Empagliflozin demonstrates cytotoxicity and synergy with tamoxifen in ER-positive breast cancer cells: anti-proliferative and anti-survival effects.

Accumulating evidence suggests that sodium-glucose cotransporter 2 (SGLT2) inhibitors may be effective at eliminating tumor cells. While empagliflozin exhibits nearly the highest selectivity for SGLT2 over SGLT1, its specific impact alone and in combination with tamoxifen remains largely unexplored in estrogen receptor α-positive (ERα +) breast cancer. This study investigated the anticancer effects of empagliflozin and its potential synergy with tamoxifen in MCF-7 breast cancer cells. The individual and combined cytotoxic effects of empagliflozin and tamoxifen were assessed using the xCELLigence system. The activities of AMP-activated protein kinase α (AMPKα), p38 mitogen-activated protein kinase (p38 MAPKα), p70-S6 kinase 1 (p70S6K1), and protein kinase B (Akt) were assessed using Western blotting. The gene expression levels of peroxisome proliferator-activated receptor-gamma coactivator-1α (PGC-1α) and Forkhead box O3a (FOXO3a) were assessed via qPCR. Our results revealed time- and concentration-dependent cytotoxic effects of empagliflozin and tamoxifen whether administered separately or in combination. While tamoxifen exhibits potency with an IC50 value of 17 µM, approximately ten times greater than that of empagliflozin (IC50 = 177 µM), synergistic effects are observed when the concentrations of the two agents approach their respective IC50 values. Additionally, empagliflozin significantly increases AMPKα activity while concurrently inhibiting Akt, p70S6K1, and p38 MAPKα, and these effects are significantly enhanced when empagliflozin is combined with tamoxifen. Moreover, empagliflozin modulates the gene expression, downregulating PGC-1α while upregulating FOXO3a. Empagliflozin exerts anti-proliferative and anti-survival effects by inhibiting mTOR, Akt, and PGC-1α, and it exhibits synergy with tamoxifen in MCF-7 breast cancer cells.

Detection of natural compounds by virtual screening, molecular docking and dynamics studies and evaluation of their effects on tau level in vitro Alzheimer's model.

In Alzheimer's disease (AD), neurofibrillary tangles are composed of hyperphosphorylated tau protein, and tau hyperphosphorylation reduces microtubule binding. Many protein kinases are thought to be involved in tau hyperphosphorylation. Based on the fact that tau hyperphosphorylation can be prevented by inhibition of glycogen synthase kinase-3ß (GSK-3ß), which is one of the tau kinases, the effectiveness of potential GSK-3ß inhibitors determined by virtual screening, molecular docking, and dynamics simulations studies on Alzheimer's pathology has been examined and its role in neurodegeneration has been investigated by studies. Neomangiferin was determined as the most effective molecule according to the results of studies with potential compounds determined by virtual screening and molecular docking to be GSK-3ß inhibitors in the in vitro Alzheimer's model created by neuronal differentiation studies. Neomangiferin has been shown to have a protective role in induced neurodegeneration by the MTT method and Real Time Cell Analysis. It has been determined that Neomangiferin inhibits GSK-3ß and reduces the level of phosphorylated tau. In summary, our findings suggested Neomangiferin can be a therapeutic candidate for AD treatment.Communicated by Ramaswamy H. Sarma.

Investigation of Gold Nanoparticle Naproxen-Derived Conjugations in Ovarian Cancer.

