Therapeutic potential of ramipril, losartan, and spironolactone against sepsis-associated liver tissue injury induced by cecal ligation and puncture in rats.

OBJECTIVE: Sepsis-associated liver injury is responsible for the high morbidity and mortality rates seen with septic shock. Activation of the renin-angiotensin-aldosterone system (RAAS) is an essential counteractive mechanism during the hypotensive phase of sepsis; however, excessive activation is associated with exaggerated pro-oxidant and inflammatory response, which aggravates organ damage. This study aimed to evaluate the effect of RAAS inhibition on sepsis-induced liver damage. MATERIALS AND METHODS: The cecal ligation and puncture (CLP) model was employed as a model of sepsis. Rats were divided into five groups: sham-operated, vehicle-treated septic rats, septic rats treated with ramipril in a dose of 10 mg/kg, septic rats treated with losartan in a dose of 20 mg/kg, and finally septic rats treated with spironolactone in a dose of 25 mg/kg. Rats received the treatment one hour after induction. Twenty-four hours later, rats were euthanized, and serum samples and liver tissue were collected to evaluate liver function and hepatic oxidative, anti-oxidative, inflammatory, and apoptotic markers. The microscopic integrity of the hepatic tissue was also assessed. RESULTS: The results of our study showed that all the treatments used ameliorated sepsis-induced liver injury. This was reflected by improved liver function parameters and histopathological appearance of liver tissue. Treatment with ramipril, losartan, or spironolactone reduced tissue malondialdehyde (MDA), nitric oxide, activated caspase-3, and TNF-α. Moreover, these drugs increased hepatic reduced-glutathione (GSH) levels, superoxide dismutase (SOD) activity, and proliferating cell nuclear antigen (PCNA) expression. CONCLUSIONS: Administration of ramipril, losartan, or spironolactone after CLP produced a hepatoprotective effect in rats, possibly by reducing oxidative stress, inflammation, and apoptosis.

Design, synthesis, molecular docking and biological evaluation of 1,3,5-trisubstituted-1H-pyrazole derivatives as anticancer agents with cell cycle arrest, ERK and RIPK3- kinase activities.

The need for new ERK and RIPK3 kinase modulators arises from their central roles in cellular processes, especially in diseases like cancer. This research focused on a ligand-based strategy, incorporating previously documented 1,3,5-trisubstituted-1H-pyrazole derivatives, to craft innovative inhibitors specifically targeting ERK and RIPK3 kinases. Compounds 6, 7, 10a, 10c, and 10d exhibited significant cytotoxicity against PC-3 and MCF-7 cancer cell lines, with IC50 values ranging from 21.9 to 28.6 µM and 3.90-35.5 µM, respectively values surpassing those of the reference compound Doxorubicin. Additionally, cell cycle analysis revealed intriguing results, particularly with 10d inducing cell cycle arrest at the S phase in treated PC-3 cells, indicating potential DNA replication phase inhibition. Moreover, compounds 6, 10a, and 10d exhibited promising results in the in vitro kinase assay supported by molecular docking studies. The core scaffold of these compounds established interactions with vital amino acids within the active pockets of ERK and RIPK3 kinases, thereby securely anchoring them in place. These findings underscore the development of promising modulators for ERK and RIPK3 kinases, suggesting their potential for future contributions to cancer treatments.

Sign language recognition using the fusion of image and hand landmarks through multi-headed convolutional neural network.

Sign Language Recognition is a breakthrough for communication among deaf-mute society and has been a critical research topic for years. Although some of the previous studies have successfully recognized sign language, it requires many costly instruments including sensors, devices, and high-end processing power. However, such drawbacks can be easily overcome by employing artificial intelligence-based techniques. Since, in this modern era of advanced mobile technology, using a camera to take video or images is much easier, this study demonstrates a cost-effective technique to detect American Sign Language (ASL) using an image dataset. Here, "Finger Spelling, A" dataset has been used, with 24 letters (except j and z as they contain motion). The main reason for using this dataset is that these images have a complex background with different environments and scene colors. Two layers of image processing have been used: in the first layer, images are processed as a whole for training, and in the second layer, the hand landmarks are extracted. A multi-headed convolutional neural network (CNN) model has been proposed and tested with 30% of the dataset to train these two layers. To avoid the overfitting problem, data augmentation and dynamic learning rate reduction have been used. With the proposed model, 98.981% test accuracy has been achieved. It is expected that this study may help to develop an efficient human-machine communication system for a deaf-mute society.

