Enzyme Responsive Vaginal Microbicide Gels Containing Maraviroc and Tenofovir Microspheres Designed for Acid Phosphatase-Triggered Release for Pre-Exposure Prophylaxis of HIV-1: A Comparative Analysis of a Bigel and Thermosensitive Gel

The challenges encountered with conventional microbicide gels has necessitated the quest for alternative options. This study aimed to formulate and evaluate a bigel and thermosensitive gel, designed to combat the challenges of leakage and short-residence time in the vagina. Ionic-gelation technique was used to formulate maraviroc and tenofovir microspheres. The microspheres were incorporated into a thermosensitive gel and bigel, then evaluated. Enzyme degradation assay was used to assess the effect of the acid phosphatase enzyme on the release profile of maraviroc and tenofovir microspheres. HIV efficacy and cytotoxicity of the microspheres were assessed using HIV-1-BaL virus strain and HeLa cell lines, respectively. Maraviroc and tenofovir release kinetics followed zero-order and Higuchi model kinetics. However, under the influence of the enzyme, maraviroc release was governed by first-order model, while tenofovir followed a super case II transport-mechanism. The altered mode of release and drug transport mechanism suggests a triggered release. The assay of the microspheres suspension on the HeLa cells did not show signs of cytotoxicity. The thermosensitive gel and bigel elicited a progressive decline in HIV infectivity, until at concentrations of 1 μg/mL and 0.1 μg/mL, respectively. The candidate vaginal gels have the potential for a triggered release by the acid phosphatase enzyme present in the seminal fluid, thus, serving as a strategic point to prevent HIV transmission.

Combination of cytostatic chemotherapy with cisplatin and photodynamic therapy with Radachlorin reduced resistance of K562 and Hela cell lines

In this work were study combination effect of photodynamic therapy and cisplatin on the proliferation activity of K562 human leukemia cells and Hela cervical carcinoma cells. A decrease in cell viability and an increase the fraction of apoptotic cells for combination treatment compared with single therapy were observed. It has been shown that the G2/M-phase of cell cycle decreases compared with cisplatin treatment alone, which demonstrates an increase anti-proliferative effect. The combination index of the photodynamic therapy with Radachlorin and cisplatin was calculated and indicates a synergistic effect.

Total phenolic and flavonoid contents, cytotoxic, immunomodulatory and anti-inflammatory potential of whole plant of Astragalus creticus (Fabaceae)

Purpose: To determine total phenolic and flavonoid contents, as well as the cytotoxic, immunemodulatoryand anti-inflammatory potentials of the whole plant of Astragalus creticus (Fabaceae).Methods: Folin-Ciocalteu (FCR) method was used for determination of total phenolic and flavonoid contents of the methanol and dichloromethane extracts of Astragalus creticus. The cytotoxic potential of the extracts on 3T3 and HeLa cell lines were evaluated using MTT assay. Brine shrimp larvae mortality was determined by lethality bioassay, while inhibitory effects were determined on mouse fibroblast (3T3)and cervical cancer (HeLa) cell lines. In vitro immunomodulatory and in vivo anti-inflammatory effectswere assessed using reactive oxygen species (ROS) chemiluminescence and formalin-induced rat paw edema assays, respectively.Results: Dichloromethane extract had higher contents of phenolics (TPC = 324.75 ± 2.47 mg GAE/g) and flavonoids (TFC = 95.51 ± 0.82 QE/g) than the methanol extract (TPC = 79.82 ± 1.53 mg GAE/g, TFC = 56.11 ± 0.93 QE/g). The dichloromethane extract exhibited high cytotoxic andimmunomodulatory potentials, with 76.66 % mortality in brine shrimp lethality bioassay and 83.9 % inhibition (IC50 = 18.0 ± 1.1 μg/mL) in chemiluminescence assay. The extract also resulted in 22 and 13 % inhibition of viability of HeLa and 3T3 cells, respectively, while the methanol extract produced 13 % inhibition of both cell lines. The methanol extract produced very significant anti-inflammatory activity,with a maximum of 49 % inhibition of paw edema at a dose of 160 mg/kg (p < 0.01).Conclusion: These results suggest that the dichloromethane and methanol extracts of Astragalus creticus (Fabaceae) exert cytotoxic, immunomodulatory and anti-inflammatory effects. These findings provide scientific validation for the traditional medicinal use of the Astragalus genus.

