CAR T cells and time-limited ibrutinib as treatment for relapsed/refractory mantle cell lymphoma: the phase 2 TARMAC study.

ABSTRACT: CD19-directed chimeric antigen receptor T cells (CAR-T) achieve high response rates in patients with relapsed/refractory mantle cell lymphoma (MCL). However, their use is associated with significant toxicity, relapse concern, and unclear broad tractability. Preclinical and clinical data support a beneficial synergistic effect of ibrutinib on apheresis product fitness, CAR-T expansion, and toxicity. We evaluated the combination of time-limited ibrutinib and CTL019 CAR-T in 20 patients with MCL in the phase 2 TARMAC study. Ibrutinib commenced before leukapheresis and continued through CAR-T manufacture for a minimum of 6 months after CAR-T administration. The median prior lines of therapy was 2; 50% of patients were previously exposed to a Bruton tyrosine kinase inhibitor (BTKi). The primary end point was 4-month postinfusion complete response (CR) rate, and secondary end points included safety and subgroup analysis based on TP53 aberrancy. The primary end point was met; 80% of patients demonstrated CR, with 70% and 40% demonstrating measurable residual disease negativity by flow cytometry and molecular methods, respectively. At 13-month median follow-up, the estimated 12-month progression-free survival was 75% and overall survival 100%. Fifteen patients (75%) developed cytokine release syndrome; 12 (55%) with grade 1 to 2 and 3 (20%) with grade 3. Reversible grade 1 to 2 neurotoxicity was observed in 2 patients (10%). Efficacy was preserved irrespective of prior BTKi exposure or TP53 mutation. Deep responses correlated with robust CAR-T expansion and a less exhausted baseline T-cell phenotype. Overall, the safety and efficacy of the combination of BTKi and T-cell redirecting immunotherapy appears promising and merits further exploration. This trial was registered at www.ClinicalTrials.gov as #NCT04234061.

What Are the Predictors of Post-traumatic Stress Disorder Among Road Traffic Accident Survivors: A Systematic Review.

ABSTRACT: Traffic accidents put tremendous burdens on the psychosocial aspects of communities. Post-traumatic stress disorder (PTSD), after an accident, is one of the most prevalent and incapacitating psychiatric conditions worldwide. In this systematic review, we aimed to investigate the predictors of PTSD in traffic accident victims. Primary search was conducted in November 2021 and updated in 2023. Studies were excluded if they used any analysis except regression for predictors. Cumulatively, primary and update searches retrieved 10,392 articles from databases, and of these, 87 studies were systematically reviewed. The predictors were categorized into sociodemographics, pretrauma, peritrauma, and post-trauma factors. The PTSD assessment time varied between 2 weeks and 3 years. Being a woman, having depression and having a history of road traffic accidents pretraumatically, peritraumatic dissociative experiences, acute stress disorder diagnosis, rumination, higher injury severity, and involvement in litigation or compensation after the trauma were significant predictors of PTSD.

Clinical efficacy and safety of melatonin supplementation in multiple sclerosis: a systematic review.

BACKGROUND: Melatonin is a neurohormone secreted predominantly by the pineal gland that is demonstrated to be associated with the pathogenesis of multiple sclerosis (MS). This research desires to evaluate the tolerability and beneficial effects of exogenous melatonin supplementations in patients with MS. METHODS: This study was executed following the PRISMA 2020 statement. Both observational and interventional studies which reported the clinical effectiveness and/or safety of melatonin supplementation in patients with MS were included in this systematic review. Ovid, PubMed, Scopus, Embase, and Web of Science databases were searched and the risk of bias in included studies was assessed using the Joanna Briggs Institute (JBI) critical appraisal tools based on study design. RESULTS: Out of 1304 results of database searches, finally, 14 articles, including 7 randomized controlled trials (RCTs), 6 case-control studies, and one quasi-experimental study, were included based on the full-text review. Included phenotypes of MS were mostly relapsing-remitting MS (RRMS) (in 11 studies); it was secondary progressive MS (SPMS) in only one study, and two other studies had a mixture of the different phenotypes. The course of treatment with melatonin supplementation was between 2 weeks and 12 months. There were no substantial safety issues. Although melatonin was associated with enhanced oxidative stress and inflammation status, concerning the clinical benefits, limited studies suggested improvements in sleep conditions, cognitive outcomes, and fatigue in MS. DISCUSSION: There are insufficient data to support the regular melatonin prescription in MS. Limitations such as the small number of included studies, the diversity of the dosage, route, and duration of melatonin administration, and the diversity of assessment tests lead to unconvincing findings in this study. There is a need for future studies to achieve a comprehensive judgment on this subject.

Signaling, metabolism, and cancer: An important relationship for therapeutic intervention.

