Myeloprotective effects of C-type natriuretic peptide on cisplatin-induced bone marrow granulocytopenia in mice

Abstract

Purpose

Cisplatin is an effective chemotherapeutic agent used to treat a variety of malignant tumors. The major toxicity associated with cisplatin treatment is granulocytopenia. C-type natriuretic peptide (CNP), a member of the natriuretic peptide family, protects against toxicity in many organs, including the heart, blood vessels, lung, and kidney. The objective of this study was to investigate the myeloprotective effects of CNP in a mouse model of cisplatin-induced granulocytopenia.

Methods

The mice were divided into two groups: cisplatin with vehicle and cisplatin with CNP. CNP (2.5 μg/kg/min via osmotic pump, subcutaneously) or vehicle administration was started two day before cisplatin injection, and continued until the mice were killed. At 0, 2, 4, 8, and 14 days after cisplatin injection (16 mg/kg, intraperitoneally as a single dose), we counted total and living cells and granulocyte/macrophage colony-forming units (CFU-GM) in bone marrow. In addition, at 0, 1, 2, and 4 days after cisplatin injection, we measured mRNA levels of CXC chemokine receptor 4 (CXCR4) and chemokine CXC ligand 12 (CXCL12) in bone marrow.

Results

CNP significantly attenuated the reduction in bone marrow nucleated cell count and CFU-GM in bone marrow at 4 days after cisplatin injection. Four days after cisplatin injection, CNP significantly decreased the CXCR4 mRNA level in bone marrow, but had no effect on the level of CXCL12 mRNA.

Conclusions

CNP exerts myeloprotective effects in cisplatin-induced granulocytopenia and decreases CXCR4 expression.

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A mini-review of c-Met as a potential therapeutic target in melanoma

Publication date: April 2017
Source:Biomedicine & Pharmacotherapy, Volume 88
Author(s): Doa'a G.F. Al-U'datt, Belal A.A. Al-Husein, Ghazi Raji Qasaimeh
Melanoma is the third highest rated cancer in prevalence. Surgery, radiotherapy and targeted/biological therapies in addition to chemotherapy are available options for management of this cancer. Met is an appealing target for management of this type of cancer, since it targets many cancer vital processors, such as angiogenesis, cell growth, scattering and differentiation. In this review, we provide an overview about pathway abnormalities associated with melanoma. We also provide a summary about the events involved in Met signaling and related signaling molecules. We also show the evidence of the importance of Met signaling pathway as a target in cancer management. We also summarize clinical evidence about the use of Met signaling in management of cancer and summarize available trials related to targeting Met in other cancers.



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Antibacterial activity, computational analysis and host toxicity study of thymol-sulfonamide conjugates

Publication date: April 2017
Source:Biomedicine & Pharmacotherapy, Volume 88
Author(s): Shasank S. Swain, Sudhir K. Paidesetty, Rabindra N. Padhy
Methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin resistant Enterococcus faecalis (VRE) are notorious pathogenic multidrug resistant (MDR) bacteria in both hospital and community sectors, and today the first antibacterial drug sulfamethoxazole is ineffective. The monoterpene phenol, thymol was conjugated with seven sulfa drug derivatives individually, adopting the dye-azo synthesis protocol, and conjugates were characterized using spectral analysis techniques such as, UV, FTIR, MS, HPLC, ¹H NMR, ¹³C NMR and SEM. Conjugates were assessed for antibacterial activity in vitro and in silico; the zone of inhibition, MIC and MBC values of each conjugate were determined against isolated MRSA and VRE strains from clinical samples. As 3-dimentional structures of dihydropteroate synthases (DHPSs) of targeted bacteria are not available in protein database, homology models of DHPS enzymes of both bacteria were generated and validated by Ramachandran plots. Seven conjugates were used as ligands in molecular docking against MRSA-DHPS and VRE-DHPS. Additionally bioinformatics tools, PASS prediction, Lipinski rules of five, computational LD50 value, toxicity class, HOMO, LUMO and EPS plots were carried out to assess standard drug-likeliness properties of conjugates. Zone size inhibition of the conjugate, 4b (thymol+sulfadiazine) against MRSA and VRE strains on agar plates were 20 and 40μg/mL as the lowest MIC and MBC values, respectively; while the reference antibiotic ampicillin had the lowest MIC and MBC values at 80 to 180μg/mL. In vitro host-toxicity testing was carried out with cultured human-lymphocytes from umbilical cord blood, and 4b was broadly non-toxic to human cells at 15,000mg/L. Thus, 4b could be promoted a newer antibacterial, against gruesome MDR bacteria.

