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Mutation Research. Genetic Toxicology... Dec 2021Arbutin is a simple phenolic glucoside biosynthesised in many plant families. Some of the everyday foods that contain arbutin are species of the genus Origanum, peaches,...
Arbutin is a simple phenolic glucoside biosynthesised in many plant families. Some of the everyday foods that contain arbutin are species of the genus Origanum, peaches, cereal products, coffee and tea and Arctostaphyllos uva ursi L. leaves. Arbutin possesses various beneficial effects in the organism, and was confirmed effective in the treatment of urinary tract infections as well as in preventing skin hyperpigmentation. It shows antioxidant and anti-inflammatory properties, and antitumor activity. The aim of this study was to explore potential radioprotective properties of arbutin in concentrations of 11.4 μg/mL, 57 μg/mL, 200 μg/mL and 400 μg/mL administered as a pre-treatment for one hour before exposing human leukocytes to ionising radiation at a therapeutic dose of 2 Gy. The alkaline comet assay was used to establish the levels of primary DNA damage, and cytokinesis-block micronucleus (CBMN) cytome assay to determine the level of cytogenetic damage. None of the tested concentrations of single arbutin showed genotoxic and cytotoxic effects. Even at the lowest tested concentration, 11.4 μg/mL, arbutin demonstrated remarkable potential for radioprotection in vitro, observed both at the level of primary DNA damage, and using CBMN cytome assay. The best dose reduction compared with amifostine was observed after pre-treatment with the highest concentration of arbutin, corresponding to 400 μg/mL. Promising results obtained on the leukocyte model speak in favour of extending similar experiments on other cell and animal models.
Topics: Arbutin; Comet Assay; DNA Damage; Humans; Leukocytes; Micronucleus Tests; Radiation, Ionizing; Radiation-Protective Agents
PubMed: 34798933
DOI: 10.1016/j.mrgentox.2021.503413 -
Clinical Colorectal Cancer Mar 2022There has been an increase in the incidence of rectal cancer diagnosed in young adults (age < 50 years). We evaluated outcomes among young adults treated with...
PURPOSE
There has been an increase in the incidence of rectal cancer diagnosed in young adults (age < 50 years). We evaluated outcomes among young adults treated with pre-operative long course chemoradiation (CRT) and total mesorectal excision (TME).
METHODS
The medical records of 219 patients, age 18-49, with non-metastatic, cT3-4, or cN1-2 rectal adenocarcinoma treated from 2000 to 2017 were reviewed for demographic and treatment characteristics, as well as pathologic and oncologic outcomes. The Kaplan-Meier test, log-rank test, and Cox regression analysis were used to evaluate survival outcomes.
RESULTS
The median age at diagnosis was 44 years. CRT followed by TME and post-operative chemotherapy was the most frequent treatment sequence (n = 196), with FOLFOX (n = 115) as the predominant adjuvant chemotherapy. There was no difference in sex, stage, MSS/pMMR, or pCR by age (< 45 years [n = 111] vs. ≥ 45 years [n = 108]). The 5-year rates of DFS were 77.2% for all patients, 69.8% for age < 45 years and 84.7% for age ≥ 45 years (P = .01). The 5-year rates of OS were 89.6% for all patients, 85.1% for patients with age < 45 years and 94.3% for patients with age ≥ 45 years (P = .03). Age ≥ 45 years was associated with a lower risk of disease recurrence or death on multivariable Cox regression analysis (HR = 0.55, 95% CI 0.31-0.97, P = .04).
CONCLUSION
Among young adults, patients with age < 45 years had lower rates of DFS and OS, compared to those with age ≥ 45 years. These outcomes could serve as a benchmark by which to evaluate newer treatment approaches.
Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Benchmarking; Chemoradiotherapy; Disease-Free Survival; Humans; Middle Aged; Neoadjuvant Therapy; Neoplasm Staging; Rectal Neoplasms; Retrospective Studies; Treatment Outcome; Young Adult
PubMed: 34794903
DOI: 10.1016/j.clcc.2021.09.012 -
Chemical Science Oct 202114-3-3 proteins are an important family of hub proteins that play important roles in many cellular processes a large network of interactions with partner proteins. Many...
14-3-3 proteins are an important family of hub proteins that play important roles in many cellular processes a large network of interactions with partner proteins. Many of these protein-protein interactions (PPI) are implicated in human diseases such as cancer and neurodegeneration. The stabilisation of selected 14-3-3 PPIs using drug-like 'molecular glues' is a novel therapeutic strategy with high potential. However, the examples reported to date have a number of drawbacks in terms of selectivity and potency. Here, we report that WR-1065, the active species of the approved drug amifostine, covalently modifies 14-3-3σ at an isoform-unique cysteine residue, Cys38. This modification leads to isoform-specific stabilisation of two 14-3-3σ PPIs in a manner that is cooperative with a well characterised molecular glue, fusicoccin A. Our findings reveal a novel stabilisation mechanism for 14-3-3σ, an isoform with particular involvement in cancer pathways. This mechanism can be exploited to harness the enhanced potency conveyed by covalent drug molecules and dual ligand cooperativity. This is demonstrated in two cancer cell lines whereby the cooperative behaviour of fusicoccin A and WR-1065 leads to enhanced efficacy for inducing cell death and attenuating cell growth.
