Redox-Sensitive Poly(lactic-co-glycolic acid) Nanoparticles of Palbociclib: Development, Ultrasound/Photoacoustic Imaging, and Smart Breast Cancer Therapy.

Breast cancer is one of the leading causes of mortality in women globally. The efficacy of breast cancer treatments, notably chemotherapy, is hampered by inadequate localized delivery of anticancer agents to the tumor site, resulting in compromised efficacy and increased systemic toxicity. In this study, we have developed redox-sensitive poly(lactic-co-glycolic acid) (PLGA) nanoparticles for the smart delivery of palbociclib (PLB) to breast cancer. The particle size of formulated PLB@PLGA-NPs (nonredox-sensitive) and RS-PLB@PLGA-NPs (redox-sensitive) NPs were 187.1 ± 1.8 nm and 193.7 ± 1.5 nm, respectively. The zeta potentials of nonredox-sensitive and redox-sensitive NPs were +24.99 ± 2.67 mV and +9.095 ± 1.87 mV, respectively. The developed NPs were characterized for morphological and various physicochemical parameters such as SEM, TEM, XRD, DSC, TGA, XPS, etc. The % entrapment efficiency of PLB@PLGA-NPs and RS-PLB@PLGA-NPs was found to be 85.48 ± 1.29% and 87.72 ± 1.55%, respectively. RS-PLB@PLGA-NPs displayed a rapid drug release at acidic pH and a higher GSH concentration compared to PLB@PLGA-NPs. The cytotoxicity assay in MCF-7 cells suggested that PLB@PLGA-NPs and RS-PLB@PLGA-NPs were 5.24-fold and 14.53-fold higher cytotoxic compared to the free PLB, respectively. Further, the cellular uptake study demonstrated that redox-sensitive NPs had significantly higher cellular uptake compared to nonredox-sensitive NPs and free Coumarin 6 dye. Additionally, AO/EtBr assay and reactive oxygen species analysis confirmed the superior activity of RS-PLB@PLGA-NPs over PLB@PLGA-NPs and free PLB. In vivo anticancer activity in dimethyl-benz(a)anthracene-induced breast cancer rats depicted that RS-PLB@PLGA-NPs was highly effective in reducing the tumor size, hypoxic tumor, and tumor vascularity compared to PLB@PLGA-NPs and free PLB. Further, hemocompatibility study reveals that the developed NPs were nonhemolytic to human blood. Moreover, an in vivo histopathology study confirmed that both nanoparticles were safe and nontoxic to the vital organs.

Nanofibers of N,N,N-trimethyl chitosan capped bimetallic nanoparticles: Preparation, characterization, wound dressing and in vivo treatment of MDR microbial infection and tracking by optical and photoacoustic imaging.

Recent advancements in wound care have led to the development of interactive wound dressings utilizing nanotechnology, aimed at enhancing healing and combating bacterial infections while adhering to established protocols. Our novel wound dressings consist of N,N,N-trimethyl chitosan capped gold­silver nanoparticles (Au-Ag-TMC-NPs), with a mean size of 108.3 ± 8.4 nm and a zeta potential of +54.4 ± 1.8 mV. These optimized nanoparticles exhibit potent antibacterial and antifungal properties, with minimum inhibitory concentrations ranging from 0.390 µg ml-1 to 3.125 µg ml-1 and also exhibited promising zones of inhibition against multi-drug resistant strains of S. aureus, E. coli, P. aeruginosa, and C. albicans. Microbial transmission electron microscopy reveals substantial damage to cell walls and DNA condensation post-treatment. Furthermore, the nanoparticles demonstrate remarkable inhibition of microbial efflux pumps and are non-hemolytic in human blood. Incorporated into polyvinyl alcohol/chitosan nanofibers, they form Au-Ag-TMC-NPs-NFs with diameters of 100-350 nm, facilitating efficient antimicrobial wound dressing. In vivo studies on MDR microbial-infected wounds in mice showed 99.34 % wound healing rate within 12 days, corroborated by analyses of wound marker protein expression levels and advanced imaging techniques such as ultrasound/photoacoustic imaging, providing real-time visualization and blood flow assessment for a comprehensive understanding of the dynamic wound healing processes.

Cetuximab decorated redox sensitive D-alpha-tocopheryl- polyethyleneglycol-1000-succinate based nanoparticles for cabazitaxel delivery: Formulation, lung targeting and enhanced anti-cancer effects.