Reduction of Radar Cross Section by Adopting Symmetrical Coding Metamaterial Design for Terahertz Frequency Applications.

This work focused on the novel and compact 1-bit symmetrical coding-based metamaterial for radar cross section reduction in terahertz frequencies. A couple of coding particles were constructed to impersonate the elements '0' and '1', which have phase differences of 180°. All the analytical simulations were performed by adopting Computer Simulation Technology Microwave Studio 2019 software. Moreover, the transmission coefficient of the element '1' was examined as well by adopting similar software and validated by a high-frequency structure simulator. Meanwhile, the frequency range from 0 to 3 THz was set in this work. The phase response properties of each element were examined before constructing various coding metamaterial designs in smaller and bigger lattices. The proposed unit cells exhibit phase responses at 0.84 THz and 1.54 THz, respectively. Meanwhile, the analysis of various coding sequences was carried out and they manifest interesting monostatic and bistatic radar cross section (RCS) reduction performances. The Coding Sequence 2 manifests the best bistatic RCS reduction values in smaller lattices, which reduced from -69.8 dBm2 to -65.5 dBm2 at 1.54 THz. On the other hand, the monostatic RCS values for all lattices have an inclined line until they reach a frequency of 1.0 THz from more than -60 dBm2. However, from the 1.0 THz to 3.0 THz frequency range the RCS values have moderate discrepancies among the horizontal line for each lattice. Furthermore, two parametric studies were performed to examine the RCS reduction behaviour, for instance, multi-layer structures and as well tilt positioning of the proposed coding metamaterial. Overall it indicates that the integration of coding-based metamaterial successfully reduced the RCS values.

Vitamin D ameliorates diethylnitrosamine-induced liver preneoplasia: A pivotal role of CYP3A4/CYP2E1 via DPP-4 enzyme inhibition.

Growing evidence has indicated that vitamin D (Vit D) regulates cell proliferation and differentiation in cancer cells. Accordingly, the present study was conducted to investigate the possible beneficial effects of Vit D on diethylnitrosamine (DEN)-induced liver preneoplasia. The effect of Vit D on HepG2 cells was investigated using MTT assay. Additionally, liver preneoplasia was induced in Swiss male albino mice by giving overnight fasted animals 5 consecutive doses of DEN (75 mg/kg/week). Oral treatment with Vit D (200 IU/kg/day) was initiated either 2 weeks before DEN (first protocol) or 1 week after the first dose of DEN injection (second protocol). At the end of the experiment, tissue levels of GGT, DPP-4, TNF-α, IL-6, CYP2E1, and CYP3A4 were also estimated. Moreover, the histopathological study of liver tissue and immunohistochemical detection of GST-P, PCNA, and NF-κB were performed. Vit D exerted a significant cytotoxic effect on HepG2 cells via significantly increasing BAX, p53, and BAX/Bcl2 ratio, and significantly decreasing Bcl2 mRNA expression. In both in vivo protocols, Vit D was capable of normalizing relative liver weight, PCNA, altered hepatocellular foci, and ductular proliferation. Moreover, Vit D significantly reduced the DEN-induced elevation of AST, ALT, ALP, GGT, DDP-4, TNF-α, IL-6, CYP2E1, liver DNA damage, GST-P, NF-κB, nuclear hyperchromasia/pleomorphism, cholestasis, and inflammatory cell aggregates, but significantly increased CYP3A4 content. In conculsion, current results reflect the potential impact of Vit D in the management of early stages of liver cancer.

