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Journal of Advanced Research Dec 2023Crush syndrome (CS) is a kind of traumatic and ischemic injury that seriously threatens life after prolonged compression. It is characterized by systemic inflammatory... (Review)
Review
BACKGROUND
Crush syndrome (CS) is a kind of traumatic and ischemic injury that seriously threatens life after prolonged compression. It is characterized by systemic inflammatory reaction, myoglobinuria, hyperkalemia and acute kidney injury (AKI). Especially AKI, it is the leading cause of death from CS. There are various cell death forms in AKI, among which ferroptosis is a typical form of cell death. However, the role of ferroptosis has not been fully revealed in CS-AKI.
AIM OF REVIEW
This review aimed to summarize the evidence of ferroptosis in CS-AKI and its related molecular mechanism, discuss the therapeutic significance of ferroptosis in CS-AKI, and open up new ideas for the treatment of CS-AKI.
KEY SCIENTIFIC CONCEPTS OF REVIEW
One of the main pathological manifestations of CS-AKI is renal tubular epithelial cell dysfunction and cell death, which has been attributed to massive deposition of myoglobin. Large amounts of myoglobin released from damaged muscle deposited in the renal tubules, impeding the normal renal tubules function and directly damaging the tubules with oxidative stress and elevated iron levels. Lipid peroxidation damage and iron overload are the distinguishing features of ferroptosis. Moreover, high levels of pro-inflammatory cytokines and damage-associated molecule pattern molecules (HMGB1, double-strand DNA, and macrophage extracellular trap) in renal tissue have been shown to promote ferroptosis. However, how ferroptosis occurs in CS-AKI and whether it can be a therapeutic target remains unclear. In our current work, we systematically reviewed the occurrence and underlying mechanism of ferroptosis in CS-AKI.
Topics: Humans; Acute Kidney Injury; Cell Death; Crush Syndrome; Ferroptosis; Myoglobin
PubMed: 36702249
DOI: 10.1016/j.jare.2023.01.016 -
Medicine Oct 2023Biological agents are commonly used for the first-line treatment of ulcerative colitis (UC). However, small-molecule drugs and microbiome therapies are now being used as... (Meta-Analysis)
Meta-Analysis
Comparative of the effectiveness and safety of biological agents, small molecule drugs, and microbiome therapies in ulcerative colitis: Systematic review and network meta-analysis.
BACKGROUND
Biological agents are commonly used for the first-line treatment of ulcerative colitis (UC). However, small-molecule drugs and microbiome therapies are now being used as new treatments for ulcerative colitis. We aimed to compare the relative efficacy and safety of biologics, small-molecule drugs, and microbiome therapies for the treatment of patients with moderate-to-severe ulcerative colitis.
METHODS
We searched the Cochrane, Embase, and PubMed databases from their inception to December 2022. RCTs that recruited patients with moderate-to-severe ulcerative colitis treated with biological agents, small-molecule drugs, and microbiome therapies. Efficacy outcomes were induction of clinical remission and mucosal healing; safety outcomes were adverse events and serious adverse events. A network meta-analysis with multivariate consistency model random-effect meta-regression was done, with rankings based on surface under the cumulative ranking curve (SUCRA) values. Higher SUCRA scores correlate with better efficacy, whereas lower SUCRA scores correlate with better safety.
RESULTS
A total of 31 RCTs comprising 7933 UC patients were included in our studies. A risk of bias assessment showed a low risk of bias for most of the included studies. Upadacitinib ranked highest for induction of clinical remission (SUCRA, 0.83) and mucosal healing (SUCRA, 0.44). Moreover, no treatments were found to increase the occurrence of adverse events compared with placebos. Ustekinumab ranked lowest for adverse events (SUCRA 0.26) and probiotic ranked lowest for serious adverse events (0·21), whereas tofacitinib ranked highest for adverse events (0·43) and upadacitinib ranked highest for serious adverse events (0·43).
CONCLUSION
In this systematic review and network meta-analysis, we found upadacitinib to be ranked highest for the induction of clinical remission and mucosal healing, but the worst performing agent in terms of adverse events in UC patients. Probiotics were the best-performing agent for safety outcomes. More trials of direct comparisons are needed to inform clinical decision-making with greater confidence.