In cancerous cells, significant changes occur in the activity of signaling pathways affecting a wide range of cellular activities ranging from growth and proliferation to apoptosis, invasiveness, and metastasis. Extensive changes also happen with respect to the metabolism of a cancerous cell encompassing a wide range of functions that include: nutrient acquisition, biosynthesis of macromolecules, and energy generation. These changes are important and some therapeutic approaches for treating cancers have focused on targeting the metabolism of cancerous cells. Oncogenes and tumor suppressor genes have a significant effect on the metabolism of cells. There appears to be a close interaction between metabolism and the signaling pathways in a cancerous cell, in which the interaction provides the metabolic needs of a cancerous cell for uncontrolled proliferation, resistance to apoptosis, and metastasis. In this review, we have reviewed the latest findings in this regard and briefly review the most recent research findings regarding targeting the metabolism of cancer cells as a therapeutic approach for treatment of cancer.

Valorization of Waste Water of Rosa damascena Oil Distillation Process by Ion Exchange Chromatography.

Water steam distillation is a classical method of rose oil production from the flowers of Rosa damascena Mill. This process produces considerable amount of waste water. In this study, ion-exchange column chromatography (Amberlite was the stationary phase) was used to prepare polyphenol-enriched fraction of waste water with improved biological activity. Phenol, flavonoid, and anthocyanin contents were examined before and after using column. Antioxidant activities, DNA protection ability, xanthine oxidase inhibition, and cytotoxicity of this fraction were also determined. The use of Amberlite increased phenol, flavonoid, and anthocyanin contents in fraction compared to the sample before fractionation. The IC50 values of various antioxidant assays comprises 2,2-diphenyl-1-picryl-hydrazyl-hydrate (DPPH), ferric-reducing antioxidant power assay (FRAP), and 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) which were 226.66 ± 1.25, 126.03 ± 0.11, and 241.43 ± 0.33 for waste water, and these values for fraction were 63.21 ± 0.90, 34.6 ± 0.17, and 50.59 ± 0.75 µg/ml, respectively. The Trolox equivalent values of fraction in oxygen radical absorbance capacity (ORAC) assay were 0.34 ± 0.04, and the EC50 values in cellular antioxidant activity were 91.24 ± 0.32 µg/ml. The xanthine oxidase inhibition capacity of fraction (100 µg/ml) was 96.4 ± 0.02% µg/ml. The comet assay analysis showed that this fraction (25-100 µg/ml) protects human lymphocytes against H2O2-induced DNA damages significantly. The IC50 values of cytotoxicity assay were 248.145 ± 35.56 and 227.14 ± 16.51 µg/ml after 24 and 48 h, respectively. There has been great attention to the valorization of waste materials. Recovered fraction could be considered as a proper antioxidant, DNA damage-protection agent, and xanthine oxidase inhibitor. Using a nontoxic solid phase such as Amberlite is a fruitful way to concentrate bioactive ingredients which can be used in pharmaceutical and nutraceutical industry.

A new labdane diterpenoid, in vitro and in silico cytotoxicity, and protease inhibitory effects of phytochemicals from Juniperus polycarposK. Koch leaves.

Cytotoxicity-guided purification of Juniperus polycarpos K. Koch leaves (Cupressaceae) led to the isolation of a new labdane diterpenoid, 3-(acetyloxy)-acetylisocupressic acid (1), together with isocupressic acid (2), 3,4-dimethoxycinnamoyl alcohol (3) and deoxypodophyllotoxin (4). The chemical structures of 1-4 were established by detailed 1D and 2D NMR, HRFAB-MS and LRESI-MS, as well as by comparing the spectral data with those reported in the literature. Compound 1 was ineffective against HepG2 cells and protease enzyme, while 2 showed potent cytotoxicity against HepG2 cells (IC50 of 3.73 µg/mL) compared to cisplatin (IC50 of 12.65 µg/mL). Computational analyses with CDK1 protein (a prominent protein in the cell cycle of HepG2 cells) revealed the binding affinity of 2 (-31.86 kcal/mol) was better than 1 (-19.70 kcal/mol) because the acetoxy groups did not allow binding deeply to the ATP binding site. Compounds 2 and 4 moderately inhibited the protease activity (IC50 = 52.7 and 63.0 µg/mL, respectively). Further in vitro and in vivo studies on the plant are strongly recommended.

Development of a Visually Calculated SUVmean (HIT Score) on Screening PSMA PET/CT to Predict Treatment Response to 177Lu-PSMA Therapy: Comparison with Quantitative SUVmean and Patient Outcomes.