Co-Delivery System of Curcumin and Colchicine Using Functionalized Mesoporous Silica Nanoparticles Promotes Anticancer and Apoptosis Effects.

Purpose: Many natural agents have a high anticancer potential, and their combination may be advantageous for improved anticancer effects. Such agents, however, often are not water soluble and do not efficiently target cancer cells, and the kinetics of their action is poorly controlled. One way to overcome these barriers is to combine natural agents with nanoparticles. Our aim in the current study was to fabricate an anticancer nanoformulation for co-delivery of two natural agents, curcumin (CR) and colchicine (CL), with a core-shell structure. Using cancer cell lines, we compared the anticancer efficacy between the combination and a nanoformulation with CL alone. Methods: For the single-drug nanoformulation, we used phosphonate groups to functionalize mesoporous silica nanoparticles (MSNs) and loaded the MSNs with CL. Additional loading of this nanoformulation with CR achieved the co-delivery format. To create the structure with a core shell, we selected a chitosan−cellulose mixture conjugated with targeting ligands of folic acid for the coating. For evaluating anticancer and apoptosis effects, we assessed changes in important genes and proteins in apoptosis (p53, caspase-3, Bax, Bcl-2) in several cell lines (MCF-7, breast adenocarcinoma; HCT-116, colon carcinoma; HOS, human osteosarcoma; and A-549, non−small cell lung cancer). Results: Nanoformulations were successfully synthesized and contained 10.9 wt.% for the CL single-delivery version and 18.1 wt.% for the CL+CR co-delivery nanoformulation. Anticancer effects depended on treatment, cell line, and concentration. Co-delivery nanoformulations exerted anticancer effects that were significantly superior to those of single delivery or free CL or CR. Anticancer effects by cell line were in the order of HCT-116 > A549 > HOS > MCF-7. The lowest IC50 value was obtained for the nanoformulation consisting of CL and CR coated with a polymeric shell conjugated with FA (equivalent to 4.1 ± 0.05 µg/mL). With dual delivery compared with the free agents, we detected strongly increased p53, caspase-3, and Bax expression, but inhibition of Bcl-2, suggesting promotion of apoptosis. Conclusions: Our findings, although preliminary, indicate that the proposed dual delivery nanoformulation consisting of nanocore: MSNs loaded with CL and CR and coated with a shell of chitosan−cellulose conjugated folic acid exerted strong anticancer and apoptotic effects with potent antitumor activity against HCT-116 colon cells. The effect bested CL alone. Evaluating and confirming the efficacy of co-delivery nanoformulations will require in vivo studies.

Development of spiro-3-indolin-2-one containing compounds of antiproliferative and anti-SARS-CoV-2 properties.

A series of 1″-(alkylsulfonyl)-dispiro[indoline-3,2'-pyrrolidine-3',3″-piperidine]-2,4″-diones 6a‒o has been synthesized through regioselective multi-component azomethine dipolar cycloaddition reaction of 1-(alkylsulfonyl)-3,5-bis(ylidene)-piperidin-4-ones 3a‒h. X-ray diffraction studies (6b‒d,h) confirmed the structures. The majority of the synthesized analogs reveal promising antiproliferation properties against a variety of human cancer cell lines (MCF7, HCT116, A431 and PaCa2) with good selectivity index towards normal cell (RPE1). Some of the synthesized agents exhibit potent inhibitory properties against the tested cell lines with higher efficacies than the standard references (sunitinib and 5-fluorouracil). Compound 6m is the most potent. Multi-targeted inhibitory properties against EGFR and VEGFR-2 have been observed for the synthesized agents. Flow cytometry supports the antiproliferation properties and shows the tested agents as apoptosis and necrosis forming. Vero cell viral infection model demonstrates the anti-SARS-CoV-2 properties of the synthesized agents. Compound 6f is the most promising (about 3.3 and 4.8 times the potency of the standard references, chloroquine and hydroxychloroquine). QSAR models explain and support the observed biological properties.

