A natural compound from Hydnophytum formicarium induces apoptosis of MCF-7 cells via up-regulation of Bax

<p>Abstract</p> <p>Background</p> <p><it>Hydnophytum formicarium </it>Jack is an epyphytic shrub that belongs to the family of Rubiaceae and is native to the tropical rain forests of the Asean region, which includes Malaysia. A flavanoid derivative, 7, 3', 5'-trihydroxyflavanone (3HFD), isolated from <it>H. formicarium </it>has been reported to have cytotoxic effects on the human breast carcinoma cell line MCF-7. The aim of the current study was to investigate the mode of cell death in MCF-7 cells treated with 3HFD. A DNA fragmentation assay was conducted on isolated genomic DNA, a TUNEL assay was used to determine the mode of cell death and Western blotting was used to evaluate the expression levels of Bax and Bcl-2. Immunofluorescence staining of MCF-7 cells was also performed to confirm the up-regulation of the Bax protein.</p> <p>Results</p> <p>The ladder pattern resulting from the DNA fragmentation assay was a multimer of 180 kb. The morphological changes of cells undergoing apoptosis were visualised by a TUNEL assay over time. The percentage of apoptotic cells increased as early as 6 hours post treatment compared to untreated cells. Western blotting revealed up-regulation of the pro-apoptotic protein Bax. However, 3HFD did not affect expression of the anti-apoptotic protein Bcl-2.</p> <p>Conclusions</p> <p>Our results provide evidence that plant-derived 3HFD was able to induce the apoptotic cell death of MCF-7 cells by increasing Bax expression level and makes 3HFD a promising agent for chemotherapy, which merits further study.</p

QSAR studies of macrocyclic diterpenes with P-glycoprotein inhibitory activity

Multidrug resistance (MDR) represents a major limitation for cancer chemotherapy. There are several mechanisms of MDR but the most important is associated with P-glycoprotein (P-gp) overexpression. The development of modulators of P-gp that are able to re-establish drug sensitivity of resistant cells has been considered a promising approach for overcoming MDR. Macrocyclic lathyrane and jatro phane-type diterpenes from Euphorbia species were found to be strong MDR reversing agents. In this study we applied quantitative structure–activity relationship (QSAR) methodology in order to identify the most relevant molecular features of macrocyclic diterpenes with P-gp inhibitory activity and to deter mine which structural modifications can be performed to improve their activity. Using experimental bio logical data at two concentrations (4 and 40 lg/ml), we developed a QSAR model for a set of 51 bioactive diterpenic compounds which includes lathyrane and jatrophane-type diterpenes and another model just for jatrophanes. The cross-validation correlation values for all diterpenes QSAR models developed for bio logical activities at compound concentrations of 4 and 40 lg/ml were 0.758 and 0.729, respectively. Regarding the prediction ability, we get R2 pred values of 0.765 and 0.534 for biological activities at com pound concentrations of 4 and 40 lg/ml, respectively. Applying the cross-validation test to jatrophanes QSAR models, we obtained 0.680 and 0.787 for biological activities at compound concentrations of 4 and 40 lg/ml concentrations, respectively. For the same concentrations, the obtained R2 pred values for jatro phanes models were 0.541 and 0.534, respectively. The obtained models were statistically valid and showed high prediction ability.info:eu-repo/semantics/publishedVersio

The Anticancer Activity of the Old Neuroleptic Phenothiazine-type Drug Thioridazine

Thioridazine (TZ), an antipsychotic drug, renders multidrug-resistant (MDR) cancer cells susceptible to cytotoxic agents to which they were initially resistant, has anti-prolilferative activity and apoptosis- inducing properties in various tumor cell lines and cancer stem cells. Whereas the anti-proliferative activity takes place at high concentrations that ensure the intercalation of the compound between nucleic bases (especially rich in G/C bases), much lower concentrations inhibit the export function of the ABCB1 (P-glycoprotein), which is responsible for the MDR phenotype of the cancer cell. The co-administration of TZ with doxorubicin inhibits efflux of doxorubicin and, hence increases the intracellular concentration of anticancer drug. The (+) and (-) enantiomers of TZ have the same activities as TZ. The main focus of this review is to present extensive evidence provided by our work, confirmed by much later studies, as it supports adjuvant use of TZ with an anticancer drug for MDR cancer therapy

Biological activity of hydantoin derivatives on P-Glycoprotein (ABCB1) of mouse lymphoma cells