177Lu-PSMA therapy is an effective treatment in patients with metastatic castration-resistant prostate cancer. SUVmean is a valuable screening biomarker to assess the suitability for 177Lu-PSMA therapy but requires quantitative software. This study aims to develop a simple, clinically applicable prostate-specific membrane antigen PET/CT score that encompasses the elements of SUVmean without requiring additional quantification. Methods: Datasets from ethics-approved trials of patients with metastatic castration-resistant prostate cancer after androgen receptor signaling inhibition and taxane chemotherapy (or unfit for taxane), who were treated with 177Lu-PSMA-617 and 177Lu-PSMA I&T with a pretreatment screening with 68Ga-PSMA-11 PET/CT, and clinical outcome data, including a prostate-specific antigen (PSA) 50% response rate (PSA50), PSA progression-free survival (PSA-PFS), and overall survival (OS), were included. The screening 68Ga-PSMA-11 PET/CT of all participants was analyzed both semiquantitatively and visually. Semiquantitative analysis was used to derive the SUVmean Visual analysis of the 68Ga-PSMA-11 PET/CT images involved a binary visual heterogeneity assessment (homogeneous or heterogeneous), allocating a tumor SUVmax range (<15, 15-29, 30-49, 50-79, or ≥80). A 4-category score incorporating both heterogeneity and intensity of tumors (HIT) was then developed as a combination of heterogeneity and intensity (SUVmax range). The SUVmax was less than 15 for score 1, 15-79 with heterogeneous intensity for score 2, 15-79 with homogeneous intensity for score 3, and 80 or greater for score 4. This score was evaluated according to clinical outcomes (PSA50, PSA-PFS, and OS) and compared with SUVmean Results: Data from 139 participants were analyzed. In total, 75 (54%) patients achieved a PSA50 with a median PSA-PFS of 5.5 mo (95% CI, 4.1-6.0 mo) and an OS of 13.5 mo (95% CI, 11.1-17.9 mo). SUVmean was associated with PSA50 and survival outcomes when analyzed as a continuous variable or as quartiles. The PSA50 for HIT scores 1-4 was 0%, 39%, 65%, and 76%, respectively. The HIT score was strongly related to PSA-PFS and OS (log-rank test, P < 0.001 and P = 0.002). The median PSA-PFS for HIT scores 1-4 was 1.0, 4.1, 6.0, and 8.5, respectively, and the median OS was 7.6, 12.0, 18.5, and 16.9 mo, respectively. Cohen κ between readers for the HIT score was 0.71. Conclusion: A prostate-specific membrane antigen PET/CT score incorporating HIT derived from tools on a standard PET workstation is comparable with quantitative SUVmean as a prognostic tool following 177Lu-PSMA therapy.

Synthesis, design, biological evaluation, and computational analysis of some novel uracil-azole derivatives as cytotoxic agents.

The design and synthesis of novel cytotoxic agents is still an interesting topic for medicinal chemistry researchers due to the unwanted side effects of anticancer drugs. In this study, a novel series of uracil-azole hybrids were designed and synthesized. The cytotoxic activity, along with computational studies: molecular docking, molecular dynamic simulation, density functional theory, and ADME properties were also, evaluated. The compounds were synthesized by using 3-methyl-6-chlorouracil as the starting material. Cytotoxicity was determined using MTT assay in the breast carcinoma cell line (MCF-7) and Hepatocellular carcinoma cell line (HEPG-2). These derivatives demonstrated powerful inhibitory activity against breast and hepatocellular carcinoma cell lines in comparison to Cisplatin as positive control. Among these compounds, 4j displayed the best selectivity profile and good activity with IC50 values of 16.18 ± 1.02 and 7.56 ± 5.28 µM against MCF-7 and HEPG-2 cell lines respectively. Structure-activity relationships revealed that the variation in the cytotoxic potency of the synthesized compounds was affected by various substitutions of benzyl moiety. The docking output showed that 4j bind well in the active site of EGFR and formed a stable complex with the EGFR protein. DFT was used to investigate the reactivity descriptors of 4a and 4j. The outputs demonstrated that these uracil-azole hybrids can be considered as potential cytotoxic agents.

Utility of 64Cu-Sarcophagine-Bombesin PET/CT in Men with Biochemically Recurrent Prostate Cancer and Negative or Equivocal Findings on 68Ga-PSMA-11 PET/CT.