Ovarian cancer, which is one of the most diagnosed cancer types among women, maintains its significance as a global health problem. Several drug candidates have been investigated for the potential treatment of ovarian cancer. Nonsteroidal anti-inflammatory drugs (NSAIDs) demonstrated anti-cancer activity through the inhibition of cyclooxygenase 2 (COX-2) and by inhibiting COX-2-dependent prostaglandin (PG) production. Naproxen is one of the most used NSAIDs and Naproxen-derived compounds (NDCs) may show potential treatment effects on cancer as chemotherapeutic drugs. Although there are successful drug development studies, the lack of solubility of these drug candidates in aqueous media results in limited bioavailability and high variability of patient responses during treatment. Low aqueous solubility is one of the main problems in the pharmaceutical industry in terms of drug development. Nanotechnology-based strategies provide solutions to hydrophobic drug limitations by increasing dispersion and improving internalization. In this study, two different NDCs (NDC-1 and NDC-2) bearing a thiosemicarbazide/1,2,4-triazole moiety were synthesized and tested for chemotherapeutic effects on ovarian cancer cells, which have a high COX-2 expression. To overcome the limited dispersion of these hydrophobic drugs, the drug molecules were conjugated to the surface of 13 nm AuNPs. Conjugation of drugs to AuNPs increased the distribution of drugs in aqueous media, and NDC@AuNP conjugates exhibited excellent colloidal stability for up to 8 weeks. The proposed system demonstrated an increased chemotherapeutic effect than the free drug counterparts with at least 5 times lower IC50 values. NDC@AuNP nanosystems induced higher apoptosis rates, which established a simple and novel way to investigate activity of prospective drugs in drug discovery research.

Cancer and Nutrients.

Editorial: Over the last few decades, the scientific community has recognized the enormous potential of bioactive dietary nutrients/components in the management and prevention of cancer [...].

Risk factors for early onset acute kidney injury after allogeneic haematopoietic stem cell transplantation and the role of drug-drug interactions.

INTRODUCTION: Acute kidney injury (AKI) is an important and life-threatening complication following allogeneic haematopoietic stem cell transplantation (allo-HSCT). This is therefore an active research area with studies aiming to understand the factors that cause this complication. MATERIALS AND METHODS: We conducted a retrospective study to identify the factors that caused AKI in 100 patients who underwent allo-HSCT in the first 100 days after transplantation using logistic regression analysis. RESULTS: The mean time of onset of AKI was 45.58 days (range 13-97) and the mean±SD maximum serum creatinine value was 1.53±0.78 mg/dL. In 47 patients, level 1 or higher AKI occurred in the first month of transplantation and 38 of these patients were diagnosed with a higher level of AKI 31-100 days after transplantation. According to multivariate analysis, use of cyclophosphamide (adjusted odds ratio (AOR) 4.01, p=0.012), mean ciclosporin blood levels ≥250 ng/mL (AOR 2.81, p=0.022) and ciclosporin blood levels ≥450 ng/mL in the first month of transplantation (AOR 3.30, p=0.007) were found to be potential factors for early onset AKI. Ciclosporin blood levels exceeded 450 ng/mL in 35% of those using posaconazole and voriconazole during administration route change of ciclosporin. Use of ≥2 nephrotoxic anti-infective drugs (AOR 3, p=0.026) and developing AKI in the first month of transplantation (AOR 4.14, p=0.002) were found to be potential factors in the development of advanced AKI. CONCLUSION: Nephrotoxic drugs, cyclophosphamide use and ciclosporin blood levels are factors to be considered to prevent the development of AKI in patients undergoing allo-HSCT.

Neuroprotective Effects of Vapreotide on Tau Transfection-Induced Neurodegeneration.

Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by loss of neurons and synapses. The aim of this study was to investigate the effect of somatostatin analogue Vapreotide in an in vitro Alzheimer's model and its effects based on the relationship between somatostatinergic transmission and neurodegenerative functions. In this study, tau transfection was performed using the MAPT gene cloned into the pcDNA3.1 vector and transfection reagent into the SH-SY5Y cell line. In viability experiments using 10 µM Memantine as a positive control, it was observed that Vapreotide at 50 µM (p < 0.0001) and 100 µM (p < 0.05) had a protective effect on cell viability, 100 µM CYN154806 was found to decrease (p < 0.05) cell viability. It was determined that Vapreotide, decreased the expression levels (50 µM-p < 0.001; 100 µM-p < 0.001; 200 µM-p < 0.0001) and phosphorylation of Tau and p-Tau proteins by western blots. With the qRT-PCR method, it was found that Vapreotide, decreased the BAX/BCL2 (50 µM-p < 0.001; 100 µM-p < 0.01; 200 µM-p < 0.001) expression level and decreased the expression level (50 µM-p < 0.01; 100 µM-p < 0.01; 200 µM-p < 0.001) of the APOE4 gene, which constitutes a genetic risk for AD. This study demonstrates a potential therapeutic role for a somatostatin analogue Vapreotide in Alzheimer's disease.

