SYRCLE's Tool Research Articles

Fracture Fusion on Fast-Forward: Locally Administered Deferoxamine Significantly Enhances Fracture Healing in Animal Models: A Systematic Review and Meta-Analysis.

Fractures, with a yearly incidence of 1.2%, can lead to healing complications in up to 10% of cases. The angiogenic stimulant deferoxamine (DFO) is recognized for enhancing bone healing when administered into the fracture gap. This systematic review with meta-analysis investigates the effect of local DFO application on bone healing in rat and mouse models. EMBASE, MEDLINE (PubMed), and Web of Science are systematically searched in January 2024. The study is prospectively registered in PROSPERO (CRD42024492533), and the SYRCLE tool is used to assess study quality and risk of bias. Outcome values contain the primary endpoint bone volume fraction (BV/TV) as well as the secondary endpoints bone volume, tissue volume, bone mineral density, trabecular separation, trabecular thickness, vessel formation and the mechanical properties, assessed by µCT, angiography and mechanical strength tests. Out of 21 included studies, 18 qualify for meta-analysis, involving 539 animals. DFO-treated groups exhibit significantly higher BV/TV values (p<0.0001) compared to controls, with similarly significant improvements in secondary outcomes. These findings highlight the substantial benefit of DFO in promoting bone healing, especially after radiotherapy. Rapid clinical implementation is recommended to help patients at high risk of fracture healing complications.

Efficacy of melatonin on drug- or contrast-induced acute kidney injury: a systematic review and GRADE-assessed meta-analysis of experimental and clinical studies.

The objective of this systematic review and meta-analysis was to assess the efficacy of melatonin in drug- or contrast-induced AKI in preclinical and clinical studies. PubMed, Embase, Scopus, Web of Science (WOS), the Cochrane Database of Systematic Reviews (CDSR), and clinical trials.GOV from the beginning until August 1, 2024. On the basis of the inclusion and exclusion criteria, the articles were included by two independent researchers. Data regarding study design, patient characteristics, the number of patients with and without AKI, and the means and SDs of the serum creatinine and BUN levels were extracted from relevant studies. STATA version 17.0 was used to compute pooled measures of standardized mean differences, standardized mean differences, risk ratios and risk differences. I2 and chi-square tests were used to assess heterogeneity between studies. Funnel plots, Egger tests and the trim-and-fill method were used to evaluate small study effects (publication bias). The risk of bias of the included clinical and preclinical studies was assessed via the Cochrane ROB tool and SYRCLE tool, respectively. The credibility of the results was evaluated via GRADE. Sensitivity analysis was performed via the one-out removal method. We identified 1,696 nonduplicate records, of which the full texts of 159 articles were examined. Twenty-nine animal experimental studies and 5 clinical trials met the inclusion criteria and were included in the review. The results of the meta-analysis confirmed that melatonin was significantly effective at reducing the serum creatinine level (standardized mean difference: -3.04; 95% CI -3.904 to -2.183, with 95% prediction interval: -7.201 to 1.163) and the BUN level (standardized mean difference: -3.464; 95% CI -4.378 to -2.549, with 95% prediction interval: -7.839 to 0.911) in drug-induced AKI animal studies. Melatonin did not have a significant effect on the serum creatinine level (standardized mean difference: -2.67; 95% CI -9.69 to -4.35, with 95% prediction interval: -42.618 to 37.278) or the BUN level (standardized mean difference: -1.77; 95% CI -5.533 to -1.994, with 95% prediction interval: -22.943 to 19.404) in contrast-induced AKI animal studies. Furthermore, in clinical studies, melatonin had no significant effect on reducing the serum creatinine level (standardized mean difference: 0.183; 95% CI -1.309 to 1.675, with 95% prediction interval: -7.975 to 8.340), BUN level (standardized mean difference: 0.206; 95% CI -0.0871 to 1.283, with 95% prediction interval: -5.115 to 5.528) or risk of AKI incidence (risk ratio: 0.877; 95% CI 0.46 to 1.64, with 95% prediction interval: -0.238 to 3.174; risk difference: -0.06mg/dl; 95% CI -0.259 to 0.40mg/dl, with 95% prediction interval: -0.467 to 0.348). There were no significant publication biases, and after sensitivity analysis, no considerable changes were observed, indicating the robustness of the results. This meta-analysis indicates that melatonin may protect against drug-induced AKI in animal models but is not effective in clinical studies and that melatonin has no significant effect on contrast-induced AKI. Owing to the inconclusive results in clinical trials and very low certainty of evidence, further research with higher methodological quality is needed to reach a more certain conclusion.

