Emerging application of nanotechnology for mankind.

Nanotechnology has proven to be the greatest multidisciplinary field in the current years with potential applications in agriculture, pollution remediation, environmental sustainability, as well as most recently in pharmaceutical industries. As a result of its physical, chemical, and biological productivity, resistance, and matricular organization at a larger scale, the potential of nanocomposites revealed different sorts of assembling structures via testing. Biosensors are known some specifically promising inventions whereas carbon nanotube, magnetic nanoparticles (NPs), quantum dots, and gold NPs showed capability to repair damaged cells, molecular docking, drug-delivery, and nano-remediation of toxic elements. PEGylated(Poly ethyl glycol amyl gated) redox-responsive nanoscale COFs drug delivery from AgNPs and AuNPs are known to be sun blockers in sunscreen lotions. The emerging trends and yet more to be discovered to bridge the gaps forming in the field of nanotechnology, especially insights into environmental concerns and health issues most importantly the food web which is connected with the well beings of mankind to perform its tasks giving necessary results. The current review detailed emerging role of nanomaterials in human life. Supplementary Information: The online version contains supplementary material available at 10.1007/s42247-023-00461-8.

Applications of nanomaterials for gastrointestinal tumors: A review.

Nanotechnology is the emerging and advance field of research for the diagnosis and treatment of various diseases. With the development of nanotechnology, different nanoparticles are used in the treatment of cancer due to their unique optical properties, excellent biocompatibility, surface effects, and small size effects. Nanoparticles are the particles which have the particular size from 1 to 100 nm. These nanoparticles are zero dimension, one dimension, two dimension and three dimension etc. In present scenario a variety of research is focused on the tailored synthesis of nanoparticles for medicinal applications that can be used for cancer treatment based on the morphology, composition, interaction with target cell. The gastrointestinal (GI) tumors are found one of the deadest cancer types with highest reoccurrence rates. The diagnosis and treatment of gastrointestinal cancer is very challenging due to its deep location and complicated surgery. Nanotechnology provides fast diagnosis and immediate treatment for the gastrointestinal disease. A variety of nanomaterials are used for the diagnosis and treatment of GI disease. Nanoparticles target directly to the tumor cell as diagnostic and therapeutic tools facilitating the identification and removal of tumor cells. A number of nanoparticles are developed for the uses are quantum dots (QDs), carbon nanotubes (CNTs), metallic nanoparticles (MNPs), Dendrimers etc. This review article gives an overview of the most promising nanomaterials used for the diagnosis and treatment of GI diseases. This review attempts to incorporate numerous uses for the most current nanomaterials, which have great potential for treating gastrointestinal diseases.

Counteraction of Biofilm Formation and Antimicrobial Potential of Terminalia catappa Functionalized Silver Nanoparticles against Candida albicans and Multidrug-Resistant Gram-Negative and Gram-Positive Bacteria.

Biofilms not only protect bacteria and Candida species from antibiotics, but they also promote the emergence of drug-resistant strains, making eradication more challenging. As a result, novel antimicrobial agents to counteract biofilm formation are desperately needed. In this study, Terminalia catappa leaf extract (TCE) was used to optimize the TCE-capped silver nanoparticles (TCE-AgNPs) via a one-pot single-step method. Varied concentrations of TCE have yielded different sized AgNPs. The physico-chemical characterization of TCE-AgNPs using UV-Vis, SEM, TEM, FTIR, and Raman spectroscopy have confirmed the formation of nanostructures, their shape and size and plausible role of TCE bio-active compounds, most likely involved in the synthesis as well as stabilization of NPs, respectively. TCE-AgNPs have been tested for antibiofilm and antimicrobial activity against multidrug-resistant Pseudomonas aeruginosa (MDR-PA), methicillin-resistant Staphylococcus aureus (MRSA), and Candida albicans using various microbiological protocols. TCE-Ag-NPs-3 significantly inhibits biofilm formation of MDR-PA, MRSA, and C. albicans by 73.7, 69.56, and 63.63%, respectively, at a concentration of 7.8 µg/mL, as determined by crystal violet microtiter assay. Furthermore, SEM micrograph shows that TCE-AgNPs significantly inhibit the colonization and adherence of biofilm forming cells; individual cells with loss of cell wall and membrane integrity were also observed, suggesting that the biofilm architecture and EPS matrix were severely damaged. Moreover, TEM and SEM images showed that TCE-AgNPs brutally damaged the cell wall and membranes of MDR-PA, MRSA, and C. albicans. Additionally, extreme ultrastructural changes such as deformation, disintegration, and separation of cell wall and membrane from the cells, have also been observed, indicating significant loss of membrane and cell wall integrity, which eventually led to cell death. Overall, the research revealed a simple, environmentally friendly, and low-cost method for producing colloidal TCE-AgNPs with promising applications in advanced clinical settings against broad-spectrum biofilm-forming antibiotic-resistant bacteria and candida strains.

