Bacterial resistance to antimicrobial peptides

Antimicrobial peptides (AMPs) or host defense peptides (HDPs) are vital components of human innate defense system targeting human‐related bacteria. Many bacteria have various mechanisms interfering with AMP activity, causing resistance to AMPs. Since AMPs are considered as potential novel antimicrobial drugs, understanding the mechanisms of bacterial resistance to direct killing of AMPs is of great significance. In this review, a comparative overview of bacterial strategies for resistance to direct killing of various AMPs is presented. Such strategies include bacterial cell envelope modification, AMP degradation, sequestration, expelling, and capsule.     

Autophagy regulates neuronal excitability by controlling cAMP/protein kinase A signaling at the synapse

Autophagy provides nutrients during starvation and eliminates detrimental cellular components. However, accumulating evidence indicates that autophagy is not merely a housekeeping process. Here, by combining mouse models of neuron‐specific ATG5 deficiency in either excitatory or inhibitory neurons with quantitative proteomics, high‐content microscopy, and live‐imaging approaches, we show that autophagy protein ATG5 functions in neurons to regulate cAMP‐dependent protein kinase A (PKA)‐mediated phosphorylation of a synapse‐confined proteome. This function of ATG5 is independent of bulk turnover of synaptic proteins and requires the targeting of PKA inhibitory R1 subunits to autophagosomes. Neuronal loss of ATG5 causes synaptic accumulation of PKA‐R1, which sequesters the PKA catalytic subunit and diminishes cAMP/PKA‐dependent phosphorylation of postsynaptic cytoskeletal proteins that mediate AMPAR trafficking. Furthermore, ATG5 deletion in glutamatergic neurons augments AMPAR‐dependent excitatory neurotransmission and causes the appearance of spontaneous recurrent seizures in mice. Our findings identify a novel role of autophagy in regulating PKA signaling at glutamatergic synapses and suggest the PKA as a target for restoration of synaptic function in neurodegenerative conditions with autophagy dysfunction.     

miRNA-143 replacement therapy harnesses the proliferation and migration of colorectal cancer cells in vitro

miR-143 is a tumor suppressor miRNA which its downregulation is frequently reported in colorectal cancer (CRC). This miRNA is a negative regulator of K-RAS, c-MYC, BCL-2, and MMP-9 genes which are engaged in tumor growth and metastasis. In the present study, miR-143 restoration was performed by transfection of the pCMV-miR-143 vector into the SW-480 CRC cells. Subsequently, alterations in proliferative and migratory potential of the cells were investigated by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) and wound-healing assays, respectively. Moreover, to detect apoptosis incidence in the transfected cells, 4',6-diamidino-2-phenylindole (DAPI) staining was used. Furthermore, mRNA levels of c-MYC, K-RAS, MMP-9, and BCL-2, as potential targets of miR-143, were assessed by quantitative Real-Time PCR (qRT-PCR). Also the expression levels of c-MYC, K-RAS, and MMP-9 proteins were investigated by the western blot analysis. Finally, the ratio of BAX to BCL-2 expression, as a potential marker of the response to apoptosis stimuli, was compared between the control and test groups. Furthermore, the trypan blue test was performed to determine the cell viability in cell suspension. According to the results, a decreased viability and migratory potential was observed for the miR-143 receiving cells. The DAPI staining also confirmed the occurrence of apoptosis. Moreover, BCL-2, K-RAS, MMP-9, and c-MYC mRNAs were significantly downregulated in the miR-143 grafted cells. The BAX/BCL-2 ratio also indicated a notable increase in the cells with miR-143 overexpression. In brief, miR-143 replacement could be considered as an effective strategy for the management of CRC and attenuating its invasive features.     

Validation of the ‘FeMorph’ software in planning cam osteochondroplasty by incorporating labral morphology