PubMed: 34745529
DOI: 10.1039/d1sc02120f -
International Journal of Radiation... 2022Freshwater fish was used in this study as a vertebrate model. We evaluated the induction of certain antioxidant enzymes in various vital organs. The radioprotective...
PURPOSE
Freshwater fish was used in this study as a vertebrate model. We evaluated the induction of certain antioxidant enzymes in various vital organs. The radioprotective efficacy of leaves extract (GS) [25mg/kg Body Weight (B.W)] and its bioactive compound Gymnemagenin (GG) [0.3mg/kg B.W] was compared with Amifostine (Ami), the only radioprotector clinically approved by the US-FDA [Ami- 83.3mg/kg B.W] against different doses of gamma radiation - Co (Lethal Dose: LD-9.2Gy, LD-10.2Gy and LD-11.4Gy).
MATERIALS AND METHODS
This study was done via stress marker enzymes, cell cycle analysis (CCA) and DNA damage assay prediction with molecular docking, which are reported here for the first time. The results indicate an elevated LPO level and decreased level of CAT, SOD and GSH due to oxidative stress initiation by Co Ionizing Radiation (IR) on 4th day and slightly reduced on 32nd day while the reverse observed when the fishes were pretreated with Ami, GS and GG. Similarly, CCA and dead/live cells counts were conducted with pretreatment of Ami, GS and GG against Co IR dose (LD-10.2Gy).
RESULTS
In CCA, G0/G1 phase was observed to be the highest in Ami and lowest in GG, against Co IR doses 10.2Gy which was 51.76±7.55. The dead cells range observed in pretreated group of Ami, GS and GG was lowest in Ami and highest in GG and live cells (highest in Ami and lowest in GG) as compared to Co IR group (86.43±3.42 and 8.77±5.95). Thus, antioxidant profile improvement by oxidative stress reduction and gradual progression of different phases of cell cycle except the apoptotic phase along with the live cells counts indicates that the radio-protective efficacy of GS is similar to Ami.
CONCLUSION
Predictive assessment was carried out by docking of Ami, various components of GS with p53, NF-κβ cells and Rad51 proteins structures responsible for CCA, apoptosis and repair mechanism. These structural proteins were docked with other structural proteins like USP7, TNF-α and partner and localizer of BRCA2 associated (PALB2/BRCA2) complex which made us perform these systemic efforts to find the functional activity of these known radio-protectants.
Topics: Amifostine; Animals; Antioxidants; Catfishes; Gamma Rays; Gymnema sylvestre; Lethal Dose 50; Molecular Docking Simulation; Radiation-Protective Agents
PubMed: 34705596
DOI: 10.1080/09553002.2022.1998701 -
Reproductive Biology Dec 2021This minireview will briefly outline the basic knowledge concerning the provenance, biological active constituents of ginkgo (Ginkgo biloba, L.) and its general health... (Review)
Review
This minireview will briefly outline the basic knowledge concerning the provenance, biological active constituents of ginkgo (Ginkgo biloba, L.) and its general health effects. Ginkgo has been shown to affect female reproductive functions: it can affect ovarian folliculo- and oogenesis, embryogenesis, promote ovarian granulosa cell apoptosis, reduce their proliferation and the release of ovarian hormones. Usually, ginkgo extract mainly suppresses, but its constituents like amifostine, leuprorelin, quercetin and kaempherol can promote ovarian functions. This may indicate the existence of anti-reproductive ginkgo constituent(s), such as ginkgolide B and allopregnenolone which, like ginkgo extract, can promote ovarian cell apoptosis and suppress ovarian follicullogenesis and oogenesis. Ginkgo effects could be mediated by an action on brain functions, ovarian steroidogenesis, oxidative processes, intracellular regulators of ovarian cell proliferation and apoptosis and GABA receptors. Ginkgo and its molecules, ginkgolide B and allopregnenolone can be useful for prevention and treatment of reproduction-related disorders like ovarian cancer, ovarian ischemia and menopausal syndrome. On the other hand, its constituents amifostine, leuprorelin, quercetin and kaempherol could be potentially applicable as biostimulators of female reproductive processes in human and veterinary medicine and animal production. Nevertheless, application of ginkgo is still limited by insufficient or contradictory knowledge concerning its active constituents, characters, targets and mediators of its action and their functional interrelationships. Impact of ginkgo action on reproductive organs other than ovaries remains largely unknown. Addressing these issues with proper animal and clinical studies could help to understand the distinct efficacy and consequences of medical application of ginkgo.
