Curcumin is known for its anticancer and migrastatic activity in various cancers, including breast cancer. Newer curcumin derivatives are being explored to overcome limitations of curcumin like low ...bioavailability, stability, and side effects due to its higher dose. In this study, the synthesis of ST09, a novel curcumin derivative, and its antiproliferative, cytotoxic, and migrastatic properties have been explored both in vitro and in vivo.
After ST09 synthesis, anticancer activity was studied by performing standard cytotoxicity assays namely, lactate dehydrogenase (LDH) release assay, 3-(4, 5-dimethylthiazol-2-yl)-2-5-diphenyletrazolium bromide (MTT), and trypan blue exclusion assay. Annexin-FITC, cell cycle analysis using flow cytometry, and Western blotting were performed to elucidate cell death mechanisms. The effect on the inhibition of cell migration was studied by transwell migration assay. An EAC (Ehrlich Ascites carcinoma) induced mouse tumor model was used to study the effect of ST09 on tumor regression. Drug toxicity was measured using aspartate aminotransferase (AST), alanine aminotransferase (ALT), blood urea nitrogen (BUN), and flow-cytometry based lymphocyte count. Histological analysis was performed for assessment of any tissue injury post ST09 treatment.
ST09 shows an approximate 100-fold higher potency than curcumin, its parent compound, on breast tumor cell lines MCF-7 and MDA-MB231. ST09 arrests the cell cycle in a cell type-specific manner and induces an intrinsic apoptotic pathway both in vitro and in vivo. ST09 inhibits migration by downregulating matrix metalloprotease 1,2 (MMP1,2) and Vimentin. In vivo, ST09 administration led to decreased tumor volume in a mouse allograft model by boosting immunity with no significant drug toxicity.
ST09 exhibits antiproliferative and cytotoxic activity at nanomolar concentrations. It induces cell death by activation of the intrinsic pathway of apoptosis both in vitro and in vivo. It also inhibits migration and invasion. This study provides evidence that ST09 can potentially be developed as a novel antitumor drug candidate for highly metastatic and aggressive breast cancer.
DNA Ligase IV is responsible for sealing of double-strand breaks (DSBs) during nonhomologous end-joining (NHEJ). Inhibiting Ligase IV could result in amassing of DSBs, thereby serving as a strategy ...toward treatment of cancer. Here, we identify a molecule, SCR7 that inhibits joining of DSBs in cell-free repair system. SCR7 blocks Ligase IV-mediated joining by interfering with its DNA binding but not that of T4 DNA Ligase or Ligase I. SCR7 inhibits NHEJ in a Ligase IV-dependent manner within cells, and activates the intrinsic apoptotic pathway. More importantly, SCR7 impedes tumor progression in mouse models and when coadministered with DSB-inducing therapeutic modalities enhances their sensitivity significantly. This inhibitor to target NHEJ offers a strategy toward the treatment of cancer and improvement of existing regimens.
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► SCR7, a Ligase IV inhibitor, blocks NHEJ in vitro and in vivo ► Inhibitor interferes with DNA binding domain association with double-strand breaks ► SCR7 impedes progression of tumors in mouse models, leading to enhanced lifespan ► Persistent breaks potentiate the effects of radio- and chemotherapy
Inhibition of Ligase IV, a key factor in nonhomologous end-joining, fosters apoptosis, impairs tumor growth, and enhances the efficacy of other chemotherapeutics in mouse models of cancer.
Resveratrol is one of the most widely studied bioactive plant polyphenols which possesses anticancer properties. Previously we have reported synthesis, characterization and identification of a novel ...resveratrol analog, SS28. In the present study, we show that SS28 induced cytotoxicity in several cancer cell lines ex vivo with an IC
value of 3-5 μM. Mechanistic evaluation of effect of SS28 in non-small cell lung cancer cell line (A549) and T-cell leukemic cell line (CEM) showed that it inhibited Tubulin polymerization during cell division to cause cell cycle arrest at G2/M phase of the cell cycle at 12-18 h time period. Immunofluorescence studies confirmed the mitotic arrest upon treatment with SS28. Besides, we show that SS28 binds to Tubulin with a dissociation constant of 0.414 ± 0.11 μM. Further, SS28 treatment resulted in loss of mitochondrial membrane potential, activation of Caspase 9 and Caspase 3, leading to PARP-1 cleavage and finally cell death via intrinsic pathway of apoptosis. Importantly, treatment with SS28 resulted in regression of tumor in mice. Hence, our study reveals the antiproliferative activity of SS28 by disrupting microtubule dynamics by binding to its cellular target Tubulin and its potential to be developed as an anticancer molecule.
