Improved angiogenic activity of endothelial progenitor cell in diabetic patients treated with insulin plus metformin

Type 2 diabetes (T2DM) is associated with an increased vascular disease. Moreover, endothelial progenitor cell (EPC) function is impaired in diabetic patients. Decreased EPC number plays a critical role in reduced endothelial repair and development of the vascular disorder. To determine the effect of metformin and insulin plus metformin on functional activity of EPCs, 130 participants were divided into three groups (group 1: healthy control; group 2: metformin; group 3: insulin plus metformin). The concentration of EPCs in the circulation was first quantified. Thereafter, circulating EPCs (cEPCs) were harvested and the biological features of these cells including proliferative, clonogenicity, tubulogenic, and migratory properties were analyzed after expansion. The serum protein levels of some proangiogenic factors were also measured. Our results showed greater numbers of cEPCs in control and in diabetic patients treated with insulin plus metformin than in metformin-treated patients. Insulin plus metformin therapy was associated with augmented proliferative, clonogenicity, migratory, and tubulogenic activity of cEPCs in patients with T2DM. Increased serum concentrations of angiogenic factors were also observed in patients treated with insulin plus metformin. Western blot analysis showed increased protein levels of pTie-2/Tie2 and Pakt/AKT in cEPCs harvested from T2DM, treated with insulin metformin plus. This study showed that treatment with insulin plus metformin in diabetic patients is associated with increased mobilization of EPCs into the circulation, with potential beneficial effect in vascular protection in diabetic patients.     

Do arbuscular mycorrhizas or heterotrophic soil microbes contribute toward plant acquisition of a pulse of mineral phosphate?

Aims

We investigated the role of arbuscular mycorrhizal fungi (AMF) and heterotrophic soil microbes in the uptake of phosphorus (P) by Trifolium subterraneum from a pulse.

Methods

Plants were grown in sterilised pasture field soil with a realistic level of available P. There were five treatments, two of which involved AMF: 1) unsterilised field soil containing a community of AMF and heterotrophic organisms; 2) Scutellospora calospora inoculum (AMF); 3) microbes added as filtrate from the field soil; 4) microbes added as filtrate from the S. calospora inoculum; 5) no additions, i.e. sterilised field soil. After 11 weeks, plants were harvested: 1 day before (day 0), 1 day after (day 2) and 7 days after (day 8) the pulse of P (10 mg kg^?1).

Results

There was no difference among treatments in shoot and root dry weight, which increased from day 0 to day 8. At day 0, shoots and roots of plants in the colonised treatments had higher P and lower Mn concentrations. After the pulse, the rate of increase in P concentration in the shoots was slower for the colonised plants, and the root Mn concentration declined by up to 50 % by day 2.

Conclusions

Plants colonised by AMF had a lower rate of increase in shoot P concentration after a pulse, perhaps because intraradical hyphae accumulated P and thus reduced its transport to the shoots.     

Computational model of excitatory/inhibitory ratio imbalance role in attention deficit disorders

Impairments in attentional behaviors, including over-selectivity, under-selectivity, distractibility and difficulty in shift of attention, are widely reported in several developmental disorders, including autism. Uncharacteristic inhibitory to excitatory neuronal number ratio (IER) and abnormal synaptic strength levels in the brain are two broadly accepted neurobiological disorders observed in autistic individuals. These neurobiological findings are contrasting and their relation to the atypical attentional behaviors is not clear yet. In this paper, we take a computational approach to investigate the relation of imbalanced IER and abnormal synaptic strength to some well-documented spectrum of attentional impairments. The computational model is based on a modified version of a biologically plausible neural model of two competing minicolumns in IT cortex augmented with a simple model of top-down attention. Top-down attention is assumed to amplify (attenuates) attended (unattended) stimulus. The inhibitory synaptic strength parameter in the model is set such that typical attentional behavior is emerged. Then, according to related findings, the parameter is changed and the model's attentional behavior is considered. The simulation results show that, without any change in top-down attention, the abnormal inhibitory synaptic strength values - and IER imbalance- result in over-selectivity, under-selectivity, distractibility and difficulty in shift of attention in the model. It suggests that the modeled neurobiological abnormalities can be accounted for the attentional deficits. In addition, the atypical attentional behaviors do not necessarily point to impairments in top-down attention. Our simulations suggest that limited changes in the inhibitory synaptic strength and variations in top-down attention signal affect the model's attentional behaviors in the same way. So, limited deficits in the inhibitory strength may be alleviated by appropriate change in top-down attention biasing. Nevertheless, our model proposes that this compensation is not possible for very high and very low values of the inhibitory strength.     