Topics: Animals; Female; Genitalia, Female; Ginkgo biloba; Humans; Phytotherapy; Plant Extracts; Reproduction
PubMed: 34656881
DOI: 10.1016/j.repbio.2021.100568 -
Current Oncology (Toronto, Ont.) Sep 2021We report long-term results (median follow-up 12 years) of hypofractionated accelerated radiotherapy (HypoAR) in patients treated with breast-conserving surgery. In...
We report long-term results (median follow-up 12 years) of hypofractionated accelerated radiotherapy (HypoAR) in patients treated with breast-conserving surgery. In total, 367 women were treated with HypoAR. Axillary and supraclavicular area (ASA) were treated in patients with involved nodes. In total, 290 patients (scheme A) received 3.5 Gy/day ×10 fractions (breast/ASA) followed by two 4 Gy fractions with electrons to the affected breast quadrant within 16 days. In total, 77 patients (Scheme B) received 2.7 Gy/day for 16 consecutive fractions (breast/ASA) within 22 days, while concurrently, the affected breast quadrant received an electron booster dose of 0.8 Gy for the first 13 fractions. Amifostine was offered to 252/367 patients. Early radiation toxicity was minimal. Regarding late toxicities, symptomatic breast edema was noted in 2.2%, asymptomatic breast fibrosis in 1.9%, and arm lymphedema in 3.7% of patients. Amifostine reduced early radiation dermatitis ( = 0.001). In total, 2.2% of patients developed contralateral breast and 1.6% other carcinomas. Locoregional recurrence (LR) occurred in 3.1% of patients (0% for in situ carcinomas). Positive margins after surgery, extracapsular node invasion, and HER2-enriched/triple-negative tumors were linked with significantly worse LR-free survival. The involvement of more than three nodes and luminal type other than A were independent prognostic variables of metastasis and death events. HypoAR delivering a biological dose of 50-52 Gy to the breast/ASA is a safe and effective therapy for patients treated with conservative surgery. The risk of carcinogenesis is low. Positive surgical margins, extracapsular node invasion, and HER2-enriched/triple-negative phenotypes appear as a cluster of features linked with a higher risk for locoregional relapse.
Topics: Amifostine; Female; Humans; Lymph Nodes; Mastectomy, Segmental; Radiation Dose Hypofractionation; Radiodermatitis
PubMed: 34590607
DOI: 10.3390/curroncol28050300 -
Materials Science & Engineering. C,... Oct 2021Metal-organic frameworks (MOFs) are useful as drug delivery carriers with high loading capacity and excellent biocompatibility. We fabricated a new drug carrier based on...
Metal-organic frameworks (MOFs) are useful as drug delivery carriers with high loading capacity and excellent biocompatibility. We fabricated a new drug carrier based on MIL-101(Cr) environmentally and loaded it with 47.2 wt% WR-1065 (active metabolite of amifostine). Moreover, the permeability and stability of these nanoparticles increased after PEGylation by the N-hydroxysuccinimide active ester protocol. Then, a "green" continuous-flow system equipped with an ultrasound applicator was newly designed to prepare the nanoparticles under the effect of acoustic cavitation. Response surface methodology (RSM) was used to optimize the large-scale process conditions with Box-Behnken design to obtain high space-time yield (5785 kg m day). These less toxic MOFs nanoparticles increased cell viability by scavenging the accumulated reactive oxygen species and resisting DNA damage after irradiation. They are capable of mitigating radiation injury, achieving a 30-d survival rate of 90% in mice after lethal total body irradiation (8.0 Gy). This countermeasure significantly improved the peripheral blood cell count, hematopoietic stem and progenitor cells frequency, and clonogenic function of hematopoietic progenitor cells. It probably prevents irradiation-induced hematopoietic damage through the p53-dependent apoptotic pathway. Therefore, ultrasound-assisted continuous-flow synthesis is a sustainable method to produce MOFs on a large scale for radioprotection.
Topics: Animals; Metal-Organic Frameworks; Mice; Nanoparticles; Polyethylene Glycols
PubMed: 34579888
DOI: 10.1016/j.msec.2021.112369 -
Metabolites Sep 2021Mitochondria are dynamic organelles that constantly alter their shape through the recruitment of specialized proteins, like mitofusin-2 (Mfn2) and dynamin-related...