This research work aims to fabricate cetuximab (CTX) decorated cabazitaxel (CBZ) loaded redox-sensitive D-alpha-tocopheryl-polyethyleneglycol-1000-succinate (TPGS-SS) nanoparticles (NPs) for epidermal growth factor receptor (EGFR)-targeted lung tumor therapy.The NPs were prepared using a dialysis bag diffusion method to produce, non-redox sensitive non targeted (TPGS-CBZ-NPs), redox-sensitive nontargeted (TPGS-SS-CBZ-NPs), and targeted redox-sensitive NPs (CTX-TPGS-SS-CBZ-NPs). Developed NPs were characterized for particle sizes, polydispersity, surface charge, surface morphologies, and entrapment efficiency. Moreover, additional in vitro studies have been conducted, including in vitro drug release, cytotoxicity, and cellular uptake studies.The particle size and charge over the surface were found to be in the range of 145.6 to 308.06 nm and -15 to -23 mV respectively. The IC50 values of CBZ clinical injection (Jevtana®), TPGS-CBZ-NPs, TPGS-SS-CBZ-NPs, and CTX-TPGS-SS-NPs were found to be 17.54 ± 3.58, 12.8 ± 2.45, 9.28 ± 1.13 and 4.013 ± 1.05 µg/ml, suggesting the 1.37, 1.89 and 4.37-folds respectively, enhancement of cytotoxicity as compared to CBZ clinical injection, demonstrating a significant augmentation in cytotoxicity. In addition, the in-vitro cellular uptake investigation showed that CTX-TPGS-SS-CMN6-NPs accumulated significantly compared to pure CMN6, TPGS-CMN6-NPs, and TPGS-SS-CMN6-NPs in the A549 cells. Furthermore, the targeting efficiency of developed NPs were analysed by ultrasound/photoacoustic and IVIS imaging.

Nanotheranostics: Molecular Diagnostics and Nanotherapeutic Evaluation by Photoacoustic/Ultrasound Imaging in Small Animals.

Nanotheranostics is a rapidly developing field that integrates nanotechnology, diagnostics, and therapy to provide novel methods for imaging and treating wide categories of diseases. Targeted nanotheranostics offers a platform for the precise delivery of theranostic agents, and their therapeutic outcomes are monitored in real-time. Presently, in vivo magnetic resonance imaging, fluorescence imaging, ultrasound imaging, and photoacoustic imaging (PAI), etc. are noninvasive imaging techniques that are preclinically available for the imaging and tracking of therapeutic outcomes in small animals. Additionally, preclinical imaging is essential for drug development, phenotyping, and understanding disease stage progression and its associated mechanisms. Small animal ultrasound imaging is a rapidly developing imaging technique for theranostics applications due to its merits of being nonionizing, real-time, portable, and able to penetrate deep tissues. Recently, different types of ultrasound contrast agents have been explored, such as microbubbles, echogenic exosomes, gas-vesicles, and nanoparticles-based contrast agents. Moreover, an optical image obtained through photoacoustic imaging is a noninvasive imaging technique that creates ultrasonic waves when pulsed laser light is used to expose an object and creates a picture of the tissue's distribution of light energy absorption on the object. Contrast agents for photoacoustic imaging may be endogenous (hemoglobin, melanin, and DNA/RNA) or exogenous (dyes and nanomaterials-based contrast agents). The integration of nanotheranostics with photoacoustic and ultrasound imaging allows simultaneous imaging and treatment of diseases in small animals, which provides essential information about the drug response and the disease progression. In this review, we have covered various endogenous and exogenous contrast agents for ultrasound and photoacoustic imaging. Additionally, we have discussed various drug delivery systems integrated with contrast agents for theranostic application. Further, we have briefly discussed the current challenges associated with ultrasound and photoacoustic imaging.

Epithelial IFNγ signalling and compartmentalized antigen presentation orchestrate gut immunity.

