Changing patterns of bacterial profile and antimicrobial resistance in high-risk patients during the COVID-19 pandemic at a tertiary oncology hospital.

The widespread evolution of phenotypic resistance in clinical isolates over the years, coupled with the COVID-19 pandemic onset, has exacerbated the global challenge of antimicrobial resistance. This study aimed to explore changes in bacterial infection patterns and antimicrobial resistance during the COVID-19 pandemic. This study involved the periods before and during COVID-19: the pre-pandemic and pandemic eras. The surveillance results of bacterial isolates causing infections in cancer patients at an Egyptian tertiary oncology hospital were retrieved. The Vitek®2 or Phoenix systems were utilized for species identification and susceptibility testing. Statistical analyses were performed comparing microbiological trends before and during the pandemic. Out of 2856 bacterial isolates, Gram-negative bacteria (GNB) predominated (69.7%), and Gram-positive bacteria (GPB) comprised 30.3% of isolates. No significant change was found in GNB prevalence during the pandemic (P = 0.159). Elevated rates of Klebsiella and Pseudomonas species were demonstrated during the pandemic, as was a decrease in E. coli and Acinetobacter species (P < 0.001, 0.018, < 0.001, and 0.046, respectively) in hematological patients. In surgical patients, Enterobacteriaceae significantly increased (P = 0.012), while non-fermenters significantly decreased (P = 0.007). GPB species from either hematological or surgical wards exhibited no notable changes during the pandemic. GNB resistance increased in hematological patients to carbapenems, amikacin, and tigecycline and decreased in surgical patients to amikacin and cefoxitin (P < 0.001, 0.010, < 0.001, < 0.001, and 0.016, respectively). The study highlights notable shifts in the microbial landscape during the COVID-19 pandemic, particularly in the prevalence and resistance patterns of GNB in hematological and surgical wards.

An efficient methodological approach for synthesis of selenopyridines: generation, reactions, anticancer activity, EGFR inhibitory activity and molecular docking studies.

In the present work, we successfully synthesized Se-alkyl selenopyridines 1 and 3, selenopheno[2,3-b]pyridine 2, and bis-selenopyridine 4 derivatives using an eco-friendly method by utilizing NaHSe instead of toxic hydrogen selenide. The effect of the temperature on the reaction was screening at various temperatures. The regiospecific reaction of selenopyridine 1 with bromine afforded an unexpected product 4,6-diamino-5-bromo-2-[(cyanomethyl)selenyl]-pyridine-3-carbonitrile (5), which was cyclized to selenopheno[2,3-b]pyridine (7) by refluxing in the presence of TEA. While its treatment with thiophenol and/or p-chlorothiophenol gave 8a, b. On the other hand, its reaction with aminothiophenol afforded 2-(benzo[d]-thiazol-2-yl)-5-bromoselenopheno[2,3-b]pyridine-3,4,6-triamine (9). Also, N-(2-cyano-4-methyl-5H-1-seleno-3,5,8-triazaacenaphthylen-7-yl)acetamide (11) and a novel series of selenoazo dyes 12a-d were synthesized by treatment of selenopheno[2,3-b]pyridine 2 with acetic anhydride and/or diazonium chlorides of aromatic amines, respectively. Then, we ascertained the potential activity of synthesized compounds against highly metastatic prostate cancer cells (PC-3) and osteosarcoma cells (MG-63) and found that 12a, 12b, 12c, and 12d were more cytotoxic than doxorubicin in both tested cell lines, showing nearly the same anticancer activity with IC50 values ranging from 2.59 ± 0.02 µM to 3.93 ± 0.23 µM. Mechanistically, the most potent compounds 12a and 12b proved to be potent EGFR inhibitors with IC50 values of 0.301 and 0.123 µM, respectively, compared to lapatinib as a positive reference (IC50 = 0.049 µM). Moreover, the docking results are in good agreement with the anticancer activity as well as the EGFR inhibitory activity, suggesting these two compounds as promising EGFR anticancer candidates.

Benzimidazole-oxindole hybrids as multi-kinase inhibitors targeting melanoma.