Regulation of KATP Channel Trafficking in Pancreatic ß-Cells by Protein Histidine Phosphorylation.

Protein histidine phosphatase 1 (PHPT-1) is an evolutionarily conserved 14-kDa protein that dephosphorylates phosphohistidine. PHPT-1-/- mice were generated to gain insight into the role of PHPT-1 and histidine phosphorylation/dephosphorylation in mammalian biology. PHPT-1-/- mice exhibited neonatal hyperinsulinemic hypoglycemia due to impaired trafficking of KATP channels to the plasma membrane in pancreatic ß-cells in response to low glucose and leptin and resembled patients with congenital hyperinsulinism (CHI). The defect in KATP channel trafficking in PHPT-1-/- ß-cells was due to the failure of PHPT-1 to directly activate transient receptor potential channel 4 (TRPC4), resulting in decreased Ca2+ influx and impaired downstream activation of AMPK. Thus, these studies demonstrate a critical role for PHPT-1 in normal pancreatic ß-cell function and raise the possibility that mutations in PHPT-1 and/or TRPC4 may account for yet to be defined cases of CHI.

Phosphatidlyinositol-3-kinase C2 beta (PI3KC2ß) is a potential new target to treat IgE mediated disease.

Cross linking of the IgE receptor (FcεRI) on mast cells plays a critical role in IgE-dependent allergy including allergic rhinitis, asthma, anaphylaxis, and delayed type hypersensitivity reactions. The Ca2+ activated K+ channel, KCa3.1, plays a critical role in IgE-stimulated Ca2+ entry and degranulation in mast cells by helping to maintain a negative membrane potential, which provides an electrochemical gradient to drive Ca2+ influx. Of the 3 classes of PI3K, the class II PI3Ks are the least studied and little is known about the roles for class II PI3Ks in vivo in the context of the whole organism under normal and pathological conditions. Studying bone marrow derived mast cells (BMMC) isolated from PI3KC2ß-/- mice, we now show that the class II PI3KC2ß is critical for FcεRI stimulated KCa3.1 channel activation and the subsequent activation of mast cells. We found FcεRI-stimulated Ca2+ entry, cytokine production, and degranulation are decreased in BMMC isolated from PI3KC2ß-/- mice. In addition, PI3KC2ß-/- mice are markedly resistant to both passive cutaneous and passive systemic anaphylaxis. These findings identify PI3KC2ß as a new pharmacologic target to treat IgE-mediated disease.

PLCε1 regulates SDF-1α-induced lymphocyte adhesion and migration to sites of inflammation.

Regulation of integrins is critical for lymphocyte adhesion to endothelium and migration throughout the body. Inside-out signaling to integrins is mediated by the small GTPase Ras-proximate-1 (Rap1). Using an RNA-mediated interference screen, we identified phospholipase Cε 1 (PLCε1) as a crucial regulator of stromal cell-derived factor 1 alpha (SDF-1α)-induced Rap1 activation. We have shown that SDF-1α-induced activation of Rap1 is transient in comparison with the sustained level following cross-linking of the antigen receptor. We identified that PLCε1 was necessary for SDF-1α-induced adhesion using shear stress, cell morphology alterations, and crawling on intercellular adhesion molecule 1 (ICAM-1)-expressing cells. Structure-function experiments to separate the dual-enzymatic function of PLCε1 uncover necessary contributions of the CDC25, Pleckstrin homology, and Ras-associating domains, but not phospholipase activity, to this pathway. In the mouse model of delayed type hypersensitivity, we have shown an essential role for PLCε1 in T-cell migration to inflamed skin, but not for cytokine secretion and proliferation in regional lymph nodes. Our results reveal a signaling pathway where SDF-1α induces T-cell adhesion through activation of PLCε1, suggesting that PLCε1 is a specific potential target in treating conditions involving migration of T cells to inflamed organs.

