Molecular and Biological Investigation of Isolated Marine Fungal Metabolites as Anticancer Agents: A Multi-Target Approach.

Cancer is the leading cause of death globally, with an increasing number of cases being annually reported. Nature-derived metabolites have been widely studied for their potential programmed necrosis, cytotoxicity, and anti-proliferation leading to enrichment for the modern medicine, particularly within the last couple of decades. At a more rapid pace, the concept of multi-target agents has evolved from being an innovative approach into a regular drug development procedure for hampering the multi-fashioned pathophysiology and high-resistance nature of cancer cells. With the advent of the Red Sea Penicillium chrysogenum strain S003-isolated indole-based alkaloids, we thoroughly investigated the molecular aspects for three major metabolites: meleagrin (MEL), roquefortine C (ROC), and isoroquefortine C (ISO) against three cancer-associated biological targets Cdc-25A, PTP-1B, and c-Met kinase. The study presented, for the first time, the detailed molecular insights and near-physiological affinity for these marine indole alkaloids against the assign targets through molecular docking-coupled all-atom dynamic simulation analysis. Findings highlighted the superiority of MEL's binding affinity/stability being quite in concordance with the in vitro anticancer activity profile conducted via sulforhodamine B bioassay on different cancerous cell lines reaching down to low micromolar or even nanomolar potencies. The advent of lengthy structural topologies via the metabolites' extended tetracyclic cores and aromatic imidazole arm permitted multi-pocket accommodation addressing the selectivity concerns. Additionally, the presence decorating polar functionalities on the core hydrophobic tetracyclic ring contributed compound's pharmacodynamic preferentiality. Introducing ionizable functionality with more lipophilic characters was highlighted to improve binding affinities which was also in concordance with the conducted drug-likeness/pharmacokinetic profiling for obtaining a balanced pharmacokinetic/dynamic profile. Our study adds to the knowledge regarding drug development and optimization of marine-isolated indole-based alkaloids for future iterative synthesis and pre-clinical investigations as multi-target anticancer agents.

Exploring the Synergistic Effect of Bergamot Essential Oil with Spironolactone Loaded Nano-Phytosomes for Treatment of Acne Vulgaris: In Vitro Optimization, In Silico Studies, and Clinical Evaluation.

The foremost target of the current work was to formulate and optimize a novel bergamot essential oil (BEO) loaded nano-phytosomes (NPs) and then combine it with spironolactone (SP) in order to clinically compare the efficiency of both formulations against acne vulgaris. The BEO-loaded NPs formulations were fabricated by the thin-film hydration and optimized by 32 factorial design. NPs' assessments were conducted by measuring entrapment efficiency percent (EE%), particle size (PS), polydispersity index (PDI), and zeta potential (ZP). In addition, the selected BEO-NPs formulation was further combined with SP and then examined for morphology employing transmission electron microscopy and three months storage stability. Both BEO-loaded NPs selected formula and its combination with SP (BEO-NPs-SP) were investigated clinically for their effect against acne vulgaris after an appropriate in silico study. The optimum BEO-NPs-SP showed PS of 300.40 ± 22.56 nm, PDI of 0.571 ± 0.16, EE% of 87.89 ± 4.14%, and an acceptable ZP value of -29.7 ± 1.54 mV. Molecular modeling simulations showed the beneficial role of BEO constituents as supportive/connecting platforms for favored anchoring of SP on the Phosphatidylcholine (PC) interface. Clinical studies revealed significant improvement in the therapeutic response of BEO-loaded NPs that were combined with SP over BEO-NPs alone. In conclusion, the results proved the ability to utilize NPs as a successful nanovesicle for topical BEO delivery as well as the superior synergistic effect when combined with SP in combating acne vulgaris.

Metabolic Profiling of Heliotropium crispum Aerial Parts Using HPLC and FTIR and In Vivo Evaluation of Its Anti-Ulcer Activity Using an Ethanol Induced Acute Gastric Ulcer Model.

This study explored the antiulcer potential of methanol extract and fractions of Heliotropium crispum roots against the ethanol-induced gastric ulcer model in rats. Metabolic profiling of H. crispum aerial parts using Fourier-transform infrared spectroscopy (FTIR) revealed the presence of different metabolites with various functional groups. Meanwhile, High Performance Liquid Chromatography (HPLC) revealed the presence of three main peaks assigned to myricetin, quercetin, and kaempferol. In vivo, antiulcer activity results showed that the disease control group displayed five tiny ulcers less than 2 mm in diameter in addition to two hemorrhagic streaks. However, in the standard control group, only one small ulcer was visible for the total methanol extract. Gastric tissues and contents were evaluated to determine many parameters such as ulcer score, ulcer index, percentage inhibition of ulcer, gastric pH, gastric juice volume, and acidity. Results were endorsed by histopathological evaluation; gastric pH and mucus content were significantly increased, but gastric juice volume was significantly decreased. All fractions showed a significant decrease in ulcer index and % inhibition except the n-hexane fraction, whose results were insignificant compared to the disease control group. Thus, it was concluded that H. crispum shows an antiulcer effect by decreasing gastric juice volume and acidity, whereas gastric pH and mucus contents were increased that is attributed to the synergistic action of its detected polyphenolic compounds.