In the current study, a series of benzimidazole-oxindole conjugates 8a-t were designed and synthesized as type II multi-kinase inhibitors. They exhibited moderate to potent inhibitory activity against BRAFWT up to 99.61 % at 10 µM. Notably, compounds 8e, 8k, 8n and 8s demonstrated the most promising activity, with 99.44 to 99.61 % inhibition. Further evaluation revealed that 8e, 8k, 8n and 8s exhibit moderate to potent inhibitory effects on the kinases BRAFV600E, VEGFR-2, and FGFR-1. Additionally, compounds 8a-t were screened for their cytotoxicity by the NCI, and several compounds showed significant growth inhibition in diverse cancer cell lines. Compound 8e stood out with a GI50 range of 1.23 - 3.38 µM on melanoma cell lines. Encouraged by its efficacy, it was further investigated for its antitumor activity and mechanism of action, using sorafenib as a reference standard. The hybrid compound 8e exhibited potent cellular-level suppression of BRAFWT, VEGFR-2, and FGFR-1 in A375 cell line, surpassing the effects of sorafenib. In vivo studies demonstrate that 8e significantly inhibits the growth of B16F10 tumors in mice, leading to increased survival rates and histopathological tumor regression. Furthermore, 8e reduces angiogenesis markers, mRNA expression levels of VEGFR-2 and FGFR-1, and production of growth factors. It also downregulated Notch1 protein expression and decreased TGF-ß1 production. Molecular docking simulations suggest that 8e binds as a promising type II kinase inhibitor in the target kinases interacting with the key regions in their kinase domain.

New pyrazolylindolin-2-one based coumarin derivatives as anti-melanoma agents: design, synthesis, dual BRAFV600E/VEGFR-2 inhibition, and computational studies.

Malignant melanoma is the most invasive skin cancer with the highest risk of death. The inhibition of BRAFV600E appears relevant for overcoming secondary resistance developed during melanoma treatment. BRAFV600E triggers angiogenesis via modification of the expression of angiogenic inducers, which play a crucial role in the metastasis of melanoma. Accordingly, the dual inhibition of the BRAFV600E/VEGFR-2 signaling pathway is considered a rational approach in the design of anti-melanoma candidates. In this study, a new class of pyrazolylindolin-2-one linked coumarin derivatives as dual BRAFV600E/VEGFR-2 inhibitors targeting A375 melanoma cells was designed. Target compounds were tailored to occupy the pockets of BRAFV600E and VEGFR-2. Most of the synthesized compounds demonstrated potent mean growth inhibitory activity against A375 cells. Compound 4j was the most active cytotoxic derivative, displaying an IC50 value at a low micromolar concentration of 0.96 µM with a significant safety profile. Moreover, 4j showed dual potent inhibitory activity against BRAFV600E and VEGFR-2 (IC50 = 1.033 and 0.64 µM, respectively) and was more active than the reference drug sorafenib. Furthermore, derivative 4j caused significant G0/G1 cell cycle arrest, induced apoptosis, and inhibited the migration of melanoma cells. Molecular docking showed that compound 4j achieved the highest ΔG value of -9.5 kcal mol-1 against BRAFV600E and significant ΔG of -8.47 kcal mol-1 against VEGFR-2. Furthermore, the structure-activity relationship study revealed that TPSA directly contributed to the anticancer activity of the tested compounds.

Novel quinoxaline-3-propanamides as VGFR-2 inhibitors and apoptosis inducers.

Vascular endothelial growth factor receptor-2 is a vital target for therapeutic mediation in various types of cancer. This study was aimed at exploring the cytotoxic activity of seventeen novel quinoxaline-3-propanamides against colon cancer (HCT-116) and breast cancer (MCF-7) using MTT assay. Results revealed that compounds 8, 9, and 14 elicited higher cytotoxicity than the reference drugs, doxorubicin (DOX) and sorafenib. Interestingly, they are more selective for HCT-116 (SI 11.98-19.97) and MCF-7 (SI 12.44-23.87) compared to DOX (SI HCT-116 0.72 and MCF-7 0.9). These compounds effectively reduced vascular endothelial growth factor receptor-2; among them, compound 14 displayed similar VEGFR-2 inhibitory activity to sorafenib (IC50 0.076 M). The ability of 14 to inhibit angiogenesis was demonstrated by a reduction in VEGF-A level compared to control. Furthermore, it induced a significant increase in the percentage of cells at pre-G1 phase by almost 1.38 folds (which could be indicative of apoptosis) and an increase in G2/M by 3.59 folds compared to the control experiment. A flow cytometry assay revealed that compound 14 triggered apoptosis via the programmed cell death and necrotic pathways. Besides, it caused a remarkable increase in apoptotic markers, i.e., caspase-3 p53 and BAX. When compared to the control, significant increase in the expression levels of caspase-3 from 47.88 to 423.10 and p53 from 22.19 to 345.83 pg per ml in MCF-7 cells. As well, it increased the proapoptotic protein BAX by 4.3 times while lowering the antiapoptotic marker BCL2 by 0.45 fold. Docking studies further supported the mechanism, where compound 14 showed good binding to the essential amino acids in the active site of VEGFR-2. Pharmacokinetic properties showed the privilege of these hits over sunitinib: they are not substrates of P-gp protein; this suggests that they have less chance to efflux out of the cell, committing maximum effect; and in addition, they do not allow permeation to the BBB.

