Antimicrobial host defense peptides (HDPs) are a critical component of the innate immunity with microbicidal, endotoxin-neutralizing, and immunostimulatory properties. HDPs kill bacteria primarily ...through non-specific membrane lysis, therefore with a less likelihood of provoking resistance. Extensive structure–activity relationship studies with a number of HDPs have revealed that net charge, amphipathicity, hydrophobicity, and structural propensity are among the most important physicochemical and structural parameters that dictate their ability to interact with and disrupt membranes. A delicate balance among these factors, rather than a mere alteration of a single factor, is critically important for HDPs to ensure the antimicrobial potency and target cell selectivity. With a better understanding of the structural determinants of HDPs for their membrane-lytic activities, it is expected that novel HDP-based antimicrobials with minimum toxicity to eukaryotic cells can be developed for resistant infections, which have become a global public health crisis.
The role of CD133 (Prominin-1) as a cancer stem cell marker may be useful for therapeutic approaches and prognostication in prostate cancer patients. We investigated the stem-cell-related function ...and biological features of a subpopulation of CD133+ cells isolated from established primary human prostate cancer cell lines. The CD133+ cells sorted from human prostate cancer 22Rv1 exhibited high clonogenic and tumorigenic capabilities, sphere forming capacity and serially reinitiated transplantable tumors in NOD-SCID mice. Gene profiling analysis of CD133+ cells showed upregulation of markers of stem cell differentiation (CD44, Oct4, SOX9 and Nanog), epithelial-to-mesenchymal transition (c-myc and BMI1), osteoblastic differentiation (Runx2), and skeletal morphogenesis (BMP2), compared to side population of CD133- cells. These cells are highly malignant and resistant to γ-radiation and chemotherapeutic drug, docetaxel. Importantly, a docetaxel-resistant subclone was more enriched in CD133+ cells with significant increase in Runx2 expression, compared to CD133- cells. Furthermore, knockdown of Runx2 in these cells resulted in differential response to chemotherapy, sensitizing them to increased cell death. These results demonstrate therapy-resistant population with stem-like features are distinct subpopulation of malignant cells that resides within parental cell lines. The molecular signature of CD133+ cells may lead to identification of novel therapeutic targets and prognostic markers in the treatment of prostate cancer.
•CD133+ cells possess self-renewal and sphere forming capabilities.•CD133+ cells are highly tumorigenic, compared to CD133- cells.•CD133+ cells are highly therapy resistant, compared to CD133- cells.•CD133+ cells demonstrate stem-cell properties in prostate cancer.
Elicitors have a substantial impact on the accumulation of phytochemical components in wild plants. The present study aimed to evaluate the impact of salicylic acid (SA) and methyl jasmonate (MJ) on ...the enrichment of carbazole alkaloids (CAs) in the leaves of
Murraya koenigii
under controlled environment. Effect of elicitors at 1.0, 1.5 and 2.0 mM and their time of exposition 6 h, 12 h, 24 h, 2 days and 5 days were evaluated. Methanolic extracts of the treated samples were subjected to UPLC-ESI-QTRAP LC-MS/MS analysis for the separation and subsequent quantification of seven identified CAs, viz
.
murrayamine A, koenigine, koenimbidine, koenimbine, mahanine, 8,8′-biskoenigine and mahanimbine. Accumulation of all the CAs was found to be enhanced with both the elicitors, but it was dependent on the type of elicitor, its concentration, and time of exposition. The data were analyzed through multivariate statistical models, like PCA, HCA and PLS-DA. The analysis revealed that 1.5 mM dose of MJ and SA had a significant influence on CAs accumulation at 24 and 12 h, respectively. Five marker CAs from both MJ and SA-treated samples were identified using VIP scoring. These findings suggest that MJ and SA with their specific concentration and exposition time could be used for the accumulation of particular CA to a substantial limit in this plant.
