Enhancing the Bioavailability of Resveratrol: Combine It, Derivatize It, or Encapsulate It?

Overcoming the limited bioavailability and extensive metabolism of effective in vitro drugs remains a challenge that limits the translation of promising drugs into clinical trials. Resveratrol, despite its well-reported therapeutic benefits, is not metabolically stable and thus has not been utilized as an effective clinical drug. This is because it needs to be consumed in large amounts to overcome the burdens of bioavailability and conversion into less effective metabolites. Herein, we summarize the more relevant approaches to modify resveratrol, aiming to increase its biological and therapeutic efficacy. We discuss combination therapies, derivatization, and the use of resveratrol nanoparticles. Interestingly, the combination of resveratrol with established chemotherapeutic drugs has shown promising therapeutic effects on colon cancer (with oxaliplatin), liver cancer (with cisplatin, 5-FU), and gastric cancer (with doxorubicin). On the other hand, derivatizing resveratrol, including hydroxylation, amination, amidation, imidation, methoxylation, prenylation, halogenation, glycosylation, and oligomerization, differentially modifies its bioavailability and could be used for preferential therapeutic outcomes. Moreover, the encapsulation of resveratrol allows its trapping within different forms of shells for targeted therapy. Depending on the nanoparticle used, it can enhance its solubility and absorption, increasing its bioavailability and efficacy. These include polymers, metals, solid lipids, and other nanoparticles that have shown promising preclinical results, adding more "hype" to the research on resveratrol. This review provides a platform to compare the different approaches to allow directed research into better treatment options with resveratrol.

Molecular properties prediction, anticancer and anti-inflammatory activities of some pyrimido[1,2-b]pyridazin-2-one derivatives.

Introduction: The anticancer and anti-inflammatory activities of a novel series of eleven pyrimido[1,2-b]pyridazin-2-one analogues substituted at position 7 were assessed in the current study. Methods: The physicochemical characteristics were studied using MolSoft software. The antiproliferative activity was investigated by MTT cell viability assay, and cell cycle analysis elucidated the antiproliferative mechanism of action. Western blot analysis examined the expression levels of key pro-apoptotic (Bax, p53) and pro-survival (Bcl-2) proteins. The anti-inflammatory activity was assessed by measuring the production levels of nitric oxide in RAW264.7 cells, and the expression levels of COX-2 enzyme in LPS-activated THP-1 cells. In addition, the gene expression of various pro-inflammatory cytokines (IL-6, IL-8, IL-1ß, TNF-α) and chemokines (CCL2, CXCL1, CXCL2, CXCL3) was assessed by RT-qPCR. Results: Compound 1 bearing a chlorine substituent displayed the highest cytotoxic activity against HCT-116 and MCF-7 cancer cells where IC50 values of 49.35 ± 2.685 and 69.32 ± 3.186 µM, respectively, were achieved. Compound 1 increased the expression of pro-apoptotic proteins p53 and Bax while reducing the expression of pro-survival protein Bcl-2. Cell cycle analysis revealed that compound 1 arrested cell cycle at the G0/G1 phase. Anti-inflammatory assessments revealed that compound 1 displayed the strongest inhibitory activity on NO production with IC50 of 29.94 ± 2.24 µM, and down-regulated the expression of COX-2. Compound 1 also induced a statistically significant decrease in the gene expression of various cytokines and chemokines. Conclusion: These findings showed that the pyrimidine derivative 1 displayed potent anti-inflammatory and anticancer properties in vitro, and can be selected as a lead compound for further investigation.

Fluorinated Benzofuran and Dihydrobenzofuran as Anti-Inflammatory and Potential Anticancer Agents.

