A systematic review of second-generation FLT3 inhibitors for treatment of patients with relapsed/refractory acute myeloid leukemia.

BACKGROUND: Acute myeloid leukemia (AML) is a complex disease with diverse mutations, including prevalent mutations in the FMS-like receptor tyrosine kinase 3 (FLT3) gene that lead to poor prognosis. Recent advancements have introduced FLT3 inhibitors that have improved outcomes for FLT3-mutated AML patients, however, questions remain on their application in complex conditions such as relapsed/refractory (R/R) disease. Therefore, we aimed to evaluate the clinical effectiveness of second-generation FLT3 inhibitors in treating patients with R/R AML. METHODS: A systematic literature search of PubMed, MEDLINE, SCOPUS and Google Scholar databases was made to identify relevant studies up to January 30, 2024. This study was conducted following the guidelines of the PRISMA. RESULTS: The ADMIRAL trial revealed significantly improved overall survival and complete remission rates with gilteritinib compared to salvage chemotherapy, with manageable adverse effects. Ongoing research explores its potential in combination therapies, showing synergistic effects with venetoclax and promising outcomes in various clinical trials. The QuANTUM-R trial suggested longer overall survival with quizartinib compared to standard chemotherapy, although concerns were raised regarding trial design and cardiotoxicity. Ongoing research explores combination therapies involving quizartinib, such as doublet or triplet regimens with venetoclax, showing promising outcomes in FLT3-mutated AML patients. CONCLUSION: These targeted therapies offer promise for managing this subgroup of AML patients, but further research is needed to optimize their use. This study underscores the importance of personalized treatment based on genetic mutations in AML, paving the way for more effective and tailored approaches to combat the disease.

Impacts of Supplementation with Silymarin on Cardiovascular Risk Factors: A Systematic Review and Dose-Response Meta-Analysis.

It has been suggested that silymarin (SIL) supplementation has positive effects on cardiovascular health and reduces the risk of cardiometabolic syndrome (CMS). This systematic review and dose-response meta-analysis assessed the impacts of SIL administration on cardiovascular risk factors. A systematic search of multiple databases was performed to identify eligible controlled trials published up to January 2023. The analysis used a random-effects model and included 33 trials with 1943 participants. It was revealed that SIL supplementation led to a notable reduction in serum levels of fasting blood glucose (FBG) (weighted mean difference (WMD): -21.68 mg/dL, 95% CI: -31.37, -11.99; p < 0.001), diastolic blood pressure (DBP) (WMD: -1.25 mmHg; 95% CI: -2.25, -0.26; p = 0.013), total cholesterol (TC) (WMD: -13.97 mg/dL, 95% CI: -23.09, -4.85; p = 0.003), triglycerides (TG) (WMD: -26.22 mg/dL, 95% CI: -40.32, -12.12; p < 0.001), fasting insulin (WMD: -3.76 mU/mL, 95% CI: -4.80, -2.72; p < 0.001), low-density lipoprotein (LDL) (WMD: -17.13 mg/dL, 95% CI: -25.63, -8.63; p < 0.001), and hemoglobin A1C (HbA1c) (WMD: -0.85%, 95% CI: -1.27, -0.43; p < 0.001) in the SIL-treated groups compared to their untreated counterparts. In addition, there were no substantial differences in body mass index (BMI), systolic blood pressure (SBP), C-reactive protein (CRP), body weight, and high-density lipoprotein (HDL) between the two groups. These outcomes suggest that SIL consumption reduces certain CMS risk factors and has favorable impacts on lipid and glycemic profiles with potential hypotensive effects. These findings should be supported by additional trials with larger sample sizes and longer durations.

Effects of silymarin supplementation on liver and kidney functions: A systematic review and dose-response meta-analysis.