Graphical abstract

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EGCG, a tea polyphenol, as a potential mitigator of hematopoietic radiation injury in mice

Publication date: April 2017
Source:Biomedicine & Pharmacotherapy, Volume 88
Author(s): Mrinalini Tiwari, Bhakti Dixit, Suhel Parvez, Paban K. Agrawala
Agents capable of providing protection, mitigation or therapy against radiation injuries have long been of interest of radiation biologists owing to the ever expanding application of radiation in our day to day life despite the well reported ill effects of exposure. The current study investigates radiomitigating potential of EGCG (epigallocatechin gallate), a tea polyphenol with known DNMT inhibitory property, in C57 Bl/6 mice model. Treatment with 0.1833mg/kg body weight EGCG, 1.5h post-irradiation to lethally whole body irradiated mice rendered 45% survival for 30days and also helped restoring the body weight of the animals. An early recovery of various hematological parameters was observed in EGCG treated animals compared to radiation alone group. Significant recovery in the number of bone marrow colony forming cells was observed in EGCG treated irradiated animals. EGCG reduced cytogenetic damage to bone marrow cells in radiation exposed mice significantly as studied by micronucleus assay without any significant affect on cell cycle distribution of the bone marrow cells. ELISA assay with bone marrow cell lysates showed EGCG as an inhibitor of HDAC activity and DNase accessibility assay showed EGCG treatment increased the accessibility of chromatin to the enzyme. The results suggest EGCG provides mitigation against radiation injury to the hemopoietic system of mice and also inhibits HDAC enzyme activity. However, further studies are required to understand its mechanism of action.



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The natural flavonoid apigenin sensitizes human CD44+ prostate cancer stem cells to cisplatin therapy

Publication date: April 2017
Source:Biomedicine & Pharmacotherapy, Volume 88
Author(s): Suat Erdogan, Kader Turkekul, Rıza Serttas, Zeynep Erdogan
Prostate cancer (PCa) is the second most common type of cancer and the fifth leading cause of cancer-related death among men. Development of chemoresistance, tumor relapse and metastasis remain major barriers to effective treatment and all been identified to be associated with cancer stem cells (CSCs). Natural flavonoids such as apigenin have been shown to have the ability to improve the therapeutic efficacy of common chemotherapy agents through CSCs sensitization. Thus, the aim of this study was to evaluate the combination of apigenin with cisplatin on CD44⁺ PCa stem cell growth and migration. Platinum-based anti-neoplastic drugs have been used to treat a number of malignancies including PCa. However, acquired resistance and side effects unfortunately have limited cisplatin's use. A CD44⁺ subpopulation was isolated from human androgen-independent PC3 PCa cells by using human CD44-PE antibody. IC50 values were determined by MTT test. RT-qPCR, Western blot analyses and image-based cytometer were used to investigate apoptosis, cell cycle and their underlying molecular mechanisms. Cell migration was evaluated by wound healing test. The combination of the IC50 doses of apigenin (15μM) and cisplatin (7.5μM) for 48h significantly enhanced cisplatin's cytotoxic and apoptotic effects through downregulation of Bcl-2, sharpin and survivin; and upregulation of caspase-8, Apaf-1 and p53 mRNA expression. The combined therapy suppressed the phosphorylation of p-PI3K and p-Akt, inhibited the protein expression of NF-κB, and downregulated the cell cycle by upregulating p21, as well as cyclin dependent kinases CDK-2, −4, and −6. Apigenin significantly increased the inhibitory effects of cisplatin on cell migration via downregulation of Snail expression. In conclusion, our study showed the possible therapeutic approach of using apigenin to potentially increase the effects of cisplatin by targeting CSCs subset in prostate cancer.



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What is the role of postoperative re-irradiation in recurrent and second primary squamous cell cancer of head and neck? A literature review according to PICO criteria

Publication date: Available online 17 January 2017
Source:Critical Reviews in Oncology/Hematology
Author(s): Anna Merlotti, Rosario Mazzola, Daniela Alterio, Filippo Alongi, Almalina Bacigalupo, Pierluigi Bonomo, Marta Maddalo, Elvio Grazioso Russi, Ester Orlandi
Re-irradiation has been increasingly offered as a potential effective treatment for head and neck squamous cell carcinoma (HNSCC) loco-regional recurrence as well as second primary tumor in previously irradiated area. This review focused on the role of postoperative re-irradiation (POreRT) in terms of feasibility, toxicity and long-term outcomes in HNSCC patients. The key issue for the research was formulated in two questions according to the PICO (population, intervention, control, and outcomes) criteria. A total of 16 publications met the inclusion criteria for a total of 919 patients; in 522 patients POreRT was performed. POreRT in recurrent and second primary HNSCC seems to be feasible in highly selected patients with the intent to guarantee an acceptable LC compared to surgery alone. The optimal RT schedule remains unclear due to the heterogeneity of literature data.



