Green polymer altered in-situ gel oral liquid sustainable release preparation of vildagliptin suitable for dysphagic diabetic patients: assessment in-vitro & in-vivo.

PURPOSE: This work aimed to fabricate alginate based in-situ gelling matrix of vildagliptin improved by calcium and carboxy methyl cellulose (CMC) for appropriate adjustment of the onset and duration of action. This easy-to-swallow thickened liquid preparation aimed to improve compliance for dysphagic or elderly diabetic patients. METHODS: Vildagliptin dispersions containing alginate were fabricated in the presence or absence of calcium chloride to assess the effect of calcium ion, then a matrix containing 1.5% w/v of sodium alginate with calcium was further examined after the addition of CMC with different concentrations ranging from 0.1% to 0.3%. The viscosity, gelling forming property, Differential scanning calorimetry, and in-vitro drug release were assessed before monitoring the hypoglycemic effect of the selected formulation. RESULTS: In-situ gel matrixes were fabricated at gastric pH with and without calcium ions. The best formula concerning viscosity and the gel-forming property was achieved with higher CMC concentrations, which in turn decreased the rate of vildagliptin release in stimulated gastric pH. In-vivo results confirmed the extended hypoglycemic effect of the vildagliptin in-situ gelling matrix compared to the vildagliptin aqueous solution. CONCLUSION: This study represents a green polymeric-based in-situ gel as a liquid oral retarded release preparation intended for reducing dose frequency, easier administration of vildagliptin, and improving compliance in geriatric and dysphagic diabetic patients.

Identification of new 4-(6-oxopyridazin-1-yl)benzenesulfonamides as multi-target anti-inflammatory agents targeting carbonic anhydrase, COX-2 and 5-LOX enzymes: synthesis, biological evaluations and modelling insights.

Multiple inhibitions of CA, COX-2 and 5-LOX enzymes has been recognised as a useful strategy for the development of anti-inflammatory drugs that can avoid the disadvantages of using NSAIDs alone. Here, we report new pyridazine-based sulphonamides (5a-c and 7a-f) as potential multi-target anti-inflammatory candidates. First, the furanone heterocycle in the dual CA/COX-2 inhibitor Polmacoxib was replaced with the pyridazinone one. Then, a hydrophobic tail was appended through benzylation of the 3-hydroxyl group of the pyridazinone scaffold to afford benzyloxy pyridazines 5a-c. Furthermore, the structures were adorned with the polar sulphonate functionality, in pyridazine sulphonates 7a-f, that are expected to be engaged in interactions with the hydrophilic half of the CA binding sites. All of the disclosed pyridazinones were tested for inhibitory activities against 4 hCA isoforms (I, II, IX, and XII), as well as against COX-1/2, and 5-LOX. Furthermore, in vivo anti-inflammatory and analgesic effects of pyridazinones 7a and 7b were examined.

4-(5-Amino-pyrazol-1-yl)benzenesulfonamide derivatives as novel multi-target anti-inflammatory agents endowed with inhibitory activity against COX-2, 5-LOX and carbonic anhydrase: Design, synthesis, and biological assessments.

In the current medical era, the single target inhibition paradigm of drug discovery has given way to the multi-target design concept. As the most intricate pathological process, inflammation gives rise to a variety of diseases. There are several drawbacks to the single target anti-inflammatory drugs currently available. Herein, we present the design and synthesis of a novel series of 4-(5-amino-pyrazol-1-yl)benzenesulfonamide derivatives (7a-j) with COX-2, 5-LOX and carbonic anhydrase (CA) inhibitory activities as potential multi-target anti-inflammatory agents. The pharmacophoric 4-(pyrazol-1-yl)benzenesulfonamide moiety in Celecoxib was used as the core scaffold and different substituted phenyl and 2-thienyl tails were grafted via a hydrazone linker to enhance inhibitory activity against hCA IX and XII isoforms, yielding target pyrazoles 7a-j. All reported pyrazoles were evaluated for their inhibitory activity against COX-1, COX-2, and 5-LOX. Pyrazoles 7a, 7b, and 7j showed the best inhibitory activities against the COX-2 isozyme (IC50 = 49, 60 and 60 nM, respectively) and against 5-LOX (IC50 = 2.4, 1.9, and 2.5 µM, respectively) with excellent SI indices (COX-1/COX-2) of 212.24, 208.33, and 158.33, respectively. In addition, the inhibitory activities of pyrazoles 7a-j were evaluated against four different hCA isoforms I, II, IX, and XII. Both transmembrane hCA IX and XII isoforms were potently inhibited by pyrazoles 7a-j with KI values in the nanomolar range; 13.0-82.1 nM and 5.8-62.0 nM, respectively. Furthermore, pyrazoles 7a and 7b with the highest COX-2 activity and selectivity indices were evaluated in vivo for their analgesic, anti-inflammatory, and ulcerogenic activities. The serum level of the inflammatory mediators was then measured in order to confirm the anti-inflammatory activities of pyrazoles 7a and 7b.

