Retracted: Icariin attenuates methotrexate chemotherapy-induced bone marrow microvascular damage and bone loss in rats

Methotrexate (MTX), a widely used antimetabolite in paediatric cancer to treatment, has been widely reported to cause bone loss and bone marrow (BM) microvascular (particularly sinusoids) damage. Investigations must now investigate how MTX-induced bone loss and microvasculature damage can be attenuated/prevented. In the present study, we examined the potency of icariin, an herbal flavonoid, in reducing bone loss and the dilation/damage of BM sinusoids in rats caused by MTX treatment. Groups of young rats were treated with five daily MTX injections (0.75 mg/kg) with and without icariin oral supplementation until Day 9 after the first MTX injection. Histological analyses showed a significant reduction in the bone volume/tissue volume (BV/TV) fraction (%) and trabecular number in the metaphysis trabecular bone of MTX-treated rats, but no significant changes in trabecular thickness and trabecular spacing. However, the BV/TV (%) and trabecular number were found to be significantly higher in MTX + icariin-treated rats than those of MTX alone-treated rats. Gene expression analyses showed that icariin treatment maintained expression of osteogenesis-related genes but suppressed the induction of adipogenesis-related genes in bones of MTX-treated rats. In addition, icariin treatment attenuated MTX-induced dilation of BM sinusoids and upregulated expression of endothelial cell marker CD31 in the metaphysis bone of icariin + MTX-treated rats. Furthermore, in vitro studies suggest that icariin treatment can potentially enhance the survival of cultured rat sinusoidal endothelial cells against cytotoxic effect of MTX and promote their migration and tube formation abilities, which is associated with enhanced production of nitric oxide.     

Flavonoid genistein protects bone marrow sinusoidal blood vessels from damage by methotrexate therapy in rats

Cancer chemotherapy can cause significant damage to the bone marrow (BM) microvascular (sinusoidal) system. Investigations must now address whether and how BM sinusoidal endothelial cells (SECs) can be protected during chemotherapy. Herein we examined the potential protective effects of genistein, a soy-derived flavonoid, against BM sinusoidal damage caused by treatment with methotrexate (MTX). The groups of young adult rats were gavaged daily with genistein (20 mg/kg) or placebo. After 1 week, rats also received daily injections of MTX (0.75 mg/kg) or saline for 5 days and were killed after a further 4 days. Histological analyses showed that BM sinusoids were markedly dilated ( p < 0.001) in the MTX-alone group but were unaffected or less dilated in the genistein+MTX group. In control rats, genistein significantly enhanced expression of vascular endothelial growth factor (VEGF; p < 0.01), particularly in osteoblasts, and angiogenesis marker CD31 ( p < 0.001) in bone. In MTX-treated rats, genistein suppressed MTX-induced apoptosis of BM SECs ( p < 0.001 vs MTX alone group) and tended to increase expression of CD31 and VEGF ( p < 0.05). Our in vitro studies showed that genistein in certain concentrations protected cultured SECs from MTX cytotoxic effects. Genistein enhanced tube formation of cultured SECs, which is associated with its ability to induce expression of endothelial nitric oxide synthase and production of nitric oxide. These data suggest that genistein can protect BM sinusoids during MTX therapy, which is associated, at least partially, with its indirect effect of promoting VEGF expression in osteoblasts and its direct effect of enhancing nitric oxide production in SECs.     

Temporal expression profile of CXC chemokines in serum of patients with spinal cord injury

Chemokines, a subclass of cytokine superfamily have both pro-inflammatory and migratory role and serve as chemoattractant of immune cells during the inflammatory responses ensuing spinal cord injury (SCI). The chemokines, especially CXCL-1, CXCL-9, CXCL-10 and CXCL-12 contribute significant part in the inflammatory secondary damage of SCI. Inhibiting chemokine’s activity and thereby the secondary damage cascades has been suggested as a chemokine-targeted therapeutic approach to SCI. To optimize the inhibition of secondary injury through targeted chemokine therapy, accurate knowledge about the temporal profile of these cytokines following SCI is required. Hence, the present study was planned to determine the serum levels of CXCL-1, CXCL-9, CXCL-10 and CXCL-12 at 3–6 h, 7 and 28 days and 3 m after SCI in male and female SCI patients (n = 78) and compare with age- and sex-matched patients with non-spinal cord injuries (NSCI, n = 70) and healthy volunteers (n = 100). ANOVA with Tukey post hoc analysis was used to determine the differences between the groups. The data from the present study show that the serum level of CXCL-1, CXCL-9 and CXCL-10 peaked on day 7 post-SCI and then declined to the control level. In contrast, significantly elevated level of CXCL-12 persisted for 28 days post SCI. In addition, post-SCI expression of CXCL-12 was found to be sex-dependent. Male SCI patients expressed significantly higher CXCL-12 when compared to control and SCI female. We did not observe any change in chemokines level of NSCI. Further, the age of the patients did not influence chemokines expression after SCI. These observations along with SCI-induced CSF-chemokine level should contribute to the identification of selective and temporal chemokine targeted therapy after SCI.     

Ectopic expression of micro-RNA-1, 21 and 125a in peripheral blood immune cells is associated with chronic HBV infection

Micro-RNAs (miRNAs) play key roles in regulating genes of the immune system. The aim of this study was to examine the expression of miR-1, 21 and 125a in the immune cells taken from the peripheral blood of patients suffering from chronic HBV infection (CHB). This cross-sectional study was performed on 60 CHB patients and 60 healthy controls and expression of miR-1, 21 and 125a was evaluated using quantitative Real-Time PCR. The results showed that expression of miR-1, 21 and 125a was significantly increased in CHB patients in comparison to healthy controls. Based on our results it may be concluded that increased expression of miR-1, 21 and 125a is significantly associated with CHB and may play key roles in the induction of impaired immune responses in CHB patients.     

