Oral co-polymeric raft-forming nano gels for targeted empagliflozin delivery against stomach cancer (SGC7901).

Empagliflozin (EMP) is known for its poor safety and efficacy profile due to its fast body distribution and poor solubility. Accordingly, an oral long-acting and floating/raft-forming nano gel was optimized to release coated EMP nanoparticles, and the released EMP nanoparticles showed enhanced dissolution compared to raw EMP particles. To repurpose EMP for cancer treatment, EMP shows anti-cancer and anti-inflammatory effects against cancer cells. EMP nanoparticles were characterized using FT-IR, PXRD, SEM, EMP encapsulation assay, and release studies. The raft-forming gel encapsulating the EMP was optimized and characterized. The EMP co-polymeric nanoparticles were studied to investigate EMP anti-cancer and anti-inflammatory activities against stomach cancer cells. The solubility of EMP nanoparticles was enhanced in 0.1 N HCl and pH 6.8 by 5 and 12 folds, respectively, compared to raw EMP powder. The particle size and zeta-potential values of improved EMP nanoparticles were 135.40 ± 18.60 nm, and -19.30 ± 0.80 mV, respectively. FT-IR, PXRD, SEM and TEM characterizations revealed polymeric coating of EMP particles. The study suggested that this optimized controlled-release raft-forming gel is a promising local oral approach against stomach cancer. The repurposing of EMP co-polymeric nanoparticles for stomach cancer and associated gastritis treatment was justified.

Parthenolide alleviates indomethacin-induced gastric ulcer in rats via antioxidant, anti-inflammatory, and antiapoptotic activities.

Parthenolide (PTL) is a sesquiterpene lactone that occurs naturally. It demonstrates a variety of beneficial effects, such as antioxidant, anti-inflammatory, and antiapoptotic properties. The study investigated the potential protective impact of PTL on indomethacin (INDO) induced stomach ulcers in rats. The rats were classified into 5 distinct categories. Group 1 served as the "control" group. Rats in the second group received a single oral dosage of INDO (50 mg kg-1). Rats in Groups three and four received 20 and 40 mg kg-1 oral PTL 1 h before INDO. Omeprazole (30 mg kg-1) was given orally to Group 5 rats 1 h before INDO. Pretreatment with PTL increased stomach pH and decreased gastric volume as well as reduced the morphological and histological changes induced by INDO. Analysis of probable pathways showed that pre-treatment with PTL successfully reduced oxidative, inflammatory, and apoptotic consequences caused by INDO. The ingestion of PTL leads to a notable increase in the levels of glutathione reduced (GSH) and the activities of superoxide dismutase (SOD) and catalase (CAT). Furthermore, PTL decreased the concentration of malondialdehyde (MDA). In contrast, it was shown that PTL increased both cyclooxygenase-1 (COX-1) and prostaglandin E2 (PGE2). PTL shows a significant decrease in the expression of interleukin-1 beta (IL-1ß), tumor necrosis factor-alpha (TNF-α), inducible nitric oxide synthase (iNOS), and nuclear factor kappa B (NF-κB). PTL therapy resulted in a decrease in Bcl-2-associated X protein (Bax) levels and an increase in B-cell lymphoma 2 (Bcl2) levels. In conclusion, PTL offers gastroprotection by its antioxidant, anti-inflammatory, and anti-apoptotic qualities.

Cordycepin- melittin nanoconjugate intensifies wound healing efficacy in diabetic rats.