Despite a high detection rate of 68Ga-prostate-specific membrane antigen (PSMA) PET/CT in biochemical recurrence (BCR) of prostate cancer, a significant proportion of men have negative 68Ga-PSMA-11 PET/CT results. Gastrin-releasing peptide receptor, targeted by the copper-chelated bombesin analog 64Cu-sarcophagine-bombesin (SAR-BBN) PET/CT, is also overexpressed in prostate cancer. In this prospective imaging study, we investigate the detection rate of 64Cu-SAR-BBN PET/CT in patients with BCR and negative or equivocal 68Ga-PSMA-11 PET/CT results. Methods: Men with confirmed adenocarcinoma of the prostate, prior definitive therapy, and BCR (defined as a prostate-specific antigen [PSA] level > 0.2 ng/mL) with negative or equivocal 68Ga-PSMA-11 PET/CT results within 3 mo were eligible for enrollment. 64Cu-SAR-BBN PET/CT scans were acquired at 1 and 3 h after administration of 200 MBq of 64Cu-SAR-BBN, with further delayed imaging undertaken optionally at 24 h. PSA (ng/mL) was determined at baseline. All PET (PSMA and bombesin) scans were assessed visually. Images were read with masking of the clinical results by 2 experienced nuclear medicine specialists, with a third reader in cases of discordance. Accuracy was defined using a standard of truth that included biopsy confirmation, confirmatory imaging, or response to targeted treatment. Results: Twenty-five patients were enrolled. Prior definitive therapy was radical prostatectomy (n = 24, 96%) or radiotherapy (n = 1, 4%). The median time since definitive therapy was 7 y (interquartile range [IQR], 4-11 y), and the Gleason score was 7 or less (n = 15, 60%), 8 (n = 3, 12%), or 9 (n = 7, 28%). The median PSA was 0.69 ng/mL (IQR, 0.28-2.45 ng/mL). Baseline PSMA PET scans were negative in 19 patients (76%) and equivocal in 6 (24%). 64Cu-SAR-BBN PET-avid disease was identified in 44% (11/25): 12% (3/25) with local recurrence, 20% (5/25) with pelvic node metastases, and 12% (3/25) with distant metastases. The κ-score between readers was 0.49 (95% CI, 0.16-0.82). Patients were followed up for a median of 10 mo (IQR, 9-12 mo). Bombesin PET/CT results were true-positive in 5 of 25 patients (20%), false-positive in 2 of 25 (8%), false-negative in 7 of 25 (28%), and unverified in 11 of 25 (44%). Conclusion: 64Cu-SAR-BBN PET/CT demonstrated sites of disease recurrence in 44% of BCR cases with negative or equivocal 68Ga-PSMA-11 PET/CT results. Further evaluation to confirm diagnostic benefit is warranted.

Comparison of Protective Effects of Phenolic Acids on Protein Glycation of BSA Supported by In Vitro and Docking Studies.

Several diabetic complications are associated with forming advanced glycation end products (AGEs). Different chemical and natural compounds are able to prevent the development of these products. In this study, glycosylation was induced as a model by incubating bovine serum albumin (BSA) with glucose. Consequently, BSA was treated with glucose and different concentrations (1.25, 2.5, and 5 µM) of syringic acid, gallic acid, ellagic acid, ferulic acid, paracoumaric acid, and caffeic acid for 4 and 6 weeks. Biochemical experiments comprise measurements of fluorescent AGEs, protein carbonyl contents, total thiol, hemolysis tests, and also malondialdehyde (MDA) levels in RBC. These demonstrated the antiglycating mechanism of these phenolic acids. Most of the phenolic acids used in this study reduced MDA levels and protected thiol residues in protein structures. They also inhibited the formation of fluorescent AGEs and RBC lysis, except gallic acid. Moreover, ferulic acid, paracoumaric acid, and caffeic acid proteins significantly prevent carbonylation. Molecular docking and simulation studies showed that ellagic, caffeic, gallic, and syringic acids could interact with lysine and arginine residues in the active site of BSA and stabilize its structure to inhibit the formation of AGEs. Our results suggest that phenolic acid could be used as a potential phytochemical against protein glycation and related diabetic complications.

A systematic review of the safety and efficacy of monoclonal antibodies for progressive multiple sclerosis.

BACKGROUND: Progressive multiple sclerosis (PMS) is a debilitating condition characterized by progressively worsening symptoms. Monoclonal antibodies are novel therapies for MS, but their safety and efficacy in the progressive form have not been comprehensively studied. In this systematic review, we aimed to evaluate the available evidence regarding monoclonal antibody treatment for PMS. METHODS: After registration of the study protocol in PROSPERO, we systematically searched three major databases for clinical trials involving monoclonal antibodies administration for PMS treatment. All the retrieved results were imported into the EndNote reference manager. After removing the duplicates, two independent researchers did the study selection and data extraction. The risk of bias was assessed using the Joanna Briggs Institute (JBI) checklist. RESULTS: Of the 1846 studies in the preliminary search, 13 clinical trials investigating monoclonal antibodies (Ocrelizumab, Natalizumab, Rituximab, and Alemtuzumab) in PMS patients were included. Ocrelizumab was significantly effective in reducing clinical disease progression measures in primary PMS patients. The results for Rituximab were not completely reassuring and only showed significant changes for some endpoints on MRI and clinical measures. Natalizumab decreased the relapse rate and improved MRI features for secondary PMS patients, but not clinical endpoints. The studies on Alemtuzumab treatment revealed conflicting outcomes, with improvements observed in MRI endpoints but clinical worsening in patients. Additionally, among the studied adverse events, upper respiratory infections, urinary tract infections, and nasopharyngitis were frequently reported. CONCLUSION: Based on our findings, Ocrelizumab is the most efficient monoclonal antibody for primary PMS, although it is associated with a higher risk of infection. While other monoclonal antibodies did not show significant promise in treating PMS, more research is necessary.