Rational design of biodegradable sulphonamide candidates treating septicaemia by synergistic dual inhibition of COX-2/PGE2 axis and DHPS enzyme.

A new series of co-drugs was designed based on hybridising the dihydropteroate synthase (DHPS) inhibitor sulphonamide scaffold with the COX-2 inhibitor salicylamide pharmacophore through biodegradable linkage to achieve compounds with synergistic dual inhibition of COX-2/PGE2 axis and DHPS enzyme to enhance antibacterial activity for treatment of septicaemia. Compounds 5 b, 5j, 5n and 5o demonstrated potent in vitro COX-2 inhibitory activity comparable to celecoxib. 5j and 5o exhibited ED50 lower than celecoxib in carrageenan-induced paw edoema test with % PGE2 inhibition higher than celecoxib. Furthermore, 5 b, 5j and 5n showed gastric safety profile like celecoxib. Moreover, in vivo antibacterial screening revealed that, 5j showed activity against S.aureus and E.coli higher than sulfasalazine. While, 5o revealed activity against E.coli higher than sulfasalazine and against S.aureus comparable to sulfasalazine. Compound 5j achieved the target goal as potent inhibitor of COX-2/PGE2 axis and in vivo broad-spectrum antibacterial activity against induced septicaemia in mice.

Evening Primrose Oil Enhances Tamoxifen's Anticancer Activity against Breast Cancer Cells by Inducing Apoptosis, Inhibiting Angiogenesis, and Arresting the Cell Cycle.

BACKGROUND: Despite advancements in cancer treatment, breast cancer (BC) is still one of the leading causes of death among women. The majority of anti-breast-cancer medications induce serious side effects and multidrug resistance. Although several natural compounds, such as evening primrose oil (EPO), have been shown to have anticancer properties when used alone, their combination with the anticancer medicine tamoxifen (TAM) has yet to be investigated. The present study aimed to investigate the anticancer efficacy of EPO, alone or in combination with TAM, in the BC cell lines MCF-7 and MDA-MB-231, as well as to elucidate the mechanism of action. METHODS: The MTT assay was used to investigate the cytotoxic effect of EPO on the two cell lines, and we discovered an acceptable IC50 that was comparable to TAM. The ELISA, qRT-PCR, flow cytometry and colorimetric techniques were used. RESULTS: The combination of EPO and TAM suppressed the VEGF level, VEGF gene expression and Cyclin D1 signaling pathways, arrested the cell cycle, and induced the apoptotic signaling pathways by increasing the Bax/Bcl-2 ratio and caspase 3 activity; this revealed significant anti-tumor activity. CONCLUSIONS: The most significant finding of this study was the confirmation of the anticancer activity of the natural product EPO, which potentiated the activity of the anticancer drug TAM against MCF-7 and MDA-MB-231 BC cell lines through the induction of apoptosis, inhibiting angiogenesis and halting cell proliferation.

Comparative metabolomics reveal intraspecies variability in bioactive compounds of different cultivars of pomegranate fruit (Punica granatum L.) and their waste by-products.

BACKGROUND: The different parts of pomegranate fruit are considered a powerful mixture of bioactive compounds yet the peels and pulps of the fruits are usually discarded and considered as industrial waste. In this work, ultra-performance liquid chromatography coupled with triple quadrupole mass spectrometry (UPLC-QqQ-MS) was utilized for metabolomics analysis of different parts (peel, pulp, seed and juice) of pomegranate fruit cultivars to verify possible variations among the fruits and their waste products as potential sources of functional constituents. RESULTS: Orthogonal projection to latent structure-discriminant analysis (OPLS-DA) coefficient-plot showed enrichment of phenolic compounds such as punicalagin and ellagic acid derivatives in pulp samples while seeds class was enriched in phlorizin, catechin and quercetin, juice class showed abundance of naringenin and pelargonidin-3-pentoside while peels were enriched in anthocyanins and flavonoids including cyanidin diglycoside, quercetin and luteolin glycosides. Although the juice samples of almost all tested cultivars showed remarkable cytotoxic activity, the pulp samples, particularly the Manfalouti cultivar, exhibited the most potent [half maximal inhibitory concentration (IC50 ) = 2.367 ± 0.14 µg/mL in MCF-7, IC50  = 3.854 ± 0.23 µg/mL in Hep-G2 cell lines]. OPLS models were constructed for determination of cytotoxicity-associated metabolites among where the coefficients plots revealed tannins; granatin A, ellagic acid derivatives, punicalagin α and ß, in addition to anthocyanins and phenolic compounds; cyanidin diglycoside, quercetin, phlorizin, 3-O-caffeoylquinic acid, naringenin and liquiritin were more pertinent with cytotoxicity of the different parts of pomegranate fruit. CONCLUSION: The results obtained allow for the full utilization of the resources of pomegranate fruit and its industrial waste as sources of bioactive compounds. © 2022 Society of Chemical Industry.