Genetic Mutations Leading to Dento-Maxillofacial Abnormalities in Mice: A Systematic Review.

To systematically review the available literature reporting on genetic mutations leading to dento-maxillofacial malformations in mice. An electronic search was performed across Embase, PubMed, Web of Science, and Scopus databases up to May 2024, targeting all invivo studies on gene mutations causing dento-maxillofacial deformities in mice. Studies reporting oral clefts were excluded. Data collected included genetic background, sex distribution, observation times, sample sizes, interventions, affected genes, zygosity, dento-maxillofacial anomalies, and associated human syndromes. Risk of bias was evaluated using the SYRCLE tool. Of 12,968 articles, 215 were included. The most common genetic background was C57BL6/J (B6) (n = 83), and knock-out was the most common intervention (n = 142). A total of 172 studies included homozygous mice. The five most studied genes were Amelx, Bmp-2, Dspp, Enam, and Runx2. Dento-alveolar anomalies were more commonly reported (n = 175) than skeletal (n = 65). Skeletal anomalies were mostly related to micrognathia (n = 14), agnathia (n = 5), dysplasia (n = 1), or reduced jaw size (n = 14). Risk of bias was moderate. Key genes such as Amelx, Bmp-2, Dspp, Enam, and Runx2 implicated in dento-maxillofacial abnormalities in mice, detailing the most prevalent skeletal and dento-alveolar anomalies. These findings offer insights for developing gene therapy and diagnosing congenital malformations.

Efficacy of low-intensity pulsed ultrasound in orthodontic tooth movement and orthodontically induced root resorption in animal and human studies: a systematic review and meta-analysis.

To evaluate the efficacy of low-intensity pulsed ultrasound (LIPUS) in orthodontic tooth movement (OTM) and orthodontically induced root resorption (OIRR) across animal and human studies. An electronic search in MEDLINE, Embase, Web of Science, Cochrane Library, National Knowledge Infrastructure, and Wanfang Database up to May 2024 identified 931 records screened using predefined PICOS criteria. 18 animal and 8 human studies met the inclusion criteria, with 12 suitable for meta-analysis. Methodological qualities for animal studies were assessed using the SYRCLE tool and ARRIVE guidelines. For clinical trials, the Cochrane RoB 2.0 tool and ROBINS-I were applied to evaluate the risk of bias in randomized clinical trials (RCTs) and controlled clinical trials (CCTs), respectively. Evidence quality was assessed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach, and quantitative analysis employed RevMan software with an inverse variance method and random effects models for all included studies. Most animal and human studies had a high or unclear risk of bias. LIPUS significantly accelerated OTM in rats, showing increases of 0.08mm (95% CI, 0.02 to 0.13; P = 0.006), 0.11mm (95% CI, 0.04 to 0.17; P = 0.001), and 0.11mm (95% CI, 0.06 to 0.16; P < 0.0001) on days 5, 7, and 14. In clinical trials, LIPUS reduced treatment duration with clear aligners by 352.07 days (95% CI, -524.81 to -179.34; P < 0.0001), but had no significant effect on OIRR (P > 0.05). GRADE analysis indicated very low evidence quality for both outcomes. LIPUS may accelerate OTM but shows weak evidence for alleviating OIRR. More well-designed studies with standardized methodology are needed. LIPUS could benefit OTM acceleration, but its effect on OIRR remains inconclusive.

Adipose tissue-derived injectable products combined with platelet-rich plasma for the treatment of osteoarthritis: the promising preclinical results are not confirmed by the clinical evidence.