Luteolin, a Potent Anticancer Compound: From Chemistry to Cellular Interactions and Synergetic Perspectives.

Increasing rates of cancer incidence and the toxicity concerns of existing chemotherapeutic agents have intensified the research to explore more alternative routes to combat tumor. Luteolin, a flavone found in numerous fruits, vegetables, and herbs, has exhibited a number of biological activities, such as anticancer and anti-inflammatory. Luteolin inhibits tumor growth by targeting cellular processes such as apoptosis, cell-cycle progression, angiogenesis and migration. Mechanistically, luteolin causes cell death by downregulating Akt, PLK-1, cyclin-B1, cyclin-A, CDC-2, CDK-2, Bcl-2, and Bcl-xL, while upregulating BAX, caspase-3, and p21. It has also been reported to inhibit STAT3 signaling by the suppression of STAT3 activation and enhanced STAT3 protein degradation in various cancer cells. Therefore, extensive studies on the anticancer properties of luteolin reveal its promising role in chemoprevention. The present review describes all the possible cellular interactions of luteolin in cancer, along with its synergistic mode of action and nanodelivery insight.

Assessment of clinical, biochemical, and radiological outcomes following intra-articular injection of Wharton jelly-derived mesenchymal stromal cells in patients with knee osteoarthritis: A prospective clinical study.

The aim of the present study was to perform clinical, biochemical, and radiological evaluation of the efficacy of mesenchymal stem cells derived from Wharton jelly (WJ) present within the human umbilical cord in the treatment of knee osteoarthritis. Between 2018 and 2019, 10 patients with knee osteoarthritis for whom the conservative treatment was not beneficial were included in the study. Patients were clinically, radiologically, and biochemically evaluated before treatment initiation. Thereafter, the patients were intra-articularly injected using a solution containing 1 × 108 WJ-derived MSCs. Evaluations were performed on day 21 (V1) and 42 (V2) and month 3 (V3), 6 (V4), and 12 (V5) after the procedure. At 1-year post-injection, visual analogue scale, Western Ontario and McMaster Universities Osteoarthritis Index, and Lequesne scores of patients were lower than those observed during the initial evaluation, whereas the mean 36-Item Short Form Health Survey score was higher. Cartilage thicknesses were found to be increased in all regions except in the medial femur, medial posterior femur, lateral posterior femur, and lateral posterior tibia regions in magnetic resonance imaging. A significant increase was observed in tumor necrosis factor-alpha, interleukin-1ß, adiponectin, resistin, and interleukin-6 levels compared with pre-injection values. The leptin levels at 6-month and 1-year controls were lower than the pre-injection levels, and the decrease observed at 6 months was significant. In patients with knee osteoarthritis, intra-articular WJ-derived MSC injection causes significant pain reduction, satisfactory functional improvement, and increased patient satisfaction following a 1-year follow-up. These clinical improvements were supported by magnetic resonance images, along with changes in adiponectin and leptin levels in synovial fluid. Level of evidence: IV.

Xanthorrhizol, a potential anticancer agent, from Curcuma xanthorrhiza Roxb.

BACKGROUND: Xanthorrhizol (XTZ), a bisabolene sesquiterpenoid, is abundantly found in the plant Curcuma xanthorrhiza Roxb. Traditionally, C. xanthorrhiza is widely used for the treatment of different health conditions, including common fever, infection, lack of appetite, fatigue, liver complaints, and gastrointestinal disorders. XTZ exhibits wide-ranging pharmacological activities, including anticancer, antioxidative, anti-inflammatory, antimicrobial, and antidiabetic activities, in addition to a protective effect on multiple organs. The present review provides detailed findings on the anticancer activities of XTZ and the underlying cellular and molecular mechanisms. METHODS: Literature was searched systematically in main databases following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, with keywords "tumor AND xanthorrhizol" or "cancer AND xanthorrhizol". RESULTS: Studies show that XTZ has preventive and therapeutic activities against different types of cancer, including breast, cervical, colon, liver, lung, oral and esophageal, and skin cancers. XTZ regulates multiple signaling pathways that block carcinogenesis and proliferation. In vitro and in vivo studies showed that XTZ targets different kinases, inflammatory cytokines, apoptosis proteins, and transcription factors, leading to the suppression of angiogenesis, metastasis, and the activation of apoptosis and cell cycle arrest. CONCLUSION: The potential anticancer benefits of XTZ recommend further in vivo studies against different types of cancer. Further, XTZ needs to be confirmed for its toxicity, bioavailability, protective, antifatigue, and energy booster activities. Future studies for the therapeutic development of XTZ may be directed to cancer-related fatigue.