Identification of Spiro-Fused Pyrrolo[3,4-a]pyrrolizines and Tryptanthrines as Potential Antitumor Agents: Synthesis and In Vitro Evaluation

A series of heterocyclic compounds containing a spiro-fused pyrrolo[3,4-a]pyrrolizine and tryptanthrin framework have been synthesized and studied as potential antitumor agents. Cytotoxicity of products was screened against human erythroleukemia (K562) and human cervical carcinoma (HeLa) cell lines. Among the screened compounds. 4a, 4b and 5a were active against human erythroleukemia (K562) cell line, while 4a and 5a were active against cervical carcinoma (HeLa) cell line. In agreement with the DNA cytometry studies, the tested compounds have achieved significant cell-cycle perturbation with higher accumulation of cells in G2/M phase and induced apoptosis. Using confocal microscopy, we found that with 4a and 5a treatment of HeLa cells, actin filaments disappeared, and granular actin was distributed diffusely in the cytoplasm in 76–91% of cells. We discovered that HeLa cells after treatment with compounds 4a and 5a significantly reduced the number of cells with filopodium-like membrane protrusions (from 63 % in control cells to 29% after treatment) and a decrease in cell motility.

Synthesis and Biological Evaluation of Xanthone Derivatives as Anti-Cancer Agents Targeting Topoisomerase II and DNA

Topoisomerase is one of the most important targets of anticancer drugs. In order to develop effective and low-toxic topoisomerase inhibitors, a series of xanthone derivatives have been designed and synthesized using the principles of skeleton transition. In vitro growth inhibition experiments of human breast cancer(MCF-7), gastric cancer (MGC-803), and cervical cancer(Hela) cell lines were used to evaluate the compound's anti-tumor cell proliferation activity. Most of the compounds showed anti-tumor growth activity, and also showed low toxicity to human normal cells L929. In the enzyme activity inhibition experiment, compounds 7d and 8d showed the best inhibitory activity. The DNA binding studies disclosed that the most potent compounds 7d and 8d can intercalate into DNA, induce apoptosis in MGC-803 cells and arrested at G2/M phase. Molecular docking showed that compounds 7d and 8d could bind with topoisomerase II and DNA through hydrogen bonds and π-stacking interactions.

Enhanced photocatalytic and photodynamic activity of chitosan and garlic loaded CdO–TiO2 hybrid bionanomaterials

Herein, the work addresses the synthesis of biomaterials (chitosan and garlic) loaded CdO–TiO2 hybrid nanocomposites for photocatalytic water treatment and photodynamic cancer therapeutic applications that were reported the first time. CdO–TiO2 (CT) nanocomposites were synthesized and loaded with the biomaterials such as chitosan and garlic by simple sol–gel method. The nanomaterials were characterized and the photodegradation of three model pollutants, Methylene blue (MB), Methyl orange (MO) and Rhodamine B (Rh-B) was opted to investigate the efficiency of the synthesized photocatalyst under the solar light. From the results, the garlic-loaded CdO–TiO2 (AS-CT) hybrid nanocomposites exhibit a superior photocatalytic activity than the chitosan-loaded CdO–TiO2 (CS-CT) and CdO–TiO2 (CT) nanocomposites under the irradiation of solar light. Additionally, the cell viability of the synthesized nanocomposites was carried out in HeLa cell lines under different concentrations, light doses and incubation periods using an LED light source. Compared to the CS-CT and CT nanocomposites, an efficient photodynamic activity was achieved in the case of AS-CT hybrid nanocomposites. Actually, the end-use properties required for both processes in AS-CT nanocomposites appear similar due to the presence of organo sulphurus compounds.

Development of pH-Sensitive Chitosan-g-poly(acrylamide-co-acrylic acid) Hydrogel for Controlled Drug Delivery of Tenofovir Disoproxil Fumarate

The present study aimed to develop a pH-sensitive chitosan-based hydrogel for controlled delivery of an anti-hepatitis B drug, tenofovir disoproxil fumarate (TDF). Free radical polymerization was utilized to graft acrylamide and acrylic acid using N,N-methylene bisacrylamide as the crosslinker. Physicochemical characterization confirmed the synthesis of thermally stable chitosan-g-poly(acrylamide-co-acrylic acid) hydrogels with well-defined pores within a fibrous surface. The prepared hydrogels exhibited pH and ionic strength sensitivity, with the swelling significantly lower under acidic and strong ionic strength conditions but higher in neutral and basic solutions. In addition, cytotoxicity studies on HeLa cell lines proved the cytocompatibility of the drug delivery material and its readiness for physiological applications. The encapsulation of TDF in the hydrogels was optimized and an encapsulation efficiency and a drug loading percentage of 96% and 10% were achieved, respectively. More interestingly, in vitro release studies demonstrated a pH-dependent release of TDF from hydrogels. The release at pH 7.4 was found to be up to five times higher than at pH 1.2 within 96 h. This further suggested that the newly developed hydrogel-loaded TDF could be proposed as a smart delivery system for oral delivery of anti-hepatitis B drugs.