It is suggested that supplementation with silymarin (SIL) has beneficial impacts on kidney and liver functions. This systematic review and dose-response meta-analysis assessed the impact of SIL administration on certain hepatic, renal, and oxidative stress markers. A systematic search was conducted in various databases to identify relevant trials published until January 2023. Randomized controlled trials (RCTs) that evaluated the effects of SIL on kidney and liver markers were included. A random-effects model was used for the analysis and 41 RCTs were included. The pooled results indicated that SIL supplementation led to a significant reduction in serum levels of alkaline phosphatase, alanine transaminase, creatinine, and aspartate aminotransferase, along with a substantial elevation in serum glutathione in the SIL-treated group compared to their untreated counterparts. In addition, there was a nonsignificant decrease in serum levels of gamma-glutamyl transferase, malondialdehyde (MDA), total bilirubin, albumin (Alb), total antioxidant capacity, and blood urea nitrogen. Sub-group analyses revealed a considerable decline in MDA and Alb serum values among SIL-treated participants with liver disease in trials with a longer duration (≥12 weeks). These findings suggest that SIL may ameliorate certain liver markers with potential hepatoprotective effects, specifically with long-term and high-dose supplementation. However, its nephroprotective effects and impact on oxidative stress markers were not observed. Additional high-quality RCTs with longer durations are required to determine the clinical efficacy of SIL supplementation on renal and oxidative stress markers.

CCN3/NOV Serum Levels in Non-Alcoholic Fatty Liver Disease (NAFLD) Patients in Comparison with the Healthy Group and their Correlation with TNF-α and IL-6.

INTRODUCTION: Adipokine irregularity leads to inflammation, endothelial dysfunction, insulin resistance (IR), and Non-Alcoholic Fatty Liver Disease (NAFLD). Previous studies linked NOV/CCN3 to obesity, IR, and inflammation, but no research has explored the connection between CCN3 serum levels and NAFLD. METHODS: This case-control study assessed CCN3, IL-6, adiponectin, and TNF-α serum levels in 80 NAFLD patients and 80 controls using ELISA kits. Biochemical parameters were measured with commercial kits and an auto analyzer. RESULTS: NAFLD patients exhibited significantly higher CCN3 (2399.85 ± 744.53 vs. 1712.84 ± 478.19 ng/ml), TNF-α, and IL-6 levels, and lower adiponectin levels compared to controls (P<0.0001). In the NAFLD group, CCN3 showed positive correlations with FBG, insulin, HOMA-IR, and TNF-α. Binary logistic regression analysis revealed increased NAFLD risk in the adjusted model (OR [95% CI] = 1.220 [1.315 -1.131]). A CCN3 cut-off value of 1898.0050 pg/mL differentiated NAFLD patients from controls with 78.8% sensitivity and 73.2% specificity. CONCLUSION: It was found that elevated CCN3 serum levels directly correlate with NAFLD incidence and inflammation markers (IL-6 and TNF-α). CCN3 could serve as a potential biomarker for NAFLD, but further research is needed to validate this finding and assess its clinical utility.

CCN3/NOV serum levels in coronary artery disease (CAD) patients and its correlation with TNF-α and IL-6.

INTRODUCTION: Dysregulation in the secretion of adipokines or adipocytokines plays a significant role in triggering a pro-inflammatory state, leading to endothelial dysfunction and insulin resistance, and ultimately elevating the risk of atherosclerosis and coronary artery disease (CAD). Previous studies have shown a link between NOV/CCN3 (an adipokine) and obesity, insulin resistance, and inflammation. However, no research has explored the relationship between CCN3 serum levels and CAD. Therefore, we conducted the first investigation to examine the correlation between CCN3 and CAD risk factors in patients. METHODS: In a case-control study, we measured the serum levels of CCN3, IL-6, adiponectin, and TNF-α in 88 angiography-confirmed CAD patients and 88 control individuals using ELISA kits. Additionally, we used an auto analyzer and commercial kits to measure the biochemical parameters. RESULTS: In patients with CAD, the serum levels of CCN3, TNF-α, and IL-6 were significantly higher compared to the control group, whereas lower levels of adiponectin were observed in the CAD group (P < 0.0001). A positive correlation was found between CCN3 and IL-6 and TNF-α in the CAD group ([r = 0.38, P < 0.0001], [r = 0.39, P < 0.0001], respectively). A binary logistic regression analysis showed the risk of CAD in the model adjusted (OR [95% CI] = 1.29 [1.19 - 1.41]), (P < 0.0001). We determined a cut-off value of CCN3 (3169.6 pg/mL) to distinguish CAD patients from the control group, with good sensitivity and specificity obtained for this finding (83.8% and 87.5%, respectively). CONCLUSION: This study provides evidence of a positive association between CCN3 serum levels and CAD, as well as inflammation markers such as IL-6 and TNF-α. These findings suggest that CCN3 may serve as a potential biomarker for CAD, and further investigations are necessary to validate this association and explore its potential use in clinical settings.