Hypophyllanthin and Phyllanthin from Phyllanthus niruri Synergize Doxorubicin Anticancer Properties against Resistant Breast Cancer Cells.

Doxorubicin (DOX) is a cornerstone chemotherapeutic agent for the treatment of several malignancies such as breast cancer; however, its activity is ameliorated by the development of a resistant phenotype. Phyllanthus species have been studied previously for their potential anticancer properties. The current work is aimed to study the potential cytotoxicity and chemomodulatory effects of hypophyllanthin (PN4) and phyllanthin (PN5) isolated from Phyllanthus niruri to DOX against the adriamycin multidrug-resistant breast cancer cells (MCF-7ADR) and elucidate their mechanism of action. The major compounds of the active methylene chloride fraction were isolated and assessed for their potential cytotoxicity and chemomodulatory effects on DOX against naïve (MCF-7) and resistant breast (MCF-7ADR) cancer cells. The mechanism of action of both compounds in terms of their impacts on programmed/non-programmed cell death (apoptosis and autophagy/necrosis), cell cycle progression/arrest, and tumor cell migration/invasion was investigated. Both compounds PN4 and PN5 showed a moderate but similar potency against MCF-7 as well as MCF-7ADR and significantly synergized DOX-induced anticancer properties against MCF-7ADR. The chemomodulatory effect of both compounds to DOX was found to be via potentiating DOX-induced cell cycle interference and apoptosis induction. It was found that PN4 and PN5 blocked the apoptosis-escape autophagy pathway in MCF-7ADR. On the molecular level, both compounds interfered with SIRT1 expression and consequently suppressed Akt phosphorylation, and PN5 blocked apoptosis escape. Furthermore, PN4 and PN5 showed promising antimigratory and anti-invasive effects against MCF-7ADR, as confirmed by suppression of N-cadherin/ß-catenin expression. In conclusion, for the first time, hypophyllanthin and phyllanthin isolated from P. niruri showed promising chemomodulatory effects to the DOX-induced chemotherapeutic activity against MCF-7ADR. Both compounds significantly synergized DOX-induced anticancer properties against MCF-7ADR. This enhanced activity was explained by further promoting DOX-induced apoptosis and suppressing the apoptosis-escape autophagy feature of the resistant breast cancer cells. Both compounds (hypophyllanthin and phyllanthin) interfered with the SIRT1/Akt pathway and suppressed the N-cadherin/ß-catenin axis, confirming the observed antiproliferative, cytotoxic, and anti-invasive effects of hypophyllanthin and phyllanthin.

Novel quinoxaline-based VEGFR-2 inhibitors to halt angiogenesis.

Vascular endothelial growth factor receptor-2 is a dynamic target for therapeutic intervention in various types of cancer. This study was aimed at exploring the VEGFR-2 inhibitory activity of a novel library of quinoxalin-2-one derivatives such as 3-furoquinoxaline carboxamides, 3-pyrazolylquinoxalines, and 3-pyridopyrimidyl-quinoxalines. Among them, 6c, 7a, and 7d-f produced remarkable cytotoxicity against HCT-116 (IC50's 4.28-9.31 µM) and MCF-7 (IC50's 3.57-7.57 µM) cell lines using the MTT assay and doxorubicin (DOX) as a reference standard. Interestingly, results of cytotoxicity towards the human fibroblast cell line WI38 revealed that these hits demonstrated higher selectivity indices towards both HCT-116 (SI 8.69-23.19) and MCF-7 (SI 9.48-27.80) than DOX, SI 0.72 and 0.90, respectively. Then, these hits were subjected to a mechanistic study; they showed direct inhibition of VEGFR-2. Impressively, compound 7f displayed 1.2 times the VEGFR-2 inhibitory activity of sorafenib. The antiangiogenic potential of 7f was proved via lowering the level of VEGF-A, than that of control. It as well, exhibited scratch closure percent of 61.8%, compared with 74.5% of control at 48 hrs, indicating the potential anti-migratory effect of the compound 7f. It significantly increased the expression of tumor suppressor gene (p53) on MCF-7 cells by almost 18 folds and upregulated the caspase-3 level by 10.7 folds, compared to the control. Cell cycle analysis revealed cell cycle arrest at G2/M together with a PreG increase which indicated apoptosis induction potential. Annexin V-FITC apoptosis results proposed the two modes of cell death (apoptosis and necrosis) as an inherent mechanism of cytotoxicity of compound 7f. Molecular docking further supported the mechanism showing the affinity of target compounds for VEGFR-2 active site. Moreover, physicochemical and drug-like properties were assessed from the ADME properties.

Jatrophone: a cytotoxic macrocylic diterpene targeting PI3K/AKT/NF-κB pathway, inducing apoptosis and autophagy in resistant breast cancer cells.