Histidine phosphorylation relieves copper inhibition in the mammalian potassium channel KCa3.1.

KCa2.1, KCa2.2, KCa2.3 and KCa3.1 constitute a family of mammalian small- to intermediate-conductance potassium channels that are activated by calcium-calmodulin. KCa3.1 is unique among these four channels in that activation requires, in addition to calcium, phosphorylation of a single histidine residue (His358) in the cytoplasmic region, by nucleoside diphosphate kinase-B (NDPK-B). The mechanism by which KCa3.1 is activated by histidine phosphorylation is unknown. Histidine phosphorylation is well characterized in prokaryotes but poorly understood in eukaryotes. Here, we demonstrate that phosphorylation of His358 activates KCa3.1 by antagonizing copper-mediated inhibition of the channel. Furthermore, we show that activated CD4(+) T cells deficient in intracellular copper exhibit increased KCa3.1 histidine phosphorylation and channel activity, leading to increased calcium flux and cytokine production. These findings reveal a novel regulatory mechanism for a mammalian potassium channel and for T-cell activation, and highlight a unique feature of histidine versus serine/threonine and tyrosine as a regulatory phosphorylation site.

Identification of PGAM5 as a Mammalian Protein Histidine Phosphatase that Plays a Central Role to Negatively Regulate CD4(+) T Cells.

Whereas phosphorylation of serine, threonine, and tyrosine is exceedingly well characterized, the role of histidine phosphorylation in mammalian signaling is largely unexplored. Here we show that phosphoglycerate mutase family 5 (PGAM5) functions as a phosphohistidine phosphatase that specifically associates with and dephosphorylates the catalytic histidine on nucleoside diphosphate kinase B (NDPK-B). By dephosphorylating NDPK-B, PGAM5 negatively regulates CD4(+) T cells by inhibiting NDPK-B-mediated histidine phosphorylation and activation of the K(+) channel KCa3.1, which is required for TCR-stimulated Ca(2+) influx and cytokine production. Using recently developed monoclonal antibodies that specifically recognize phosphorylation of nitrogens at the N1 (1-pHis) or N3 (3-pHis) positions of the imidazole ring, we detect for the first time phosphoisoform-specific regulation of histidine-phosphorylated proteins in vivo, and we link these modifications to TCR signaling. These results represent an important step forward in studying the role of histidine phosphorylation in mammalian biology and disease.

Metabolic inflexibility impairs insulin secretion and results in MODY-like diabetes in triple FoxO-deficient mice.

Pancreatic ß cell failure in type 2 diabetes is associated with functional abnormalities of insulin secretion and deficits of ß cell mass. It's unclear how one begets the other. We have shown that loss of ß cell mass can be ascribed to impaired FoxO1 function in different models of diabetes. Here we show that ablation of the three FoxO genes (1, 3a, and 4) in mature ß cells results in early-onset, maturity-onset diabetes of the young (MODY)-like diabetes, with abnormalities of the MODY networks Hnf4α, Hnf1α, and Pdx1. FoxO-deficient ß cells are metabolically inflexible, i.e., they preferentially utilize lipids rather than carbohydrates as an energy source. This results in impaired ATP generation and reduced Ca(2+)-dependent insulin secretion. The present findings demonstrate a secretory defect caused by impaired FoxO activity that antedates dedifferentiation. We propose that defects in both pancreatic ß cell function and mass arise through FoxO-dependent mechanisms during diabetes progression.

Regulation of the epithelial Ca²âº channel TRPV5 by reversible histidine phosphorylation mediated by NDPK-B and PHPT1.