All nucleated cells express major histocompatibility complex I and interferon-γ (IFNγ) receptor1, but an epithelial cell-specific function of IFNγ signalling or antigen presentation by means of major histocompatibility complex I has not been explored. We show here that on sensing IFNγ, colonic epithelial cells productively present pathogen and self-derived antigens to cognate intra-epithelial T cells, which are critically located at the epithelial barrier. Antigen presentation by the epithelial cells confers extracellular ATPase expression in cognate intra-epithelial T cells, which limits the accumulation of extracellular adenosine triphosphate and consequent activation of the NLRP3 inflammasome in tissue macrophages. By contrast, antigen presentation by the tissue macrophages alongside inflammasome-associated interleukin-1α and interleukin-1ß production promotes a pathogenic transformation of CD4+ T cells into granulocyte-macrophage colony-stimulating-factor (GM-CSF)-producing T cells in vivo, which promotes colitis and colorectal cancer. Taken together, our study unravels critical checkpoints requiring IFNγ sensing and antigen presentation by epithelial cells that control the development of pathogenic CD4+ T cell responses in vivo.

EGFR Targeted Redox Sensitive Chitosan Nanoparticles of Cabazitaxel: Dual-Targeted Cancer Therapy, Lung Distribution, and Targeting Studies by Photoacoustic and Optical Imaging.

In this research, we have modified tocopheryl polyethylene glycol succinate (TPGS) to a redox-sensitive material, denoted as TPGS-SH, and employed the same to develop dual-receptor-targeted nanoparticles of chitosan loaded with cabazitaxel (CZT). The physicochemical properties and morphological characteristics of all nanoparticle formulations were assessed. Dual-receptor targeting redox-sensitive nanoparticles of CZT (F-CTX-CZT-CS-SH-NPs) were developed by a combination of pre- and postconjugation techniques by incorporating synthesized chitosan-folate (F) and TPGS-SH during nanoparticle synthesis and further postconjugated with cetuximab (CTX) for epidermal growth factor receptor (EGFR) targeting. The in vitro release of the drug was seemingly higher in the redox-sensitive buffer media (GSH, 20 mM) compared to that in physiological buffer. However, the extent of cellular uptake of dual-targeted nanoparticles was significantly higher in A549 cells than other control nanoparticles. The IC50 values of F-CTX-CZT-CS-SH-NPs against A549 cells was 0.26 ± 0.12 µg/mL, indicating a 6.3-fold and 60-fold enhancement in cytotoxicity relative to that of dual-receptor targeted, nonredox sensitive nanoparticles and CZT clinical injection, respectively. Furthermore, F-CTX-CZT-CS-SH-NPs demonstrated improved anticancer activity in the benzo(a)pyrene lung cancer model with a higher survival rate. Due to the synergistic combination of enhanced permeability and retention (EPR) effect of small-sized nanoparticles, the innovative and redox sensitive TPGS-SH moiety and the dual folate and EGFR mediated augmented endocytosis have all together significantly enhanced their biodistribution and targeting exclusively to the lung which is evident from their ultrasound/photoacoustic and in vivo imaging system (IVIS) studies.

Advances in solid-phase extraction techniques: Role of nanosorbents for the enrichment of antibiotics for analytical quantification.

Antibiotics are life-saving medications for treating bacterial infections; however it has been discovered that resistance developed by bacteria against these incredible agents is the primary contributing factor to rising global mortality rates. The fundamental cause of the emergence of antibiotic resistance in bacteria is the presence of antibiotic residues in various environmental matrices. Although antibiotics are present in diluted form in environmental matrices like water, consistent exposure of bacteria to these minute levels is enough for the resistance to develop. So, identifying these tiny concentrations of numerous antibiotics in various and complicated matrices will be a crucial step in controlling their disposal in those matrices. Solid phase extraction, a popular and customizable extraction technology, was developed according to the aspirations of the researchers. It is a unique alternative technique that could be implemented either alone or in combination with other approaches at different stages because of the multitude of sorbent varieties and techniques. Initially, sorbents are utilized for extraction in their natural state. The basic sorbent has been modified over time with nanoparticles and multilayer sorbents, which have indeed helped to accomplish the desired extraction efficiencies. Among the current traditional extraction techniques such as liquid-liquid extraction, protein precipitation, and salting out techniques, solid-phase extractions (SPE) with nanosorbents are most productive because, they can be automated, selective, and can be integrated with other extraction techniques. This review aims to provide a broad overview of advancements and developments in sorbents with a specific emphasis on the applications of SPE techniques used for antibiotic detection and quantification in various matrices in the last two decades.

Vitamin E TPGS-Based Nanomedicine, Nanotheranostics, and Targeted Drug Delivery: Past, Present, and Future.