The golden spice curcumin in cancer: A perspective on finalized clinical trials during the last 10 years.

Curcumin, the key bioactive phytochemical present in turmeric (Curcuma longa L.), is the most studied natural compound in cancer. Preclinical studies (in vitro and in vitro) and clinical trials have demonstrated curcumin's effectiveness as an anti-inflammatory agent. The existing evidence supports that curcumin inhibits the proliferation of many types of cancer cells and can play an important role in cancer therapy. This study analyses the existing evidence in the literature on finalized clinical trials (2010-2020) related to the effect of curcumin and turmeric-derived products that focused on different types of cancers, such as chronic myeloid leukemia, multiple myeloma, prostate, colorectal and pancreatic cancer as well as cancer therapy-related complications, including oral mucositis and radiation dermatitis. Original English language articles and clinical trials published between 2010 and 2020 were searched using mainstream scholarly databases, such as PubMed, ScienceDirect, Google Scholar, and ClinicalTrials.gov. The keywords, such as "curcumin," "turmeric," "cancer," "anti-inflammatory," and "clinical trials," were used in various combinations. A total of 21 clinical trials were selected, reviewed, and included in this study. Sixteen out of 21 clinical trials were associated with the effectiveness of curcumin or turmeric on various types of cancer, and the other five clinical trials were related to the evaluation of the efficacy of curcumin or turmeric in relieving the side effects of cancer chemotherapy and radiotherapy. The emerging data from the clinical trials confirm that curcumin has the potential for cancer prevention and intervention. However, it is not yet clear whether long-term curcumin supplementation has similar benefits.

STAT signaling as a target for intervention: from cancer inflammation and angiogenesis to non-coding RNAs modulation.

As a landmark, scientific investigation in cytokine signaling and interferon-related anti-viral activity, signal transducer and activator of transcription (STAT) family of proteins was first discovered in the 1990s. Today, we know that the STAT family consists of several transcription factors which regulate various molecular and cellular processes, including proliferation, angiogenesis, and differentiation in human carcinoma. STAT family members play an active role in transducing signals from cell membrane to nucleus through intracellular signaling and thus activating gene transcription. Additionally, they are also associated with the development and progression of human cancer by facilitating inflammation, cell survival, and resistance to therapeutic responses. Accumulating evidence suggests that not all STAT proteins are associated with the progression of human malignancy; however, STAT3/5 are constitutively activated in various cancers, including multiple myeloma, lymphoma, breast cancer, prostate hepatocellular carcinoma, and non-small cell lung cancer. The present review highlights how STAT-associated events are implicated in cancer inflammation, angiogenesis and non-coding RNA (ncRNA) modulation to highlight potential intervention into carcinogenesis-related cellular processes.

Isolation, Characterization and in Silico Studies of Secondary Metabolites from Jurinea macrocephala DC. with Antiproliferative Activity.

In the present work, cytotoxic potential of Jurinea macrocephala DC. (Asteraceae) was evaluated on A549 lung cancer and MCF-7 breast cancer cell lines. Isolation studies were carried out using various and repetitive chromatographic methods in order to determine the phytochemical profile of the extracts. These studies led to the identification of twelve compounds; four triterpenes (1-4) and eight flavonoids (5-12). Spectroscopic examination (1D and 2D NMR, ESI-MS) and comparison with relevant literature data were used to deduce the structures of all isolated molecules. To rationalize the obtained cytotoxicity data against breast cancer cell lines, the isolated compounds were docked into the binding site of aromatase, an important target enzyme for the treatment of breast cancer. Molecular docking studies revealed that flavonoids without sugar moieties (5-8) showed the best binding affinities. Overall, these mentioned compounds turned out to be also the most appropriate oral drug candidates after the calculation of their Lipinski parameters.