BACKGROUND: Breast cancer is a prevalent malignant tumor that affects women worldwide. The primary challenge in treating breast cancer is combating drug resistance, which contributes to relapse and metastasis. Jatrophone is a unique macrocyclic jatrophane diterpene found in various Jatropha and Euphorbia species. It possesses diverse biological and pharmacological activities, including anticancer activity. However, it is unclear whether jatrophone can overcome drug resistance in breast cancer. METHODS: This study includes the investigation of the cytotoxicity of jatrophone on doxorubicin-resistant breast cancer cells (MCF-7ADR) and the underlying molecular mechanisms. The effects of jatrophone on cell viability were determined using the sulforhodamine B (SRB) assay, while flow cytometry was used to evaluate cell cycle progression, apoptosis, and autophagy. A scratch assay was conducted to observe cell migration, and western blotting was used to measure downstream protein levels (PI3K, AKT, and NF-κB). Unpaired Student's t-tests were used for comparison between the two groups and the results were analyzed by one-way ANOVA with Tukey- Kremer post hoc test. RESULTS: It was shown that jatrophone exhibited potent cytotoxic activity on MCF-7ADR cells in a dose-dependent manner, with an IC50 value of 1.8 µM. It also significantly induced cell cycle S and G/M phase arrest. Interestingly, jatrophone induced both early and late apoptotic cell death, as well as autophagic cell death, with negligible necrosis. Furthermore, jatrophone treatment diminished the migration of MCF-7ADR cells. At the molecular level, jatrophone treatment significantly down-regulated the expression levels of PI3K, AKT, and NF-κB. ß. CONCLUSIONS: The results of the study suggest that jatrophone decreases the proliferation of MCF-7/ADR cells at a low micromolar concentration; induces cell cycle arrest; promotes apoptotic, and autophagic cell death; inhibits migration and EMT; and works on resistance by a mechanism involving the inhibition of the PI3K/Akt/ NF-κB pathway. These findings provide evidence of the potential of jatrophone to be a promising lead compound for targeting doxorubicin-resistant breast cancer cells and could be further investigated for its clinical application as a chemotherapy adjuvant.

L-arginase from Streptomyces diastaticus MAM5 as a potential therapeutic agent in breast cancer: Purification, characterization, G1 phase arrest and autophagy induction.

Targeting cancer metabolic processes has increased interest over the last century. Cancer cells have an enhanced proliferation rate that requires high quantities of amino acids, including arginine. Therefore, arginine deprivation by L-arginase impairs tumor growth resulting in cell death. In the present study, L-arginine amidinohydrolase (L-arginase) from Streptomyces diastaticus was purified successfully by heat treatment, ethanol precipitation, and Sephadex G75-120 column. The molecular mass of the purified enzyme was 39 kDa. It showed maximum activity at pH 9.0 and a temperature of 50 °C. Moreover, the enzyme stability was observed at temperatures up to 50 °C and a pH range of 7.5 to 9.0. Then, the potential cytotoxicity of L-arginase was examined. L-arginase has an IC50 value of 595 µg/ml for MCF-7 (breast adenocarcinoma cells), 915 µg/ml for HepG2 (hepatocellular carcinoma cells), and 1200 µg/ml for SW620 cells (colorectal carcinoma cells) at 72 h post-treatment. Noteworthy, MCF-7 showed the lowest IC50 value of arginase treatment, therefore was further investigated for the underlying cytotoxic mechanisms using flow cytometric analysis of cell-cycle distribution, apoptosis, and autophagy. Moreover, SI values indicating a high selective cytotoxicity of arginase toward MCF-7 cells. L-arginase induced significant cell cycle arrest at the G1 phase, and no apparent apoptosis was detected. Interestingly, arginine deprivation by arginase leads to a prominent activation of autophagy in the apoptosis defected MCF-7 cells. Moreover, treatment with arginase significantly attenuated MCF-7 cell migration compared with control medium-treated cells. Collectively, L-arginase might potentially be involved in treating breast cancer.

Protective effects of royal jelly and Echinacea against moxifloxacin-induced renal and hepatic injury in rats.