The kidney, together with bone and intestine, plays a crucial role in maintaining whole-body calcium (Ca(2+)) homoeostasis, which is primarily mediated by altering the reabsorption of Ca(2+) filtered by the glomerulus. The transient receptor potential-vanilloid-5 (TRPV5) channel protein forms a six- transmembrane Ca(2+)-permeable channel that regulates urinary Ca(2+) excretion by mediating active Ca(2+) reabsorption in the distal convoluted tubule of the kidney. Here we show that the histidine kinase, nucleoside diphosphate kinase B (NDPK-B), activates TRPV5 channel activity and Ca(2+) flux, and this activation requires histidine 711 in the carboxy-terminal tail of TRPV5. In addition, the histidine phosphatase, protein histidine phosphatase 1, inhibits NDPK-B-activated TRPV5 in inside/out patch experiments. This is physiologically relevant to Ca(2+) reabsorption in vivo, as short hairpin RNA knockdown of NDPK-B leads to decreased TRPV5 channel activity, and urinary Ca(2+) excretion is increased in NDPK-B(-/-) mice fed a high-Ca(2+) diet. Thus these findings identify a novel mechanism by which TRPV5 and Ca(2+) reabsorption is regulated by the kidney and support the idea that histidine phosphorylation plays other, yet-uncovered roles in mammalian biology.

Two cases of meningococcal purpura fulminans: the 'less is more' approach.

This study presents a case series of patients with meningococcal purpura fulminans who were treated at a tertiary referral centre within a few days of each other. Presenting with signs and symptoms of florid meningococcal sepsis, they were managed initially by physicians and intensivists, whereas the development of large purpuric areas and tissue necrosis was managed expectantly by plastic surgeons. When the patients were deemed to have recovered clinically and the necrosis delineated, surgical management was implemented with subsequent involvement of various rehabilitation services. This article highlights the cases of two patients, and their clinical presentation, management and rehabilitation together with a current literature review on this area.

Phosphatidylinositol-3-kinase C2ß and TRIM27 function to positively and negatively regulate IgE receptor activation of mast cells.

Cross-linking of the IgE receptor (FcεRI) on mast cells plays a critical role in IgE-dependent allergy, including allergic rhinitis, asthma, anaphylaxis, and immediate-type hypersensitivity reactions. Previous studies have demonstrated that the K(+) channel, KCa3.1, plays a critical role in IgE-stimulated Ca(2+) entry and degranulation in both human and mouse mast cells. We now have shown that the class II phosphatidylinositol-3-kinase C2ß (PI3KC2ß) is necessary for FcεRI-stimulated activation of KCa3.1, Ca(2+) influx, cytokine production, and degranulation of bone marrow-derived mast cells (BMMC). In addition, we found that the E3 ubiquitin ligase, tripartite motif containing protein 27 (TRIM27), negatively regulates FcεRI activation of KCa3.1 and downstream signaling by ubiquitinating and inhibiting PI3KC2ß. TRIM27(-/-) mice are also more susceptible in vivo to acute anaphylaxis. These findings identify TRIM27 as an important negative regulator of mast cells in vivo and suggest that PI3KC2ß is a potential new pharmacologic target to treat IgE-mediated disease.

Tripartite motif containing protein 27 negatively regulates CD4 T cells by ubiquitinating and inhibiting the class II PI3K-C2ß.

The K(+) channel KCa3.1 is required for Ca(2+) influx and the subsequent activation of CD4 T cells. The class II phosphatidylinositol 3 kinase C2ß (PI3KC2ß) is activated by the T-cell receptor (TCR) and is critical for KCa3.1 channel activation. Tripartite motif containing protein 27 (TRIM27) is a member of a large family of proteins that function as Really Interesting New Gene (RING) E3 ubiquitin ligases. We now show that TRIM27 functions as an E3 ligase and mediates lysine 48 polyubiquitination of PI3KC2ß, leading to a decrease in PI3K enzyme activity. By inhibiting PI3KC2ß, TRIM27 also functions to negatively regulate CD4 T cells by inhibiting KCa3.1 channel activity and TCR-stimulated Ca(2+) influx and cytokine production in Jurkat, primary human CD4 T cells, and Th0, Th1, and Th2 CD4 T cells generated from TRIM27(-/-) mice. These findings provide a unique mechanism for regulating class II PI3Ks, and identify TRIM27 as a previously undescribed negative regulator of CD4 T cells.