Glial cells constitute nearly half of the mammalian nervous system's cellular composition. The glia in
C. elegans
perform majority of tasks comparable to those conducted by their mammalian ...equivalents. The cephalic sheath (CEPsh) glia, which are known to be the counterparts of mammalian astrocytes, are enriched with two nuclear hormone receptors (NHRs)—NHR-210 and NHR-231. This unique enrichment makes the CEPsh glia and these NHRs intriguing subjects of study concerning neuronal health. We endeavored to assess the role of these NHRs in neurodegenerative diseases and related functional processes, using transgenic
C. elegans
expressing human alpha-synuclein. We employed RNAi-mediated silencing, followed by behavioural, functional, and metabolic profiling in relation to suppression of NHR-210 and 231. Our findings revealed that depleting
nhr-210
changes dopamine-associated behaviour and mitochondrial function in human alpha synuclein-expressing strains NL5901 and UA44, through a putative target,
pgp-9
, a transmembrane transporter. Considering the alteration in mitochondrial function and the involvement of a transmembrane transporter, we performed metabolomics study via HR-MAS NMR spectroscopy. Remarkably, substantial modifications in ATP, betaine, lactate, and glycine levels were seen upon the absence of
nhr-210
. We also detected considerable changes in metabolic pathways such as phenylalanine, tyrosine, and tryptophan biosynthesis metabolism; glycine, serine, and threonine metabolism; as well as glyoxalate and dicarboxylate metabolism. In conclusion, the deficiency of the nuclear hormone receptor
nhr-210
in alpha-synuclein expressing strain of
C. elegans
, results in altered mitochondrial function, coupled with alterations in vital metabolite levels. These findings underline the functional and physiological importance of
nhr-210
enrichment in CEPsh glia.
Graphical abstract
Maintenance of oxygen homeostasis is an indispensable criterion for the existence of multicellular life-forms. Disruption of this homeostasis due to inadequate oxygenation of the respiring tissues ...leads to pathological hypoxia, which acts as a significant stressor in several pathophysiological conditions including cancer, cardiovascular defects, bacterial infections, and neurological disorders. Consequently, the hypoxic tissues develop necessary adaptations both at the tissue and cellular level. The cellular adaptations involve a dramatic alteration in gene expression, post-transcriptional and post-translational modification of gene products, bioenergetics, and metabolism. Among the key responses to oxygen-deprivation is the skewing of cellular alternative splicing program. Herein, we discuss the current concepts of oxygen tension-dependent alternative splicing relevant to various pathophysiological conditions. Following a brief description of cellular response to hypoxia and the pre-mRNA splicing mechanism, we outline the impressive number of hypoxia-elicited alternative splicing events associated with maladies like cancer, cardiovascular diseases, and neurological disorders. Furthermore, we discuss how manipulation of hypoxia-induced alternative splicing may pose promising strategies for novel translational diagnosis and therapeutic interventions.
Life-threatening diseases, especially those caused by pathogens and harmful ultraviolet radiation (UV-R), have triggered increasing demands for comfortable, antimicrobial, and UV-R protective ...clothing with a long service life. However, developing such textiles with exceptional wash durability is still challenging. Herein, we demonstrate how to fabricate wash durable multifunctional cotton textiles by growing in situ ZnO-TiO
2
hybrid nanocrystals (NCs) on the surface of cellulosic fabrics. The ZnO-TiO
2
hybrid NCs presented high functional efficiency, owing to their high charge transfer/separation. Ultrafine fiber surface pores, utilized as nucleating sites, endowed the uniform growth of NCs and their physical locking. The resulting fabrics presented excellent UV protection factors up to 54, displayed bactericidal efficiency of 100% against
Staphylococcus aureus
and
Escherichia coli
, and optimum self-cleaning efficacy. Moreover, the functionalized textiles exhibited robust washing durability, maintaining antibacterial and anti-UV-R efficiency even after 30 extensive washing cycles.