Brucella epidydimo-orchitis successfully treated with dual oral drug regimen: A case report with differential diagnoses of malignancy and tuberculosis.

Brucellosis is a zoonotic disease caused by Brucella spp. When complicated, Brucella may affect any organ system, including the genitourinary system in the form of epidydimo-orchitis. Brucella orchitis is the second most common form of complicated brucellosis. The present case is for an adolescent who is otherwise healthy but presented with right testicular pain. Ultrasound imaging showed heterogeneous enlarged right testis with large heterogeneous mass and central necrosis. α-fetoprotein was normal and ß-human choriogonadotropin was negative. Malignancy and tuberculosis were excluded based on histopathology and microbiology of the tissue biopsy, respectively. The history of raw dairy consumption and positive serology for B. melitensis and B. abortus established the diagnosis of Brucella epidydimo-orchitis. Treatment was successful with doxycycline and rifampin for four weeks. In pediatrics, it is important to rule out malignancy and make every attempt to avoid orchidectomy by making necessary investigations and involving infectious diseases consultation.

Antimicrobial Pharmacotherapy Management of Urinary Tract Infections in Pediatric Patients.

Objective: To discuss the risk factors, microbial resistance rates, and pharmacotherapy, including antimicrobial choices and medication dosage regimens, for urinary tract infections (UTIs) in pediatric patients. Data Sources: A MEDLINE literature search (1985 to December 2017) was performed using the following keywords and associated medical subject headings: urinary tract infection, antimicrobial, treatment, and children. Study Selection and Data Extraction: Search was conducted to identify clinical trials, systematic reviews, and guidelines. Search was filtered to include studies with age range between birth and 18 years and published in English. Additional references were identified from selected review articles. Data Synthesis: In total, 27 studies investigating microbial resistance, 31 studies assessing antimicrobial efficacy, 34 studies describing prophylaxis, and 6 systematic reviews were included. The resistance patterns differed across age groups and affected the choice of empirical therapy. If pyelonephritis is suspected, empiric antimicrobials should have high urinary and sufficient parenchymal concentrations. Nitrofurantoin has low microbial resistance rates and can generally be used empirically for treating uncomplicated cystitis in children >1 month of age. Trimethoprim-sulfamethoxazole resistance has increased and should be avoided unless local susceptibility data are available. Certain patients with recurrent UTIs or renal abnormalities may require antimicrobial prophylaxis, which may be associated with adverse effects, such as intolerability or an increased risk of microbial resistance. Conclusion: The resistance pattern of uropathogens should be considered prior to initiating therapy. Controlled trials with large samples are needed to compare the treatment duration of various antimicrobial regimens and the specific role of prophylactic antimicrobials.

Evaluation of the antiproliferative and cytotoxic activities of marine invertebrates-derived fungi.

The present study focuses on the evaluation of the cytotoxicity and antiproliferative activities of the organic extracts of 70 fungal strains associated with twelve Red Sea marine invertebrates. The fungal strains were obtained 10 sponges, one tunicate and one soft coral. Three different media including Sabouraud dextrose agar, malt extract agar and Czapek-Dox agar were used for the purification of the fungal isolates. The purified fungal isolates were cultured in their corresponding media (Sabouraud dextrose broth, Malt extract broth and Czapek-Dox broth) on shaker for 14 days at 26° C. After that, the cultures were lyophilized and the dried cultures were extracted with methanol. The methanolic extracts of these cultures were evaluated for their in vitro cytotoxicity and antiproliferative activities against three human cancer cell lines including breast adenocarcinoma (MCF-7), liver hepatocellular carcinoma (HepG2) and colorectal carcinoma (HCT-116). Nine extracts displayed potent and selective activity against MCF-7 with IC50 4.96-8.28µ g/mL without any significant effect on the other two cell lines. In addition, six extracts showed strong and selective activity against MCF-7 with IC50 11.37-15.53µ g/mL. On the other hand, most of the fungal extracts were inactive or weakly active against HepG2 and HCT-116.