Working memory assessment using cambridge neuropsychological test automated battery can help in the diagnosis of mild cognitive impairment: a systematic review and meta-analysis.

Mild cognitive impairment (MCI) is an interstitial state between normal aging and dementia. Objective: In this study, we investigated working memory (WM) profiles of MCI patients using the Cambridge Neuropsychological Test Automated Battery (CANTAB). We also examined the diagnostic accuracy and possible associated factors as secondary outcomes of the study. Methods: We conducted an electronic search on EMBASE, PubMed, and ScienceDirect databases. Studies with MCI participants and using CANTAB battery subtests for the assessment of WM were included. Meta-analysis was conducted using the CMA2 software. Results: Out of 1537 records, 14 studies were covered in this systematic review, and 7 of them were included in the meta-analysis. There was a significant difference between MCI patients and healthy controls in spatial working memory (SWM) (SDM: 0.535; 95%CI 11-96; p-value=0.014), spatial span (SSP) (SDM: 0.649 95%CI 0.297-0.100; p-value<0.01), and rapid visual information processing (RVP) (SDM: 0.52; 95%CI 0.386-0.654; p-value<0.01). WM function of MCI patients was associated with the cerebrospinal fluid (CSF) levels of tau-protein and amyloid-beta (Aß). Conclusions: WM is an impaired cognitive domain in MCI. CANTAB WM subtests including SSP, SWM, and RVP are accurate enough to be used as a proper assessment tool for the diagnosis of MCI in clinical settings. Tau-protein and Aß are associated with lower WM scores in MCI patients; however, sex, age, psychiatric disorders, apolipoprotein 4 allele, and functional activity scores cannot affect WM.

O comprometimento cognitivo leve (CCL) é um estado intersticial entre o envelhecimento normal e a demência. Objetivo: Neste estudo, investigamos os perfis de memória de trabalho (MT) de pacientes com CCL usando a bateria automatizada de testes neuropsicológicos de Cambridge (Cambridge Neuropsychological Test Automated Battery ­ CANTAB). Também examinamos a acurácia diagnóstica e possíveis fatores associados como desfechos secundários do estudo. Métodos: Foi realizada uma busca eletrônica nas bases de dados EMBASE, PubMed e ScienceDirect. Foram incluídos estudos com participantes com CCL e utilizando subtestes da bateria CANTAB para avaliação da MT. A meta-análise foi realizada usando o software CMA2. Resultados: Dos 1.537 registros, esta revisão sistemática abordou 14 estudos, e 7 deles foram incluídos na meta-análise. Houve uma diferença significativa entre pacientes com CCL e controles saudáveis na memória de trabalho espacial (MTE) (DPM: 0,535; IC95% 11­96; valor p=0,014), spatial span (SSP) (SDM: 0,649; IC95% 0,297­0,100; valor p<0,01) e processamento rápido de informação visual (PRV) (DPM: 0,52; IC95% 0,386­0,654; valor p<0,01). A MT de pacientes com CCL foi associada com os níveis de proteína tau e beta-amiloide (Aß) no líquido cefalorraquidiano (CSF). Conclusões: A MT é um domínio cognitivo prejudicado no CCL. Os subtestes CANTAB WM, incluindo SSP, MTE e PRV, são precisos o suficiente para serem usados como uma ferramenta de avaliação adequada para o diagnóstico de CCL em ambientes clínicos. A proteína Tau e Aß estão associadas a pontuações de MT mais baixas em pacientes com CCL; entretanto, sexo, idade, transtornos psiquiátricos, alelo da apolipoproteína 4 e escores de atividade funcional não podem afetar a MT.

Antiproliferative Effects of Ferulic, Coumaric, and Caffeic Acids in HepG2 Cells by hTERT Downregulation.