The current study was designed to develop a nanoconjugate of cordycepin-melittin (COR-MEL) and assess its healing property in wounded diabetic rats. The prepared nanoconjugate has a particle size of 253.5 ± 17.4 nm with a polydispersity index (PDI) of 0.35 ± 0.04 and zeta potential of 17.2 ± 0.3 mV. To establish the wound healing property of the COR-MEL nanoconjugate, animal studies were pursued, where the animals with diabetes were exposed to excision and treated with COR hydrogel, MEL hydrogel, or COR-MEL nanoconjugate topically. The study demonstrated an accelerated wound contraction in COR-MEL nanoconjugate -treated diabetic rats, which was further validated by histological analysis. The nanoconjugate further exhibited antioxidant activities by inhibiting the accumulation of malondialdehyde (MDA) and exhaustion of superoxide dismutase (SOD) and glutathione peroxidase (GPx) enzymatic activities. The nanoconjugate further demonstrated an enhanced anti-inflammatory activity by retarding the expression of interleukin (IL)-6 and tumor necrosis factor (TNF)-α. Additionally, the nanoconjugate exhibits a strong expression of transforming growth factor (TGF)-ß1, vascular endothelial growth factor (VEGF)-A, and platelet-derived growth factor (PDGFR)-ß, indicating enrichment of proliferation. Likewise, nanoconjugate increased the concentration of hydroxyproline as well as the mRNA expression of collagen, type I, alpha 1 (Col 1A1). Thus, it is concluded that the nanoconjugate possesses a potent wound-healing activity in diabetic rats via antioxidant, anti-inflammatory, and pro-angiogenetic mechanisms.

Lipid-Based Nanoparticles as a Pivotal Delivery Approach in Triple Negative Breast Cancer (TNBC) Therapy.

Triple-negative breast cancer is considered the most aggressive type of breast cancer among women and the lack of expressed receptors has made treatment options substantially limited. Recently, various types of nanoparticles have emerged as a therapeutic option against TNBC, to elevate the therapeutic efficacy of the existing chemotherapeutics. Among the various nanoparticles, lipid-based nanoparticles (LNPs) viz. liposomes, nanoemulsions, solid lipid nanoparticles, nanostructured lipid nanocarriers, and lipid-polymer hybrid nanoparticles are developed for cancer treatment which is well confirmed and documented. LNPs include various therapeutic advantages as compared to conventional therapy and other nanoparticles, including increased loading capacity, enhanced temporal and thermal stability, decreased therapeutic dose and associated toxicity, and limited drug resistance. In addition to these, LNPs overcome physiological barriers which provide increased accumulation of therapeutics at the target site. Extensive efforts by the scientific community could make some of the liposomal formulations the clinical reality; however, the relatively high cost, problems in scaling up the formulations, and delivery in a more targetable fashion are some of the major issues that need to be addressed. In the present review, we have compiled the state of the art about different types of LNPs with the latest advances reported for the treatment of TNBC in recent years, along with their clinical status and toxicity in detail.

Piceatannol SNEDDS Attenuates Estradiol-Induced Endometrial Hyperplasia in Rats by Modulation of NF-κB and Nrf2/HO-1 Axes.

Endometrial hyperplasia (EH) is the most common risk factor for endometrial malignancy in females. The pathogenesis of EH has been directly linked to uterine inflammation, which can result in abnormal cell division and decreased apoptosis. Piceatannol (PIC), a natural polyphenolic stilbene, is known to exert anti-inflammatory, antioxidant and anti-proliferative activities. The aim of the present study was to examine the potential preventive role of PIC in estradiol benzoate (EB)-induced EH in rats. A self-nanoemulsifying drug delivery system (SNEDDS) was prepared to improve the solubility of the PIC. Therefore, thirty female Wistar rats were divided into five groups: (1) control, (2) PIC SNEDDS (10 mg/kg), (3) EB (0.6 mg/kg), (4) EB + PIC SNEDDS (5 mg/kg) and (5) EB + PIC SNEDDS (10 mg/kg). The administration of PIC SNEDDS prevented EB-induced increases in uterine weights and histopathological changes. Additionally, it displayed pro-apoptotic and antioxidant activity in the endometrium. Immunohistochemical staining of uterine sections co-treated with PIC SNEDDS showed significantly decreased expression of tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6) and nuclear transcription factor-kappa B (NF-κB). This anti-inflammatory effect was further confirmed by a significant increase in Nrf2 and heme oxygenase-1 (HO-1) expression. These results indicate that SNEDDS nanoformulation of PIC possesses protective effects against experimentally induced EH.