The Phytochemistry and Anticarcinogenic Activity of Noni Juice

Noni juice, obtained from the fruit of the noni tree (Morinda citrifolia L.), is a popular commodity in the market, particularly in the South Pacific. It is widely used by consumers for the prevention of several lifestyle diseases. Although there is increasing interest in the potential therapeutic use of noni plants, there are no comparative studies on the various commercialized noni fruit juices available to decipher their phytochemical composition and properties against carcinomas. The present study, therefore, aims to fill this research gap and investigate the juice’s anecdotal use as complementary alternative medicine to manage cancer. Five commercial brands of noni juice were included in this study, namely, Tahitian Organic Noni (TON), Cook Island Noni (CIN), Dynamic Health Noni (DHN), Fijian Noni (FN), and Life Health Noni (LHN). The juice samples were vacuum-filtered and freeze-dried to obtain crystal products for methanolic extraction. Total phenolic content (TPC) and antioxidant capacity (FRAP—ferric reducing antioxidant power) were determined on the methanolic extracts. The cytotoxicity of the noni juices was also tested on human cervical adenocarcinoma (HeLa cell lines) by dissolving 2 mg of the crystal product in sterile deionized water and diluting to 1000 μg/mL in the media culture. The final concentration of the extracts in the well plate was 500 μg/mL. The MTS cell viability assay was performed after the cells were incubated with the extracts for 48 h at 37 °C with 5% CO2. The DHN and FN extracts were found to have the highest TPC of 5393 ± 298 and 5060 ± 23 mg gallic acid equivalent /100 g dry weight (DW), respectively, whereas the highest antioxidant capacity was seen in the CIN extract (6389 ± 49 mg Trolox equivalent/100 g DW). The CIN extract also showed the most promising effect with only 63 ± 1% cell viability, whilst the other extracts showed lower cytotoxic effects (76–90% cell viability) on the HeLa cell line. It is possible that greater cytotoxicity could be observed over long exposure times. The noni juice samples contain high levels of TP and antioxidant capacity and appear to show some level of cytotoxic activity, which were statistically different from the negative control. Further work involving more extensive in vitro and in vivo studies are necessary to elucidate its anticarcinogenic activities.

“Beneficial Role of Skim Milk Against Drug Resistant Escherichia Coli Associated With Pediatric Diarrhoea"

Background: Antibiotic-resistance in E. coli is a global issue affecting humans especially the pediatric population. Antibiotic-resistant E. coli is a pathogen frequently pediatric population as well as healthy adults. Methods: This study aimed to examine the antibiotic resistance of E. coli causing pediatric diarrhea and its drug-resistant rates, its adhering abilities to cell line in vitro, and inhibition efficiency of a few selected chemical compounds. Clinical strains were isolated from both the healthy and infected pediatric population of Mizoram. Results: Adhesion is a significant pathogenic process during bacterial infections, which has been employed for pathotyping of DEC by comparing adhesion efficiency in both normal (CHO-k1) and cancer (HeLa) cell lines. E. coli adherent pathotypes were identified by both PCR assay and in-vitro cell adhesion assays; the study also evaluated the adhesion inhibition ability of human skimmed milk, gentamicin, and cephalexin in-vitro. Of all isolates, 20.05% of adherent DEC (EPEC, DAEC, and EIEC) and 11.39 % of non-adherent DEC (STEC and ETEC) were found to be associated with pediatric diarrhoea in Mizoram. Human skimmed milk has a high potential adhesion inhibition against EAEC (50.25/90.90 µg/mL), EPEC (53.42/259.70 µg/mL), and EIEC (59.13/30.30 µg/mL) in both cell lines in comparison with gentamicin and cephalexin. Conclusion: This study concludes that as a dietary supplement- human skimmed milk has high potential to prevent adhesion of DEC pathotypes in cells in-vitro thus in in-vivo.

Exploiting the Potential of Bioactive Molecules Extracted by Ultrasounds from Avocado Peels—Food and Nutraceutical Applications

Natural bioactive compounds from food waste have fomented interest in food and pharmaceutical industries for the past decade. In this work, it purposed the recovery of bioactive avocado peel extract using an environmentally friendly technique: the ultrasound assisted extraction. The response surface methodology was applied in order to optimize the conditions of the extraction, ethanol-water mixtures and time. The optimized extracts (ethanol 38.46%, 44.06 min, and 50 °C) were chemically characterized by HPLC-ESI-MS and FTIR. Its antioxidant ability, as well as, its effect on cell metabolic activity of normal (L929) and cancer (Caco-2, A549 and HeLa) cell lines were assessed. Aqueous ethanol extracts presented a high content in bioactive compounds with high antioxidant potential. The most representative class of the phenolic compounds found in the avocado peel extract were phenolic acids, such as hydroxybenzoic and hydroxycinnamic acids. Another important chemical group detected were the flavonoids, such as flavanols, flavanonols, flavones, flavanones and chalcone, phenylethanoids and lignans. In terms of its influence on the metabolic activity of normal and cancer cell lines, the extract does not significantly affect normal cells. On the other hand, it can negatively affect cancer cells, particularly HeLa cells. These results clearly demonstrated that ultrasound is a sustainable extraction technique, resulting in extracts with low toxicity in normal cells and with potential application in food, pharmaceutical or nutraceutical sectors.