Benzofuran and 2,3-dihydrobenzofuran scaffolds are heterocycles of high value in medicinal chemistry and drug synthesis. Targeting inflammation in cancer associated with chronic inflammation is a promising therapy. In the present study, we investigated the anti-inflammatory effects of fluorinated benzofuran and dihydrobenzofuran derivatives in macrophages and in the air pouch model of inflammation, as well as their anticancer effects in the human colorectal adenocarcinoma cell line HCT116. Six of the nine compounds suppressed lipopolysaccharide-stimulated inflammation by inhibiting the expression of cyclooxygenase-2 and nitric oxide synthase 2 and decreased the secretion of the tested inflammatory mediators. Their IC50 values ranged from 1.2 to 9.04 µM for interleukin-6; from 1.5 to 19.3 µM for Chemokine (C-C) Ligand 2; from 2.4 to 5.2 µM for nitric oxide; and from 1.1 to 20.5 µM for prostaglandin E2. Three novel synthesized benzofuran compounds significantly inhibited cyclooxygenase activity. Most of these compounds showed anti-inflammatory effects in the zymosan-induced air pouch model. Because inflammation may lead to tumorigenesis, we tested the effects of these compounds on the proliferation and apoptosis of HCT116. Two compounds with difluorine, bromine, and ester or carboxylic acid groups inhibited the proliferation by approximately 70%. Inhibition of the expression of the antiapoptotic protein Bcl-2 and concentration-dependent cleavage of PARP-1, as well as DNA fragmentation by approximately 80%, were described. Analysis of the structure-activity relationship suggested that the biological effects of benzofuran derivatives are enhanced in the presence of fluorine, bromine, hydroxyl, and/or carboxyl groups. In conclusion, the designed fluorinated benzofuran and dihydrobenzofuran derivatives are efficient anti-inflammatory agents, with a promising anticancer effect and a combinatory treatment in inflammation and tumorigenesis in cancer microenvironments.

A ten-year surveillance of P aeruginosa bloodstream infections in a tertiary care hospital: Trends and risk factors for mortality.

BACKGROUND: Pseudomonas aeruginosa (P aeruginosa) is a leading cause of nosocomial bloodstream infections worldwide. This study aimed to evaluate the incidence of P aeruginosa bloodstream infections and to identify predictors of 30-day mortality. METHODS: A retrospective study was conducted in an academic tertiary hospital in Jordan. The medical records of patients hospitalised over ten years (1 January 2008-31 December 2017) were reviewed to identify patients' positive blood culture of P aeruginosa. Annual incidence, antimicrobial susceptibility patterns and risk factors for 30-day mortality were analysed. RESULTS: A total of 169 cases of P aeruginosa bloodstream infection were identified, with an overall incidence rate of 0.23 case/1000 admission. The overall crude 30-day mortality was 36.7%. Receipt of corticosteroids (OR = 4.5; P = .0017), severe sepsis and septic shock (OR = 2.7; P = .0476), admission to intensive care unit (OR = 5.9; P = .0004), end-stage renal disease (OR = 4.1; P = .0123), inappropriate empirical therapy (OR = 3.2; P = .0143) and inappropriate definitive therapy (OR = 2.9; P = .0110) were identified as independent risk factors for mortality. CONCLUSION: The annual incidence of P aeruginosa BSIs was fluctuating over ten years period. Several predictors for 30-day mortality in patients with P aeruginosa BSIs were identified, including inappropriate empirical and definitive therapy.

Effects of the Oncoprotein PAX3-FOXO1 on Modulation of Exosomes Function and Protein Content: Implications on Oxidative Stress Protection and Enhanced Plasticity.