Development of Isatin-Based Schiff Bases Targeting VEGFR-2 Inhibition: Synthesis, Characterization, Antiproliferative Properties, and QSAR Studies.

Three sets of isatin-based Schiff bases were synthesized utilizing the molecular hybridization approach. Some of the synthesized Schiff bases show significant to moderate antiproliferative properties against MCF7 (breast), HCT116 (colon), and PaCa2 (pancreatic) cancer cell lines with potency compared to reference drugs 5-fluorouracil (5-FU) and Sunitinib. Among all, compound 17 f (3-((1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)imino)-1-((1-(2-methoxyphenyl)-1H-1,2,3-triazol-4-yl)methyl)-5-methylindolin-2-one) exhibits promising antiproliferative properties against the MCF7 cancer cell line with 2.1-fold more potency than Sunitinib. However, among all the synthesized compounds, three (5-methylisatin derivatives) were the most effective against HCT116 in comparison to 5-FU. Compound 17 f exhibited the highest anti-angiogenic effect on the vasculature as it significantly reduced BV from 43 mm to 2 mm in comparison to 5.7 mm for Sunitinib and flow cytometry supports the arrest of the cell cycle at G1/S phases. In addition, compound 17 f also showed high VEGFR-2 inhibition properties against breast cancer cell lines. Robust 2D-QSAR studies supported the biological data.

Use of a Quality Scorecard to Enhance Quality and Safety in Community Hospital Newborn Nurseries.

OBJECTIVE: To implement a quality improvement (QI) scorecard as a tool for enhancing quality and safety efforts in level 1 and 2 community hospital nurseries affiliated with Nationwide Children's Hospital. STUDY DESIGN: A QI scorecard was developed for data collection, analytics, and reporting of neonatal quality metrics and cross-sector collaboration. Newborn characteristics were included for risk stratification, as were clinical and process measures associated with neonatal morbidity and mortality. Quality and safety activities took place in community hospital newborn nurseries in Ohio, and education was provided in both online and in-person collaborations, followed by local team sessions at partner institutions. Baseline (first 12 months) and postbaseline comparisons of clinical and process measures were analyzed by logistic regression, adjusting for potential confounders. RESULTS: In logistic regression models, at least 1 center documented improvements in each of the 4 process measures, and 3 of the 4 centers documented improvements in compliance with glucose checks obtained within 90 minutes of birth among at-risk infants. CONCLUSION: Collaborative QI projects led to improvements in perinatal metrics associated with important outcomes. Formation of a center-driven QI scorecard is feasible and provides community hospitals with a framework for collecting, analyzing, and reporting neonatal QI metrics.

Synthetic Analogs of Marine Alkaloid Aplysinopsin Suppress Anti-Apoptotic Protein BCL2 in Prostate Cancer.

Aplysinopsins are a class of indole alkaloids that possess various pharmacological activities. Although their action has been studied in regard to many diseases, their effect on prostate cancer has not yet been examined. Therefore, we synthesized a new series of aplysinopsin analogs and investigated their cytotoxic activity against prostate cancer. Five analogs showed high antitumor activity via suppressing the expression of the anti-apoptotic gene Bcl2, simulationously increasing the expression of the pro-apoptotic genes p53, Bax and Caspase 3. The inhibition of BCL2 led to the activation of BAX, which in turn activated Caspase 3, leading to apoptosis. This dual mechanism of action via apoptosis and cell cycle arrest induction is responsible for aplysinopsin analogs antitumor activity. Hence, our newly synthesized analogs are highly promising candidates for further preclinical studies against prostate cancer.

3-Alkenyl-2-oxindoles: Synthesis, antiproliferative and antiviral properties against SARS-CoV-2.