Antibiotic use, especially fluoroquinolones, has been linked to extensive renal and hepatic injury thus inflicts a considerable health problem. Fifty rats were allocated into five groups (n = 10). Group 1 represented the normal-control group. Group 2 received moxifloxacin only (MOX; 8 mg/kg/day, i.p.) for seven days and represented the MOX-control group. Groups 3, 4, and 5 received MOX for seven days accompanied by royal jelly (RJ; 100 mg/kg/day, p.o.), Echinacea (ECH; 40 mg/kg/day, p.o.), and a combination of both at the aforementioned doses respectively for 30 days. All groups were investigated for renal and hepatic function tests. Renal tissue content of kidney injury molecule-1 (KIM-1) along with renal and hepatic tissue contents of reduced glutathione (GSH) and malondialdehyde (MDA) were assessed for all groups. Histopathological examination was performed followed by immunohistochemical staining for caspase-3 in renal and hepatic tissues. MOX administration resulted in significant renal and hepatic damage. RJ and ECH significantly improved the serum parameters of renal and hepatic functions along with increasing GSH and decreasing MDA in renal and hepatic tissues. Renal contents of KIM-1 were also reduced. Moreover, RJ, ECH, and their combination amended MOX-induced histopathological changes and significantly reduced caspase-3 immunohistochemical staining in both renal and hepatic tissues. The current study is the first to elucidate the effect of RJ, ECH, and their combination against MOX-induced renal and hepatic injury in rats. The study suggests that these protective effects are mainly via the reduction of oxidative stress induced by MOX administration.

Design, synthesis, and molecular docking of novel pyrazole-chalcone analogs of lonazolac as 5-LOX, iNOS and tubulin polymerization inhibitors with potential anticancer and anti-inflammatory activities.

Uncontrolled inflammation predisposes to pleiotropic effects leading to cancer development thanks to promoting all stages of tumorigenesis. Therefore, cancer-associated inflammation has been delegated as the seventh hallmark of cancer. Thus, raging the war against both inflammation and cancer via the innovation of bioactive agents with dual anti-inflammatory and anticancer activities is a necessity. Herein, a novel series of pyrazole-chalcone analogs of Lonazolac (7a-g and 8a-g) have been synthesized and investigated for their in vitro anticancer activity against four cancer cell lines using the MTT assay method. Among all, hybrid 8g was the most potent against three cancer cell lines, HeLa, HCT-116, and RPMI-822 with IC50 values of 2.41, 2.41, and 3.34 µM, respectively. In contrast, hybrid 8g showed moderate inhibitory activity against MCF-7 with IC50 28.93 µM and with a selectivity profile against MCF-10A (non-cancer cells). Mechanistically, hybrid 8g was the most potent inhibitor against tubulin polymerization (IC50 = 4.77 µM), suggesting tubulin as a molecular target and explaining the observed cytotoxicity of hybrid 8g. This was mirrored by the detected potent pre-G1 apoptosis induction and G2/M cell cycle arrest. Moreover, hybrid8gexhibited selectivity against COX-2 (IC50 = 5.13 µM) more than COX-1 (IC50 = 33.46 µM), indicating that 8g may have lower cardiovascular side effects, but is still not potent as celecoxib (COX-2 IC50 = 0.204 µM, COX-1 = 35.8 µM). Notably, hybrid 8g showed promising inhibitory activity towards 5-LOX (IC50 = 5.88 µM). Finally, the anti-inflammatory activity of hybrid8 g was confirmed by high iNOS and PGE2 inhibitory activities in LPS-stimulated RAW cells with IC50 values of4.93 µM and 10.98 µM, respectively, that accompanied by showingthe most potent inhibition of NO release (70.61 % inhibition rate). Molecular docking studies of hybrid 8g confirmed good correlations with the executed biological results. Furthermore, hybrid 8g had good drug-likeness and suitable physicochemical properties. Taken together, the combined results suggested hybrid8gas a promising orally administered candidate in the journey of repurposing NSAIDs for cancer chemopreventionand treatment.

Obeticholic acid orchestrates the crosstalk between ileal autophagy and tight junctions in non-alcoholic steatohepatitis: Role of TLR4/TGF-ß1 axis.

An interplay exists between non-alcoholic steatohepatitis (NASH) and intestinal barrier dysfunction. A plethora of mechanisms are implicated in the regulation of intestinal integrity, among which is autophagy. Farnesoid X receptor (FXR) is a key metabolic regulator in the liver, however, its impact on ileal autophagy and barrier integrity in the context of NASH has not yet been unraveled. Accordingly, the present study aimed at investigating the impact of the FXR agonist, obeticholic acid (OCA), on modulating the aberrant ileal autophagy and barrier dysfunction in NASH, exploring the possible implication of the TLR4/TGF-ß1 axis. High-fat diet (HFD) and dextran sulfate sodium (DSS, MW ∼40 kDa) were used for 13 weeks to induce NASH with distorted intestinal integrity in Swiss albino male mice. Post-treatment with OCA (5 mg/kg/day; p.o; 4 weeks), histopathological evaluation revealed a restoration of normal hepatic and ileal architectures. OCA partially restored intestinal permeability, as evidenced by the FITC-dextran leakage assay, with no change in serum LPS or LBP levels. Meanwhile, ileal expression of the tight junctions; claudin-1, zonulin-1, and occludin, was upregulated. Hepatic and ileal TLR-4 and TGF-ß1 immunoreactivities were also decreased with no change observed in ileal phosphorylated Akt. In addition, ATG5 gene expression and LC3II/I protein ratio were upregulated in the ileum. Overall, the present study suggests a protective role of OCA on intestinal integrity in NASH, possibly through autophagy induction via interfering with the TLR4/TGF-ß1 pathway.