Rhabdomyosarcoma (RMS) is a highly malignant soft tissue sarcoma classified into two major histologic subtypes: embryonal (ERMS) and alveolar (ARMS). ARMS subtype is clinically more aggressive, and characterized by an oncogenic fusion protein PAX3-FOXO1 (P3F) that drives oncogenic cellular properties. To understand the role of the fusion oncoprotein in paracrine signaling, we focused on secreted exosomes, which have been demonstrated to contribute to metastasis in multiple tumor types. Advanced Proteomics-bioinformatics analysis of the protein cargo of exosomes isolated from C2C12 myoblasts transduced with P3F fusion gene revealed 52 deregulated proteins compared to control cells, with 26 enriched and 26 depleted proteins. Using both PANTHER gene classification and Ingenuity Pathway Analysis (IPA) software, we found that the main biological processes in which the 52 deregulated proteins are involved, include "catalytic activity," "binding," "metabolic process," and "cellular process." The pathways engaging the 26 enriched proteins include the "14-3-3 mediated signaling," "cell cycle," and "ERK5, VEGF, IGF1,and p70S6K signaling." Furthermore, the main nodes in which deregulated exosome proteins and miRNAs intersected revealed pathways conferring protection from stress and promoting plasticity. Based on the bioinformatics analysis and the altered exosome proteome profile, we performed biochemical functional analysis to study the diverse properties of these exosomes where angiogenesis, stemness, and anti-oxidative stress properties were validated using different platforms. P3F-modulated exosomes activated ERK, 4-EBP1, and MMP-2 in recipient cells, and enhanced angiogenesis and stemness. In addition, P3F led to lower cellular reactive oxygen species levels and enhanced resistance against oxidative stress; and treatment of stromal cells with P3F-modulated exosomes also conferred protection against exogenous oxidative stress. Our findings highlight the role of P3F fusion protein in modulating exosome cargo to confer a protective effect on recipient cells against oxidative stress and to promote plasticity and survival, potentially contributing to the known aggressive phenotype of the fusion gene-positive subtype of RMS.

gem-Difluorobisarylic derivatives: design, synthesis and anti-inflammatory effect.

INTRODUCTION: New fluorinated diaryl ethers and bisarylic ketones were designed and evaluated for their anti-inflammatory effects in primary macrophages. METHODS: The synthesis of the designed molecules started from easily accessible and versatile gem-difluoro propargylic derivatives. The desired aromatic systems were obtained using Diels-Alder/aromatization sequences and this was followed by Pd-catalyzed coupling reactions and, when required, final functionalization steps. Both direct inhibitory effects on cyclooxygenase-1 or -2 activities, protein expression of cyclooxygenase-2 and nitric oxide synthase-II and the production of prostaglandin E2, the pro-inflammatory nitric oxide and interleukin-6 were evaluated in primary murine bone marrow-derived macrophages in response to lipopolysaccharide. Docking of the designed molecules in cyclooxygenase-1 or -2 was performed. RESULTS: Only fluorinated compounds exerted anti-inflammatory activities by lowering the secretion of interleukin-6, nitric oxide, and prostaglandin E2, and decreasing the protein expression of inducible nitric oxide synthase and cyclooxygenase-2 in mouse primary macrophages exposed to lipopolysaccharide, as well as cyclooxygenase activity for some inhibitors with different efficiencies depending on the R-groups. Docking observation suggested an inhibitory role of cyclooxygenase-1 or -2 for compounds A3, A4 and A5 in addition to their capacity to inhibit nitrite, interleukin-6, and nitric oxide synthase-II and cyclooxygenase-2 expression. CONCLUSION: The new fluorinated diaryl ethers and bisarylic ketones have anti-inflammatory effects in macrophages. These fluorinated compounds have improved potential anti-inflammatory properties due to the fluorine residues in the bioactive molecules.

The PAX3-FOXO1 oncogene alters exosome miRNA content and leads to paracrine effects mediated by exosomal miR-486.

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children. The alveolar subtype (ARMS) is clinically more aggressive, and characterized by an oncogenic fusion protein PAX3-FOXO1 that drives oncogenic cellular properties. Exosomes are small, secreted vesicles that affect paracrine signaling. We show that PAX3-FOXO1 transcript alters exosome content of C2C12 myoblasts, leading to pro-tumorigenic paracrine effects in recipient cells. Microarray analysis revealed alteration in miRNA content of exosomes, affecting cellular networks involved in cell metabolism, growth signaling, and cellular invasion. Overexpression and knockdown studies showed that miR-486-5p is an effector of PAX3-FOXO1, and mediates its paracrine effects in exosomes, including promoting recipient cell migration, invasion, and colony formation. Analysis of human RMS cells showed miR-486-5p is enriched in both cells and exosomes, and to a higher extent in ARMS subtypes. Analysis of human serum samples showed that miR-486-5p is enriched in exosomes of patients with RMS, and follow-up after chemotherapy showed decrease to control values. Our findings identify a novel role of both PAX3-FOXO1 and its downstream effector miR-486-5p in exosome-mediated oncogenic paracrine effects of RMS, and suggest its possible use as a biomarker.