Topics: Humans; Biological Factors; Colitis, Ulcerative; Network Meta-Analysis; Ustekinumab; Biological Products
PubMed: 37904440
DOI: 10.1097/MD.0000000000035689 -
Nutrients Aug 2023The use of nutraceutical products to enhance male sexual performance has a long history, especially with regard to the treatment of erectile dysfunction (ED).... (Meta-Analysis)
Meta-Analysis Review
The use of nutraceutical products to enhance male sexual performance has a long history, especially with regard to the treatment of erectile dysfunction (ED). Alternative treatments for ED are becoming increasingly popular, with growing interest from consumers, as well as increased revenue for manufacturers. Dietary supplements (DSs), which are a mixture of active ingredients, are mainly sold online. In randomized controlled trials, the molecules contained in DSs have demonstrated varying degrees of effectiveness, or even have no evidence to support their use. However, none of the studies carried out provided sufficient evidence to consider these products a first-line therapy. Therefore, the combination of the various active ingredients, especially in relation to the daily dose, leaves doubts about the real effectiveness. In order to evaluate the potential efficacy of DS formulations, we analyzed the products marketed in Italy using a scoring approach. A systematic review of the literature was performed to evaluate the effect of DS and to detect the active ingredients able to improve erectile function-called effective ingredients (EIs)-and their minimal effective daily dose (mED). A metanalysis identified some nutraceuticals, such as Panax ginseng, Tribulus terrestris and L-arginine, that are able to improve male sexual function. Based on the scoring system, 2 (8%) supplements matched with the cluster of higher expected efficacy, 3 (12%) with the lower efficacy cluster and 20 (80%) matched with the criterion of no expected efficacy. DSs marketed in Italy are usually blends of many substances that are frequently employed at a negligible dose or without any evidence.
Topics: Humans; Male; Arginine; Dietary Supplements; Emotions; Erectile Dysfunction; Italy
PubMed: 37686709
DOI: 10.3390/nu15173677 -
Biomolecules Mar 2024Cholesterol is an essential molecule of life, and its synthesis can be inhibited by both genetic and nongenetic mechanisms. Hundreds of chemicals that we are exposed to... (Review)
Review
Cholesterol is an essential molecule of life, and its synthesis can be inhibited by both genetic and nongenetic mechanisms. Hundreds of chemicals that we are exposed to in our daily lives can alter sterol biosynthesis. These also encompass various classes of FDA-approved medications, including (but not limited to) commonly used antipsychotic, antidepressant, antifungal, and cardiovascular medications. These medications can interfere with various enzymes of the post-lanosterol biosynthetic pathway, giving rise to complex biochemical changes throughout the body. The consequences of these short- and long-term homeostatic disruptions are mostly unknown. We performed a comprehensive review of the literature and built a catalogue of chemical agents capable of inhibiting post-lanosterol biosynthesis. This process identified significant gaps in existing knowledge, which fall into two main areas: mechanisms by which sterol biosynthesis is altered and consequences that arise from the inhibitions of the different steps in the sterol biosynthesis pathway. The outcome of our review also reinforced that sterol inhibition is an often-overlooked mechanism that can result in adverse consequences and that there is a need to develop new safety guidelines for the use of (novel and already approved) medications with sterol biosynthesis inhibiting side effects, especially during pregnancy.
Topics: Animals; Humans; Biosynthetic Pathways; Cholesterol; Lanosterol; Sterols
PubMed: 38672427
DOI: 10.3390/biom14040410 -
Frontiers in Microbiology 2023Human cytomegalovirus (HCMV) is one of the main causes of serious complications in immunocompromised patients and after congenital infection. There are currently drugs... (Review)
Review
Human cytomegalovirus (HCMV) is one of the main causes of serious complications in immunocompromised patients and after congenital infection. There are currently drugs available to treat HCMV infection, targeting viral polymerase, whose use is complicated by toxicity and the emergence of resistance. Maribavir and letermovir are the latest antivirals to have been developed with other targets. The approval of letermovir represents an important innovation for CMV prevention in hematopoietic stem cell transplant recipients, whereas maribavir allowed improving the management of refractory or resistant infections in transplant recipients. However, in case of multidrug resistance or for the prevention and treatment of congenital CMV infection, finding new antivirals or molecules able to inhibit CMV replication with the lowest toxicity remains a critical need. This review presents a range of molecules known to be effective against HCMV. Molecules with a direct action against HCMV include brincidofovir, cyclopropavir and anti-terminase benzimidazole analogs. Artemisinin derivatives, quercetin and baicalein, and anti-cyclooxygenase-2 are derived from natural molecules and are generally used for different indications. Although they have demonstrated indirect anti-CMV activity, few clinical studies were performed with these compounds. Immunomodulating molecules such as leflunomide and everolimus have also demonstrated indirect antiviral activity against HCMV and could be an interesting complement to antiviral therapy. The efficacy of anti-CMV immunoglobulins are discussed in CMV congenital infection and in association with direct antiviral therapy in heart transplanted patients. All molecules are described, with their mode of action against HCMV, preclinical tests, clinical studies and possible resistance. All these molecules have shown anti-HCMV potential as monotherapy or in combination with others. These new approaches could be interesting to validate in clinical trials.