The influence of antioxidant dietary-derived polyphenolic combination on breast cancer: Molecular study.

Breast cancer remains a leading cause of female mortality worldwide. Therefore, novel complementary treatments have been sought. Recently, there has been a growing interest in investigating the possible complementary effects of polyphenolic compounds against various malignancies. In the present study, using MCF-7 and MDA-MB-231 human breast adenocarcinoma cells, the anticancer efficacy of a polyphenolic mixture (PFM) was investigated. PFM is composed of curcumin, resveratrol, epigallocatechin gallate, and quercetin. PFM treatment led to a dose-dependent inhibition of cell proliferation, with IC50 values of 25.9 ± 3 µg/ml and 29.4 ± 0.9 µg/ml for MCF-7 and MDA-MB-231 cells, respectively. In addition, PFM induced apoptosis in MDA-MB-231 cells and cell cycle arrest at the S phase in MCF-7 cells. Using RT-qPCR, PFM treatment was observed to result in significant downregulation of the oncogenic miR-155 (P < 0.05), as well as significant downregulation of the rate-limiting glycolytic enzyme, hexokinase 2 (HK2) (P < 0.05), while upregulating the expression of the zinc finger E-box binding homeobox 2 gene (P < 0.01). PFM was also found to exert an anti-migration effect in breast cancer cells using the wound healing assay, as well as significantly (P < 0.05) increasing the median survival of Ehrlich ascites carcinoma (EAC) tumor-bearing mice. These results suggest that PFM possesses potential antitumor effects against breast cancer. A possible mechanism of action could be due to PFM's effect in modulating the expression of the glycolytic enzyme HK2 through suppression of miR-155 in MCF-7 cells. Combining polyphenolic compounds that interact with one another could result in synergistic effects that potentially target various tumour hallmarks.

1,8 Cineole and Ellagic acid inhibit hepatocarcinogenesis via upregulation of MiR-122 and suppression of TGF-ß1, FSCN1, Vimentin, VEGF, and MMP-9.

Hepatocellular carcinoma (HCC) is one of the most burdened tumors worldwide, with a complex and multifactorial pathogenesis. Current treatment approaches involve different molecular targets. Phytochemicals have shown considerable promise in the prevention and treatment of HCC. We investigated the efficacy of two natural components, 1,8 cineole (Cin) and ellagic acid (EA), against diethylnitrosamine/2-acetylaminofluorene (DEN/2-AAF) induced HCC in rats. DEN/2-AAF showed deterioration of hepatic cells with an impaired functional capacity of the liver. In addition, the levels of tumor markers including alpha-fetoprotein, arginase-1, alpha-L-fucosidase, and ferritin were significantly increased, whereas the hepatic miR-122 level was significantly decreased in induced-HCC rats. Interestingly, treatment with Cin (100mg/kg) and EA (60mg/kg) powerfully restored these biochemical alterations. Moreover, Cin and EA treatment exhibited significant downregulation in transforming growth factor beta-1 (TGF-ß1), Fascin-1 (FSCN1), vascular endothelial growth factor (VEGF), matrix metalloproteinase-9 (MMP-9), and epithelial-mesenchymal transition (EMT) key marker, vimentin, along with a restoration of histopathological findings compared to HCC group. Such effects were comparable to Doxorubicin (DOX) (2mg/kg); however, a little additive effect was evident through combining these phytochemicals with DOX. Altogether, this study highlighted 1,8 cineole and ellagic acid for the first time as promising phytochemicals for the treatment of hepatocarcinogenesis via regulating multiple targets.

Application of the dual-tail approach for the design and synthesis of novel Thiopyrimidine-Benzenesulfonamide hybrids as selective carbonic anhydrase inhibitors.