Anticancer and cytotoxic effects of troxerutin on HeLa cell line: an in-vitro model of cervical cancer

Cervical cancer is one of the grave uterine tumors which leads to death in women worldwide. Troxerutin (TRX) as a bioflavonoid compound has many pharmacological effects such as anti-neoplastic, radioprotective, and anti-cancer. The present study was designed to examine the cytotoxic effect of TRX on human HeLa tumor cells. Human HeLa cells were cultured and treated with different doses of TRX (20–640?mg/ml) to evaluate the effective half-maximal inhibitory concentration (IC₅₀) after 24?h. MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) test was used for cell proliferation assay. Also, the Bax, Bcl-2, cleaved caspase-3, and tumor necrosis factor-α (TNF-α) protein expression levels were detected with immunoblotting analysis. The malondialdehyde (MDA) concentration, glutathione peroxidase (GPx) and superoxide dismutase (SOD) activity levels were measured via their commercial kits. Data were analyzed using one-way ANOVA. The result showed that TRX at 320?mg/ml concentration (IC₅₀) has a growth inhibitory effect against HeLa cells at 24?h treatment (P???0.01). Moreover, it increased the MDA concentration and also decreased the GPx and SOD activity levels at 320?mg/ml concentration versus control (P?<?0.001). Also, TRX significantly up-regulated the Bax, cleaved caspase-3 and TNF-α proteins expression levels (P ?<??0.01) and down-regulated the Bcl-2 protein expression in HeLa tumor cells at 320?mg/ml concentration compared to control (P?<?0.05). Our study showed that 24?h of treatment with TRX (320?mg/ml) has apoptotic and growth inhibitory effects against HeLa cells. It can induce inflammation (at least via up-regulating the TNF-α protein expression) and oxidative stress in human HeLa cells.

     

Adipose-derived stem cells for wound healing

Wound healing is a complex but a fine-tuned biological process in which human skin has the ability to regenerate itself following damage. However, in particular conditions such as deep burn or diabetes the process of wound healing is compromised. Despite investigations on the potency of a wide variety of stem cells for wound healing, adipose-derived stem cells (ASCs) seem to possess the least limitations for clinical applications, and literature showed that ASCs can improve the process of wound healing very likely by promoting angiogenesis and/or vascularisation, modulating immune response, and inducing epithelialization in the wound. In the present review, advantages and disadvantages of various stem cells which can be used for promoting wound healing are discussed. In addition, potential mechanisms of action by which ASCs may accelerate wound healing are summarised. Finally, clinical studies applying ASCs for wound healing and the associated limitations are reviewed.     

Critical limb ischemia: Current and novel therapeutic strategies

Critical limb ischemia (CLI) is the advanced stage of peripheral artery disease spectrum and is defined by limb pain or impending limb loss because of compromised blood flow to the affected extremity. Current conventional therapies for CLI include amputation, bypass surgery, endovascular therapy, and pharmacological approaches. Although these conventional therapeutic strategies still remain as the mainstay of treatments for CLI, novel and promising therapeutic approaches such as proangiogenic gene/protein therapies and stem cell-based therapies have emerged to overcome, at least partially, the limitations and disadvantages of current conventional therapeutic approaches. Such novel CLI treatment options may become even more effective when other complementary approaches such as utilizing proper bioscaffolds are used to increase the survival and engraftment of delivered genes and stem cells. Therefore, herein, we address the benefits and disadvantages of current therapeutic strategies for CLI treatment and summarize the novel and promising therapeutic approaches for CLI treatment. Our analyses also suggest that these novel CLI therapeutic strategies show considerable advantages to be used when current conventional methods have failed for CLI treatment.     

The effect of oleuropein on unilateral ureteral obstruction induced-kidney injury in rats: the role of oxidative stress,inflammation and apoptosis

Molecular Biology Reports - Unilateral ureteral obstruction (UUO) induces kidney injury. Oleuropein as a major compound of olive leaves modulates the inflammatory parameters and decreases oxidative...     

Methotrexate chemotherapy–induced damages in bone marrow sinusoids: An in vivo and in vitro study

Chemotherapeutic agents are very well evident extrinsic stimuli for causing damage to endothelial cells. Methotrexate is an antimetabolite commonly used to treat solid tumours and paediatric cancers. However, studies on the effect(s) of methotrexate on bone marrow microvascular system are inadequate. In the current study, we observed a significant bone marrow microvascular dilation following methotrexate therapy in rats, accompanied by apoptosis induction in bone marrow sinusoidal endothelial cells, and followed by recovery of bone marrow sinusoids associated with increased proliferation of remaining bone marrow sinusoidal endothelial cells. Our in vitro studies revealed that methotrexate is cytotoxic for cultured sinusoidal endothelial cells and can also induce apoptosis which is associated with upregulation of expression ratio of Bax and Bcl-2 genes and Bax/Bcl-2 expression ratio. Furthermore, it was shown that methotrexate can negatively affect proliferation of cultured sinusoidal endothelial cells and also inhibit their abilities of migration and formation of microvessel like tubes. The data from this study indicates that methotrexate can cause significant bone marrow sinusoidal endothelium damage in vivo and induce apoptosis and inhibit proliferation, migration and tube-forming abilities of sinusoidal endothelial cells in vitro.     

The protective effect of carvacrol on acetaminophen-induced renal damage in male rats

Molecular Biology Reports - Acetaminophen overdose causes renal injury via oxidative stress and apoptosis induction. Carvacrol has several pharmacological properties such as antioxidant,...