Impingement resulting from a cam deformity may cause pain, limit the hip joint range of motion (RoM) and lead to osteoarthritis. We have previously developed FeMorph software to quantify and plan corrective surgery and predict hip RoM post surgery. This study aimed to validate the software and evaluate the influence of the acetabular labrum on hip RoM. Computed tomography data from 92 femur-pelvis pairs were analysed in conjunction with the inter/intra-observer reliability. Four cadaveric hips were dissected, and the three-dimensional (3D) shape and size of the acetabular labrum for these hips was obtained using laser scan. The influence of the acetabular labrum in the RoM and subsequent planning for corrective surgery were then evaluated in cadavers for models with and without a labrum, and used as a first step towards validation of FeMorph RoM prediction. FeMorph was successfully used to model cam deformities and plan corrective surgery. Three-dimensional alpha angles were reduced to below 50° after virtual surgery without an excessive reduction in femoral neck cross-sectional area, which could increase fracture risk. A mean increase of 8° ± 2° in permitted internal rotation was observed during impingement testing following removal of the labrum. FeMorph provides a reliable and useful method to model and plan cam deformity correction. This study indicates that the presence of the labrum is responsible for a substantial decrease in permitted internal rotation at the hip joint. This has implications for surgical planning models which often only account for bony impingement.     

Resveratrol targeting the Wnt signaling pathway: A focus on therapeutic activities

Wingless-type MMTV integration site (Wnt) signaling pathway is considered as an important pathway regulating a variety of biological processes such as tissue formation and homeostasis, cell proliferation, cell migration, cell differentiation, and embryogenesis. Impairment in the Wnt signaling pathway is associated with pathological conditions, particularly cancer. So, modulation of this pathway can be considered as a promising strategy and several drugs have been developed in line with this strategy. Resveratrol (Res) is a naturally occurring nutraceutical compound exclusively found in different fruits and nuts such as grape, peanut, and pistachio. This compound has favorable biological and therapeutic activities such as antioxidant, anti-inflammatory, antitumor, hepatoprotective, cardioprotective, and antidiabetic. At the present review, we demonstrate how Res modulates Wnt signaling pathway to exert its pharmacological effects.     

Methylation of progesterone receptor isoform A promoter in normal breast tissue: An epigenetic link between early age at menarche and risk of breast cancer?

Emerging evidence indicates that some altered patterns of methylation that occur in breast tumors may also be found in breast tissue of healthy women in relation to the breast cancer (BC) risk factors. Progesterone receptor (PR) isoform α is a crucial regulator of breast hormone responsiveness and its hypermethylation plays an important role in the initiation and development of breast tumors. However, such a methylation change in healthy women and its link with the different risk factors has not yet been investigated. In the present study, we aimed to examine the relationship of possible methylation changes within a critical region in the promoter CpG island of PGR-α (progesterone receptor α) gene in the healthy women with a set of reproductive and nonreproductive BC risk factors. The breast tissues were collected from 120 cancer-free women who had undergone cosmetic mammoplasty. The genomic DNA was extracted from the breast tissues and the methylation level of PGR-α promoter CpG island was determined by using MeDIP-qPCR assay. Using regression analysis, we found that increasing menarche age is inversely associated with the high methylation of PGR-α promoter ( β = −0.790, SE = 0.362; P = 0.031). Although lactating women had more methylation than nonlactating women (P = 0.026, the t test), this result was not confirmed by regression models. Such an observation may be helpful in better understanding of the underlying mechanisms by which early age at menarche increases the risk of BC. However, this perspective requires further validations in larger studies of more subjects as well as the inclusion of other related genes.     

Acute toxicity of kaolin and essential oils from Mentha pulegium and Zingiber officinale against different stages of Callosobruchus maculatus under laboratory conditions

Naturally derived compounds such as essential oils and natural mineral are relatively cheap, non-toxic to food grains and environmentally friendly and would be suitable alternatives for currently used chemical insecticides if they have high insecticidal effectiveness. In the present study, acute toxicity of kaolin and essential oils from Mentha pulegium and Zingiber officinale were assessed on different stages of Callosobruchus maculatus at 28?±?2?°C, 65?±?5% R. H and dark condition. The calculated LC₅₀ values on the egg, larvae and adult stages of C. maculatus were 1.15, 2.33 and 2.18?μl/ml air for Z. officinale and 0.07, 0.11 and 0.09?μl/ml air for M. pulegium, respectively. The result showed that M. pulegium was more effective essential oil against different stages of C. maculatus compared with the Z. officinale, and also the egg and adult stages of C. maculatus were more susceptible against essential oils compared with larval stage. The LC₅₀ values of kaolin were 0.71 and 0.18?mg/cm² on egg and adult of C. maculatus, respectively. The combination of tested essential oils with kaolin increased mortality of C. maculatus adults compared with their application alone. It was found that tested essential oils and kaolin had high potential in controlling different stages of C. maculatus.