Piceatannol Affects Gastric Ulcers Induced by Indomethacin: Association of Antioxidant, Anti-Inflammatory, and Angiogenesis Mechanisms in Rats.

One of the major aggressive factors that affect gastric injury is non-steroidal anti-inflammatory drugs (NSAIDs). Indomethacin (Indo) showed higher potentiality in gastric injury over conventional NSAIDs. Piceatannol (PIC) is a natural polyphenolic stilbene that possesses potent antioxidant and anti-inflammatory properties. The gastroprotective properties of PIC have been overlooked previously. Hence, we aim to study gastric injury induced by Indo and the protective action manifested by PIC, as well as to elucidate the likely underlying mechanisms of action in a rat model. The rats have been treated with vehicle, Indo alone, combined treatment with Indo, and PIC at (5 mg/kg or 10 mg/kg), respectively. The rats were also treated with Indo and omeprazole. In our study, we found that PIC at both 5 and 10 mg/kg doses was effective by averting the rise in ulcer and lesion indices, acid production, and histological variations persuaded by Indo. Mechanistically, PIC significantly reduced lipid peroxidation product (MDA), increased the GSH content, and enhanced SOD and CAT activity. In addition, PIC exhibits a distinct reduction in the levels of inflammatory parameters (Cox-2, IL-6, TNF-α, and NFκB). Contrastingly, PIC augmented both mucin and PGE2 content. Moreover, PIC fostered angiogenesis by increasing the expression of proangiogenic factors (VEGF, bFGF, and PDGF). Overall, the above results suggest PIC exhibits a potential protective effect against Indo-induced gastric ulcers by the antioxidant, anti-inflammatory, and angiogenic mechanisms.

Mokko Lactone Alleviates Doxorubicin-Induced Cardiotoxicity in Rats via Antioxidant, Anti-Inflammatory, and Antiapoptotic Activities.

Doxorubicin (DOX), a commonly utilized anthracycline antibiotic, suffers deleterious side effects such as cardiotoxicity. Mokko lactone (ML) is a naturally occurring guainolide sesquiterpene with established antioxidant and anti-inflammatory actions. This study aimed at investigating the protective effects of ML in a DOX-induced cardiotoxicity model in rats. Our results indicated that ML exerted protection against cardiotoxicity induced by DOX as indicated by ameliorating the rise in serum troponin and creatine kinase-MB levels and lactate dehydrogenase activity. Histological assessment showed that ML provided protection against pathological alterations in heart architecture. Furthermore, treatment with ML significantly ameliorated DOX-induced accumulation of malondialdehyde and protein carbonyl, depletion of glutathione, and exhaustion of superoxide dismutase and catalase. ML's antioxidant effects were accompanied by increased nuclear translocation of NF-E2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) expression. Moreover, ML exhibited significant anti-inflammatory activities as evidenced by lowered nuclear factor κB, interleukin-6, and tumor necrosis factor-α expression. ML also caused significant antiapoptotic actions manifested by modulation in mRNA expression of Bax, Bcl-2, and caspase-3. This suggests that ML prevents heart injury induced by DOX via its antioxidant, anti-inflammatory, and antiapoptotic activities.

Formulation, Optimization and Evaluation of Cytarabine-Loaded Iron Oxide Nanoparticles: From In Vitro to In Vivo Evaluation of Anticancer Activity.