Objective: Phenolic acids are well-known phytochemicals that are detected in a wide variety of medicinal plants, and their antiproliferative effects on cancer cells are known, but their mechanisms are poorly revealed. In most of cancer cells, telomerase reverse transcriptase (hTERT) is a dominant factor of telomere length regulation. The hTERT expression promotes invasiveness in tumor cells and is a hallmark of cancer. Therefore, in this study, the probable inhibitory effects of caffeic (Caf), coumaric (Cum), and ferulic acids (Fer) are investigated on the hTERT expression pattern in HepG2 cells. Methods: The MTT, apoptosis assays, and real-time PCR analysis were applied to evaluate viability, cytotoxicity, and hTERT gene expression level, respectively. Results: All of the studied phenolic acids showed cytotoxic effects on HepG2 cells in a timely manner and presented a time-dependent inhibitory effect on the growth of HepG2 cells. They reduced percentage of viable cells and induced apoptosis. Also, these phenolic acids had significant inhibitory effects on hTERT gene expression. Conclusion: These findings suggest that cell viability along with hTERT gene expression in HepG2 cells could be reduced by Cum, Caf, and Fer. As different cancer cells are resistant to conventional chemotherapeutics, this type of results proposes the telomerase as a proper target of cancer therapy development by natural products.

Improvement of Phenolic Compound Extraction by Using Ion Exchange Chromatography and Evaluation of Biological Activities of Polyphenol-enriched Fraction of Rosa canina Fruits.

Background: Rosa canina has been traditionally known as a medicinal plant. Different applications of fruits (Rose hip) comprise the food, perfume, and cosmetic industries. Objectives: This study aimed to prepare an enriched polyphenolic fraction from Rosa canina in addition to its biological activities. Methods: Poly phenolic enriched fraction was prepared using Amberlite XAD-7 for removing unwanted components. Phenols, flavonoids, and anthocyanins content analyses showed that they increased significantly compared to the extract. HPLC analysis showed that this fraction is a rich source of ascorbic acid. Results: The results of the DPPH, ferric-reducing antioxidant power (FRAP), ABTS, and nitric oxide assay confirmed that the antioxidant activities of the fraction had been increased compared to the extract. The oxygen radical absorbance capacity (ORAC) assay and cellular antioxidant activity of the fraction also confirmed its potential antioxidant activity. This fraction showed xanthine oxidase inhibitory activity at 100 µg/mL concentration. Comet assay analysis revealed that this fraction at 25 - 100 µg/mL concentrations inhibited H2O2 genotoxicity in human lymphocytes. Conclutions: This study suggests that the fruit of Rosa canina could be considered as a potential antioxidant, a xanthine oxidase inhibitor, and an antigenotoxic source, and the application of Amberlite XAD-7 improves extraction efficiencies through enrichment of phenolic compounds in this plant.

Syringic Acid Attenuates Cardiomyopathy in Streptozotocin-Induced Diabetic Rats.

OBJECTIVES: Diabetic cardiomyopathy (DC) has become one of the serious complications in diabetic cases. In this study, we aimed to explore the syringic acid (SYR) protective effect against diabetes-induced cardiac injury in experimental rats. METHODS: Rats were divided in control and streptozotocin-induced diabetic rats which were subdivided into diabetic controls, and three test groups (SYR at 25, 50, and 100 mg/kg) and the nondiabetic group received 100 mg/kg of SYR. All treatments were given SYR for 6 weeks. SYR effects on cardiac diagnostic markers, heart lipid peroxidation, protein carbonylation, antioxidant system, and changes of the heart mitochondrial mass and biogenesis were measured. RESULTS: Diabetes induction prompted CK-MB, LDH levels in serum, cardiac catalase, and superoxide dismutase activity, as well as cardiac TBARs and carbonylated protein. SYR administration (100 m/kg) attenuated CK-MB and LDH levels. Also, 50 and 100 mg/kg of SYR reduced cardiac TBARs and carbonylated protein in diabetic rats. These treatments did not show any effects on GSH content, mtDNA, and mitochondrial biogenesis indices (PGC1- α, NRF1, NRF2, and TFAM) in heart tissue. CONCLUSIONS: SYR treatment showed protective effects on diabetic cardiomyopathy in rats by reducing lipid peroxidation and protein carbonylation. The possible mechanisms could be related to antioxidant activity of this phenolic acid. SYR might play a role of a protective factor in cardiac challenges in diabetes.

Green Synthesis of Selenium Nanoparticles by Cyanobacterium Spirulina platensis (abdf2224): Cultivation Condition Quality Controls.