The association of adipose tissue-derived injectable products with platelet-rich plasma (PRP) has been promoted for osteoarthritis (OA) treatment. The aim of this study was to investigate the preclinical and clinical evidence supporting the potential of this combined approach to treat OA. A systematic review was performed in January 2024 on five databases (PubMed, Embase, Scopus, Cochrane, and Web-of-Science) to identify preclinical in vivo and clinical studies. Safety, OA biomarker changes, and outcomes in terms of clinical and imaging results were analyzed. The quality of studies was assessed with the SYRCLE's tool for preclinical studies and the Downs and Black checklist for clinical studies. Ten preclinical studies (223 animals) and 14 clinical studies (594 patients) were included. Preclinical results documented improvements at the cartilage histological and immunohistochemical evaluation and at the biomarkers level. Clinical studies confirmed the procedure's safety, and the case series suggested satisfactory results in different joints in terms of symptoms and function improvement, with positive findings at the biomarker level. However, the randomized controlled trials did not document any clinical benefit, nor any changes in the imaging analysis. A large heterogeneity and overall poor quality were documented in both preclinical and clinical studies. There is an increasing interest in the use of adipose tissue-derived injectable products associated with PRP for the treatment of OA joints, with preclinical studies showing promising results with this combined approach. However, clinical studies did not confirm the benefits offered by PRP augmentation to adipose tissue-derived injectable products in patients affected by OA.

The role of neutrophils in pain: systematic review and meta-analysis of animal studies.

The peripheral inflammatory response is an attractive therapeutic target for pain treatment. Neutrophils are the first circulating inflammatory cells recruited to sites of injury, but their contribution to pain outcomes is unclear. We performed a systematic review and meta-analysis of original preclinical studies, which evaluated the effect of preemptive neutrophil depletion on pain outcomes (PROSPERO registration number: CRD42022364004). Literature search (PubMed, January 19, 2023) identified 49 articles, which were meta-analyzed using a random-effects model. The risk of bias was evaluated using SYRCLE's tool. The pooled effect considering all studies showed that neutrophil depletion induced a consistent pain reduction. Inflammatory, joint, neuropathic, and visceral pain showed significant pain alleviation by neutrophil depletion with medium-large effect sizes. However, muscle and postoperative pain were not significantly alleviated by neutrophil depletion. Further analysis showed a differential contribution of neutrophils to pain outcomes. Neutrophils had a higher impact on mechanical hyperalgesia, followed by nociceptive behaviors and mechanical allodynia, with a smaller contribution to thermal hyperalgesia. Interspecies (mice or rats) differences were not appreciated. Analyses regarding intervention unveiled a lower pain reduction for some commonly used methods for neutrophil depletion, such as injection of antineutrophil serum or an anti-Gr-1 antibody, than for other agents such as administration of an anti-Ly6G antibody, fucoidan, vinblastine, CXCR1/2 inhibitors, and etanercept. In conclusion, the contribution of neutrophils to pain depends on pain etiology (experimental model), pain outcome, and the neutrophil depletion strategy. Further research is needed to improve our understanding on the mechanisms of these differences.

Radio-protective effects of melatonin therapy against testicular oxidative stress: a systematic review and meta-analysis of rodent models.

Radiation exposure is a concern in today's world, given the widespread use of electronic devices and medical procedures involving ionizing and non-ionizing radiation. Radiations may cause male infertility by inducing oxidative stress in testicular tissue. Melatonin has antioxidant properties. The authors systematically reviewed the literature for the studies that have investigated the effects of melatonin therapy on radiation-induced oxidative stress in rodents' testicular tissue. PubMed, Scopus, and Web of Science were searched for relevant animal trials. Standardized mean difference and 95% CIs were used to pool the data. Subgroup and sensitivity analyses were done. The risk of bias was assessed using SYRCLE tool. Outcomes: histopathology and sperm analyses (testicular apoptotic cells, Johnsen's testicular biopsy score, seminiferous epithelial height, tubular diameter, sperm motility, viability, count, and morphology, concentration of spermatid, spermatocyte, and spermatogonia), body and testes weights (absolute and relative body and testicular weights), reproductive hormones (serum prolactin, FSH, and testosterone), and oxidative stress tissue markers (TBARS, CAT, GSH, GSH-Px, MDA, SOD, and XO, and total antioxidant capacity). Rats and mice were exposed to electromagnetic radiations (gamma, roentgen, microwave, radiofrequency, and high-power line energy) and particle waves (radioiodine and carbon-ion). Melatonin therapy was significantly associated with improved male reproduction. Radiation exposure harms male fertility, but melatonin, as an antioxidant, is potentially associated with improved male reproductive function in rodents. Inconsistencies in research require further investigations.