Prior observations have documented the process of cloud cleansing, through which cloudy, polluted air from a continent is slowly transformed into cloudy, clean air typical of a maritime environment. ...During that process, cloud albedo changes gradually, followed by a sudden reduction in cloud fraction and albedo as drizzle forms and convection changes from closed to open cellular. Experiments in a cloud chamber that generates a turbulent environment show a similar cloud cleansing process followed by rapid cloud collapse. Observations of (1) cloud droplet size distribution, (2) interstitial aerosol size distribution, (3) cloud droplet residual size distribution, and (4) water vapor supersaturation are all consistent with the hypothesis that turbulent fluctuations of supersaturation accelerate the cloud cleansing process and eventual cloud collapse. Decay of the interstitial aerosol concentration occurs slowly at first then more rapidly. The accelerated cleansing occurs when the cloud phase relaxation time exceeds the turbulence correlation time.
Plain Language Summary
Initially, polluted clouds can slowly transform into clean clouds when there is no significant source of aerosol particles. The rate at which this aerosol removal occurs, which can be thought of as cloud cleansing, undergoes a sudden acceleration when a cloud becomes sufficiently clean. Cloud chamber experiments show that random, turbulent fluctuations become large when a cloud becomes sufficiently clean, and these large fluctuations in temperature and the concentration of water vapor cause rapid activation of aerosol particles and rapid growth of cloud droplets. In the atmosphere these large droplets would be expected to aid in initiating the formation of precipitation by collisions and coalescence of droplets.
Key Points
Cloud cleansing of aerosols is simulated in a cloud chamber with steady state turbulence
Turbulent fluctuations in supersaturation become more pronounced as cloud is cleansed
Aerosol removal process is accelerated, leading to cloud collapse during the cleansing process
Summary Background The topical use of chlorhexidine gluconate (CHG) is intended to reduce bacterial density on patients' skin. Aim To assess the impact of body bath or skin cleansing with ...CHG-impregnated or CHG-saturated washcloths in preventing healthcare-associated infections and colonization. Methods This systematic review included published randomized controlled trials, cross-over trials, cohort studies and before-and-after studies. Studies were included if they compared the use of CHG in washcloths with any of the following; soap and water bathing, routine advice, no intervention. Findings Sixteen published studies and four conference abstracts were included for systematic review. Nine studies reported the impact of CHG on incidence of central-line-associated bloodstream infection (CLABSI); the incidence rate ratio (IRR) was 0.43 95% confidence interval (CI): 0.26–0.71. Five studies assessed the impact of CHG washcloths on incidence of surgical site infection (SSI); the RR was 0.29 (95% CI: 0.17–0.49). Four studies reported the impact on vancomycin-resistant enterococci (VRE) colonization; the IRR was 0.43 (95% CI: 0.32–0.59). Three studies reported the impact on meticillin-resistant Staphylococcus aureus (MRSA) colonization rate; the IRR was 0.48 (95% CI: 0.24–0.95). Six studies reported the impact on VRE infection; the IRR was 0.90 (95% CI: 0.42–1.93). Six studies reported the impact on MRSA infection; the IRR was 0.82 (95% CI: 0.51–1.30). There was no reduction in acinetobacter infection rates in the three studies where this was reported. Conclusion These results suggest that the use of non-rinse CHG application significantly reduces the risk of CLABSI, SSI and colonization with VRE or MRSA, but not infection.
Despite several treatment options for blood cancer, mortality remains high due to relapse and the disease's aggressive nature. Elevated levels of HSP90, a molecular chaperone essential for protein ...folding, are associated with poor prognosis in leukemia and lymphoma. HSP90 as a target for chemotherapy has been met with limited success due to toxicity and induction of heat shock. This study tested the activity of an HSP90 inhibitor, SP11, against leukemic cells, mouse lymphoma allograft, and xenograft models. SP11 induced cytotoxicity in vitro in leukemic cell lines and induced cell death via apoptosis, with minimal effect on normal cells. SP11 induced cell death by altering the status of HSP90 client proteins both in vitro and in vivo. SP11 reduced the tumor burden in allograft and xenograft mouse models without apparent toxicity. The half-life of SP11 in the plasma was approximately 2 h. SP11 binding was observed at both the N-terminal and C-terminal domains of HSP90. C-terminal binding was more potent than N-terminal binding of HSP90 in silico and in vitro using isothermal calorimetry. SP11 bioavailability and minimal toxicity in vivo make it a potential candidate to be developed as a novel anticancer agent.