Baicalin; a promising chemopreventive agent, enhances the antitumor effect of 5-FU against breast cancer and inhibits tumor growth and angiogenesis in Ehrlich solid tumor.

Despite considerable advances in cancer treatment, chemotherapy remains a cornerstone in breast cancer therapy. Therefore, reducing chemoresistance and adverse effects of chemotherapy is a priority. In this regard, Baicalin (BA) is the dominant natural flavonoid extracted from the roots of Scutellaria baicalensis showed fascinating antitumor activity in many types of cancers, including breast cancer. The present study aimed to explore the chemopreventive and antitumor action of baicalin alone and in combination with 5-FU in addition to its ability to enhance the antitumor effect of 5-FU on breast cancer using the Ehrlich solid tumor-mice model. MATERIALS AND METHODS: A total of 70 female mice were divided into seven groups (1st group, saline group; 2nd group, DMSO group; 3rd group, BA+EST group; 4th group, EST group; 5th group, EST+5-FU; 6th group, EST+BA group; 7th group, EST+5-FU+BA).tumors were assessed by weight and histopathological examination. Inflammation, angiogenesis, and apoptosis were examined by ELISA, qRT-PCR, and immunohistochemical examinations. RESULTS: showed that pre-treatment with baicalin and treatment with baicalin and/or 5-FU significantly reduced inflammation and angiogenesis indicated by suppression of NF-kB/ IL-1ß and VEGF amplification loop with marked elevation in apoptosis indicated by up-regulation of apoptotic caspase-3, pro-apoptotic p53, Bax and downregulation of anti-apoptotic Bcl-2. CONCLUSION: BA is a promising preventive or adjuvant therapy in breast cancer treatment with 5-FU mainly via cooperative inhibition of inflammation, angiogenesis, and triggering apoptotic cell death.

Rosmarinic acid suppresses inflammation, angiogenesis, and improves paclitaxel induced apoptosis in a breast cancer model via NF3 κB-p53-caspase-3 pathways modulation.

Rosmarinic acid is a natural polyphenolic compound that is found in different plant species and used for different medicinal purposes. This study aimed to investigate the chemo-preventive effect of rosmarinic acid and evaluate its antitumor efficacy alone or in combination with Paclitaxel in breast cancer mice model. Ehrlich induced mice mammary solid tumor model was used in the study. Mice were treated with oral rosmarinic acid and intraperitoneal Paclitaxel. Inflammation, angiogenesis, and apoptosis were checked. Enzyme linked immunosorbent assay (ELISA), quantitative real time PCR, and immunohistochemical methods were performed. Rosmarinic acid used prior to tumor induction suppressed NF-κB, TNF-α, vascular endothelial growth factor (VEGF) serum levels, and VEGF receptors. It also triggered apoptosis by restoring the levels of P53, Bcl-2, Bax, and caspase-3. Furthermore, in Ehrlich solid tumor mice, rosmarinic acid, and/or Paclitaxel significantly suppressed tumor growth with an increase in apoptotic markers P53 and Caspase-3 levels, and suppressed the Bcl2/Bax ratio. Rosmarinic acid exerted chemo-preventive and therapeutic potential alone or in combination with Paclitaxel. Moreover, rosmarinic acid targets numerous signaling pathways associated with breast cancer.

Transforming iodoquinol into broad spectrum anti-tumor leads: Repurposing to modulate redox homeostasis.