Impacts of micro- and nanoplastic exposure on the cardiovascular system: a systematic review focused on in vivo studies

Microplastics and nanoplastics, degraded plastic polymers, are increasing in the environment, raising concerns about their potential health impacts, particularly on the cardiovascular system. This systematic review aimed to investigate the prospective effects of MPs and NPs on cardiovascular toxicity. This study was written following the PRISMA 2020 guidelines. The risk of bias in the included studies was assessed using the SYRCLE tool. Our review included 38 in vivo studies dating back from 2017 to 2024 from several databases, including PubMed, ScienceDirect, SpringerLink, Taylor & Francis, ProQuest, and Wiley Online Library, with inclusion criteria of (PECOS) (1) Population: Animal; (2) Exposure: All types of exposure to micro nanoplastics; (3) Comparison: Placebo/ Control; (4) Outcome: Cardiotoxicity, inhibition of development of cardiovascular tissue, oxidative stress, inflammation, and abnormal structure; and (5) Study design: In vivo experimental study. Studies reveal that MPs and NPs cause cardiovascular toxicity through deposition, morphological changes, biomarker alterations, metabolism changes, and genetic regulation related to injury, inflammation, and oxidative stress. This study is limited to the comparison of the different particle sizes, dose of exposure, and duration of exposure effects toward cardiotoxicity, and does not compare the different effects of toxicity between different particle types.

Effects of Dietary Intake of Marine Ingredients on the Circulating Total Cholesterol Concentration in Domestic Dogs: A Systematic Review and Meta-Analysis.

A high circulating total cholesterol (TC) concentration increases the risk for atherosclerosis in the domestic dog. Intake of marine foods is associated with a lowering effect on circulating TC concentration in humans and rodents, but the reported effects of marine ingredients on the TC concentration in domestic dogs has not yet been reviewed. The main aim was to investigate the effects of consuming marine ingredients on the TC concentration in domestic dogs. A systematic literature search was performed using the databases PubMed, Web of Science and Embase, structured around the population (domestic dogs), intervention (source and type of marine ingredients, dose, duration), comparator (control diet) and the primary outcome (circulating TC). Articles were assessed for risk of bias using the SYRCLE's tool. A meta-analysis was conducted in Review Manager v. 5.4.1 (the Cochrane Collaboration), comprising 12 articles with 243 dogs. Consumption of marine oils resulted in a significantly lower circulating TC concentration relative to comparator groups (mean difference -0.70 mmol/L, 95% CI (-1.21, -0.18), p = 0.008), with high statistical heterogeneity (I2 = 78%). The risk of bias is unclear since few of the entries in the SYRCLE's tool were addressed. We did not identify any studies using marine proteins or marine organisms other that fish. To conclude, intake of marine oils results in a lower TC concentration in dogs, thus reducing an important risk factor for atherosclerosis in canines. This study was registered at www.crd.york.ac.uk/PROSPERO/ as CRD42023396943.

Methodological quality evaluation of animal experiments on traditional Chinese medicine formulas for glaucoma: A systematic review

IntroductionThis review aimed to evaluate the methodology and reporting quality of preclinical studies on traditional Chinese medicine (TCM) intervention for glaucoma, and explore areas for improvement. MethodsEight Chinese and English databases were searched for animal experiment articles on TCM formulas for glaucoma. The risk of bias was evaluated using the SYRCLE's tool, the reporting quality using the ARRIVE 2.0 guidelines and the GSPC checklist. ResultsSeventy-two articles met the inclusion/exclusion criteria for full-text review. According to the SYRCLE's tool, 7 (70%) of the 10 items had a low-risk rate of less than 50%, high-risk items were focused on selectivity bias, implementation bias, and measurement bias. Results of the ARRIVE 2.0 guidelines showed that 20 (53%) of the 38 sub-items had a high-agreement rate of less than 50%. Using the GSPC checklist, it was determined that 10 (53%) of the 19 sub-items had high-agreement rates of less than 50%. Randomization, blinding, ethical statements, housing and husbandry, animal care and monitoring, and protocol registration were low-agreement rate aspects of study reporting. ConclusionThe methodology and reporting quality of animal studies on TCM formulas for glaucoma is generally low. It is advised to further refer to the SYRCLE's tool and reporting guidelines, to enhance the design, performance, and reporting of animal experiments to ensure the reproducibility and reliability of results.