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In the February BJA ...

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'LIVES: a mnemonic for teaching advanced airway management

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Preoperative {alpha}-blockade in catecholamine-secreting tumours: fight for it or take flight?

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Efficacy of continuous intravenous glucose monitoring in perioperative glycaemic control: a randomized controlled study

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Quest to determine the ideal position of the central venous catheter tip

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Waist circumference is better than body mass index, but sagittal anterior diameter may be even better

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Transnasal humidified rapid-insufflation ventilatory exchange (THRIVE) in children: a step forward in apnoeic oxygenation, paradigm-shift in ventilation, or both?

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Children and parental anxiolysis in paediatric ambulatory surgery: a randomized controlled study comparing 0.3 mg kg-1 midazolam to tablet computer based interactive distraction

Background. The operating theatre, anaesthesia induction and separation from parents create fear and anxiety in children. Anxiety leads to adverse behavioral changes appearing and sometimes persisting during the postoperative period. Our aim was to compare the effects of midazolam (0.3 mg kg^–1: MDZ) for premedication with age-appropriate tablet game apps (TAB) on children anxiety during and after ambulatory surgery.

Methods. A randomized controlled trial was conducted from May 16th, 2013 to March 25th, 2014 at the Children Hospital of Lyon. The primary outcome of this study was the change in m-YPAS score at the time of anaesthetic mask induction. Anxiety was also assessed in the waiting surgical area, at the time of separation with parents and when back in the ambulatory surgery ward.

Results. One hundred and eighteen patients aged four-11 yr were recruited, 60 in the TAB Group and 58 in the MDZ Group. Main endpoint was missing for three patients from the MDZ Group. At the time of mask induction, there was no significant difference between MDZ and TAB Group for the m-YPAS score (40.5 (18.6) vs 41.8 (20.7), P = 0.99). There was no significant correlation between m-YPAS score and its evolution over the four period of time between subjects.

Conclusions. We were not able to show whether TAB is superior to MDZ to blunt anxiety in children undergoing ambulatory surgery. TAB is a non-pharmacological tool which has the capacity in reducing perioperative stress without any sedative effect in this population.

Clinical trial registration. NCT 02192710

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Indirect admission to intensive care after surgery: what should be considered?

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Ketamine inhalation

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Stopping antithrombotics during regional anaesthesia and eye surgery: crying wolf?

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Preoperative supplementation with fibrinogen concentrate in cardiac surgery

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Paravertebral block in paediatric abdominal surgery--a systematic review and meta-analysis of randomized trials

The increased popularity of paravertebral block (PVB) can be attributed to its relative safety and comparable efficacy when compared with epidural analgesia. It has thus been recommended for open cholecystectomy and other less painful surgeries such as inguinal herniorraphy and appendectomy. We performed a systematic review of PVB in paediatric abdominal conditions to assess its clinical efficacy and side effects compared with other analgesic therapies.

A search of Medline, Embase, and Web of Science and hand-searching references from inception date to May 2016 was done. Relevant studies were randomized clinical trials in patients 0–18 years old comparing PVB (single shot or continuous catheter) with any comparator and analgesic medication. Pain scores, rescue analgesia and adverse events were compared.

The systematic reviews identified six trials enrolling 358 paediatric patients. PVB medications included bupivacaine, ropivacaine, lidocaine, and fentanyl. Surgical procedures included inguinal herniorraphy, cholecystectomy, and appendectomy. The standardized mean difference in early pain scores favoured PVB: 0.85 [95% confidence interval (CI) 0.12–1.58] at 4–6 h and 0.64 (95% CI 0.28–1.00) at 24 h. One study reported a reduced length of stay. Parental [odds ratio (OR) 5.12 (95% CI 2.59–10.1)] and surgeon [OR 6.05 (95% CI 2.25–16.3)] satisfaction were higher in those receiving a PVB. No major complications occurred with a PVB.

PVB resulted in minimally improved pain scores for up to 24 h after surgery, reduced rescue analgesia requirements, and increased surgeon and parental satisfaction. PVB is a good alternative to caudal and ilioinguinal block in paediatric abdominal surgery.

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Surgical Pain Management: A Complete Guide to Implantable and Interventional Pain Therapies, S Narang, A Weisheipl and EL Ross (editors)

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