It has been seventy years since a water-soluble version of vitamin E called tocophersolan (also known as TPGS) was produced; it was approved by USFDA in 1998 as an inactive ingredient. Drug formulation developers were initially intrigued by its surfactant qualities, and gradually it made its way into the toolkit of pharmaceutical drug delivery. Since then, four drugs with TPGS in their formulation have been approved for sale in the United States and Europe including ibuprofen, tipranavir, amprenavir, and tocophersolan. Improvement and implementation of novel diagnostic and therapeutic techniques for disease are goals of nanomedicine and the succeeding field of nanotheranostics. Specifically, imaging and treating tumors with nanohybrid theranostics shows promising potential. Docetaxel, paclitaxel, and doxorubicin are examples of poorly bioavailable therapeutic agents; hence, much effort is applied for developing TPGS-based nanomedicine, nanotheranostics, and targeted drug delivery systems to increase circulation time and promote the reticular endothelial escape of these drug delivery systems. TPGS has been used in a number of ways for improving drug solubility, bioavailability improvement, and prevention of drug efflux from the targeted cells, which makes it an excellent candidate for therapeutic delivery. Through the downregulation of P-gp expression and modulation of efflux pump activity, TPGS can also mitigate multidrug resistance (MDR). Novel materials such as TPGS-based copolymers are being studied for their potential use in various diseases. In recent clinical trials, TPGS has been utilized in a huge number of Phase I, II, and III studies. Additionally, numerous TPGS-based nanomedicine and nanotheranostic applications are reported in the literature which are in their preclinical stage. However, various randomized or human clinical trials have been underway for TPGS-based drug delivery systems for multiple diseases such as pneumonia, malaria, ocular disease, keratoconus, etc. In this review, we have emphasized in detail the review of the nanotheranostics and targeted drug delivery approaches premised on TPGS. In addition, we have covered various therapeutic systems involving TPGS and its analogs with special references to its patent and clinical trials.

Rice Pangenome Genotyping Array: an efficient genotyping solution for pangenome-based accelerated genetic improvement in rice.

The advent of the pangenome era has unraveled previously unknown genetic variation existing within diverse crop plants, including rice. This untapped genetic variation is believed to account for a major portion of phenotypic variation existing in crop plants. However, the use of conventional single reference-guided genotyping often fails to capture a large portion of this genetic variation leading to a reference bias. This makes it difficult to identify and utilize novel population/cultivar-specific genes for crop improvement. Thus, we developed a Rice Pangenome Genotyping Array (RPGA) harboring probes assaying 80K single-nucleotide polymorphisms (SNPs) and presence-absence variants spanning the entire 3K rice pangenome. This array provides a simple, user-friendly and cost-effective (60-80 USD per sample) solution for rapid pangenome-based genotyping in rice. The genome-wide association study (GWAS) conducted using RPGA-SNP genotyping data of a rice diversity panel detected a total of 42 loci, including previously known as well as novel genomic loci regulating grain size/weight traits in rice. Eight of these identified trait-associated loci (dispensable loci) could not be detected with conventional single reference genome-based GWAS. A WD repeat-containing PROTEIN 12 gene underlying one of such dispensable locus on chromosome 7 (qLWR7) along with other non-dispensable loci were subsequently detected using high-resolution quantitative trait loci mapping confirming authenticity of RPGA-led GWAS. This demonstrates the potential of RPGA-based genotyping to overcome reference bias. The application of RPGA-based genotyping for population structure analysis, hybridity testing, ultra-high-density genetic map construction and chromosome-level genome assembly, and marker-assisted selection was also demonstrated. A web application (http://www.rpgaweb.com) was further developed to provide an easy to use platform for the imputation of RPGA-based genotyping data using 3K rice reference panel and subsequent GWAS.

Bimetallic Au-Ag Nanoparticles: Advanced Nanotechnology for Tackling Antimicrobial Resistance.