Impact of Mesenchymal Stem Cells on the Gut Microbiota and Microbiota Associated Functions in Inflammatory Bowel Disease: A Systematic Review of Preclinical Evidence on Animal Models.

Inflammatory bowel disease (IBD) is a global health problem in which gut microbiota dysbiosis plays a pivotal pathogenic role. Mesenchymal stem cells (MSCs) therapy has shown promising application prospects for its powerful immune regulation and tissue repair ability. Recent experimental data suggest that MSCs also regulate the composition of gut microbiota. The current review analyzed, for the first time, the research data linking MSCs and gut microbiota modulation in IBD models aiming at assessing the role of gut microbiota in MSCs repair of IBD. A comprehensive and structured literature search was performed up to January 2023 on the PubMed, Web of Science, and Scopus databases. The quality and risk of bias assessment followed the PRISMA guidelines and SYRCLE's tool. A total of nine pre-clinical studies on animal models were included. Although the dose and route of MSCs applied were quite heterogeneous, results showed that MSCs displayed protective effects on intestinal inflammation, including mice general assessment, immunoregulation, and intestinal barrier integrity. Meanwhile, studies showed positive effects on the composition of gut flora with MSCs administration, which had been characterized by restoration of Firmicutes/ Bacteroides balance and reduction of Proteobacteria. The beneficial bacteria Akkermansia, Bifidobacterium, and Lactobacillus were also distinctly enriched, and the pathogenic bacteria Escherichia-Shigella was conversely decreased. The alpha and beta diversity were also regulated to resemble those of healthy mice. Microbial metabolic functions, such as biosynthesis of secondary bile acid and sphingolipid metabolism, and some biological behaviors related to cell regeneration were also up-regulated, while cancer function and poorly characterized cellular function were down-regulated. Current data support the remodeling effect on gut microbiota with MSC administration, which provides a potential therapeutic mechanism for MSCs in the treatment of IBD. Additional studies in humans and animal models are warranted to further confirm the role of gut microflora in MSCs repairing IBD.

OxInflammatory Responses in the Wound Healing Process: A Systematic Review.

Significant sums are spent every year to find effective treatments to control inflammation and speed up the repair of damaged skin. This study investigated the main mechanisms involved in the skin wound cure. Consequently, it offered guidance to develop new therapies to control OxInflammation and infection and decrease functional loss and cost issues. This systematic review was conducted using the PRISMA guidelines, with a structured search in the MEDLINE (PubMed), Scopus, and Web of Science databases, analyzing 23 original studies. Bias analysis and study quality were assessed using the SYRCLE tool (Prospero number is CRD262 936). Our results highlight the activation of membrane receptors (IFN-δ, TNF-α, toll-like) in phagocytes, especially macrophages, during early wound healing. The STAT1, IP3, and NF-kβ pathways are positively regulated, while Ca2+ mobilization correlates with ROS production and NLRP3 inflammasome activation. This pathway activation leads to the proteolytic cleavage of caspase-1, releasing IL-1β and IL-18, which are responsible for immune modulation and vasodilation. Mediators such as IL-1, iNOS, TNF-α, and TGF-β are released, influencing pro- and anti-inflammatory cascades, increasing ROS levels, and inducing the oxidation of lipids, proteins, and DNA. During healing, the respiratory burst depletes antioxidant defenses (SOD, CAT, GST), creating a pro-oxidative environment. The IFN-δ pathway, ROS production, and inflammatory markers establish a positive feedback loop, recruiting more polymorphonuclear cells and reinforcing the positive interaction between oxidative stress and inflammation. This process is crucial because, in the immune system, the vicious positive cycle between ROS, the oxidative environment, and, above all, the activation of the NLRP3 inflammasome inappropriately triggers hypoxia, increases ROS levels, activates pro-inflammatory cytokines and inhibits the antioxidant action and resolution of anti-inflammatory cytokines, contributing to the evolution of chronic inflammation and tissue damage.

Evaluating the Role of Probiotics, Prebiotics, and Synbiotics Supplementation in Age-related Musculoskeletal Disorders in Older Adults: A Systematic Review.