Selenium nanoparticles (SeNPs) are well-known bioactive compounds. Various chemical and biological methods have been applied to SeNP synthesis. Spirulina platensis is a widely used blue-green microalgae in various industries. In this study, the biosynthesis of SeNPs using sodium selenite and Spirulina platens has been developed. The SeNP synthesis was performed at different cultivation condition including pH and illumination schedule variation. The SeNPs were characterized by FT-IR, XRD, size, and zeta potential measurements, and the antioxidant activities of selected SeNPs were evaluated by DPPH and FRAP assays. FT-IR analysis showed the production of SeNPs. The 12 h dark/12 h light cycles and continuous light exposure at pH 5 led to the production of stable SeNPs with sizes of 145 ± 6 and 171 ± 13 nm, respectively. Antioxidant activity of selected SeNPs was higher than sodium selenite. It seems that green synthesis is a safe method to produce SeNPs as well as a convenient method to scale-up this production.

Syringic Acid: A Potential Natural Compound for the Management of Renal Oxidative Stress and Mitochondrial Biogenesis in Diabetic Rats.

BACKGROUND: Diabetic nephropathy can lead to renal diseases; oxidative stress and mitochondrial dysfunction have critical roles in its development. OBJECTIVES: In this study, the effect of syringic acid (SYR), a natural phenolic acid, on diabetic nephropathy and mitochondrial biogenesis was examined. METHODS: Diabetes was induced in rats by injecting streptozotocin. SYR (25, 50 and 100 mg/kg/day) was orally administered for 6 weeks. SYR effects on factors, such as antioxidant activities and mRNA expression level of mitochondrial biogenesis indexes, were evaluated. RESULTS: In SYR-treated rats, blood glucose and ALP level were significantly reduced. SYR increased kidney GSH content in the diabetic group. Elevated renal catalase and superoxide dismutase activities in diabetic rats were restored to normal levels after treatment. SYR significantly reduced the renal TBARS level, which had increased in diabetic rats. This compound also significantly upregulated renal mRNA expression of PGC-1α and NRF-1, and increased mtDNA/nDNA ratio in diabetic rats. These values were reduced in the non-treated diabetic group. The results show improvement of histopathological damages of kidney in the SYR treated group in comparison with the diabetic group. CONCLUSION: According to the results, SYR alters renal antioxidant defense mechanisms. Also, it could be considered as a novel approach by targeting mitochondria in renal diabetic complications.

Neuroprotective Effect of Syringic Acid by Modulation of Oxidative Stress and Mitochondrial Mass in Diabetic Rats.

Diabetes is a metabolic complaint associated with oxidative stress and dysfunction of mitochondria. One of the most common complications of diabetes mellitus is neuropathy. This study evaluated the possible neuroprotective effects of syringic acid (SYR), a natural polyphenolic derivative of benzoic acid, on oxidative damage and mitochondria in the brain, spinal cord, and sciatic nerve of streptozotocin-induced diabetic rats. Different groups of rats including normal control, diabetics (induced by streptozotocin), diabetic groups treated with 25, 50, and 100 mg/kg of SYR, and non-diabetic group treated with only 100 mg/kg of SYR were treated for 6 weeks. Learning and memory function, physical coordination, and acetylcholinesterase (AChE) and antioxidant indexes, as well as mRNA expression of mitochondrial biogenesis, were measured in the brain, spinal cord, and sciatic nerves. Diabetic rats treated with 100 mg/kg SYR exhibited significantly improved learning, memory, and movement deficiency (p < 0.05). SYR 100 mg/kg also significantly upregulated the brain mRNA expression of PGC-1α and NRF-1, the key regulators of energy metabolism, oxidative phosphorylation, and mitochondrial biogenesis. In addition, SYR 100 mg/kg and SYR 50 mg/kg increased the mtDNA/nDNA ratio in the brain and the spinal cord of diabetic rats, respectively (p < 0.05). SYR attenuated the lipid peroxidation in all the tissues, but not significant effects were observed on GSH, AChE, catalase, and superoxide dismutase activity. In all the tests, nonsignificant differences were observed between the control and SYR 100 mg/kg groups. Moreover, SYR reduced inflammation and demyelination in sciatic nerves. This is the first study to reveal the regulation of mitochondrial biogenesis and energy metabolism by SYR, beyond its antioxidant role in the diabetic rats' brain and spinal tissues.

DNA protection, antioxidant and xanthine oxidase inhibition activities of polyphenol-enriched fraction of Berberis integerrima Bunge fruits.