PubMed: 38053548
DOI: 10.3389/fmicb.2023.1321116 -
Molecules (Basel, Switzerland) May 2024Epidemiological studies have shown that a diet rich in bioactive components significantly reduces cardiovascular disease incidence and mortality. In this sense, there is... (Meta-Analysis)
Meta-Analysis Review
Epidemiological studies have shown that a diet rich in bioactive components significantly reduces cardiovascular disease incidence and mortality. In this sense, there is a need for meta-analytical research that confirms this phenomenon and increases specific knowledge about certain bioactive compounds such as carotenoids. Thus, this systematic review and meta-analysis aim to disseminate knowledge about the sources of carotenoids in fruit consumed in the north of Brazil which are outside the Brazilian trade balance. A systematic review and a meta-analysis following the PRISMA guidelines were conducted based on a random effects synthesis of multivariable-adjusted relative risks (RRs). Searches of seven sources were carried out, including PubMed, Science Direct from Elsevier, Web of Science, Scielo, Eric Research and Google Scholar databases. The systematic review was guided by a systematic review protocol based on the POT strategy (population, outcome and type of study) adapted for use in this research. Mendeley was a resource used to organize and manage references and exclude duplicates of studies selected for review. In this review, we present the potential bioactive compounds concentrated in little-known fruit species from the Amazon and their benefits. Consuming fruits that are rich in notable constituents such as carotenoids is important for the prevention of chronic non-communicable diseases through anti-inflammatory and anticoagulant properties, as well as antivirals, immunomodulators and antioxidants agents that directly affect the immune response.
Topics: Humans; Antioxidants; Brazil; Carotenoids; Feeding Behavior; Fruit; Cardiovascular Diseases
PubMed: 38792052
DOI: 10.3390/molecules29102190 -
Nutrients Sep 2023(1) Many studies have attempted to utilize metabolomic approaches to explore potential biomarkers for the early detection of osteoarthritis (OA), but consistent and... (Meta-Analysis)
Meta-Analysis Review
(1) Many studies have attempted to utilize metabolomic approaches to explore potential biomarkers for the early detection of osteoarthritis (OA), but consistent and high-level evidence is still lacking. In this study, we performed a systematic review and meta-analysis of differential small molecule metabolites between OA patients and healthy individuals to screen promising candidates from a large number of samples with the aim of informing future prospective studies. (2) Methods: We searched the EMBASE, the Cochrane Library, PubMed, Web of Science, Wan Fang Data, VIP Date, and CNKI up to 11 August 2022, and selected relevant records based on inclusion criteria. The risk of bias was assessed using the Newcastle-Ottawa quality assessment scale. We performed qualitative synthesis by counting the frequencies of changing directions and conducted meta-analyses using the random effects model and the fixed-effects model to calculate the mean difference and 95% confidence interval. (3) Results: A total of 3798 records were identified and 13 studies with 495 participants were included. In the 13 studies, 132 kinds of small molecule differential metabolites were extracted, 58 increased, 57 decreased and 17 had direction conflicts. Among them, 37 metabolites appeared more than twice. The results of meta-analyses among four studies showed that three metabolites increased, and eight metabolites decreased compared to healthy controls (HC). (4) Conclusions: The main differential metabolites between OA and healthy subjects were amino acids (AAs) and their derivatives, including tryptophan, lysine, leucine, proline, phenylalanine, glutamine, dimethylglycine, citrulline, asparagine, acetylcarnitine and creatinine (muscle metabolic products), which could be potential biomarkers for predicting OA.
Topics: Humans; Prospective Studies; Osteoarthritis; Biomarkers; Bias; Health Status
PubMed: 37836475
DOI: 10.3390/nu15194191 -
Molecular Therapy. Nucleic Acids Sep 2023The year 2023 marks the 25th anniversary of the discovery of RNAi. RNAi-based therapeutics enable sequence-specific gene knockdown by eliminating target RNA molecules... (Review)
Review
The year 2023 marks the 25th anniversary of the discovery of RNAi. RNAi-based therapeutics enable sequence-specific gene knockdown by eliminating target RNA molecules through complementary base-pairing. A systematic review of published and ongoing clinical trials was performed. Web of Science, PubMed, and Embase were searched from January 1, 1998, to December 30, 2022 for clinical trials using RNAi. Following inclusion, data from the articles were extracted according to a predefined protocol. A total of 90 trials published in 81 articles were included. In addition, ongoing clinical trials were retrieved from ClinicalTrials.gov, resulting in the inclusion of 48 trials. We investigated how maturation of RNAi-based therapeutics and developments in delivery platforms, administration routes, and potential targets shape the current landscape of clinically applied RNAi. Notably, most contemporary clinical trials used either -acetylgalactosamine delivery and subcutaneous administration or lipid nanoparticle delivery and intravenous administration. In conclusion, RNAi therapeutics have gained great momentum during the past decade, resulting in five approved therapeutics targeting the liver for treatment of severe diseases, and the trajectory depicted by the ongoing trials emphasizes that even more RNAi-based medicines also targeting extra-hepatic tissues are likely to be available in the years to come.