Overweight and obesity among school-going children of Lucknow city.

BACKGROUND: Childhood obesity is increasingly being observed with changing lifestyles of families. The magnitude of overweight ranges from 9% to 27.5% and obesity ranges from 1% to 12.9% among Indian children. OBJECTIVES: The present study was undertaken to study the magnitude of overweight/obesity and its determinants among children in Lucknow city. MATERIALS AND METHODS: A list of government and private school was procured from Office of Basic Shiksha Adhikari. Three government and three private schools were selected by Simple Random Sampling. Students of 5th to 12th grades available at the time of study were included as study unit. Predesigned and pretested questionnaire was used to elicit the information on family characteristics and individual characteristics. Height and weight were measured and BMI was calculated. Children with BMI of 25 and above were considered overweight and children with BMI more than 30 were considered obese. RESULTS: Overweight and obesity was found to be 4.17% and 0.73%, respectively; they together constitute 4.91% for overweight/obesity. The study revealed that the important correlates of overweight/obesity were father's education, father's occupation, class, children playing outdoor games for less than 30 min, and those consuming fast foods. CONCLUSIONS: Children of higher classes (above 8th standard) belonging to higher socioeconomic group with less outdoor activities and consuming fast foods were more predisposed to overweight/obesity. As a preventive strategy, there is a need to apply health and nutritional education programs for inculcating healthy life styles, and incorporating more outdoor activities in Physical Education Department of school curriculum.

The inducible deletion of Drosha and microRNAs in mature podocytes results in a collapsing glomerulopathy.

Micro-RNAs (miRNAs) are short (average 22 nucleotides) noncoding regulatory RNAs that inhibit gene expression by targeting complementary 3'-untranslated regions of protein-encoding mRNAs for translational repression or degradation. miRNAs play key roles in both the function and differentiation of many cell types. Drosha and Dicer, two RNAase III enzymes, function in a stepwise manner to generate a mature miRNA. Previous studies have shown that podocyte-specific deletion of Dicer during development results in proteinuric renal disease and collapsing glomerulopathy (CG); however, Dicer has functions other than the generation of miRNAs. Here we found that the podocyte-specific deletion of Drosha results in a similar phenotype to Dicer mutants, confirming that the Dicer mutant phenotype is due to the loss of miRNAs. Moreover, the inducible deletion of Drosha in 2- to 3-month-old mice (Tet-On system) resulted in CG. Thus, continuous generation of miRNAs are required for the normal function of mature podocytes and their loss leads to CG. Identifying these miRNAs may provide new insight into disease pathogenesis and novel therapeutic targets in various podocytopathies.

Nucleoside diphosphate kinase B knock-out mice have impaired activation of the K+ channel KCa3.1, resulting in defective T cell activation.

Nucleoside diphosphate kinases (NDPKs) are encoded by the Nme (non-metastatic cell) gene family. Although they comprise a family of 10 genes, NDPK-A and -B are ubiquitously expressed and account for most of the NDPK activity. We previously showed that NDPK-B activates the K(+) channel KCa3.1 via histidine phosphorylation of the C terminus of KCa3.1, which is required for T cell receptor-stimulated Ca(2+) flux and proliferation of activated naive human CD4 T cells. We now report the phenotype of NDPK-B(-/-) mice. NDPK-B(-/-) mice are phenotypically normal at birth with a normal life span. Although T and B cell development is normal in NDPK-B(-/-) mice, KCa3.1 channel activity and cytokine production are markedly defective in T helper 1 (Th1) and Th2 cells, whereas Th17 function is normal. These findings phenocopy studies in the same cells isolated from KCa3.1(-/-) mice and thereby support genetically that NDPK-B functions upstream of KCa3.1. NDPK-A and -B have been linked to an astonishing array of disparate cellular and biochemical functions, few of which have been confirmed in vivo in physiological relevant systems. NDPK-B(-/-) mice will be an essential tool with which to definitively address the biological functions of NDPK-B. Our finding that NDPK-B is required for activation of Th1 and Th2 CD4 T cells, together with the normal overall phenotype of NDPK-B(-/-) mice, suggests that specific pharmacological inhibitors of NDPK-B may provide new opportunities to treat Th1- and Th2-mediated autoimmune diseases.