Sets of 3-alkenyl-2-oxindoles (6,10,13) were synthesized in a facile synthetic pathway through acid dehydration (EtOH/HCl) of the corresponding 3-hydroxy-2-oxoindolines (5,9,12). Single crystal (10a,c) and powder (12a,26f) X-ray studies supported the structures. Compounds 6c and 10b are the most effective agents synthesized (about 3.4, 3.3 folds, respectively) against PaCa2 (pancreatic) cancer cell line relative to the standard reference used (Sunitinib). Additionally, compound 10b reveals antiproliferative properties against MCF7 (breast) cancer cell with IC50 close to that of Sunitinib. CAM testing reveals that compounds 6 and 10 demonstrated qualitative and quantitative decreases in blood vessel count and diameter with efficacy comparable to that of Sunitinib, supporting their anti-angiogenic properties. Kinase inhibitory properties support their multi-targeted inhibitory activities against VEGFR-2 and c-kit in similar behavior to that of Sunitinib. Cell cycle analysis studies utilizing MCF7 exhibit that compound 6b arrests the cell cycle at G1/S phase while, 10b reveals accumulation of the tested cell at S phase. Compounds 6a and 10b reveal potent antiviral properties against SARS-CoV-2 with high selectivity index relative to the standards (hydroxychloroquine, chloroquine). Safe profile of the potent synthesized agents, against normal cells (VERO-E6, RPE1), support the possible development of better hits based on the attained observations.

A novel optimal multi-pattern matching method with wildcards for DNA sequence.

BACKGROUND: DNA sequence alignment is one of the most fundamental and important operation to identify which gene family may contain this sequence, pattern matching for DNA sequence has been a fundamental issue in biomedical engineering, biotechnology and health informatics. OBJECTIVE: To solve this problem, this study proposes an optimal multi pattern matching with wildcards for DNA sequence. METHODS: This proposed method packs the patterns and a sliding window of texts, and the window slides along the given packed text, matching against stored packed patterns. RESULTS: Three data sets are used to test the performance of the proposed algorithm, and the algorithm was seen to be more efficient than the competitors because its operation is close to machine language. CONCLUSIONS: Theoretical analysis and experimental results both demonstrate that the proposed method outperforms the state-of-the-art methods and is especially effective for the DNA sequence.

Neuroprotective activity of Ulmus pumila L. in Alzheimer's disease in rats; role of neurotrophic factors.

Alzheimer's disease (AD) is one of the most prevalent neurodegenerative disorders which affects the hippocampus and cortical neurons leading to impairment of cognitive ability. Treatment of AD depends mainly on acetylcholinesterase inhibitors, however, a novel therapeutic approach is introduced based on the maintenance of neuronal viability and functionality exerted through neurotrophic factors. In the current study, Ulmus pumila L. leaves alcoholic extract was investigated for its neuroprotective activity in AlCl3-induced AD in rats. Rats were orally treated with AlCl3 (17 mg/kg) for 4 weeks followed by U. pumila extract (150 mg/kg b.wt.) for another 6 weeks. Treatment of neuro-intoxicated rats with U. pumila extract resulted in a significant regulation in neurotrophic factors; brain derived neurotrophic factor and transforming growth factor-ß and pro-inflammatory cytokine; TNF. It also induced an elevation in serum levels of monoamine neurotransmitters; norepinephrine, dopamine and serotonin and a decline in brain acetlycholinesterase activity. U. pumila extract also showed potent antioxidant activity as indicated by the declined malondialdehyde and elevated reduced glutathione, catalase and super oxide dismutase levels in AD rats' brains. Histological improvement was detected in the cerebral cortex, the hippocampus and striatum of the treated rats. The phytochemical analysis of U. pumila extract revealed high contents of flavonoids and phenolics and the major compounds were isolated and chemically characterized. Additionally, U. pumila extract and the isolated compounds exerted a prominent activity in in-vitro acetylcholinesterase inhibition assay with kaempferol-3-O-ß-glucoside being the most potent compound showing IC50 of 29.03 ± 0.0155 µM. A molecular docking study indicated high affinity of kaempferol-3-O-ß-robinobioside on acetylcholine esterase binding site with estimated binding free energy of -8.26 kcal/mol.

Dual-function membranes based on alginate/methyl cellulose composite for control drug release and proliferation enhancement of fibroblast cells.

