Investigations of new N1-substituted pyrazoles as anti-inflammatory and analgesic agents having COX inhibitory activity.

Background: The search is ongoing for ideal anti-inflammatory and analgesic agents with promising potency and reasonable selectivity. Methods: New N1-substituted pyrazoles with or without an acetamide linkage were synthesized and evaluated for their anti-inflammatory and analgesic activities. COX inhibitory testing, molecular docking, molecular dynamics simulation and antiproliferative activity assessments were performed. Results: All compounds exhibited anti-inflammatory activity up to 90.40% inhibition. They also exhibited good analgesic activity with up to 100% protection. N1-benzensulfonamides 3d, 6c and 6h were preferentially selective agents toward COX-2. Compound 3d showed good cytotoxicity against MCF-7 and HTC116 cancer cell lines. Molecular modeling studies predicted the binding pattern of the most active compounds. Molecular dynamics confirmed the docking results. All compounds showed remarkable pharmacokinetic properties.

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.

Rhabdomyolysis-Induced Acute Kidney Injury (AKI) in a Young Bodybuilder: A Case Report.

Acute kidney injury (AKI) is a serious medical condition that can have many causes, including rhabdomyolysis. Rhabdomyolysis is the breakdown of muscle tissue that can lead to the release of muscle fiber contents into the bloodstream. This can cause serious damage to the kidneys, leading to AKI. In this case, a young bodybuilder was diagnosed with rhabdomyolysis induced by AKI after consuming Ibuprofen for a casual fever. The etiology of AKI in rhabdomyolysis is complex, with multiple factors contributing to the development of the condition. These include muscle trauma, dehydration, infection, and drug toxicity. In this case, Ibuprofen may have contributed to the development of AKI, as it can cause kidney damage when taken in large doses. Additionally, the bodybuilder's physical activity may have contributed to the development of rhabdomyolysis, as intense exercise can cause muscle damage. Treatment for AKI in rhabdomyolysis patients typically involves aggressive fluid resuscitation, electrolyte replacement, and dialysis if necessary. Additionally, the underlying cause of the rhabdomyolysis must be identified and treated. In this case, the patient should be monitored closely for any signs of kidney damage, and the Ibuprofen should be discontinued. In conclusion, this is a case of a relatively common presentation with uncommon circumstances. It is crucial to have a heightened understanding of the likelihood of AKI in patients with rhabdomyolysis and the impact of drug toxicity in exacerbating the condition. Early diagnosis and treatment are essential for the successful management of AKI.

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.

Predictors of mortality and morbidity in critically ill COVID-19 patients: An experience from a low mortality country.

Background and Aims: Clinical characteristics and factors associated with mortality in patients admitted to the intensive care unit (ICU) in countries with low case fatality rates (CFR) are unknown. We sought to determine these in a large cohort of critically ill COVID-19 patients in Qatar and explore the early mortality predictors. Methods: We retrospectively studied the clinical characteristics and outcomes in patients admitted to the ICU at the national referral hospital for COVID-19 patients in Qatar. Logistic regression analysis was used to determine factors associated with mortality. Results: Between March 7 and July 16, 2020, a total of 1079 patients with COVID-19 were admitted to the ICU. The median (IQR) age of patients was 50 (41-59) years. Diabetes (47.3%) and hypertension (42.6%) were the most common comorbidities. In-hospital mortality was 12.6% overall and 25.9% among those requiring mechanical ventilation. Factors independently associated with mortality included older age ([OR]; 2.3 [95% CI; 1.92-2.75] for each 10-year increase in age, p < 0.001), chronic kidney disease (OR; 1.9 [95% CI; 1.02-3.54], p = 0.04), active malignancy (OR; 6.15 [95% CI; 1.79-21.12], p = 0.004), lower platelet count at ICU admission (OR; 1.41 [95% CI; 1.13-1.75] for each 100 × 103/µl decrease, p = 0.002), higher neutrophil-to-lymphocyte ratio at admission (OR; 1.01 [95% CI; 1-1.02] for each 1- point increase, p = 0.016), higher serum ferritin level at admission (OR; 1.05 [(95% CI; 1.02-1.08] for each 500 µg/L increase, p = 0.002), and higher serum bilirubin level at admission (OR; 1.19 [95% CI; 1.04-1.36] for each 10 µmol/L increase, p = 0.01). Conclusions: The mortality rate among critically ill COVID-19 patients is low in Qatar compared to other countries. Older age, chronic kidney disease, active malignancy, higher neutrophil-to-lymphocyte ratios, lower platelet counts, higher serum ferritin levels, and higher serum bilirubin levels are independent predictors of in-hospital mortality.