Clinical patterns, epidemiology and risk factors of community-acquired urinary tract infection caused by extended-spectrum beta-lactamase producers: a prospective hospital case-control study.

PURPOSE: To assess incidence rate, risk factors and susceptibility patterns associated with extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli or Klebsiella pneumoniae in community-acquired urinary tract infections (CA-UTIs). METHODS: A prospective, case-control study was conducted at a tertiary teaching hospital from Jan 2015 to Dec 2016. The results of microbiology cultures were initially screened to include only patients with positive E. coli or K. pneumoniae urine cultures. Afterwards, clinical symptoms were assessed to confirm the UTI. To investigate the risk factors, patients with a positive urine culture for ESBL-producing isolates were assigned as cases, while patients with non-ESBL were assigned as controls. RESULTS: Out of 591 patients included in this study, 57.5% (n = 340) were included in the control group and 42.5% (n = 251) were in the case group. The incidence rate of ESBL-producing isolates was 3.465 cases per 1000-patient hospital admissions. Male gender (OR = 1.856, 95% CI = 1.192-2.889, p = 0.006), pediatrics (OR = 1.676, 95% CI = 1.117-2.517, p = 0.013), patients with comorbidity (OR = 1.542, 95% CI = 1.029-2.312, p = 0.036) and UTI in the previous 12 months (OR = 1.705, 95% CI = 1.106-2.628, p = 0.016) were independently associated with a higher risk of infection. The resistance rate for most commonly prescribed antibiotics was high. CONCLUSIONS: Our results suggest that the incidence of ESBL producers among CA-UTIs is high. Male gender, pediatrics, comorbidity and UTI in the previous 12 months were associated with a higher risk for infection. Continuous surveillance and prudent antibiotic use by healthcare professionals are important factors for effective control of ESBL associated infections.

The effectiveness of clinical pharmacist's intervention in improving asthma care in children and adolescents: Randomized controlled study in Jordan.

OBJECTIVE: To evaluate the effectiveness of clinical pharmacist's intervention on achieving better asthma control, quality of life and other clinical parameters. METHODS: A prospective randomized controlled study in north Jordan was conducted. Pediatric patients with asthma (aged 7-18 years old) were included and randomly allocated into two groups, intervention and control. Both groups were interviewed at the first visit and followed up twice by phone (at 3 and 6 months). Education was provided to patients and their caregivers in the intervention group only. RESULTS: Of 206 eligible patients recruited and randomized to our study, 178 patients completed the study (48.3% intervention versus 51.7% control). There were no significant differences in all baseline data between both groups. We identified significant differences in the improvement of asthma control (p<0.001) and consequently pediatric and caregiver quality of life (p<0.001) between both groups at the end of study. Significant differences were also detected in other clinical parameters (p<0.05). CONCLUSION: Implementation of clinical pharmacy service can positively influence asthma control, pediatric and caregiver's quality of life, and other clinical parameters. PRACTICE IMPLICATIONS: To maintain a good asthma status, education of pediatric patients and their caregivers should be part of routine assessment during clinic visit.

Prevalence and nature of off-label antibiotic prescribing for children in a tertiary setting: A descriptive study from Jordan.

OBJECTIVE: The aim of the present study was to evaluate the use of off-label antibiotics in neonatal intensive care units (NICUs) and paediatric wards in Jordan. METHODS: Data of patients admitted to the neonatal intensive care units and paediatric wards in King Abdulla University Hospital were collected over an 8-week survey between May and July 2012. Data collected in this study included patients' age, weight, medical history, diagnosis and the details of antibiotics prescribed to each patient. RESULTS: The study involved a total of 250 children (80 admitted to the NICU and 170 admitted to the wards). A total of 598 antibiotic prescriptions were issued for these patients (244 in NICUs and 354 in paediatricwards). The results of the present study show that off-label antibiotic prescribing to paediatric patients is very common. Off-label antibiotic prescribing to paediatric patients is related mostly to doses and indications, and rarely to age. The majority of admitted patients received at least one off-label antibiotic during their hospital stay. CONCLUSION: This study reveals the high prevalence of off-label use of antibiotic among paediatric children in Jordan. There is a serious need for robust and continuous educational programs to improve the awareness of paediatricians of guidelines surrounding the use of antibiotics in paediatric patients. Furthermore, true collaboration between paediatricians and clinical pharmacists towards safe and effective antibiotic prescribing in paediatric patients is crucial.