PubMed: 37583575
DOI: 10.1016/j.omtn.2023.07.018 -
Frontiers in Pharmacology 2023Biologics and small-molecule drugs have become increasingly accepted worldwide in the treatment of axial spondyloarthritis (axSpA), including ankylosing spondylitis...
Biologics and small-molecule drugs have become increasingly accepted worldwide in the treatment of axial spondyloarthritis (axSpA), including ankylosing spondylitis (AS) and non-radiographic axial spondyloarthritis (nr-axSpA). However, a quantitative multiple comparison of their efficacy and safety is lacking. This study aims to provide an integrated assessment of the relative benefits and safety profiles of these drugs in axSpA treatment. We included randomized clinical trials that compared biologics and small-molecule drugs in the treatment of axSpA patients. The primary outcomes assessed were efficacy, including the Assessment of SpondyloArthritis International Society (ASAS) improvement of 20% (ASAS20) and 40% (ASAS40). Safety outcomes included treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs). We used the surface under the cumulative ranking (SUCRA) curve value and ranking plot to evaluate and rank clinical outcomes and safety profiles of different treatments. The two-dimensional graphs were illustrated to visually assess both the efficacy (horizontal axis) and safety (vertical axis) of each intervention. Our analysis included 57 randomized clinical trials involving a total of 11,787 axSpA patients. We found that seven drugs (TNFRFc, TNFmAb, IL17Ai, IL17A/Fi, IL17RAi, JAK1/3i, and JAK1i) were significantly more effective in achieving ASAS20 response compared to the placebo (PLA). Except for IL17RAi, these drugs were also associated with higher ASAS40 responses. TNFmAb demonstrated the highest clinical response efficacy among all the drugs. Subgroup analyses for AS and nr-axSpA patients yielded similar results. IL17A/Fi emerged as a promising choice, effectively balancing efficacy and safety, as indicated by its position in the upper right corner of the two-dimensional graphs. Our findings highlight TNFmAb as the most effective biologic across all evaluated efficacy outcomes in this network meta-analysis. Meanwhile, IL17A/Fi stands out for its lower risk and superior performance in achieving a balance between efficacy and safety in the treatment of axSpA patients.
PubMed: 37942485
DOI: 10.3389/fphar.2023.1226528 -
World Journal of Gastroenterology Feb 2024Most patients with advanced pancreatic neuroendocrine tumors (pNETs) die due to tumor progression. Therefore, identifying new therapies with low toxicity and good... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Most patients with advanced pancreatic neuroendocrine tumors (pNETs) die due to tumor progression. Therefore, identifying new therapies with low toxicity and good tolerability to use concomitantly with the established pNET treatment is relevant. In this perspective, metformin is emerging as a molecule of interest. Retrospective studies have described metformin, a widely used agent for the treatment of patients with type 2 diabetes mellitus (T2DM), to be effective in modulating different tumor-related events, including cancer incidence, recurrence and survival by inhibiting mTOR phosphorylation. This systematic review evaluates the role of T2DM and metformin in the insurgence and post-treatment outcomes in patients with pNET.
AIM
To systematically analyze and summarize evidence related to the diagnostic and prognostic value of T2DM and metformin for predicting the insurgence and post-treatment outcomes of pNET.
METHODS
A systematic review of the published literature was undertaken, focusing on the role of T2DM and metformin in insurgence and prognosis of pNET, measured through outcomes of tumor-free survival (TFS), overall survival and progression-free survival.
RESULTS
A total of 13 studies (5674 patients) were included in this review. Analysis of 809 pNET cases from five retrospective studies (low study heterogeneity with = 0%) confirms the correlation between T2DM and insurgence of pNET (OR = 2.13, 95%CI = 1.56-4.55; < 0.001). The pooled data from 1174 pNET patients showed the correlation between T2DM and post-treatment TFS in pNET patients (hazard ratio = 1.84, 95%CI = 0.78-2.90; < 0.001). The study heterogeneity was intermediate, with = 51%. A few studies limited the possibility of performing pooled analysis in the setting of metformin; therefore, results were heterogeneous, with no statistical relevance to the use of this drug in the diagnosis and prognosis of pNET.
CONCLUSION
T2DM represents a risk factor for the insurgence of pNET and is a significant predictor of poor post-treatment TFS of pNET patients. Unfortunately, a few studies with heterogeneous results limited the possibility of exploring the effect of metformin in the diagnosis and prognosis of pNET.
Topics: Humans; Metformin; Diabetes Mellitus, Type 2; Neuroendocrine Tumors; Retrospective Studies; Pancreatic Neoplasms; Neuroectodermal Tumors, Primitive
PubMed: 38515954
DOI: 10.3748/wjg.v30.i7.759