Graphical abstract
Apigenin, a dietary plant-flavonoid has shown anti-proliferative and anticancer properties, however the molecular basis of this effect remains to be elucidated. We studied the molecular events of ...apigenin action in human prostate cancer cells. Treatment of LNCaP and PC-3 cells with apigenin causes G0-G1 phase arrest, decrease in total Rb protein and its phosphorylation at Ser780 and Ser807/811 in dose- and time- dependent fashion. Apigenin treatment caused increased phosphorylation of ERK1/2 and JNK1/2 and this sustained activation resulted in decreased ELK-1 phosphorylation and c-FOS expression thereby inhibiting cell survival. Use of kinase inhibitors induced ERK1/2 phosphorylation, albeit at different levels, and did not contribute to cell cycle arrest in comparison to apigenin treatment. Despite activation of MAPK pathway, apigenin caused a significant decrease in cyclin D1 expression that occurred simultaneously with the loss of Rb phosphorylation and inhibition of cell cycle progression. The reduced expression of cyclin D1 protein correlated with decrease in expression and phosphorylation of p38 and PI3K-Akt, which are regulators of cyclin D1 protein. Interestingly, apigenin caused a marked reduction in cyclin D1, D2 and E and their regulatory partners CDK 2, 4 and 6, operative in G0-G1 phase of the cell cycle. This was accompanied by a loss of RNA polymerase II phosphorylation, suggesting the effectiveness of apigenin in inhibiting transcription of these proteins. This study provides an insight into the molecular mechanism of apigenin in modulating various tyrosine kinases and perturbs cell cycle progression, suggesting its future development and use as anticancer agent in humans.
Pseudomonas aeruginosa
is an opportunistic pathogen that commonly causes hospital-acquired infection and is of great concern in immunocompromised patients. The quorum sensing (QS) mechanism of
P. ...aeruginosa
is well studied and known to be responsible for pathogenicity and virulence. The QS inhibitor derived from the natural product can be an important therapeutic agent for pathogen control. The present study reports the role of
Bruguiera gymnorhiza
purified fraction (BG138) in inhibiting virulence factor production, biofilm formation, quorum sensing molecules, and expression of QS-related genes of
P. aeruginosa
. Structural characterization of BG138 by high resolution mass spectrometry, Fourier transform infrared spectroscopy, 1D (
1
H and
13
C NMR) and 2D NMR reveals that the fraction is a mixture of already known cyclic disulfide diastereomer, namely, brugierol and isobrugierol. The minimum inhibitory concentration (MIC) of BG138 against
P. aeruginosa
was 32 μg/ml. Biofilm formation was significantly reduced at sub-MIC concentrations of BG138. Scanning electron microscopy analysis reports the concentration-dependent biofilm inhibition and morphological changes of
P. aeruginosa
. Flow cytometry–based cell viability assay showed that
P. aeruginosa
cells exhibit increased propidium iodide uptake on treatment with 32 and 64 μg/ml of BG138. At sub-MIC concentrations, BG138 exhibited significant inhibition of virulence factors and reduced swimming and swarming motility of
P. aeruginosa
. Furthermore, the effect of BG138 on the expression of QS-related genes was investigated by qRT-PCR. Taken together, our study reports the isolation and structural characterization of bioactive fraction BG138 from
B. gymnorhiza
and its anti-biofilm, anti-virulence, anti-quorum sensing, and cell-damaging activities against
P. aeruginosa
.
Aberrant Nuclear Factor-κappaB (NF-κB) activation due to rapid IκBα turnover and high basal IκBα kinase (IKK) activity has been frequently observed in prostate cancer. Apigenin, a naturally occurring ...plant flavone, exhibits anti-proliferative, anti-inflammatory and anti-carcinogenic activities by inhibiting NF-κB pathway, through a mechanism not fully understood. We found that apigenin feeding in microgram doses (bioavailable in humans) inhibited prostate tumorigenesis in TRAMP mice by interfering with NF-κB signaling. Apigenin feeding to TRAMP mice (20 and 50 μg/mouse/day, 6 days/week for 20 weeks) exhibited significant decrease in tumor volumes of the prostate and completely abolished metastasis, which correlated with inhibition of NF-κB activation and binding to the DNA. Apigenin intake blocked phosphorylation and degradation of IκBα by inhibiting IKK activation, which in turn led to suppression of NF-κB activation. The expression of NF-κB-regulated gene products involved in proliferation (cyclin D1, and COX-2), anti-apoptosis (Bcl-2 and Bcl-xL), and angiogenesis (vascular endothelial growth factor) were also downregulated after apigenin feeding. These events correlated with the induction of apoptosis in tumor cells, as evident by increased cleaved caspase-3 labeling index in the dorsolateral prostate. Our results provide convincing evidence that apigenin inhibits IKK activation and restores the expression of IκBα, preventing it's phosphorylation in a fashion similar to that elicited by IKK and proteasomal inhibitors through suppression of NF-κB signaling pathway.
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