We managed to repurpose the old drug iodoquinol to a series of novel anticancer 7-iodo-quinoline-5,8-diones. Twelve compounds were identified as inhibitors of moderate to high potency on an inhouse MCF-7 cell line, of which 2 compounds (5 and 6) were capable of reducing NAD level in MCF-7 cells in concentrations equivalent to half of their IC50s, potentially due to NAD(P)H quinone oxidoreductase (NQO1) inhibition. The same 2 compounds (5 and 6) were capable of reducing p53 expression and increasing reactive oxygen species levels, which further supports the NQO-1 inhibitory activity. Furthermore, 4 compounds (compounds 5-7 and 10) were qualified by the Development Therapeutic Program (DTP) division of the National Cancer Institute (NCI) for full panel five-dose in vitro assay to determine their GI50 on the 60 cell lines. All five compounds showed broad spectrum sub-micromolar to single digit micromolar GI50 against a wide range of cell lines. Cell cycle analysis and dual staining assays with annexin V-FITC/propidium iodide on MCF-7 cells confirmed the capability of the most active compound (compound 5) to induce cell cycle arrest at Pre-G1 and G2/M phases as well as apoptosis. Both cell cycle arrest and apoptosis were affirmed at the molecular level by the ability of compound 5 to enhance the expression levels of caspase-3 and Bax together with suppressing that of CDK1 and Bcl-2. Additionally, an anti-angiogenic effect was evident with compound 5 as supported by the decreased expression of VEGF. Interesting binding modes within NQO-1 active site had been identified and confirmed by both molecular docking and dymanic experiments.

Chemopreventive and anticancer activities of indomethacin and vitamin D combination on colorectal cancer induced by 1,2-dimethylhydrazine in rats.

Several studies have revealed that the combination of indomethacin, a nonsteroidal anti-inflammatory drug (NSAID), and vitamin D reduces the risk of common types of cancers. Nonetheless, research on the deal concentrations used to test the impact of vitamin D on colon cancer is deficient. Along these lines, the aim of the present study was to evaluate the possible role of indomethacin and vitamin D as a preventative as well as a therapeutic operator for colon cancer growth induced by dimethylhydrazine (DMH) in male Albino rats. Fifty male albino rats were utilized in this examination; five groups were assigned from the animals (10 animals each): i) control group considered healthy animals; ii) carcinogen group that received DMH only; iii) prophylactic group; iv) vitamin D and indomethacin-treated group; and v) 5-flurouracil (5-FU) group. Western blot technique was used to determine the expression of carcinoembryonic antigen (CEA) and platelet-derived growth factor (PDGF). Overexpression of CEA and PDGF was noted in the carcinogenic group, while expression of CEA and PDGF in the prophylactic, vitamin D and indomethacin and 5-FU groups were markedly reduced. There was a likewise decline in tissue caspase-3 activity and antioxidant parameters in the carcinogenic group, while, there was an increase in these markers in the 5-FU group as well as the prophylactic and vitamin D and indomethacin groups. The combination of vitamin D and indomethacin markedly reduced the incidence and severity of colon cancer. The molecular, biochemical and histopathological analysis related with the oral administration of vitamin D and indomethacin display its capacity to limit the frequency of colorectal cancer.

Synthesis and biological screening of some novel 6-substituted 2-alkylpyridazin-3(2H)-ones as anti-inflammatory and analgesic agents.

Some novel derivatives of 2-alkyl 6-substituted pyridazin-3(2H)-ones were synthesized by condensation of 3,6-dichloropyridazine with the sodium salt of benzyl cyanide, followed by hydrolysis and coupling with alkyl halides. The synthesized compounds were screened as cyclooxygenase (COX)-1/COX-2 inhibitors and as analgesic and anti-inflammatory agents. Among the synthesized compounds, 6-benzyl-2-methylpyridazin-3(2H)-one (4a), 6-benzoyl-2-propylpyridazin-3(2H)-one (8b), and 6-(hydroxy(phenyl)methyl)-2-methylpyridazin-3(2H)-one (9a) displayed the highest COX-2 selectivity indices of 96, 99, and 98, respectively, and analgesic efficacies of 47%, 46%, and 45% protection, respectively. Also, compounds 4a, 8b, and 9a showed anti-inflammatory activities of 65%, 60%, and 62% inhibition of edema, respectively, at a dose of 10 mg/kg, which is higher than that of diclofenac (58% inhibition of edema).

Hesperidin, piperine and bee venom synergistically potentiate the anticancer effect of tamoxifen against breast cancer cells.