The aim of this systematic review is to evaluate musculoskeletal changes in response to prebiotics, probiotics, or synbiotics supplementation in older adults or in animal models of aging musculoskeletal disorders. A comprehensive search was conducted on electronic databases, including PubMed/Medline, Cochrane, and Web of Science until April 2024. The quality assessment of clinical trials was conducted using the Cochrane Collaboration tool and for animal studies, the SYRCLE's tool was used. Our literature search resulted in 652 studies. After removing duplicates and screening the articles based on their titles and abstracts, we assessed the full text of 112 articles, which yielded 20 clinical trials and 30 animal studies in our systematic review. Most of human and animal studies reported an improvement in physical performance, a decrease in frailty index, and a lower reduction in bone mineral density in the intervention groups. Body composition tends to increase in muscle ratio, muscle mass, and reduce in appendicular lean mass and muscle atrophy. Also, the intervention induced bone turnover and mineral absorption, significantly increasing Ca, P, and Mg absorption and short-chain fatty acid concentration. Additionally, levels of inflammatory markers such as IL1, IL6, IL17, T helper 17, and TNF-α exhibited a decreasing trend, while an increase in IL10 and IFN-γ was observed. Prebiotics, probiotics, or synbiotics supplementations could effectively improve the physical performance and muscle strength and reduce the risk of bone loss and frailty in the elderly.

Intra-articular corticosteroids for the treatment of osteoarthritis: A systematic review and meta-analysis on the comparison of different molecules and doses.

The purpose of this study was to quantify and compare the clinical relevance of the different intra-articular corticosteroids (CS) effects in vivo for osteoarthritis (OA) treatment. The search was conducted on PubMed, Cochrane,and Web of Science in October 2023. The PRISMA guidelines were used. Inclusion criteria: animal or human randomized controlled trials (RCTs), English language andno time limitation, on the comparison of different intra-articular CS for OA treatment. The articles' quality was assessed using the Cochrane RoB2 and GRADE guidelines for human RCTs, and SYRCLE's tool for animal RCTs. Eighteen RCTs were selected (16 human and 2 animal studies), including 1577 patients (1837 joints) and 31 animals (51 joints). The CS used were triamcinolone (14 humanand 2 animal studies), methylprednisolone (7 humanand 1 animal study), betamethasone (3 human studies)and dexamethasone (1 human study). All studies addressed knee OA except for three human and one animal study. A meta-analysis was performed on the comparison of methylprednisolone and triamcinolone in humans with knee OA analysing VAS pain at very short- (≤2 weeks), short- (>2and ≤4 weeks), mid- (>4and ≤8 weeks), long- (>8and ≤ 12 weeks),and very long-term (>12and ≤24 weeks). Triamcinolone showed better post-injection values compared to methylprednisolone at very short-term (p = 0.028). No difference in terms of VAS improvement was observed at any follow-up. The available preclinical and clinical literature provides limited evidence on the comparison of different CS, hindering the possibility of determining the best CS approach in terms of molecule and dose for the intra-articular injection of OA joints. Level I.

The biological effects of Piezocision™ on bone for accelerated tooth movement: A systematic review of animal studies

Objectives: This systematic review aimed to assess the biological response at tissue, cellular, and molecular levels following Piezocision™ surgery, and its efficacy in accelerating orthodontic tooth movement.Material and methods: A systematic review of the literature was conducted across 4 databases following the PRISMA guidelines up to May 2022. Prospective controlled animal studies involving healthy animals under active orthodontic treatment assisted by corticotomy performed with a piezotome (Piezocision™) published in the English language without time restrictions were included. The article selection, data extraction and risk of bias assessment (SYRCLE tool) were performed by two independent blinded review authors.Results: Out of 738 articles screened, 10 studies were included with various level of bias. Biological responses were categorized into tissue, cellular, and molecular levels. Tissue-level changes included a global decrease in bone mineral content post-Piezocision™. At the cellular level, increased bone turnover activity was noted. Molecularly, elevated RANKL and OPG expression, along with increased TRAP+ and cytokines, were observed after Piezocision™. Studies confirmed Piezocision's efficacy, reporting 1.35 to 3.26 times faster tooth movements, peaking between the 3rd and 50th day post-surgery. Biological responses were transient, reversible, and proportional to surgical insult, with reactivation possible through a second Piezocision™.Conclusions: After Piezocision™ surgery, a transient and reversible biological response was described at the tissue, cellular and molecular levels, which induced faster orthodontic tooth movements. This biological response could be re-activated by an additional Piezocision™ and is proportional to the surgical injury. Systematic review registration: Prospero CRD42022303237.