Inhibition of the K+ channel KCa3.1 ameliorates T cell-mediated colitis.

The calcium-activated K(+) channel KCa3.1 plays an important role in T lymphocyte Ca(2+) signaling by helping to maintain a negative membrane potential, which provides an electrochemical gradient to drive Ca(2+) influx. To assess the role of KCa3.1 channels in lymphocyte activation in vivo, we studied T cell function in KCa3.1(-/-) mice. CD4 T helper (i.e., Th0) cells isolated from KCa3.1(-/-) mice lacked KCa3.1 channel activity, which resulted in decreased T cell receptor-stimulated Ca(2+) influx and IL-2 production. Although loss of KCa3.1 did not interfere with CD4 T cell differentiation, both Ca(2+) influx and cytokine production were impaired in KCa3.1(-/-) Th1 and Th2 CD4 T cells, whereas T-regulatory and Th17 function were normal. We found that inhibition of KCa3.1(-/-) protected mice from developing severe colitis in two mouse models of inflammatory bowel disease, which were induced by (i) the adoptive transfer of mouse naïve CD4 T cells into rag2(-/-) recipients and (ii) trinitrobenzene sulfonic acid. Pharmacologic inhibitors of KCa3.1 have already been shown to be safe in humans. Thus, if these preclinical studies continue to show efficacy, it may be possible to rapidly test whether KCa3.1 inhibitors are efficacious in patients with inflammatory bowel diseases such as Crohn's disease and ulcerative colitis.

The class II phosphatidylinositol 3 kinase C2beta is required for the activation of the K+ channel KCa3.1 and CD4 T-cells.

The Ca(2+)-activated K(+) channel KCa3.1 is required for Ca(2+) influx and the subsequent activation of T-cells. We previously showed that nucleoside diphosphate kinase beta (NDPK-B), a mammalian histidine kinase, directly phosphorylates and activates KCa3.1 and is required for the activation of human CD4 T lymphocytes. We now show that the class II phosphatidylinositol 3 kinase C2beta (PI3K-C2beta) is activated by the T-cell receptor (TCR) and functions upstream of NDPK-B to activate KCa3.1 channel activity. Decreased expression of PI3K-C2beta by siRNA in human CD4 T-cells resulted in inhibition of KCa3.1 channel activity. The inhibition was due to decreased phosphatidylinositol 3-phosphate [PI(3)P] because dialyzing PI3K-C2beta siRNA-treated T-cells with PI(3)P rescued KCa3.1 channel activity. Moreover, overexpression of PI3K-C2beta in KCa3.1-transfected Jurkat T-cells led to increased TCR-stimulated activation of KCa3.1 and Ca(2+) influx, whereas silencing of PI3K-C2beta inhibited both responses. Using total internal reflection fluorescence microscopy and planar lipid bilayers, we found that PI3K-C2beta colocalized with Zap70 and the TCR in peripheral microclusters in the immunological synapse. This is the first demonstration that a class II PI3K plays a critical role in T-cell activation.

Lymphadenectomy for melanoma in the clinically N1 neck: radical, modified radical, or selective?

The purpose of a neck dissection is to control the disease in the neck and has little influence on long-term survival. Radical neck dissection leads to significant morbidity; this morbidity is decreased in modified radical neck dissections and reduced even further in selective dissections. An analysis was made of 37 consecutive patients with melanoma for an 8-year period presenting with a clinically N1 neck (a single involved node based on clinical examination and radiologic investigation). Six patients underwent radical, 24 modified radical, and 7 selective neck dissections. There was a mean follow-up of 3 years 10 months after primary diagnosis. Minimum follow-up after lymphadenectomy was 18 months, and at this point, there were no cases of local recurrence (neck failure) in any of the survivors in the 3 groups. In our series, there was no difference in locoregional control for the 3 groups. We would recommend a modified radical neck dissection for the N1 neck in melanoma with an intraoperative decision being made on which structures to preserve based on position of involved lymph node and adjacent structures, particularly in younger patients. A selective neck dissection should be considered in those patients with significant comorbidity, distant metastatic disease, or primary sites on the back or posterior scalp.