A positive association of serum CCN5/WISP2 levels with the risk of developing gestational diabetes mellitus: a case-control study.

INTRODUCTION: CCN5/WISP2 is prominently manifest in adipose tissue and has been linked to the pathogenesis of obesity, diabetes, and insulin resistance. However, discrepancies exist in previous studies, and little is known about its association with gestational diabetes mellitus (GDM). The current investigation is designed to examine the correlation of WISP2 with risk factors in GDM patients in comparison to healthy pregnant women for the first time. METHODS: This case-control study measured serum levels of CCN5, TNF-α, IL-6, adiponectin, and fasting insulin using ELISA kits in 88 GDM patients and 88 pregnant women. RESULTS: The GDM group had remarkably higher serum levels of CCN5 (379.41 ± 83.078 ng/ml) compared to controls (212.02 ± 77.935 ng/ml). In a similar vein, it was observed that patients diagnosed with GDM exhibited elevated levels of pro-inflammatory cytokines such as IL-6 and TNF-α; while conversely, adiponectin levels were found to be significantly lower than those observed in the control group (P < 0.0001). In women with GDM, a positive and significant correlation was observed between CCN5 and BMI, FBG, insulin, HOMA-IR, as well as IL-6 and TNF-α levels. In the adjusted model, the risk of GDM was significantly increased with elevated serum CCN5 level. CONCLUSION: Our research indicates a noteworthy and affirmative correlation between the levels of CCN5 in the serum and the risk of developing GDM, along with its associated risk factors such as BMI, insulin resistance index, FBG, and inflammatory cytokines (TNF-α and IL-6). These findings suggest that CCN5 could potentially play a role in the etiology of GDM.

The effects of beetroot and nitrate supplementation on body composition: a GRADE-assessed systematic review and meta-analysis.

This systematic review and meta-analysis aimed to investigate the effects of beetroot (BR) or nitrate supplements on body composition indices. A systematic search was conducted for randomised controlled trials (RCT) published up to August 2022 among online databases including Scopus, PubMed/Medline, Web of Science and Embase. Meta-analyses were carried out using a random-effects model. The I2 index was used to assess the heterogeneity of RCT. A total of twelve RCT met the inclusion criteria for this meta-analysis. The pooled effect size of included studies indicated that BR or nitrate supplementation did not change body weight (weighted mean differences (WMD): -0·14 kg, 95 % CI -1·22, 1·51; P = 0·836; I2 = 0 %), BMI (WMD: -0·07 kg/m2, 95 % CI -0·19,0·03; P = 0·174, I2 = 0 %), fat mass (WMD: -0·26 kg, 95 % CI -1·51, 0·98; P = 0·677, I2 = 0 %), waist circumference (WMD: -0·28 cm, 95 % CI -2·30, 1·74; P = 0·786, I2 = 0 %), body fat percentage (WMD: 0·18 %, 95 % CI -0·62, 0·99; P = 0·651, I2 = 0 %), fat-free mass (WMD: 0·31 kg, 95 % CI -0·31, 1·94; P = 0·703, I2 = 0 %) and waist-to-hip ratio (WMD: 0, 95 % CI -0·01, 0·02; P = 0·676, I2 = 0 %). Subgroup analyses based on trial duration, BR or nitrate dose, study design, baseline BMI and athletic status (athlete v. non-athlete) demonstrated similar results. Certainty of evidence across outcomes ranged from low to moderate. This meta-analysis study suggests that BR or nitrate supplements cannot efficiently ameliorate body composition indices regardless of supplement dosage, trial duration and athletic status.

Ameliorative impacts of polymeric and metallic nanoparticles on cisplatin-induced nephrotoxicity: a 2011-2022 review.