Innovative drug delivery systems based on iron oxide nanoparticles (INPs) has generated a lot of interest worldwide and have prime biomedical benefits in anticancer therapy. There are still issues reported regarding the stability, absorption, and toxicity of iron oxide nanoparticles (INPs) when administered due to its rapid surface oxidation and agglomeration with blood proteins. To solve this problem, we have synthesized trehalose-coated stabilized iron oxide nanoparticles (TINPs) by a co-precipitation technique. The surface coating of INPs with trehalose helps to improve the stability, prevents protein binding, and increase absorption uptake inside the body. Developed TINPs was then loaded with anticancer drug cytarabine by chemical crosslinking encapsulation method using suitable solvent. Engineered cytarabine-loaded trehalose-coated stabilized iron oxide nanoparticles (CY-TINPs) were optimized for particle size, zeta potential (-13.03 mV), and solid-state characterization such as differential scanning calorimetry (DSC), X-ray powder diffraction (XRD), and transmission electron microscope (TEM) studies. The particle size of 50 nm was achieved for developed CY-TINPs. The developed CY-TINPs was further evaluated for in vitro cell line investigations which confirmed potential cytotoxic activity. Developed CY-TINPs show remarkable enhancement in in vivo pharmacokinetic parameters Cmax as 425.26 ± 2.11 and AUC0-72 as 11,546.64 ± 139.82 as compared to pure drug. Compared to traditional drug delivery, the CY-TINPs formulation can effectively delay release, improve bioavailability, and boost cytotoxic activity against tumors.

Development, Optimization, and In Vitro Evaluation of Novel Oral Long-Acting Resveratrol Nanocomposite In-Situ Gelling Film in the Treatment of Colorectal Cancer.

This study aimed to develop and evaluate sustained-release (SR) long-acting oral nanocomposites in-situ gelling films of resveratrol (Rv) to treat colorectal cancer. In these formulations, Rv-Soy protein (Rv-Sp) wet granules were prepared by the kneading method and then encapsulated in the sodium alginate (NA) dry films. The prepared nanocomposite in-situ gels films were characterized using dynamic light scattering, Fourier-transform infrared spectroscopy, X-ray diffraction, and scanning electron microscopy. The optimized formulations were further evaluated based on drug encapsulation efficiency, pH-drug release profile, swelling study, and storage time effects. The optimized formulation was tested for its anticancer activity against colorectal cancer cells using the cytotoxicity assessment, apoptosis testing, cell cycle analysis, gene expression analysis, and protein estimation by the reverse-transcriptase polymerase chain reaction and enzyme-linked immunosorbent assay methods, respectively. The optimum film showed encapsulation efficiency of 97.87% ± 0.51 and drug release of 14.45% ± 0.043 after 8 h. All physiochemical characterizations confirmed, reasoned, and supported the drug release experiment's findings and the encapsulation assay. The Rv nanocomposite formulation showed concentration-dependent cytotoxicity enhanced apoptotic activity as compared to free Rv (p < 0.05). In addition, Rv nanocomposite formulation caused a significant increase in Bcl-2-associated protein X (Bax) and a decrease in expression of B-cell lymphoma 2, interleukin 1 beta, IL-6, and tumor necrosis factor-alpha (Bcl2, IL-1ß, IL-6, and TNF-α respectively) compared to that of free Rv in HCT-116 cells. These results suggest that long-acting Rv nanocomposite gels could be a promising agent for colorectal cancer treatment.

Development and Evaluation of Repurposed Etoricoxib Loaded Nanoemulsion for Improving Anticancer Activities against Lung Cancer Cells.

In the present work, novel modality for lung cancer intervention has been explored. Primary literature has established the potential role of cyclooxygenase-2 (COX-2) inhibitor in regression of multiple forms of carcinomas. To overcome its poor water solubility and boost anticancer activity, etoricoxib (ETO) was chosen as a therapeutic candidate for repurposing and formulated into a nanoemulsion (NE). The prepared ETO loaded NE was characterized for the surface charge, droplet size, surface morphology, and in vitro release. The optimized ETO loaded NE was then investigated for its anticancer potential employing A549 lung cancer cell line via cytotoxicity, apoptotic activity, mitochondrial membrane potential activity, cell migration assay, cell cycle analysis, Caspase-3, 9, and p53 activity by ELISA and molecular biomarker analysis through RT-PCR test. The developed ETO-NE formulation showed adequate homogeneity in the droplet size distribution with polydispersity index (PDI) of (0.2 ± 0.03) and had the lowest possible droplet size (124 ± 2.91 nm) and optimal negative surface charge (-8.19 ± 1.51 mV) indicative of colloidal stability. The MTT assay results demonstrated that ETO-NE exhibited substantial anticancer activity compared to the free drug. The ETO-NE showed a substantially potent cytotoxic effect against lung cancer cells, as was evident from the commencement of apoptosis/necrotic cell death and S-phase cell cycle arrests in A549 cells. The study on these molecules through RT-PCR confirmed that ETO-NE is significantly efficacious in mitigating the abundance of IL-B, IL-6, TNF, COX-2, and NF-kB as compared to the free ETO and control group. The current study demonstrates that ETO-NE represents a feasible approach that could provide clinical benefits for lung cancer patients in the future.

