lipids and scaffold) differ significantly. The b-HDL lipids primarily accumulate in liver, while the b-HDL scaffold primarily accumulates in the kidney. Furthermore, both b-HDL lipids and scaffold accumulate well in the tumor tissue in tumor-bearing mice. Finally, we present essential considerations and strategies for b-HDL labeling, and discuss how the b-HDL biodistribution can be tuned through particle design and administration route. Our meta-analysis and discussions provide a detailed overview of the fate of b-HDL in mice that is highly relevant when applying b-HDL for drug delivery or in vivo imaging applications.
Topics: Animals; Apolipoprotein A-I; Biomimetics; Drug Delivery Systems; Lipids; Lipoproteins, HDL; Mice; Tissue Distribution
PubMed: 32971201
DOI: 10.1016/j.jconrel.2020.09.038 -
Pulmonary Pharmacology & Therapeutics Aug 2023COPD pathogenesis is frequently associated with endoplasmic reticulum stress (ER stress) progression. Targeting the major unfolded protein response (UPR) branches in the... (Review)
Review
COPD pathogenesis is frequently associated with endoplasmic reticulum stress (ER stress) progression. Targeting the major unfolded protein response (UPR) branches in the ER stress pathway may provide pharmacotherapeutic selection strategies for treating COPD and enable relief from its symptoms. In this study, we aimed to systematically review the potential role of the ER stress inhibitors of major UPR branches (IRE1, PERK, and ATF6) in COPD-related studies and determine the current stage of knowledge in this field. The systematic review was carried out adhering to the PRISMA checklist based on published studies obtained from specific keyword searches of three databases, namely PubMed, ScienceDirect and Springer Database. The search was limited to the year 2000-2022 which includes all in vitro studies, in vivo studies and clinical trials related to the application of ER stress inhibitors toward COPD-induced models and disease. The risk of bias was evaluated using the QUIN, SYRCLE, revised Cochrane risk of bias tool for randomized trials (RoB 2.0) and NIH tool respectively. A total of 7828 articles were screened from three databases and a final total of 37 studies were included in the review. The ER stress and UPR pathways are potentially useful to prevent COPD progression and attenuate the exacerbation of COPD and related symptoms. Interestingly, the off-target effects from inhibition of the UPR pathway may be desirable or undesirable depending on context and therapeutic applications. Targeting the UPR pathway could have complex consequences as the production of ER molecules involved in folding may be impaired which could continuously provoke misfolding of proteins. Although several emerging compounds were noted to be potentially useful for targeted therapy against COPD, clinical studies have yet to be thoroughly explored.
Topics: Humans; eIF-2 Kinase; Endoplasmic Reticulum Stress; Unfolded Protein Response; Pulmonary Disease, Chronic Obstructive
PubMed: 37201652
DOI: 10.1016/j.pupt.2023.102218 -
European Journal of Nutrition Sep 2021Cytochrome P450s (CYPs) are a class of hemoproteins involved in drug metabolism. It has been reported that body composition, proportion of dietary macronutrients,... (Review)
Review
BACKGROUND
Cytochrome P450s (CYPs) are a class of hemoproteins involved in drug metabolism. It has been reported that body composition, proportion of dietary macronutrients, fasting and nutritional status can interfere with the activity of drug-metabolizing CYPs.
OBJECTIVES
The present systematic review was conducted to summarize the effect of obesity, weight reduction, macronutrients, fasting and malnutrition on the CYP-mediated drug metabolism.
METHODS
PubMed (Medline), Scopus, Embase and Cochrane Library databases and Google Scholar were searched up to June 2020 to obtain relevant studies. The PRISMA guidelines were employed during all steps. Two reviewers independently extracted the information from the included studies. Studies investigating CYPs activity directly or indirectly through pharmacokinetics of probe drugs, were included. Increase in clearance (CL) or decrease in elimination half-life (t½) and area under the curve (AUC) of probe drugs were considered as increase in CYPs activity.
RESULTS
A total of 6545 articles were obtained through searching databases among which 69 studies with 126 datasets fully met the inclusion criteria. The results indicated that obesity might decrease the activity of CYP3A4/5, CYP1A2 and CYP2C9 and increase the activity of CYP2E1. The effect of obesity on CYP2D6 is controversial. Also, weight loss increased CYP3A4 activity. Moreover, CYP1A2 activity was decreased by high carbohydrate diet, increased by high protein diet and fasting and unchanged by malnutrition. The activity of CYP2C19 was less susceptible to alterations compared to other CYPs.
CONCLUSION
The activity of drug-metabolizing CYPs are altered by body composition, dietary intake and nutritional status. This relationship might contribute to drug toxicity or reduce treatment efficacy and influence cost-effectiveness of medical care.