In recent years, green synthesized silver nanoparticles have been increasingly investigated for their anti-cancer potential. In the present study, we aimed at the biosynthesis of silver nanoparticles ...(AgNPs) using a curcumin derivative, ST06. Although, the individual efficacies of silver nanoparticles or curcumin derivatives have been studied previously, the synergistic cytotoxic effects of curcumin derivative and silver nanoparticles in a single nanoparticulate formulation have not been studied earlier specifically on animal models. This makes this study novel compared to the earlier synthesized curcumin derivative or silver nanoparticles studies. The aim of the study was to synthesize ST06 coated silver nanoparticles (ST06-AgNPs) using ST06 as both reducing and coating agent.
The synthesized nanoparticles AgNPs and ST06-AgNPs were characterised for the particle size distribution, morphology, optical properties and surface charge by using UV-visible spectroscopy, dynamic light scattering (DLS) and transmission electron microscopy (TEM). Elemental composition and structural properties were studied by energy dispersive X-ray spectroscopy (EDX) and X-ray diffraction spectroscopy (XRD). The presence of ST06 as capping agent was demonstrated by Fourier transform infrared spectroscopy (FTIR).
The synthesized nanoparticles (ST06-AgNPs) were spherical and had a size distribution in the range of 50-100 nm. UV-Vis spectroscopy displayed a specific silver plasmon peak at 410 nm. The in vitro cytotoxicity effects of ST06 and ST06-AgNPs, as assessed by MTT assay, showed significant growth inhibition of human cervical cancer cell line (HeLa). In addition, studies carried out in EAC tumor-induced mouse model (Ehrlich Ascites carcinoma) using ST06-AgNPs, revealed that treatment of the animals with these nanoparticles resulted in a significant reduction in the tumor growth, compared to the control group animals.
In conclusion, green synthesized ST06-AgNPs exhibited superior anti-tumor efficacy than the free ST06 or AgNPs with no acute toxicity under both in vitro and in vivo conditions. The tumor suppression is associated with the intrinsic apoptotic pathway. Together, the results of this study suggest that ST06-AgNPs could be considered as a potential option for the treatment of solid tumors.
Since 1999, West Nile virus (WNV) has moved rapidly across the United States, resulting in tens of thousands of human cases. Both the number of human cases and the minimum infection rate (MIR) in ...vector mosquitoes vary across time and space and are driven by numerous abiotic and biotic forces, ranging from differences in microclimates to socio-demographic factors. Because the interactions among these multiple factors affect the locally variable risk of WNV illness, it has been especially difficult to model human disease risk across varying spatial and temporal scales. Cook and DuPage Counties, comprising the city of Chicago and surrounding suburbs, experience some of the highest numbers of human neuroinvasive cases of WNV in the United States. Despite active mosquito control efforts, there is consistent annual WNV presence, resulting in more than 285 confirmed WNV human cases and 20 deaths from the years 2014-2018 in Cook County alone.
A previous Chicago-area WNV model identified the fifty-five most high and low risk locations in the Northwest Mosquito Abatement District (NWMAD), an enclave ¼ the size of the combined Cook and DuPage county area. In these locations, human WNV risk was stratified by model performance, as indicated by differences in studentized residuals. Within these areas, an additional two-years of field collections and data processing was added to a 12-year WNV dataset that includes human cases, MIR, vector abundance, and land-use, historical climate, and socio-economic and demographic variables, and was assessed by an ultra-fine-scale (1 km spatial x 1 week temporal resolution) multivariate logistic regression model.
Multivariate statistical methods applied to the ultra-fine-scale model identified fewer explanatory variables while improving upon the fit of the previous model. Beyond MIR and climatic factors, efforts to acquire additional covariates only slightly improved model predictive performance.
These results suggest human WNV illness in the Chicago area may be associated with fewer, but increasingly critical, key variables at finer scales. Given limited resources, these findings suggest large variations in model performance occur, depending on covariate availability, and provide guidance in variable selection for optimal WNV human illness modeling.
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