Mitochondria are dynamic organelles that constantly alter their shape through the recruitment of specialized proteins, like mitofusin-2 (Mfn2) and dynamin-related protein 1 (Drp1). Mfn2 induces the fusion of nearby mitochondria, while Drp1 mediates mitochondrial fission. We previously found that the genetic or pharmacological activation of mitochondrial fusion was tumor suppressive against pancreatic ductal adenocarcinoma (PDAC) in several model systems. The mechanisms of how these different inducers of mitochondrial fusion reduce pancreatic cancer growth are still unknown. Here, we characterized and compared the metabolic reprogramming of these three independent methods of inducing mitochondrial fusion in KPC cells: overexpression of Mfn2, genetic editing of Drp1, or treatment with leflunomide. We identified significantly altered metabolites via robust, orthogonal statistical analyses and found that mitochondrial fusion consistently produces alterations in the metabolism of amino acids. Our unbiased methodology revealed that metabolic perturbations were similar across all these methods of inducing mitochondrial fusion, proposing a common pathway for metabolic targeting with other drugs.
PubMed: 34564443
DOI: 10.3390/metabo11090627 -
Journal of Nanobiotechnology Sep 2021Acute kidney injury (AKI) with high mortality rates is associated with an excess of reactive oxygen/nitrogen species (RONS) within kidney tissues. Recently, nanomedicine...
BACKGROUND
Acute kidney injury (AKI) with high mortality rates is associated with an excess of reactive oxygen/nitrogen species (RONS) within kidney tissues. Recently, nanomedicine antioxidant therapy has been used to alleviate AKI. Herein, we synthesized ultrasmall Prussian blue nanozymes (PB NZs, 4.5 nm) as theranostic agents for magnetic resonance (MR)/photoacoustic (PA) dual-modal imaging guided AKI treatment.
RESULTS
PB NZs exhibited multi-enzyme mimetic abilities, promoting the effective elimination of RONS both in vitro and in vivo. Moreover, benefiting from their imaging contrast properties, the rapid renal accumulation of PB NZs was verified by in vivo PA/MR dual-modal imaging. Due to their excellent enrichment in the kidney and unique multi-enzyme mimetic abilities, ultrasmall PB NZs displayed superior AKI treatment efficacy compared with that of amifostine in two clinically relevant types of AKI induced murine models (either by rhabdomyolysis or cisplatin).
CONCLUSION
Our findings suggested ultrasmall PB NZs, as nanozyme theranostics, have great potential for AKI management.
Topics: Acute Kidney Injury; Animals; Antioxidants; Cisplatin; Female; Ferrocyanides; Kidney; Mice; Mice, Inbred BALB C; Precision Medicine; Reactive Nitrogen Species; Reactive Oxygen Species
PubMed: 34488789
DOI: 10.1186/s12951-021-01006-z -
Annals of Surgical Oncology Jan 2022Hyperthermic intraperitoneal chemotherapy (HIPEC) combined with cytoreductive surgery (CRS) is the treatment of choice for selected patients with peritoneal...
BACKGROUND
Hyperthermic intraperitoneal chemotherapy (HIPEC) combined with cytoreductive surgery (CRS) is the treatment of choice for selected patients with peritoneal malignancies. HIPEC is accompanied by moderate-to-high patient morbidity, including acute kidney injury. The significance of nephrotoxic agents such as cisplatin versus hyperthermia in HIPEC-induced nephrotoxicity has not been defined yet.
PATIENTS AND METHODS
A total of 153 patients treated with HIPEC were divided into groups with (AKI+) and without (AKI-) kidney injury. Laboratory parameters and data concerning patient demographics, underlying disease, surgery, complications, and HIPEC were gathered to evaluate risk factors for HIPEC-induced AKI. A preclinical mouse model was applied to assess the significance of cisplatin and hyperthermia in HIPEC-induced AKI, as well as protective effects of the cytoprotective agent amifostine.
RESULTS
AKI occurred in 31.8% of patients undergoing HIPEC. Treatment with cisplatin-containing HIPEC regimens represented a major risk factor for HIPEC-related AKI (p < 0.001). Besides, angiotensin receptor blockers and increased preoperative creatinine and urea levels were independent risk factors for AKI after HIPEC. In a preclinical mouse model, intraperitoneal perfusion with cisplatin induced AKI, whereas hyperthermia alone, or in combination with cisplatin, did not induce or enhance renal injury. Amifostine failed to confer nephroprotective effects in a miniaturized HIPEC model.
CONCLUSIONS
AKI is a frequent complication after HIPEC. The risk of renal injury is particularly high in patients treated with cisplatin-containing HIPEC regimens. Hyperthermic perfusion of the abdomen by itself does not seem to induce or aggravate HIPEC-induced renal injury.
Topics: Acute Kidney Injury; Animals; Humans; Hyperthermic Intraperitoneal Chemotherapy; Laboratories; Mice; Retrospective Studies
PubMed: 34260006
DOI: 10.1245/s10434-021-10376-5