Topics: Cytochrome P-450 Enzyme System; Fasting; Humans; Nutrients; Nutritional Status; Obesity; Pharmaceutical Preparations
PubMed: 33141242
DOI: 10.1007/s00394-020-02421-y -
Expert Review of Gastroenterology &... Jan 2020: This systemic review provides an overview of metabolic perturbations and possible mechanisms in gastrointestinal cancer. The authors discuss emerging challenges of...
: This systemic review provides an overview of metabolic perturbations and possible mechanisms in gastrointestinal cancer. The authors discuss emerging challenges of technical and clinical applications.: In this systemic review, the authors summarized the currently available results of metabolomic biomarkers linked to GI cancer, and discussed the altered metabolism pathways including carbohydrate metabolism, amino acid metabolism, lipids, and nucleotide metabolism and other metabolisms. Furthermore, future efforts need to adhere to normalize analysis procedures, validate with the larger cohort and utilize multiple-omics technologies. The search was conducted in PubMed with the following search terms (biomarker, gastrointestinal cancer, colorectal cancer, and esophageal cancer) from 2013 to 2019.: This systemic review summarized the currently available results of metabolomic biomarkers linked to gastrointestinal cancer, and discussed the altered metabolism pathways. The authors believe that metabolomics will benefit deeper understandings of the pathogenic mechanism, discovery of biomarkers and aid the search for drug targets as we move toward the era of personalized medicine. Personalized medication for tumors can improve the curative effect, avoid side effects and medical resource waste. As a promisingtool, metabolomics that targets the entire cancer-specific metabolite network should be applied more widely in cancer research.
Topics: Biomarkers, Tumor; Gastrointestinal Neoplasms; Humans; Metabolomics
PubMed: 31786962
DOI: 10.1080/17474124.2020.1700112 -
Frontiers in Immunology 2022CD47-SIRPα interaction acts as a "don't eat me" signal and is exploited by cancer to downregulate innate and adaptive immune surveillance. There has been intense... (Meta-Analysis)
Meta-Analysis
CD47-SIRPα interaction acts as a "don't eat me" signal and is exploited by cancer to downregulate innate and adaptive immune surveillance. There has been intense interest to develop a mechanism of blockade, and we aimed to analyze the emerging data from early clinical trials. We performed a systematic review and meta-analysis of relevant databases and conference abstracts including clinical trials using CD47 and/or SIRPα inhibitors in cancer treatment. Nonlinear mixed models were applied for comparison of response and toxicity. We retrieved 317 articles, 24 of which were eligible. These included 771 response-evaluable patients with hematologic (47.1%) and solid tumors (52.9%). Of these, 6.4% experienced complete response, 10.4% partial response, and 26.1% stable disease for a 16.7% objective response rate (ORR), 42.8% disease control rate, and 4.8-month median duration of response. ORR was significantly higher for hematologic cancers (25.3%) than solid cancers (9.1%, p=0.042). Comparing by mechanism, seven CD47 monoclonal antibodies (mAbs) and six selective SIRPα blockers were given alone or combined with checkpoint inhibitors, targeted therapy, and/or chemotherapy. In solid cancers, selective SIRPα blockade showed a higher ORR (16.2%) than anti-CD47 mAbs (2.8%, p=0.079), which was significant for combination therapies (ORR 28.3% vs 3.0%, respectively, p=0.010). Responses were seen in head and neck, colorectal, endometrial, ovarian, hepatocellular, non-small cell lung, and HER2+gastroesophageal cancers. Dose-limiting toxicity (DLT) was seen in 3.3% of patients (5.4% anti-CD47 mAbs, 1.4% selective SIRPα blockers; p=0.01). The frequency of treatment-related adverse events (TRAEs) ≥grade 3 was 18.0%, similar between the two groups (p=0.082), and mostly laboratory abnormalities. For anti-CD47 mAbs, the most common toxicities included grade 1-2 fatigue (27.2%), headache (21.0%), and anemia (20.5%). For selective SIRPα blockers, these included grade 1-2 infusion reaction (23.1%) and fatigue (15.8%). Anti-CD47 mAbs were significantly more likely than selective SIRPα blockers to cause grade 1-2 fever, chills, nausea/vomiting, headache, and anemia. In conclusion, combination therapies using selective SIRPα blockade had higher response rates in solid tumors than anti-CD47 mAb combinations. Hematologic changes were the main TRAEs, and selective SIRPα blockers seemed to have a better grade 1-2 toxicity profile. Treatment was well-tolerated with minimal DLTs.
Topics: Humans; Protein Binding; Antibodies, Monoclonal; Fatigue; Headache; Neoplasms; CD47 Antigen
PubMed: 36439116
DOI: 10.3389/fimmu.2022.1027235