Cisplatin (CDDP) is a well-known platinum-based drug used in the treatment of various malignancies. However, the widespread side effects that this drug leaves on normal tissues make its use limited. Since cisplatin is mainly eliminated from the kidneys, CDDP-induced nephrotoxicity is the most significant dose-limiting complication attributed to cisplatin, which often leads to dose withdrawal. Considering the high efficiency of cisplatin in chemotherapy, finding renoprotective drug delivery systems for this drug is a necessity. In this regard, we can take advantages of different nanoparticle-based approaches to deliver cisplatin into tumors either using passive targeting or using specific receptors. In an effort to find more effective cisplatin-based nano-drugs with less nephrotoxic effect, the current 2011-2022 review study was conducted to investigate some of the nanotechnology-based methods that have successfully been able to mitigate CDDP-induced nephrotoxicity. Accordingly, although cisplatin can cause renal failures through inducing mitochondria dysfunction, oxidative stress, lipid peroxidation and endoplasmic reticulum stress, some CDDP-based nano-carriers have been able to reverse a wide range of these advert effects. Based on the obtained results, it was found that the use of different metallic and polymeric nanoparticles can help renal cells to strengthen their antioxidant systems and stay alive through reducing CDDP-induced ROS generation, inhibiting apoptosis-related pathways and maintaining the integrity of the mitochondrial membrane. For example, nanocurcumin could inhibit oxidative stress and acting as a ROS scavenger. CONPs could reduce lipid peroxidation and pro-inflammatory cytokines. CDDP-loaded silver nanoparticles (AgNPs) could inhibit mitochondria-mediated apoptosis. In addition, tea polyphenol-functionalized SeNPs (Se@TE) NPs could mitigate the increased level of dephosphorylated AKT, phosphorylated p38 MAPK and phosphorylated c-Jun N-terminal kinase (JNK) induced by cisplatin. Moreover, exosomes mitigated cisplatin-induced renal damage through inhibiting Bcl2 and increasing Bim, Bid, Bax, cleaved caspase-9, and cleaved caspase-3. Hence, nanoparticle-based techniques are promising drug delivery systems for cisplatin so that some of them, such as lipoplatins and nanocurcumins, have even reached phases 1-3 trials.

Isofuranodiene, a Natural Sesquiterpene Isolated from Wild Celery (Smyrnium olusatrum L.), Protects Rats against Acute Ischemic Stroke.

The myrrh-like furanosesquiterpene isofuranodiene (IFD) is the main constituent of wild celery (Smyrnium olusatrum L., Apiaceae), an overlooked vegetable that was cultivated during the Roman Empire. In the present study, we investigated the protective effects of IFD pre-treatment against oxidative stress and inflammatory response in an animal model of ischemic stroke. IFD was isolated by the crystallization of Smyrnium olusatrum essential oil, and its structure and purity were confirmed by NMR and HPLC analyses. Acute pre-treatment of IFD (10 mg/kg i.p.) significantly reduced the levels of the inflammatory cytokines IL-1ß and TNF-α, the expression of pNF-κB/NF-κB, and the lipid peroxidation indicator MDA. Finally, IFD boosted a faster recovery and better scores in grid-walking and modified neurological severity scores (mNSS) tests. Taken together, these findings indicate IFD as a promising lead compound for the discovery of new treatments of brain ischemia.

Protective effects of modafinil administration on testicular torsion/detorsion damage in rats.

Testicular torsion is a pathological condition which leads to sever scrotal pain and ischemia. After surgical reperfusion, oxidative stress factors cause to germ cell apoptosis. Thus, adjuvant therapy to surgery should be useful to decrease of ischemia/reperfusion (I/R) injury of testis. Modafinil, a drug to treat sleepiness, has been indicated to have anti-inflammatory effects. The aim was to evaluate the efficiency of modafinil administration after reperfusion surgery in a rat model of testicular torsion/detorsion (T/D). Male wistar rats were divided into three groups and each group contained 10 animals. To induce torsion right testis was rotated 720° clockwise and was left for 1 h. Modafinil group received modafinil (10 mg/kg) once daily intraperitoneally for 7 days after the surgery and the control group received physiologic saline once daily intraperitoneally for 7 days after the surgery. Thereafter, MDA, IL-1ß and TNF-α levels and histopathological changes were investigated. MDA, IL-1ß and TNF-α levels significantly increased in T/D group compared to the control group (⁎⁎P < .01 and ⁎⁎⁎P < .001, respectively). Moreover, modafinil administration significantly reduced these values compared to T/D group (#P < .05 and ##P < .01, respectively). Histopathological changes such as degeneration in germinal cells were detected in testis T/D group of rats whereas modafinil administration prevented degeneration in germinal cells, edema and hemorrhage compared with T/D group. In conclusion, administration of modafinil after reperfusion surgery had protective role on testicular torsion in rat and reduced ischemia/reperfusion cellular injury via anti-inflammatory and decrease of oxidative stress.