Membranes based on natural polymers are highly promising therapies for skin damaged sites as they can mimic its biological microstructure to support the fibroblasts cells survival and proliferation. In addition, these membranes could be loaded with active molecules that help in skin regeneration and eliminate the potential bacterial infection. This research aims to formulate novel medicated membranes for controlled release and cytocompatibility elevation of fibroblast cells for engineering of soft tissue. Pre-formulation researches have been conducted for membranes of sodium alginate (Alg)/methyl cellulose (MC) that used loaded with undoped, Bi doped and Bi, Cu co-doped SrTiO3 using solvent casting technique. In addition, another group of these membranes were loaded with DOXycycline antibiotic (DOX) as model drug as well as for eliminating the potential bacterial infections. The prepared membranes were evaluated by XRD, SEM-EDX, FTIR, Zetasizer, and swelling behaviour was also tested. Profiles of the released drug were determined using phosphate-buffered saline (PBS) (pH 7.4) at 37 °C for 30 days. The investigation of the cytocompatibility and proliferation of fibroblast cells with the prepared membranes were conducted. The XRD, FTIR and SEM data recognised the possible interaction that takes place among Alg and MC, through presence of hydrogen bonds. Existence of the nano-particles within the membrane polymer matrix enhanced the membrane stability and enhanced the drug release rate (from 20 to 45%). Medication release mechanism elucidated that DOX was released from all the fabricated membranes through the relaxation of polymer matrix that takes place after swelling. The filler type and/or dopant type possess no remarkable influence on the cytotoxicity of the membranes against the investigated cells when compared to their individual influence on the same cells. Cells attachments results have revealed an impressive effect for DOX-loaded membranes on the cells affinity and growth. These membranes are recommended for treatments of skin infections.

Hydrogel bioink based on clickable cellulose derivatives: Synthesis, characterization and in vitro assessment.

Hydrogel is considered as a promising candidate for bioink in terms of biocompatibility, biodegradability, printability and supporting cellular behavior. Recently, carbohydrates derivatives containing alkyne and azide pendant functional groups have been used in medical applications due to their improved chemical, biological, functional properties, and their amenability for chemical reactions under mild conditions. In this work, a novel bioink was developed based on azide and alkyne of cellulose derivatives. Azido-hydroxyethyl cellulose (D.Sazido = 0.04) was synthesized via open-ring reaction of 1-azido-2,3-epoxypropane and characterized spectroscopically and titrimetrically. Alkyne derivative, propargyl carboxymethyl cellulose (D.Spropargyl = 1.72) was synthesized through coupling reaction with propargylamine in the presence of EDC and NHS. The click-gel scaffold was obtained by mixing the two novel candidates in the presence of copper (I) catalyst. Extrusion bio-plotting experiment was successfully conducted of the two solutions into coagulant Cu (I)/DMSO solutions and demonstrated the possibility of using the clickable cellulose derivatives as bioink precursors. Chemical and physical properties of the click-gel were demonstrated. The biocompatibility assay of the prepared click-gels showed high level of viability in the human skin fibroblast cells (HFB4) at concentration 100 µg/mL.

Multi-layer dressing made of laminated electrospun nanowebs and cellulose-based adhesive for comprehensive wound care.

In this work, multi-layer wound dressing was made of laminated layers of electrospun fibers supported by adhesive sheet. Graft copolymerization of methyl methacrylate (MMA) and 2-Ethyl-1-hexyl acrylate (EHA) onto carboxymethyl cellulose (CMC) was conducted to obtain an adhesive sheet with 1.52 (N/cm2) loop tack, 1.7 (N/cm) peel strength and 25 s shear strength. Diclofenac sodium, anti-inflammatory drug, was loaded to the adhesive sheet with encapsulation efficiency 73%. The contact layer to wound was made of synthesized anti-bleeding agents, chitosan iodoacetamide (CI) loaded into electrospun polyvinyl alcohol (PVA) fibers. It was fabricated from fiber diameter 300 nm by electrospinning of 5% wt/v of CI (D.S. 18.7%) mixed with 10% wt/v PVA, at 20 kV and 17 cm airgap. The second, pain-relief layer was fabricated by encapsulating up to 50% wt/wt of capsaicin into gelatin nanofibers (197 nm) crosslinked by glyoxal. The third, antimicrobial layer was fabricated from PVA electrospun fibers loaded with 2% wt/wt gentamicin. Biocompatibility test showed insignificant adverse effects of the fabricated layers on fibroblast cells. Animal test on rat showed accelerated wound healing from 21 to 7 days for the multi-layer dressing. Histopathological findings corroborated the intactness of the epidermis layer of the treated samples.