OBJECTIVES: The aim of this study was to prepare fraction and determine the biological activities of the polyphenol-enriched fraction of Berberis integerrima Bunge fruits. MATERIALS AND METHODS: In this assay fraction was extracted by column chromatography, using Amberlite column as the stationary phase. Phenol and flavonoids in the extract and fraction were analyzed by high performance liquid chromatography (HPLC). DNA protection ability, antioxidant and xanthine oxidase inhibition capacities of this fraction were also examined. RESULTS: Phenol and flavonoid content measurement and HPLC analyses of this fraction confirmed that phenol and flavonoids were increased in fraction in comparison to extract (before using Amberlite column). In antioxidant measurement assay, the trolox equivalent values were 1.05± 0.04 and 0.8±0.11 in oxygen radical absorbance capacity (ORAC) and the EC50 values for cellular antioxidant activity were 55.51±0.21 and 95.67±0.13 µg/ml for quercetin and the fraction, respectively. The xanthine oxidase inhibition percentages were 97.6±0.003 and 90.2 6±0.003 in 100 µg/ml concentration of fraction and vitamin C respectively. Comet assay analysis showed that this fraction protects human lymphocytes against H2O2-induced DNA damages at 12.5 to 100 µg/ml concentrations. CONCLUSION: This study suggests that Amberlite column as the stationary phase help to improve phenolic compound in separating fractions. The results showed that B. integerrima fruits are rich in phenolic compounds and they are potent antioxidants with protective effects on oxidative damages. They might be used as functional ingredients in food and supplements.

Working memory assessment using cambridge neuropsychological test automated battery can help in the diagnosis of mild cognitive impairment: a systematic review and meta-analysis / A avaliação da memória de trabalho usando a bateria automatizada do cambridge neuropsychological test pode ajudar no diagnóstico de comprometimento cognitivo leve: uma revisão sistemática e meta-análise

ABSTRACT Mild cognitive impairment (MCI) is an interstitial state between normal aging and dementia. Objective: In this study, we investigated working memory (WM) profiles of MCI patients using the Cambridge Neuropsychological Test Automated Battery (CANTAB). We also examined the diagnostic accuracy and possible associated factors as secondary outcomes of the study. Methods: We conducted an electronic search on EMBASE, PubMed, and ScienceDirect databases. Studies with MCI participants and using CANTAB battery subtests for the assessment of WM were included. Meta-analysis was conducted using the CMA2 software. Results: Out of 1537 records, 14 studies were covered in this systematic review, and 7 of them were included in the meta-analysis. There was a significant difference between MCI patients and healthy controls in spatial working memory (SWM) (SDM: 0.535; 95%CI 11-96; p-value=0.014), spatial span (SSP) (SDM: 0.649 95%CI 0.297-0.100; p-value<0.01), and rapid visual information processing (RVP) (SDM: 0.52; 95%CI 0.386-0.654; p-value<0.01). WM function of MCI patients was associated with the cerebrospinal fluid (CSF) levels of tau-protein and amyloid-beta (Aβ). Conclusions: WM is an impaired cognitive domain in MCI. CANTAB WM subtests including SSP, SWM, and RVP are accurate enough to be used as a proper assessment tool for the diagnosis of MCI in clinical settings. Tau-protein and Aβ are associated with lower WM scores in MCI patients; however, sex, age, psychiatric disorders, apolipoprotein 4 allele, and functional activity scores cannot affect WM.

RESUMO O comprometimento cognitivo leve (CCL) é um estado intersticial entre o envelhecimento normal e a demência. Objetivo: Neste estudo, investigamos os perfis de memória de trabalho (MT) de pacientes com CCL usando a bateria automatizada de testes neuropsicológicos de Cambridge (Cambridge Neuropsychological Test Automated Battery - CANTAB). Também examinamos a acurácia diagnóstica e possíveis fatores associados como desfechos secundários do estudo. Métodos: Foi realizada uma busca eletrônica nas bases de dados EMBASE, PubMed e ScienceDirect. Foram incluídos estudos com participantes com CCL e utilizando subtestes da bateria CANTAB para avaliação da MT. A meta-análise foi realizada usando o software CMA2. Resultados: Dos 1.537 registros, esta revisão sistemática abordou 14 estudos, e 7 deles foram incluídos na meta-análise. Houve uma diferença significativa entre pacientes com CCL e controles saudáveis na memória de trabalho espacial (MTE) (DPM: 0,535; IC95% 11-96; valor p=0,014), spatial span (SSP) (SDM: 0,649; IC95% 0,297-0,100; valor p<0,01) e processamento rápido de informação visual (PRV) (DPM: 0,52; IC95% 0,386-0,654; valor p<0,01). A MT de pacientes com CCL foi associada com os níveis de proteína tau e beta-amiloide (Aβ) no líquido cefalorraquidiano (CSF). Conclusões: A MT é um domínio cognitivo prejudicado no CCL. Os subtestes CANTAB WM, incluindo SSP, MTE e PRV, são precisos o suficiente para serem usados como uma ferramenta de avaliação adequada para o diagnóstico de CCL em ambientes clínicos. A proteína Tau e Aβ estão associadas a pontuações de MT mais baixas em pacientes com CCL; entretanto, sexo, idade, transtornos psiquiátricos, alelo da apolipoproteína 4 e escores de atividade funcional não podem afetar a MT.