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.

Synthesis, Characterization, Thermal Analysis, DFT, and Cytotoxicity of Palladium Complexes with Nitrogen-Donor Ligands.

Three new palladium complexes ([Pd(DABA)Cl2], [Pd(CPDA)Cl2], and [Pd(HZPY)Cl2]) bearing dinitrogen ligands (DABA: 3,4-diaminobenzoic acid; CPDA: 4-chloro-o-phenylenediamine; HZPY: 2-hydraziniopyridine) were synthesized, characterized, and tested against breast cancer (MCF-7), prostate carcinoma cell line (PC3) and liver carcinoma cell line (HEPG2). [Pd(DABA)Cl2] complex exhibited the highest inhibition percentage, lying between 68-71%. The hydrolysis mechanism of each palladium complex, the key step preceding the binding to the biological target, as well as their photophysical properties were explored by means of DFT and TDDFT computations. Results indicate a faster hydrolysis process for the Pd(DABA)Cl2 complex. The computed activation energies for the first and second hydrolysis processes suggest that all the compounds could reach DNA in their monohydrated form.

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.

Comparison of the clinical outcomes of non-invasive ventilation by helmet vs facemask in patients with acute respiratory distress syndrome.

ABSTRACT: The main aim of this study is to compare the use of non-invasive ventilation (NIV) via helmet versus face mask where different interfaces and masks can apply NIV. However, some of the limitations of the NIV face mask were air leak, face mask intolerance, and requirement of high positive end expiratory pressure, which could be resolved with the use of the helmet NIV. NIV facemask will be applied as per the facial contour of the patient. NIV helmet is a transparent hood and size will be measured as per the head size. Both groups will have a standard protocol for titration of NIV.Patients aged more than 18 years old and diagnosed with acute respiratory distress syndrome as per Berlin definition will be enrolled in the study after signing the informed consent. Subjects who met the inclusion criteria will receive 1 of the 2 interventions; blood gases, oxygenation status [Po2/Fio2] will be monitored in both groups. The time of intubation will be the main comparison factor among the 2 groups. The primary and secondary outcomes will be measured by the number of patients requiring endotracheal intubation after application of helmet device, Improvement of oxygenation defined as PaO2/FiO2 ≥ 200 or increase from baseline by 100, duration of mechanical ventilation via an endotracheal tube, intensive care unit length of stay, death from any cause during hospitalization at the time of enrolment, need for proning during the hospital stay, intensive care unit mortality, and the degree to which overt adverse effects of a drug can be tolerated by a patient including feeding tolerance. TRIAL REGISTRATION NUMBER: NCT04507802. PROTOCOL VERSION: May 2020.

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.

New Platinum (II) Ternary Complexes of Formamidine and Pyrophosphate: Synthesis, Characterization and DFT Calculations and In vitro Cytotoxicity.

AIM AND OBJECTIVE: Platinum (II) and platinum (IV) of pyrophosphate complexes have been prepared and characterized to discover their potential as antitumor drugs. This study was conducted to prepare and characterize new ternary platinum (II) complexes with formamidine and pyrophosphate as an antitumor candidate. MATERIALS AND METHODS: The complexes have been characterized by mass, infrared, UV-Vis. spectroscopy, elemental analysis, magnetic susceptibility, thermal analyses, and theoretical calculations. They have been tested for their cytotoxicity, which was carried out using the fastcolorimetric assay for cellular growth and survival against MCF-7 (breast cancer cell line), HCT- 116 (colon carcinoma cell line), and HepG-2 (hepatocellular cancer cell line). RESULTS: All complexes are diamagnetic, and the electronic spectral data displayed the bands due to square planar Pt(II) complexes. The optimized complexes structures (1-4) indicated a distorted square planar geometry where O-Pt-O and N-Pt-N bond angles were 82.04°-96.44°, respectively. Results also show that all complexes are neutral, stable and non-hygroscopic and have noticeable cytotoxicity with IC50 (µM): 0.035-0.144 MCF-7(breast cancer cell line), 0.042-0.187 HCT-116 (colon carcinoma cell line), and 0.063-0.168 HepG-2 (hepatocellular cancer cell line). Moreover, the results show that the complex (4) has the best IC50 value. CONCLUSION: The complexes showed noticeable cytotoxicity and are considered as promising antitumor candidates for further applications.

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.