A dual-tail approach was applied to the design of a novel series of 2-thiopyrimidine-benzenesulfonamides as carbonic anhydrase (CA) inhibitors. The design strategy is based on the hybridization between a benzenesulfonamide moiety as Zn2+ binding group and 2,4-disubstituted thiopyridimidine as a tail. Among the synthesized compounds, 14h displayed the highest potency (Ki = 1.72 nM) and selectivity for CA II over the isoforms CA IX and CA XII with selectivity indexes of 50 and 5.26, respectively. Meanwhile, compounds 14a and 14l displayed a potent inhibitory activity against CA IX (Ki = 7.4 and 7.0 nM, respectively) compared with the reference drug acetazolamide (AAZ) (Ki = 25 nM), and compound 14l showed higher potency (Ki = 4.67 nM) than AAZ (Ki = 5.7 nM) against the tumor-associated isoform CA XII. Evaluation of the antiproliferative activity in NCI single-dose testing of selected hybrids revealed a pronounced potency of the selective CA II inhibitor 14h against most of the tested NCI cancer cell lines. Moreover, compound 14h demonstrated an IC50 values ranging from 2.40 to 4.50 µM against MCF-7, T-47D, MDA-MB-231, HCT-116, HT29 and SW-620. These results demonstrate that CA II inhibition can be an alternative therapeutic target for cancer treatment. A cell cycle analysis of MCF-7 and MDA-MB-231 showed that treatment with 14h arrested both cell lines at the G2/M phase with significant accumulation of cells in the pre-G1 phase. Moreover, compound 14h showed a noticeable induction of late apoptosis and necrotic cell death of both cell lines compared with untreated cells as a control. A molecular docking study suggested that the sulfonamide moiety accommodates deeply in the CA active site and interacts with the Zn2+ ion while the dual-tail extension interacts with the surrounding amino acids via several hydrophilic and hydrophobic interactions, which affects the potency and selectivity of the hybrids.

Formulation and characterization of propolis and tea tree oil nanoemulsion loaded with clindamycin hydrochloride for wound healing: In-vitro and in-vivo wound healing assessment.

This study aimed to develop propolis and tea tree oil nanoemulsion loaded with clindamycin hydrochloride to heal wound effectively. Nanoemulsion formulae were prepared and characterized by droplet size analysis, zeta potential, viscosity, ex-vivo permeation, and skin deposition. The optimal formula was evaluated in terms of morphology, cytotoxicity, and in-vitro wound healing assay. Also, the efficacy of the optimal formula was evaluated by in-vivo wound healing and histopathological studies. The optimal formula (F3) was composed of 9% tea tree oil and 0.4% propolis extracts with mean droplet size 19.42 ± 1.7 nm, zeta potential value -24.5 ± 0.2 mV, and viscosity 69.4 ± 1.8 mP. Furthermore, the optimal formula showed the highest skin deposition value 550.00 ± 4.9 µg/cm2 compared to other formulae. The TEM micrograph of the optimal formula showed that the nanoemulsion droplet has an almost spherical shape. Also, the optimal formula did not show noticeable toxicity to the human skin fibroblast cells. The in-vitro and in-vivo wound healing assay showed unexpected results that the un-loaded drug nanoemulsion formula had a comparable wound healing efficacy to the drug-loaded nanoemulsion formula. These results were confirmed with histopathological studies. Our results showed that the propolis and tea tree oil nanoemulsion, whether loaded or unloaded with an antibiotic, is an efficient local therapy for wound healing.

Panax Ginseng alleviates thioacetamide-induced liver injury in ovariectomized rats: Crosstalk between inflammation and oxidative stress.

Liver diseases impose a substantial health problem. Female hormones play a crucial role in the protection against chronic inflammatory diseases. Fifty female rats were allocated into five groups (n = 10). Group I comprised sham-operated rats. The remaining groups underwent ovariectomy at the beginning of the experiment. Group II served as the ovariectomy-control group. Groups III, IV & V received thioacetamide (TAA; 300 mg/kg; i.p.) to induce liver injury 6 weeks after ovariectomy. Group III served as the TAA-control group. Groups IV & V received panax ginseng (100 and 300 mg/kg/day, p.o.) for 6 weeks post TAA administration. All groups were investigated for liver function tests along with total antioxidant capacity (TAC), tumor necrosis factor-α (TNF-α) and advanced glycation end products (AGEs). Histopathological examination of liver tissues was performed followed by immunohistochemical staining for nuclear factor kappa-B (NF-kß p65) and myeloperoxidase (MPO). Ovariectomized-rats showed a non-significant change in the measured parameters while TAA administration resulted in significant liver damage. Panax ginseng at both dose levels significantly improved the serum liver function tests and TAC along with decreasing the AGEs and TNF-α. It also restored the histopathological picture of liver tissue and decreased hepatic tissue inflammation via reduction of MPO and NF-kß p65 immunoreactivity. The current study is the first to elucidate the effect of panax ginseng against TAA-induced liver injury in ovariectomized rats which mimic aged post-menopausal estrogen-deficient females. The study demonstrates the crosstalk between AGEs, NF-kß and MPO in the modulation of inflammation. Panax ginseng possesses antioxidant and anti-inflammatory properties.

Novel chalcone/aryl carboximidamide hybrids as potent anti-inflammatory via inhibition of prostaglandin E2 and inducible NO synthase activities: design, synthesis, molecular docking studies and ADMET prediction.