To date, there are no antimicrobial agents available in the market that have absolute control over the growing threat of bacterial strains. The increase in the production capacity of antibiotics and the growing antibacterial resistance of bacteria have majorly affected a variety of businesses and public health. Bimetallic nanoparticles (NPs) with two separate metals have been found to have stronger antibacterial potential than their monometallic versions. This enhanced antibacterial efficiency of bimetallic nanoparticles is due to the synergistic effect of their participating monometallic counterparts. To distinguish between bacteria and mammals, the existence of diverse metal transport systems and metalloproteins is necessary for the use of bimetallic Au-Ag NPs, just like any other metal NPs. Due to their very low toxicity toward human cells, these bimetallic NPs, particularly gold-silver NPs, might prove to be an effective weapon in the arsenal to beat emerging drug-resistant bacteria. The cellular mechanism of bimetallic nanoparticles for antibacterial activity consists of cell membrane degradation, disturbance in homeostasis, oxidative stress, and the production of reactive oxygen species. The synthesis of bimetallic nanoparticles can be performed by a bottom-up and top-down strategy. The bottom-up technique generally includes sol-gel, chemical vapor deposition, green synthesis, and co-precipitation methods, whereas the top-down technique includes the laser ablation method. This review highlights the key prospects of the cellular mechanism, synthesis process, and antibacterial capabilities against a wide range of bacteria. Additionally, we also discussed the role of Au-Ag NPs in the treatment of multidrug-resistant bacterial infection and wound healing.

Molecular mapping of QTLs for grain dimension traits in Basmati rice.

Basmati rice is known for its extra-long slender grains, exceptional kernel dimensions after cooking, high volume expansion, and strong aroma. Developing high yielding Basmati rice varieties with good cooking quality is a gigantic task. Therefore, identifying the genomic regions governing the grain and cooked kernel dimension traits is of utmost importance for its use in marker-assisted breeding. Although several QTLs governing grain dimension traits have been reported, limited attempts have been made to map QTLs for grain and cooked kernel dimension traits of Basmati rice. In the current study, a population of recombinant inbred lines (RIL) was generated from a cross of Sonasal and Pusa Basmati 1121 (PB1121). In the RIL population, there was a significant positive correlation among the length (RRL: rough rice length, MRL: milled rice length, CKL: cooked kernel length) and breadth (RRB: rough rice breadth, MRB: milled rice breadth and CKB: cooked kernel breadth) of the related traits, while there was significant negative correlation between them. QTL mapping has led to the identification of four major genomic regions governing MRL and CKL. Two QTLs co-localize with the earlier reported major gene GS3 and a QTL qGRL7.1, while the remaining two QTLs viz., qCKL3.2 (qMRL3.2) and qCKL4.1 (qMRL4.1) were novel. The QTL qCKL3.2 has been bracketed to a genomic region of 0.78 Mb between the markers RM15247 and RM15281. Annotation of this region identified 18 gene models, of which the genes predicted to encode pentatricopeptides and brassinosteroid insensitive 1-associated receptor kinase 1 precursor may be the putative candidate genes. Furthermore, we identified a novel QTL qKER2.1 governing kernel elongation ratio (KER) in Basmati rice.

Innate riddle of CD4+ T cells and the control of enteric infections.

Intra-epithelial T cells make up a significant proportion of immune cells in the body, yet their development and function remain an enigma. In this issue of Immunity, Parsa et al. (2022) describe the differentiation and cross-protective function of CD4+ intra-epithelial T cells against enteric viruses.

Systematic Development of Solid Lipid Nanoparticles of Abiraterone Acetate with Improved Oral Bioavailability and Anticancer Activity for Prostate Carcinoma Treatment.

In the present work, an attempt was undertaken to improve the oral bioavailability and anticancer activity of abiraterone acetate. Solid lipid nanoparticles (SLNs) were developed using the quality by design (QbD) principles and evaluated through in vitro, ex vivo, and in vivo studies. Solid lipid suitability was evaluated by equilibrium solubility study, while surfactant and cosurfactant were screened based on the ability to form microemulsion with the selected lipid. SLNs were prepared by emulsion/solvent evaporation method using glyceryl monostearate, Tween 80, and Poloxamer 407 as the solid lipid, surfactant, and cosurfactant, respectively. Box-Behnken design was applied for optimization of material attributes and evaluating their impact on particle size, polydispersity index, zeta potential, and entrapment efficiency of the SLNs. In vitro drug release study was evaluated in simulated gastric and intestinal fluids. Cell culture studies on PC-3 cells were performed to evaluate the cytotoxicity of the drug-loaded SLNs in comparison to the free drug suspension. Qualitative uptake was evaluated for Rhodamine B-loaded SLNs and compared with free dye solution. Ex vivo permeability was evaluated on Wistar rat intestine and in vivo pharmacokinetic evaluation on Wistar rats for SLNs and free drug suspension. Concisely, the SLNs showed potential for significant improvement in the biopharmaceutical performance of the selected drug candidate over the existing formulations of abiraterone acetate.