Background: Hydantoin derivatives possess a variety of biochemical and pharmacological properties. Although hydantoin compounds are studied extensively, there are not many studies that investigate their anticancer properties. Materials and Methods: Thirty hydantoin compounds were evaluated for their efflux modulating effects in cancer cells using a rhodamine 123 accumulation assay and real-time fluorometry based on the intracellular accumulation of ethidium bromide. Results: The 30 derivatives were screened by real-time fluorometry for rhodamine 123 accumulation. Among the selected derivatives, compounds SZ-7, LL-9, BS-1, MN-3, P3, RW- 15b, AD-26, RW-13, AD-29 and KF-2 significantly increased the retention of rhodamine 123. Compounds AD-26, AD-29, RW-13, KF-2, BS-1, MN-3, RW-15b and JH-63 showed synergistic effect with doxorubicin on mouse lymphoma cells. Furthermore, compound SZ-7 had indifferent effect with doxorubicin. Conclusion: These results indicated the role of chemical modifications within the hydantoin ring for its potential inhibition of the ABCB1 transporter. The most active structures contained aromatic substituents as well as some tertiary amine fragments

Safety and pharmacokinetics of MM-302, a HER2-targeted antibody–liposomal doxorubicin conjugate, in patients with advanced HER2-positive breast cancer: A phase 1 dose-escalation study

BackgroundThis phase 1 dose-escalation trial studied MM-302, a novel HER2-targeted PEGylated antibody-liposomal doxorubicin conjugate, in HER2-positive locally advanced/metastatic breast cancer.MethodsPatients were enrolled in four cohorts: MM-302 monotherapy (8, 16, 30, 40, and 50 mg/m2 every 4 weeks [q4w]); MM-302 (30 or 40 mg/m2 q4w) plus trastuzumab (4 mg/kg q2w); MM-302 (30 mg/m2) plus trastuzumab (6 mg/kg) q3w; MM-302 (30 mg/m2) plus trastuzumab (6 mg/kg) and cyclophosphamide (450 mg/m2) q3w.ResultsSixty-nine patients were treated. The most common adverse events (AEs) were fatigue and nausea. Grade 3/4 AEs of special interest included neutropenia, fatigue, mucosal inflammation, anemia, thrombocytopenia, febrile neutropenia, and palmar-plantar erythrodysesthesia. The MTD was not reached. With MM-302 ≥ 30 mg/m2, overall response rate (ORR) was 13% and median progression-free survival (mPFS) 7.4 months (95% CI: 3·5-10·9) in all arms. In 25 anthracycline-naïve patients, ORR was 28·0% and mPFS 10·9 months (95% CI: 1·8-15·3). Imaging with 64Cu-labeled MM-302 visualized tumor-drug penetrance in tumors throughout the body, including the brain.ConclusionMM-302 monotherapy, in combination with trastuzumab, or trastuzumab plus cyclophosphamide, was well tolerated and showed promising efficacy. The selected phase 2 MM-302 dose was 30 mg/m2 plus 6 mg/kg trastuzumab q3w

Antimicrobial effects of the stinging nettle (Urtica Dioica L.) review

Nowadays increasing attention is being paid to herbs, one of the reasons is to avoid the undesirable side effects of synthetic drugs. This is the reason why the analysis of the antimicrobial activities of medicinal plants are increasingly in the focus of scientific experiments as well. One of the best-known medicinal plants is nettle. Among the nettle species in Hungary, Stinging nettle (Urtica dioica L.) can be found in the country and is most commonly utilised for medical purposes, with a focus on its leaves and roots. Nettle tea consumption is widespread in folk medicine for treating diabetes, allergies, abdominal pain, benign prostatic hyperplasia, rheumatoid arthritis and treatment of infections. This study gives a widespread summary of the reseach results about the antimicrobal impact of Stinging Nettle (Urtica dioica L.) in the scientific literature. The papers documented a positive effect of nettle for more than 30 Gram positive and Gram negative bacterias, yeasts and fungis

Backstabbing P-gp: Side-Chain Cleaved Ecdysteroid 2,3-Dioxolanes Hyper-Sensitize MDR Cancer Cells to Doxorubicin without Efflux Inhibition