Two series of chalcone/aryl carboximidamide hybrids 4a-f and 6a-f were synthesised and evaluated for their inhibitory activity against iNOS and PGE2. The most potent derivatives were further checked for their in vivo anti-inflammatory activity utilising carrageenan-induced rat paw oedema model. Compounds 4c, 4d, 6c and 6d were proved to be the most effective inhibitors of PGE2, LPS-induced NO production, iNOS activity. Moreover, 4c, 4d, 6c and 6d showed significant oedema inhibition ranging from 62.21% to 78.51%, compared to indomethacin (56.27 ± 2.14%) and celecoxib (12.32%). Additionally, 4c, 6a and 6e displayed good COX2 inhibitory activity while 4c, 6a and 6c exhibited the highest 5LOX inhibitory activity. Compounds 4c, 4d, 6c and 6d fit nicely into the pocket of iNOS protein (PDB ID: 1r35) via the important amino acid residues. Prediction of physicochemical parameters exhibited that 4c, 4d, 6c and 6d had acceptable physicochemical parameters and drug-likeness. The results indicated that chalcone/aryl carboximidamides 4c, 4d, 6c and 6d, in particular 4d and 6d, could be used as promising lead candidates as potent anti-inflammatory agents.

Novel 1,2,4-oxadiazole-chalcone/oxime hybrids as potential antibacterial DNA gyrase inhibitors: Design, synthesis, ADMET prediction and molecular docking study.

New antibacterial drugs are urgently needed to tackle the rapid rise in multi-drug resistant bacteria. DNA gyrase is a validated target for the development of new antibacterial drugs. Thus, in the present investigation, a novel series of 1,2,4-oxadiazole-chalcone/oxime (6a-f) and (7a-f) were synthesized and characterized by IR, NMR (1H and 13C) and elemental analyses. The title compounds were evaluated for their in-vitro antimicrobial activity by the modified agar diffusion method as well as their E. coli DNA gyrase inhibitory activity. The minimum inhibitory concentration (MIC) and the structure activity relationships (SARs) were evaluated. Among all, compounds 6a, 6c-e, 7b and 7e were the most potent and proved to possess broad spectrum activity against the tested Gram-positive and Gram-negative organisms. Additionally, compounds 6a (against S. aureus), 6c (against B. subtilis and E. hirae), 6e (against E. hirae), 6f, 7a and 7c (against E. coli) and 7d (against B. subtilis), with MIC value of 3.12 µM were two-fold more potent than the standard ciprofloxacin (MIC = 6.25 µM). Mechanistically, compounds 6c, 7c, 7e and 7b had good inhibitory activity against E. coli gyrase with IC50 values of 17.05, 13.4, 16.9, and 19.6 µM, respectively, in comparison with novobiocin (IC50 = 12.3 µM) and ciprofloxacin (IC50 = 10.5 µM). The molecular docking results at DNA gyrase active site revealed that the most potent compounds 6c and 7c have binding mode and docking scores comparable to that of ciprofloxacin and novobiocin suggesting their antibacterial activity via inhibition of DNA gyrase. Finally, the predicted parameters of Lipinski's rule of five and ADMET analysis showed that 6c and 7c had good drug-likeness and acceptable physicochemical properties. Therefore, the hybridization of the chalcone and oxadiazole moieties could be promising lead as antibacterial candidate which merit further future structural optimizations.

Tenoxicam loaded hyalcubosomes for osteoarthritis.

The main aim is to develop transcutaneous tenoxicam (TNX) loaded vesicles to control osteoarthritis (OA) without common side effects. Different vesicles were prepared by the emulsification technique, where poloxamer and glyceryl monooleate used for cubosomes. Then, hyalcubosomes were prepared by adding sodium hyaluronate to cubosomes components. Different characterization techniques were used. The selected formulations were tested using an ex-vivo permeation study to evaluate the ability to penetrate and retained in skin layers. Also, in-vitro cell studies using human skin fibroblasts were evaluated the safety of the formulation. The anti-inflammatory efficiency was tested using an in-vivo carrageenan-induced rat paw edema model. Finally, the efficiency to control OA symptoms was tested on three patients with a medical history of knee OA. Results confirmed the successful development of spherical cubosomes with particle size <250 nm, -14.5 mV, high entrapment efficiency percentage (>90%). Moreover, the addition of sodium hyaluronate to selected cubosomes improved viscosity and spreadability. Permeation study confirmed drug penetration and deposition. Cell studies proved the safety of the selected formulation. The animal model showed high anti-inflammatory activity. Finally, the preliminary clinical study demonstrates the potential efficacy and safety of the formulation in controlling OA symptoms over 8 weeks of therapy.