Campylobacter jejuni induces autoimmune peripheral neuropathy via Sialoadhesin and Interleukin-4 axes.

Campylobacter jejuni is a leading cause of gastroenteritis that has been causally linked with development of the autoimmune peripheral neuropathy Guillain Barré Syndrome (GBS). Previously, we showed that C. jejuni isolates from human enteritis patients induced Type1/17-cytokine dependent colitis in interleukin-10 (IL-10)-/- mice, while isolates from GBS patients colonized these mice without colitis but instead induced autoantibodies that cross-reacted with the sialylated oligosaccharide motifs on the LOS of GBS-associated C. jejuni and the peripheral nerve gangliosides. We show here that infection of IL-10-/- mice with the GBS but not the colitis isolate led to sciatic nerve inflammation and abnormal gait and hind limb movements, with character and timing consistent with this syndrome in humans. Autoantibody responses and associated nerve histologic changes were dependent on IL-4 production by CD4 T cells. We further show that Siglec-1 served as a central antigen presenting cell receptor mediating the uptake of the GBS isolates via interaction with the sialylated oligosaccharide motifs found specifically on the LOS of GBS-associated C. jejuni, and the ensuing T cell differentiation and autoantibody elicitation. Sialylated oligosaccharide motifs on the LOS of GBS-associated C. jejuni therefore acted as both the Siglec-1-ligand for phagocytosis, as well as the epitope for autoimmunity. Overall, we present a mouse model of an autoimmune disease induced directly by a bacterium that is dependent upon Siglec-1 and IL-4. We also demonstrate the negative regulatory role of IL-10 in C. jejuni induced autoimmunity and provide IL-4 and Siglec-1 blockade as potential therapeutic interventions against GBS.

Population Structure of a Worldwide Collection of Tropical Japonica Rice Indicates Limited Geographic Differentiation and Shows Promising Genetic Variability Associated with New Plant Type.

Abating the approaching yield plateau in rice requires taking advantage of potential technologies that requires knowledge on genetic diversity. Hybrid breeding, particularly in indica rice, requires the recruitment of large genetic variability from outside because the available genetic diversity of the cultivated pool has already been utilized to a great extent. In this study, we examined an assembly of 200 tropical japonica lines collected worldwide for population genetic structure and variability in yield-associated traits. Tested along with 30 indica and six wild rice lines belonging to India, the tropical japonica lines indicated great phenotypic variability, particularly related to new plant type (NPT) phenology, and formed six clusters. Furthermore, a marker-based characterization using a universal diversity marker panel classified the genotype assembly into four clusters, of which three encompassed tropical japonica lines, while the last cluster included mostly indica lines. The population structure of the panel also revealed a similar pattern, with tropical japonica lines forming three subpopulations. Remarkable variation in the allelic distribution was observed between the subpopulations. Superimposing the geographical sources of the genotypes over the population structure did not reveal any pattern. The genotypes sourced closer to the center of origin of rice showed relatively little diversity compared with the ones obtained from other parts of the world, suggesting migration from a common region of origin. The tropical japonica lines can be a great source of parental diversification for hybrid development after confirming the presence of widely compatible genes.

Recent update of 3D printing technology in pharmaceutical formulation development.

In modern world, Pharma sector observes steep increase in demand of personalized medicine. Various unique ideas and technology were proposed and implemented by different researchers to prepare personalized medicine and devices. 3-dimensional printing (3DP) is one of the revolutionary technologies which can be used to prepare tailored medicine via CAD (Computer Aided Design) software. 3DP allows researchers to manufacture customized dosage form with desired modifications in geometry which would in turn alter dosage behaviour of the product with reduced side effects. Current achievement of 3DP includes personalized and adjustable dosage form, multifunction drug delivery systems, medical devices, phantoms, and implants specific to patient anatomy. Additionally, 3DP is employed for preparing tailored regenerative medicines. This review focuses on 3DP use in pharmaceuticals including drug delivery systems and medical devices with their method of fabrication. Additionally, different clinical trials as well as different patents done till date are cited in the paper. Furthermore, regulatory issues and future perspective related to 3 D printing is also well discussed.