Crude Methanol Extract of Rosin Gum Exhibits Specific Cytotoxicity against Human Breast Cancer Cells via Apoptosis Induction.

BACKGROUND: Rosin (Colophony) is a natural resin derived from species of the pine family Pinaceae. It has wide industrial applications including printing inks, photocopying paper, adhesives and varnishes, soap and soda. Rosin and its derivatives are employed as ingredients in various pharmaceutical products such as ointments and plasters. Rosin-based products contain allergens that may exert some occupational health problems such as asthma and contact dermatitis. OBJECTIVE: Our knowledge of the pharmaceutical and medicinal properties of rosin is limited. The current study aims at investigating the cytotoxic potential of Rosin-Derived Crude Methanolic Extract (RD-CME) and elucidation of its mode-of-action against breast cancer cells (MCF-7 and MDA-MB231). METHODS: Crude methanol extract was prepared from rosin. Its phenolic contents were analyzed by Reversed- Phase High-Performance Liquid Chromatography (RP-HPLC). Antioxidant activity was evaluated by DPPH radical-scavenging assay. Antiproliferation activity against MCF-7 and MDA-MB231 cancerous cells was investigated by MTT assay; its potency compared with doxorubicin as positive control and specificity were assessed compared to two non-cancerous cell lines (BJ-1 and MCF-12F). Selected apoptosis protein markers were assayed by western blotting. Cell cycle analysis was performed by Annexin V-FITC/PI FACS assay. RESULTS: RD-CME exhibited significant and selective cytotoxicity against the two tested breast cancer cells (MCF-7 and MDA-MB231) compared to normal cells as revealed by MTT assay. ELISA and western blotting indicated that the observed antiproliferative activity of RD-CME is mediated via the engagement of an intrinsic apoptosis signaling pathway, as judged by enhanced expression of key pro-apoptotic protein markers (p53, Bax and Casp 3) relative to vehicle solvent-treated MCF-7 control cells. CONCLUSION: To our knowledge, this is the first report to investigate the medicinal anticancer and antioxidant potential of crude methanolic extract derived from colophony rosin. We provided evidence that RD-CME exhibits strong antioxidant and anticancer effects. The observed cytotoxic activity against MCF-7 is proposed to take place via G2/M cell cycle arrest and apoptosis. Colophony resin has a great potential to join the arsenal of plantderived natural anticancer drugs. Further thorough investigation of the potential cytotoxicity of RD-CME against various cancerous cell lines is required to assess the spectrum and potency of its novel activity.

Synthesis and Bioactivity Assessment of Novel Spiro Pyrazole-Oxindole Congeners Exhibiting Potent and Selective in vitro Anticancer Effects.