Novel Strategies for the Bioavailability Augmentation and Efficacy Improvement of Natural Products in Oral Cancer.

Oral cancer is emerging as a major cause of mortality globally. Oral cancer occupies a significant proportion of the head and neck, including the cheeks, tongue, and oral cavity. Conventional methods in the treatment of cancer involve surgery, radiotherapy, and immunotherapy, and these have not proven to completely eradicate cancerous cells, may lead to the reoccurrence of oral cancer, and possess numerous adverse side effects. Advancements in novel drug delivery approaches have gained popularity in cancer management with an increase in the number of cases associated with oral cancer. Natural products are potent sources for drug discovery, especially for anticancer drugs. Natural product delivery has major challenges due to its low solubility, poor absorption, inappropriate size, instability, poor permeation, and first-pass metabolism. Therefore, it is of prime importance to investigate novel treatment approaches for the delivery of bioactive natural products. Nanotechnology is an advanced method of delivering cancer therapy with minimal damage to normal cells while targeting cancer cells. Therefore, the present review elaborates on the advancements in novel strategies for natural product delivery that lead to the significant enhancement of bioavailability, in vivo activity, and fewer adverse events for the prevention and treatment of oral cancer. Various approaches to accomplish the desired results involve size reduction, surface property modification, and polymer attachment, which collectively result in the higher stability of the formulation.

Role of Hypericum perforatum oil and pomegranate seed oil in wound healing: an in vitro study.

This study aimed to investigate the wound-healing efficacy of Hypericum perforatum and pomegranate seed extract oil combined with curcumin as an anti inflammatory agent. A series of experiments were carried out to determine effective concentrations for H. perforatum oil, pomegranate seed extract oil, and curcumin. Ibuprofen was used as a positive control. The wound-healing effects of the applied compounds were tested according to the migration experiment model performed in HaCaT cells. A real-time cell analyzer (xCELLigence) was used to determine the cytotoxic/proliferative effects of H. perforatum, pomegranate seed oil, ibuprofen, and curcumin in HaCaT cells alone and their combined use at specified concentrations. After examining the noncytotoxic concentrations of H. perforatum oil, pomegranate seed oil, curcumin, and ibuprofen, migration experiments were performed to examine the wound healing properties. According to the results, the wound-healing efficacy of curcumin and H. perforatum combination was better than ibuprofen combinations. Also, according to the results, the wound-healing efficacy of curcumin and pomegranate seed oil combination was better than ibuprofen combinations. It was concluded that both oils had improved wound-healing properties in combination with curcumin or Ibuprofen.

Gallic Acid: A Dietary Polyphenol that Exhibits Anti-neoplastic Activities by Modulating Multiple Oncogenic Targets.

Phytochemicals are being used for thousands of years to prevent dreadful malignancy. Side effects of existing allopathic treatment have also initiated intense research in the field of bioactive phytochemicals. Gallic acid, a natural polyphenolic compound, exists freely as well as in polymeric forms. The anti-cancer properties of gallic acid are indomitable by a variety of cellular pathways such as induction of programmed cell death, cell cycle apprehension, reticence of vasculature and tumor migration, and inflammation. Furthermore, gallic acid is found to show synergism with other existing chemotherapeutic drugs. Therefore, the antineoplastic role of gallic acid suggests its promising therapeutic candidature in the near future. The present review describes all these aspects of gallic acid at a single platform. In addition nanotechnology-mediated approaches are also discussed to enhance bioavailability and therapeutic efficacy.

Anti-Inflammatory and Anticancer Properties of Birch Bark-Derived Betulin: Recent Developments.

Birch tree bark-derived betulin has attracted scientific interest already for several centuries, being one of the first natural products identified from plants. However, the cellular events regulated by betulin and precise molecular mechanisms under these processes have been begun to be understood only recently. Today, we know that betulin can exert important anticancer activities through modulation of diverse cellular pathways. In this review article, betulin-regulated molecular signaling is unraveled and presented with a special focus on its participation in anti-inflammatory processes, especially by modulating nuclear factor-κB (NF-κB), prostaglandin/COX, and nuclear factor erythroid2-related factor 2 (Nrf2)-mediated cascades. By regulating these diverse pathways, betulin can not only affect the development and progression of different cancers, but also enhance the antitumor action of traditional therapeutic modalities. It is expected that by overcoming the low bioavailability of betulin by encapsulating it into nanocarriers, this promising natural compound may provide novel possibilities for targeting inflammation-related cancers.