P-glycoprotein (P-gp, ABCB1) over-expression, causing a multi-drug resistant (MDR) phenotype, is a major problem in cancer chemotherapy that urgently requires novel approaches. Our previous studies showed certain ecdysteroid derivatives as promising chemo-sensitizers against MDR and non-MDR cancer cell lines while also exerting mild to moderate inhibition of P-gp function. Here we report the preparation of a set of substituted 2,3-dioxolane derivatives of poststerone, a known in vivo metabolite of 20-hydroxyecdysone (20E). In contrast with previously studied ecdysteroid dioxolanes, the majority of the new compounds did not inhibit the efflux function of P-gp. Nevertheless, a strong, dose dependent sensitization to doxorubicin was observed on a P-gp transfected cancer cell line and on its susceptible counterpart. We also observed that the MDR cell line was more sensitive to the compounds’ effect than the non-MDR. Our results showed for the first time that the chemo-sensitizing activity of ecdysteroids can be fully independent of functional efflux pump inhibition, and suggest these compounds as favorable leads against MDR cancer

Before the Pandemic Ends: Making Sure This Never Happens Again

Introduction On 30 January 2020, the World Health Organization (WHO) declared a Global Health Emergency of international concern attendant to the emergence and spread of SARS-CoV-2, nearly two months after the first reported emergence of human cases in Wuhan, China. In the subsequent two months, global, national and local health personnel and infrastructures have been overwhelmed, leading to suffering and death for infected people, and the threat of socio-economic instability and potential collapse for humanity as a whole. This shows that our current and traditional mode of coping, anchored in responses after the fact, is not capable of dealing with the crisis of emerging infectious disease. Given all of our technological expertise, why is there an emerging disease crisis, and why are we losing the battle to contain and diminish emerging diseases? Part of the reason is that the prevailing paradigm explaining the biology of pathogen-host associations (coevolution, evolutionary arms races) has assumed that pathogens must evolve new capacities - special mutations – in order to colonize new hosts and produce emergent disease (e.g. Parrish and Kawaoka, 2005). In this erroneous but broadly prevalent view, the evolution of new capacities creates new opportunities for pathogens. Further, given that mutations are both rare and undirected, the highly specialized nature of pathogen-host relationships should produce an evolutionary firewall limiting dissemination; by those definitions, emergences should be rare (for a historical review see Brooks et al., 2019). Pathogens, however, have become far better at finding us than our traditional understanding predicts. We face considerable risk space for pathogens and disease that directly threaten us, our crops and livestock – through expanding interfaces bringing pathogens and hosts into increasing proximity, exacerbated by environmental disruption and urban density, fueled by globalized trade and travel. We need a new paradigm that explains what we are seeing. Additional section headers: The Stockholm Paradigm The DAMA Protocol A Sense of Urgency and Long-Term Commitment Reference

Dynamical Evolution of the Scalar Condensate in Heavy Ion Collisions

We derive the effective coarse-grained field equation for the scalar condensate of the linear sigma model in a simple and straightforward manner using linear response theory. The dissipative coefficient is calculated at tree level on the basis of the physical processes of sigma-meson decay and of thermal sigma-mesons and pions knocking sigma-mesons out of the condensate. The field equation is solved for hot matter undergoing either one or three dimensional expansion and cooling in the aftermath of a high energy nuclear collision. The results show that the time constant for returning the scalar condensate to thermal equilibrium is of order 2 fm/c.Comment: 19 pages, 3 figures are embedded at the end. The effect of the time dependence of the condensate v is included in this revised version. Numerical work is redone accordingl

MSTO1 is a cytoplasmic pro-mitochondrial fusion protein, whose mutation induces myopathy and ataxia in humans.

The protein MSTO1 has been localized to mitochondria and linked to mitochondrial morphology, but its specific role has remained unclear. We identified a c.22G > A (p.Val8Met) mutation of MSTO1 in patients with minor physical abnormalities, myopathy, ataxia, and neurodevelopmental impairments. Lactate stress test and myopathological results suggest mitochondrial dysfunction. In patient fibroblasts, MSTO1 mRNA and protein abundance are decreased, mitochondria display fragmentation, aggregation, and decreased network continuity and fusion activity. These characteristics can be reversed by genetic rescue. Short-term silencing of MSTO1 in HeLa cells reproduced the impairment of mitochondrial morphology and dynamics observed in the fibroblasts without damaging bioenergetics. At variance with a previous report, we find MSTO1 to be localized in the cytoplasmic area with limited colocalization with mitochondria. MSTO1 interacts with the fusion machinery as a soluble factor at the cytoplasm-mitochondrial outer membrane interface. After plasma membrane permeabilization, MSTO1 is released from the cells. Thus, an MSTO1 loss-of-function mutation is associated with a human disorder showing mitochondrial involvement. MSTO1 likely has a physiologically relevant role in mitochondrial morphogenesis by supporting mitochondrial fusion