Despite advances in cancer treatment, breast cancer remains one of the main life threatening diseases in women. Most anti-breast cancer drugs cause severe health complications and multidrug resistance. Although, some natural products, such as hesperidin (Hes), piperine (Pip) and bee venom (BV), showed anti-breast cancer effect when used separately, their combined effect together or with the anti-cancer drug tamoxifen (Tam) has not yet been studied. Herein, we hypothesized that these three natural products could potentiate the therapeutic effect of Tam when used together. First, we studied the cytotoxic effect of Hes, Pip, and BV on MCF7 and T47D cells using MTT assay and found reasonable IC50 comparable to that of Tam. Second, we checked the effect of all combinations (n = 67 for each cell line, prepared as non-constant ratio from fractions of IC50 of the four compounds) and found enhanced anti-proliferative effects on MCF7 and T47D and synergistic effect, revealed by combination index (CI) values below one. Next, the best 5 combinations with lowest Tam doses and CI but with highest cell death were selected for further molecular analysis in comparison to single-drug treatment. All single- and combined-treated groups showed a significant increase in apoptosis (indicated by upregulated mRNA level of the pro-apoptotic marker Bax and downregulated mRNA level of the anti-apoptotic marker Bcl2) and a significant decrease in mRNA level of the two breast cancer related receptors EGFR and ERα, with the best effect in combined groups especially that contained the 4 compounds, as compared to vehicle-treated group. Moreover, Pip, BV and all combinations, except Tam + Hes group, arrested MCF7 and T47D in G2/M phase of cell cycle, while Tam and/or Hes caused G0/G1 phase arrest. These results indicate that Hes, Pip and BV synergistically enhance the anti-cancer effect of Tam and could be used as safe adjuvant/vehicle to Tam in treatment of breast cancer after further confirmatory in vivo investigations.

Fingerprint profile and efficacy-associated markers of Nigella sativa oil for geographical origin determination using targeted and untargeted HPTLC-multivariate analysis.

Efficacy directed-fingerprint analysis of high-performance thin layer chromatography is proposed to set up fingerprint activity relationship modeling for precise discrimination of chemical and effective consistency of Nigella sativa oils from different geographical origins. A whole of 27 samples of N. sativa oils from three geographical area (Egypt, Ethiopia and Syria) were collected and their antimicrobial, cytotoxic, anti-inflammatory and analgesic activities were measured. The results revealed that there was significant difference in the biological activities of the oils collected. The fingerprints of the samples had been established by high performance thin layer chromatography, subsequently the data had been utilized for the discrimination of the samples geographical origin. The loading plots of HPTLC-Principal Component Analysis (PCA) had been used to discover the crucial marker ingredients for classification. Furthermore, targeted chemical fingerprints had been established by HPTLC, and discriminant analyses were calculated depending on five common characteristic peaks. The chosen markers were quantified by validated HPTLC methods, and then the quantitative data as well as the oils bioactive properties were subjected to partial least squares regression (PLSR) analyses. Thymoquinone and free fatty acids (FFA) were revealed as potential markers to distinguish the chemical consistency and efficacy of the oils from the three different geographical origins. The suggested technique provides an applicable integrated strategy to screen for efficacy-associated markers for discrimination of N. sativa oils from distinctive geographical origins exploiting HPTLC fingerprint activity relationship modeling.

Olmesartan potentiates the anti-angiogenic effect of sorafenib in mice bearing Ehrlich's ascites carcinoma: role of angiotensin (1-7).

Local renin-angiotensin systems exist in various malignant tumor tissues; this suggests that the main effector peptide, angiotensin II, could act as a key factor in tumor growth. The underlying mechanisms for the anti-angiogenic effect of angiotensin II type 1 receptor blockers need to be further evaluated. The present study was carried out to investigate the anti-angiogenic effect of olmesartan alone or in combination with sorafenib, an angiotensin (1-7) agonist or an angiotensin (1-7) antagonist in Ehrlich's ascites carcinoma-bearing mice. The tumor was induced by intradermal injection of Ehrlich's ascites carcinoma cells into mice. Tumor discs were used to evaluate the microvessel density; the serum levels of vascular endothelial growth factor (VEGF) and serum insulin-like growth factor I (IGF-I); and their intratumoral receptors, VEGF receptor-2 and IGF-I receptor, respectively. All parameters were determined following the treatment course, which lasted for 21 days post-inoculation. Monotherapy with olmesartan and its combination with sorafenib resulted in a significant reduction in microvessel density and serum levels of VEGF and IGF-I, as well as their intratumoral receptors. In addition, the combination of olmesartan (30 mg/kg) with an angiotensin (1-7) agonist reduced the microvessel density, IGF-I serum levels and the levels of its intratumoral receptor. In conclusion, olmesartan reduced the levels of the angiogenesis markers IGF-I and VEGF and down-regulated the intratumoral expression of their receptors in a dose-dependent manner, and these effects were dependent on the angiotensin (1-7) receptor. These results suggest that olmesartan is a promising adjuvant to sorafenib in the treatment of cancer.