Mokko Lactone Attenuates Doxorubicin-Induced Hepatotoxicity in Rats: Emphasis on Sirt-1/FOXO1/NF-κB Axis.

Doxorubicin (DOX), a common chemotherapeutic agent, suffers serious adverse effects including hepatotoxicity. Mokko lactone (ML) is a guainolide sesquiterpene with promising biological activities. The study aimed to evaluate the protection offered by ML against hepatotoxicity induced by DOX in rats. Our data indicated ML exhibited protective effects as evidenced by ameliorating the rise in serum activities of alanine transaminase, aspartate transaminase and alkaline phosphatase. This was confirmed histologically as ML prevented DOX-induced pathological alteration in liver architecture. Further, ML administration significantly prevented malondialdehyde accumulation, glutathione depletion and superoxide dismutase and catalase exhaustion. Antioxidant action of ML was associated with enhanced expression of the nuclear translocation of NF-E2-related factor 2 (Nrf2) and a lower expression of forkhead box protein O1 (FOXO1). Also, ML showed potent anti-inflammatory activities highlighted by decreased expression of interleukin 6, tumor necrosis factor α and nuclear factor κB (NF-κB). The anti-apoptotic effects of ML were associated with decreased Bax and enhanced Bcl-2 mRNA expression in liver tissues. ML caused a significant up-regulation in the expression of silent information regulator 1 (Sirt-1). Therefore, it can be concluded that ML prevents liver injury caused by DOX. This could partially be due to the ML regulatory activities on Sirt-1/FOXO1/NF-κB axis.

Auraptene nanoparticles ameliorate testosterone-induced benign prostatic hyperplasia in rats: Emphasis on antioxidant, anti-inflammatory, proapoptotic and PPARs activation effects.

Benign prostatic hyperplasia (BPH) is a disease that commonly strikes the majority of aged men. Developing new therapies to manage BPH with improved efficacy and safety is strongly needed. In this regard, auraptene is a natural compound with multiple pharmacological effects, but with poor oral bioavailability. This investigation aimed to assess the possible protection offered by auraptene-nanostructured lipid carrier (auraptene-NLC) in a BPH model induced by testosterone in rats. Auraptene-NLC had optimum particle size and drug release profile compared to raw auraptene. At doses (5 and 10 mg/kg), it hampered the rise in prostatic weights & indices relative to rats challenged with testosterone. Moreover, auraptene-NLC alleviated histopathological abnormalities in prostate architecture and decreased the glandular epithelial height. Additionally, testosterone-induced oxidative stress was alleviated by auraptene-NLC and inhibited raised lipid peroxidation, catalase and superoxide dismutase exhaustion as well as enhanced glutathione content. Moreover, it significantly reduced the prostate content of nuclear factor κB, Interleukins1ß & 6, as well as transforming growth factor ß, compared to testosterone group. The proapoptotic activity of auraptene-NLC (10 mg/kg) was confirmed by a significant increase of prostate cleaved caspase-3, boosted Bax/Bcl2 mRNA ratio that was further confirmed by assessing their protein expressions. Furthermore, the beneficial effects of auraptene-NLC against BPH were substantiated by ameliorating testosterone-induced decline of nuclear PPARα & PPARγ and inhibiting the increased expression of cyclin D1 protein. In conclusion, auraptene-NLC offers a protective effect in rats whereby BPH was induced by testosterone, via its anti-inflammatory, antioxidant and proapoptotic activities, and PPAR family activation.