Quercetin in the Prevention of Induced Periodontal Disease in Animal Models: A Systematic Review and Meta-Analysis.

Periodontitis is an inflammatory condition initiated by oral bacteria and is associated with several systemic diseases. Quercetin is an anti-inflammatory and anti-bacterial poly-phenol present in various foods. The aim of this meta-analysis was the evaluation of the effects of quercetin administration in animal models of experimental periodontitis. A systematic search was performed in electronic databases using the following search terms: "periodontitis" or "periodontal disease" or "gingivitis" and "quercetin" or "cyanidanol" or "sophoretin" or "pentahydroxyflavone". In vivo preclinical animal models of experimental periodontal disease with a measurement of alveolar bone loss were included in the analysis. The risk of bias of the included studies was assessed using the SYRCLE tool. The systematic search yielded 335 results. Five studies were included, four of them qualified for a meta-analysis. The meta-analysis showed that quercetin administration decreased alveolar bone loss (τ2 = 0.31, 1.88 mm 95%CI: 1.09, 2.67) in experimental periodontal disease animal models. However, the risk of bias assessment indicated that four SYRCLE domains had a high risk of bias. Quercetin diminishes periodontal bone loss and prevents disease progression in animal models of experimental periodontal disease. Quercetin might facilitate periodontal tissue hemostasis by reducing senescent cells, decreasing oxidative stress via SIRT1-induced autophagy, limiting inflammation, and fostering an oral bacterial microenvironment of symbiotic microbiota associated with oral health. Future research will show whether and how the promising preclinical results can be translated into the clinical treatment of periodontal disease.

VEGF and Other Gene Therapies Improve Flap Survival-A Systematic Review and Meta-Analysis of Preclinical Studies.

Surgical flaps are basic tools in reconstructive surgery. Their use may be limited by ischemia and necrosis. Few therapies address or prevent them. Genetic therapy could improve flap outcomes, but primary studies in this field present conflicting results. This systematic review and meta-analysis aimed to appraise the efficacy of external gene delivery to the flap for its survival in preclinical models. This review was registered with PROSPERO (CRD42022359982). PubMed, Embase, Web of Science, and Scopus were searched to identify studies using animal models reporting flap survival outcomes following any genetic modifications. Random-effects meta-analysis was used to calculate mean differences in flap survival with accompanying 95% CI. The risk of bias was assessed using the SYRCLE tool. Subgroup and sensitivity analyses were performed to ascertain the robustness of primary analyses, and the evidence was assessed using the GRADE approach. The initial search yielded 690 articles; 51 were eventually included, 36 of which with 1576 rats were meta-analyzed. VEGF gene delivery to different flap types significantly improved flap survival area by 15.66% (95% CI 11.80-19.52). Other interventions had smaller or less precise effects: PDGF-13.44% (95% CI 3.53-23.35); VEGF + FGF-8.64% (95% CI 6.94-10.34); HGF-5.61% (95% CI 0.43-10.78); FGF 3.84% (95% CI 1.13-6.55). Despite considerable heterogeneity, moderate risk of bias, and low quality of evidence, the efficacy of VEGF gene therapy remained significant in all sensitivity analyses. Preclinical data indicate that gene therapy is effective for increasing flap survival, but further animal studies are required for successful clinical translation.

Efficacy and Safety of Umbilical Cord-Derived Mesenchymal Stromal Cell Therapy in Preclinical Models of Sepsis: A Systematic Review and Meta-analysis.