Doxazosin and erlotinib have anticancer effects in the endometrial cancer cell and important roles in ERα and Wnt/ß-catenin signaling pathways.

ERα and Wnt/ß-catenin pathways are critical for the progression of most endometrial cancers. We aimed to investigate the cytotoxic and apoptotic effects of tamoxifen and quinazoline derivative drugs of doxazosin and erlotinib, and their roles in ERα and Wnt/ß-catenin signaling pathways in human endometrial cancer RL 95-2 cell. 3-(4,5-Dimethylthiazol-2yl)-2,5-diphenyltetrazolium bromide assay and xCELLigence systems were performed to evaluate cytotoxicity. Furthermore, apoptotic induction was tested by Annexin V analysis. Caspase-3 and -9 activity and changes in the mitochondrial membrane potential were evaluated. The level of reactive oxygen species was measured by incubating with dichlorofluorescein diacetate. Protein ratios of p-ERα/ERα, GSK3ß/p-GSK3ß, and p-ß-catenin/ß-catenin and expression levels of ESR1, EGFR, c-Myc genes were evaluated to elucidate mechanisms in signaling pathways. We found that the tested drugs showed cytotoxic and apoptotic effects in the cells. Doxazosin significantly reduced ESR1 expression, slightly reduced the p-ß-catenin/ß-catenin ratio and c-Myc expression. Erlotinib significantly increased c-Myc expression while significantly decreasing the p-ß-catenin/ß-catenin and p-ERα/ERα ratio, and ESR1 expression. However, we observed that the cells develop resistance to erlotinib over a certain concentration, suggesting that ERα, ESR1, EGFR, and c-Myc may be a new target for overcoming drug resistance in the treatment of endometrial cancer. We also observed that erlotinib and doxazosin play an important role in the ERα signaling pathway and can act as potent inhibitors of PKA and/or tyrosine kinase in the Wnt/ß-catenin signaling pathway in RL 95-2 cell. In conclusion, doxazosin and erlotinib may have a possible therapeutic potential in human endometrial cancer.

In vitro biological activity of Salvia fruticosa Mill. infusion against amyloid ß-peptide-induced toxicity and inhibition of GSK-3ß, CK-1δ, and BACE-1 enzymes relevant to Alzheimer's disease.

Salvia species have been traditionally used to improve cognition and have been proved to be a potential natural treatment for Alzheimer's disease. Salvia fruticosa Mill. (Turkish sage or Greek sage) demonstrated to have anticholinergic effects in vitro. The aim of this study was to understand the mechanism underlying the neuroprotective effects of S. fruticosa infusion and its representative compound rosmarinic acid, which was detected by LC-DAD-ESI-MS/MS. The protective effects of the S. fruticosa infusion (SFINF) and its major substance rosmarinic acid (RA) on amyloid beta 1-42 -induced cytotoxicity on SH-SY5Y cells together with p-GSK-3ß activation were investigated. Their in vitro inhibitory effects against glycogen synthase kinase 3ß, ß-secretase, and casein kinase 1δ enzymes were also evaluated. The results showed that treatment with the all tested concentrations, SFINF significantly decreased Aß 1-42-induced cytotoxicity and exhibited promising in vitro glycogen synthase kinase 3ß inhibitory activity below 10 µg/mL (IC50 6.52 ± 1.14 µg/mL), in addition to ß-secretase inhibition (IC50 86 ± 2.9 µg/mL) and casein kinase 1δ inhibition (IC50 121.57 ± 4.00). The SFINF (100 µg/mL and 250 µg/mL) also activated the expression of p-GSK-3ß in amyloid beta 1-42 treated SH-SY5Y cells. The outcomes of this study demonstrated that the S. fruticosa infusion possessed activity to prevent amyloid beta 1-42 -induced neurotoxicity and provided proof that its mechanism may involve regulation of p-GSK-3ß protein.