Crocin and Metformin suppress metastatic breast cancer progression via VEGF and MMP9 downregulations: in vitro and in vivo studies

Metastatic breast cancer remains a serious health concern and numerous investigations recommended medicinal plants as a complementary therapy. Crocin is one of the known anticancer bio-component. Recently, the inhibitory effect of metformin has been studied on the various aspects of cancer. However, no study reported their combination effects on metastatic breast cancer. In the present study, we have assessed their anti-metastatic effects on in vitro and in vivo breast cancer models. Using MTT assay, scratch, and adhesion tests, we have evaluated the cytotoxic, anti-invasive and anti-adhesion effects of crocin and metformin on 4T1 cell line, respectively. Their protective effects and MMP9 as well as VEGF protein expression levels (Western blotting) investigated in the 4T1 murine breast cancer model. Our results showed that both crocin and metformin reduced cell viability, delayed scratch healing and inhibited the cell adhesion, in vitro. While crocin alone restored the mice’s weight reduction, crocin, metformin, and their combination significantly reduced the tumor volume size and enhanced animal survival rate in murine breast cancer model, responses that were associated with VEGF and MMP9 down-regulation. These findings suggest that a combination of crocin and metformin could serve as a novel therapeutic approach to enhance the effectiveness of metastatic breast cancer therapy.

     

Application of nanoparticles in cancer therapy with an emphasis on cell cycle

Owing to their unique characteristics, nanoparticles (NPs) could be incorporated into valuable therapeutic modalities for different diseases; however, there are many concerns about risk factors in human applications. NPs carry therapeutic chemicals that could improve the outcome of cancer therapies. Nowadays, NPs are being recognized as important and strategic agents in treatment of several disorders due to their unique properties in targeting malignant cells in tumor sites. Numerous investigations have shown that the majority of chemotherapeutic agents can be modified through entrapment in submicron colloidal systems. Still, there are problems and limitations in application of NPs in cancer therapy. The aim of the present study is to focus on potential NPs usage in cancer treatment with an emphasis on the cell cycle of malignant cells.     

Neuroprotection by histone deacetylase-related protein

The expression of histone deacetylase-related protein (HDRP) is reduced in neurons undergoing apoptosis. Forced reduction of HDRP expression in healthy neurons by treatment with antisense oligonucleotides also induces cell death. Likewise, neurons cultured from mice lacking HDRP are more vulnerable to cell death. Adenovirally mediated expression of HDRP prevents neuronal death, showing that HDRP is a neuroprotective protein. Neuroprotection by forced expression of HDRP is not accompanied by activation of the phosphatidylinositol 3-kinase-Akt or Raf-MEK-ERK signaling pathway, and treatment with pharmacological inhibitors of these pathways fails to inhibit the neuroprotection by HDRP. Stimulation of c-Jun phosphorylation and expression, an essential feature of neuronal death, is prevented by HDRP. We found that HDRP associates with c-Jun N-terminal kinase (JNK) and inhibits its activity, thus explaining the inhibition of c-Jun phosphorylation by HDRP. HDRP also interacts with histone deacetylase 1 (HDAC1) and recruits it to the c-Jun gene promoter, resulting in an inhibition of histone H3 acetylation at the c-Jun promoter. Although HDRP lacks intrinsic deacetylase activity, treatment with pharmacological inhibitors of histone deacetylases induces apoptosis even in the presence of ectopically expressed HDRP, underscoring the importance of c-Jun promoter deacetylation by HDRP-HDAC1 in HDRP-mediated neuroprotection. Our results suggest that neuroprotection by HDRP is mediated by the inhibition of c-Jun through its interaction with JNK and HDAC1.