In preclinical studies, mesenchymal stromal cells (MSCs), including umbilical cord-derived MSCs (UC-MSCs), demonstrate the ability to modulate numerous pathophysiological processes related to sepsis; however, a systematic synthesis of the literature is needed to assess the efficacy of UC-MSCs for treating sepsis. To examine the effects of UC-MSCs on overall mortality (primary outcome) as well as on organ dysfunction, coagulopathy, endothelial permeability, pathogen clearance, and systemic inflammation (secondary outcomes) at prespecified time intervals in preclinical models of sepsis. A systematic search was conducted on Embase, Ovid MEDLINE, and Web of Science up to June 20, 2023. Preclinical controlled studies using in vivo sepsis models with systemic UC-MSC administration were included. Meta-analyses were conducted and expressed as odds ratios (OR) and ratios of the weighted means with 95% CI for categorical and continuous data, respectively. Risk of bias was assessed with the SYRCLE tool. Twenty-six studies (34 experiments, n = 1258 animals) were included in this review. Overall mortality was significantly reduced with UC-MSC treatment as compared to controls (OR: 0.26, 95% CI: 0.18-0.36). At various prespecified time intervals, UC-MSCs reduced surrogate measures of organ dysfunction related to the kidney, liver, and lung; reduced coagulopathy and endothelial permeability; and enhanced pathogen clearance from multiple sites. UC-MSCs also modulated systemic inflammatory mediators. No studies were rated as low risk across all SYCLE domains. These results demonstrate the efficacy of UC-MSC treatment in preclinical sepsis models and highlight their potential as a therapeutic intervention for septic shock.

Antinociceptive Efficacy of 15-Deoxy-Δ12,14-Prostaglandin J2 Therapy in Response to Experimentally Induced Temporomandibular Joint Arthritis: A Systematic Review of Studies in Rats

The aim of the present systematic review was to assess the antinociceptive efficacy of 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) therapy in rats with experimentally induced temporomandibular joint (TMJ) arthritis. The focused question was “Is 15d-PGJ2 therapy effective in the management of TMJ nociception?” Indexed databases were searched without time and language restrictions up to and including September 2023 using different key words. Original studies were included. Risk of Bias (RoB) was assessed using the SYRCLE tool. Six studies performed in male Wistar rats with experimentally induced TMJ arthritis were included. The observation or follow-up period ranged between 45 min and 14 days. Four studies reported that 15d-PGJ2 therapy retards the production of proinflammatory cytokines in TMJ tissues. Four studies reported that 15d-PGJ2 therapy inhibits leukocyte migration and plasma extravasation in TMJ tissues. In one study, the expression of decay-accelerating factor in TMJ tissues increased after 15d-PGJ2 therapy. One study showed that 15d-PGJ2 inhibits nociception in a dose-dependent manner via the activation of peripheral kappa/delta opioid receptors. Prior sample-size-estimation (SSE) was performed in none of the studies and all studies had a high RoB. Due to a high RoB, methodological variations, and the absence of prior SSE within the included studies, it is demanding to derive an absolute verdict regarding the antinociceptive efficacy of 15d-PGJ2 therapy in response to experimentally induced TMJ arthritis.

Muscarinic receptor agonists and positive allosteric modulators in animal models of psychosis: protocol for a systematic review and meta-analysis.

Muscarinic receptor agonism and positive allosteric modulation is a promising mechanism of action for treating psychosis, not present in most D2R-blocking antipsychotics. Xanomeline, an M1/M4-preferring agonist, has shown efficacy in late-stage clinical trials, with more compounds being investigated. Therefore, we aim to synthesize evidence on the preclinical efficacy of muscarinic receptor agonists and positive allosteric modulators in animal models of psychosis to provide unique insights and evidence-based information to guide drug development. We plan a systematic review and meta-analysis of in vivo animal studies comparing muscarinic receptor agonists or positive allosteric modulators with control conditions and existing D2R-blocking antipsychotics in animals subjected to any method that induces behavioural changes of relevance for psychosis. We will identify eligible studies by searching multiple electronic databases. At least two independent reviewers will conduct the study selection and data extraction using prespecified forms and assess the risk of bias with the SYRCLE's tool. Our primary outcomes include locomotor activity and prepulse inhibition measured with standardized mean differences. We will examine other behavioural readouts of relevance for psychosis as secondary outcomes, such as social interaction and cognitive function. We will synthesize the data using multi-level meta-analysis with a predefined random-effects structure, considering the non-independence of the data. In meta-regressions we will explore potential sources of heterogeneity from a predefined list of characteristics of the animal population, model, and intervention. We will assess the confidence in the evidence considering a self-developed instrument thatconsiders the internal and external validity of the evidence. PROSPERO-ID: CRD42024520914.