Prevalence and nature of off-label antibiotic prescribing for children in a tertiary setting: a descriptive study from Jordan

Objective: The aim of the present study was to evaluate the use of off-label antibiotics in neonatal intensive care units (NICUs) and paediatric wards in Jordan. Methods: Data of patients admitted to the neonatal intensive care units and paediatric wards in King Abdulla University Hospital were collected over an 8-week survey between May and July 2012. Data collected in this study included patients’ age, weight, medical history, diagnosis and the details of antibiotics prescribed to each patient. Results: The study involved a total of 250 children (80 admitted to the NICU and 170 admitted to the wards). A total of 598 antibiotic prescriptions were issued for these patients (244 in NICUs and 354 in paediatricwards). The results of the present study show that off-label antibiotic prescribing to paediatric patients is very common. Off-label antibiotic prescribing to paediatric patients is related mostly to doses and indications, and rarely to age. The majority of admitted patients received at least one off-label antibiotic during their hospital stay. Conclusion: This study reveals the high prevalence of offlabel use of antibiotic among paediatric children in Jordan. There is a serious need for robust and continuous educational programs to improve the awareness of paediatricians of guidelines surrounding the use of antibiotics in paediatric patients. Furthermore, true collaboration between paediatricians and clinical pharmacists towards safe and effective antibiotic prescribing in paediatric patients is crucial (AU)

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Brucellosis Outbreak in Children and Adults in Two Areas in Israel.

Two parallel outbreaks of Brucella melitensis infection occurred in 2014 in two geographical areas in Israel. In two medical centers in northern Israel and one medical center in Jerusalem, 102 patients (58 children, 47 adults) were diagnosed with brucellosis. Most patients (N = 76, 72%) were Muslim Arabs, 28 (27%) were Druze, and one was Jewish. The source of infection was often traced to cheese from the Palestinian Authority. Biovar-1 was evident in 98% in northern Israel but only in 42% in Jerusalem. Most common manifestations were fever (82%) and osteoarticular symptoms (49%). The major differences between the geographic areas were ethnicity and duration until diagnosis. Compared with adults, children had higher rates of hospitalization (93% versus 64%, P = 0.001), osteoarticular symptoms (60% versus 36%, P = 0.05), elevated alanine aminotransferase (12% versus 0%, P = 0.01), and lower C-reactive protein (2.28 ± 2.08 versus 5.57 ± 6.3l mg/dL, P = 0.001). Two unrelated brucellosis outbreaks occurred in 2014 in two different geographic areas of Israel and were limited to sections of the Arab and Druze populations. Most of the demographic and clinical aspects of patients were not affected by geographic variability. Clinical and laboratory differences were found between children and adults emphasizing the nonuniformity of the disease in different age groups. Effective control of unpasteurized dairy foods, health education programs, and improved regional cooperation are required to control brucellosis in Israel.

An audit of the precipitating factors for haemolytic crisis among glucose-6-phosphate dehydrogenase-deficient paediatric patients.

BACKGROUND: Glucose-6-phosphate dehydrogenase (G6PD) deficiency is one of the most common genetic enzyme deficiencies leading to haemolytic anaemia. This study aimed to investigate the precipitating factors for haemolytic crisis in G6PD-deficient paediatric patients in Jordan. METHOD: A retrospective study of data from the records of 258 paediatric patients admitted to a major paediatric hospital in North Jordan from January 2001 until April 2007. Patients included were G6PD-deficient children who were admitted to the hospital secondary to an episode of haemolytic anaemia. RESULTS: Of 258 paediatric patients, 244 (94.2%) had developed a haemolytic episode secondary to ingestion of fava beans. The remaining 14 children (5.8%) developed a haemolytic episode triggered by other factors, such as drugs and upper respiratory infections. CONCLUSION: Fava bean ingestion is the major precipitating factor for haemolytic anaemia episodes among G6PD-deficient children in Jordan.