The present work aims to design and synthesize novel series of spiro pyrazole-3,3'-oxindoles analogues and investigate their bioactivity as antioxidant and antimicrobial agents, as well as antiproliferative potency against selected human cancerous cell lines (i.e., breast, MCF-7; colon, HCT-116 and liver, HepG-2) relative to healthy noncancerous control skin fibroblast cells (BJ-1). The mechanism of their cytotoxic activity has been also examined by immunoassaying the levels of key anti- and proapoptotic protein markers. The analytical and spectral data of the all synthesized target congeners were compatible with their structures. Synthesized compounds showed diverse moderate to powerful antimicrobial and antioxidant activities. Results of MTT assay revealed that seven synthesized compounds (i.e., 11a, 11b, 12a, 12b, 13b, 13c and 13h) particularly exhibited significant cytotoxicity against the three cancerous cell lines under investigation. Ranges of IC50 values obtained were 5.7-21.3 and 5.8-37.4 µg/mL against HCT-116 and MCF-7, respectively; which is 3.8 and 6.5-fold (based on the least IC50 values) more significant relative to the reference chemotherapeutic drug doxorubicin. In HepG-2 cells, the analogue 13h the highest cytotoxicity with IC50 value of 19.2µg/mL relative to doxorubicin (IC50 = 21.6µg/mL). The observed cytotoxicity was specific to cancerous cells, as evidenced by the minimal toxicity in the noncancerous control skin-fibroblast cells. ELISA results indicated that the observed antiproliferative effect against examined cancer cell lines is mediated via engaging the activation of apoptosis as illustrated by the significant increase in proapoptotic protein markers (p53, bax and caspase-3) and reduction in the antiapoptotic marker bcl-2. Taken together, results of the present study emphasize the potential of spiro pyrazole-oxindole analogues as valuable candidate anticancer agents against human cancer cells.

Soft hydrogel based on modified chitosan containing P. granatum peel extract and its nano-forms: Multiparticulate study on chronic wounds treatment.

Punica granatum peel (PGP) is widely used in traditional medicinal purposes for chronic wounds owing to containing natural phenolics active components. In current study, active wound dressing hydrogel for chronic wound healing was prepared based on P. granatum peel crude extract (PGPC), ethyl acetate fraction (PGPEA) and their silver nanoforms (Ag-NPs). Methacrylated chitosan was synthesized as precursor to hydrogel and crosslinked by divinyl sulfone (DVS) in mild condition. Hydrogel was fully characterized by spectral morphological, mechanical and physical analyses. The integration of PGPEA silver nanoforms was formed with particle size of 15-56 nm to show minimum inhibitory concentration (MIC) equal 63 for Staphylococcus aureus and 125 for Pseudomonas aeruginosa. The hydrogel-based wound dressing with/without the active ingredients showed acceptable cytotoxicity against fibroblast human cells for PGPC and PGPEA fraction over the silver nanoforms. Rat as animal model was considered to show the impact of the active wound dressing on diabetic wounds which was proved by histopathological examination. In addition, the significant intensity of immunopositivity signals of the transforming growth factor beta (TGF-ß1) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) in the epidermal cells have revealed the efficiency of Ag NPs-PGPEA-chitosan hydrogel for chronic wound curing.

Biocompatible chitosan-based hydrogel with tunable mechanical and physical properties formed at body temperature.

Chemical crosslinking hydrogels provide irreversible matrices with reliable characteristics for wider medical applications. When hydrogels used for hosting bioactive substances, matrices have to be crosslinked at mild condition with high yield reaction and inactive to the biological molecules. In this work, chitosan was functionalized with active double bonds as a precursor to hydrogel that gels at body temperature. Free-radical crosslinking was conducted in the presence of maleic anhydride (MA) and potassium persulfate (KPS). The chemical structures of hydrogels were confirmed via spectral analysis. Mechanical and gelation characteristics of the hydrogels were tuned by using different molar ratios of MA and KPS. Pores size was controlled according to the crosslinking density in range of 313-866 µm that agrees proportionally with the swelling degree. Young's modulus values were tuned to span from 6 to 31 Pa with opposite relationship with the stress at break that varied from 6 to 17 Pa. Hydrogel release profiles were plotted representing varied releasing rates. Gels were obtained at 37 °C for 2 h using KPS (24-48 mM) and different concentration of MA (0.17, 0.35 and 0.5 M). The tetrazolium dye 3-(4,5-dimethylthiazol-2-yl)-2,5diphenyltetrazolium bromide (MTT), colorimetric, biological assay using skin fibroblast cells showed high biocompatibility of chitosan-based hydrogels.