Systematic Development and Validation of a RP-HPLC Method for Estimation of Abiraterone Acetate and its Degradation Products.

The present study described the development of a reversed-phase liquid chromatographic method for the estimation of abiraterone acetate by Quality by Design (QbD) approach. Using an isocratic solvent system for the mobile phase, the chromatographic estimation of analyte was performed on a Hypersil BDS C18 column using mobile phase mixture containing acetonitrile and water with pH adjusted with 0.1% v/v orthophosphoric acid (15:85%v/v ratio), flow rate 1.0 mL.min-1 and detection at 250 nm using photodiode array detector. Systematic development of the chromatographic method was carried out by factor screening using a half-factorial design which suggested organic modifier (%), flow rate (mL.min-1) and autosampler temperature (°C) as influential variables. Further, the method was optimized by Box-Behnken design and trials performed were evaluated for the area under peak, retention time, theoretical plate count and tailing factor as the responses. Validation of the developed method showed good linearity, accuracy, precision and sensitivity. Evaluation of the stability-indicating profile of the method using forced degradation studies revealed the formation of a possible degradation product under acidic and alkaline conditions, while no such degradation product peaks were observed under the oxidative environment. Overall, the study construed the successful development of HPLC assay method for pharmaceutical applications.

RIPK3 Promotes Mefv Expression and Pyrin Inflammasome Activation via Modulation of mTOR Signaling.

Mutations in MEFV, the gene encoding pyrin in humans, are associated with the autoinflammatory disorder familial Mediterranean fever. Pyrin is an innate sensor that assembles into an inflammasome complex in response to Rho-modifying toxins, including Clostridium difficile toxins A and B. Cell death pathways have been shown to intersect with and modulate inflammasome activation, thereby affecting host defense. Using bone marrow-derived macrophages and a murine model of peritonitis, we show in this study that receptor-interacting protein kinase (RIPK) 3 impacts pyrin inflammasome activation independent of its role in necroptosis. RIPK3 was instead required for transcriptional upregulation of Mefv through negative control of the mechanistic target of rapamycin (mTOR) pathway and independent of alterations in MAPK and NF-κB signaling. RIPK3 did not affect pyrin dephosphorylation associated with inflammasome activation. We further demonstrate that inhibition of mTOR was sufficient to promote Mefv expression and pyrin inflammasome activation, highlighting the cross-talk between the mTOR pathway and regulation of the pyrin inflammasome. Our study reveals a novel interaction between molecules involved in cell death and the mTOR pathway to regulate the pyrin inflammasome, which can be harnessed for therapeutic interventions.

Fecal microbiota transplant rescues mice from human pathogen mediated sepsis by restoring systemic immunity.

Death due to sepsis remains a persistent threat to critically ill patients confined to the intensive care unit and is characterized by colonization with multi-drug-resistant healthcare-associated pathogens. Here we report that sepsis in mice caused by a defined four-member pathogen community isolated from a patient with lethal sepsis is associated with the systemic suppression of key elements of the host transcriptome required for pathogen clearance and decreased butyrate expression. More specifically, these pathogens directly suppress interferon regulatory factor 3. Fecal microbiota transplant (FMT) reverses the course of otherwise lethal sepsis by enhancing pathogen clearance via the restoration of host immunity in an interferon regulatory factor 3-dependent manner. This protective effect is linked to the expansion of butyrate-producing Bacteroidetes. Taken together these results suggest that fecal microbiota transplantation may be a treatment option in sepsis associated with immunosuppression.

An antibiotic depleted microbiome drives severe Campylobacter jejuni-mediated Type 1/17 colitis, Type 2 autoimmunity and neurologic sequelae in a mouse model.

The peripheral neuropathy Guillain-Barré Syndrome can follow Campylobacter jejuni infection when outer core lipooligosaccharides induce production of neurotoxic anti-ganglioside antibodies. We hypothesized that gut microbiota depletion with an antibiotic would increase C. jejuni colonization, severity of gastroenteritis, and GBS. Microbiota depletion increased C. jejuni colonization, invasion, and colitis with Type 1/17 T cells in gut lamina propria. It also stimulated Type 1/17 anti-C. jejuni and -antiganglioside-antibodies, Type 2 anti-C. jejuni and -antiganglioside antibodies, and neurologic phenotypes. Results indicate that both C. jejuni strain and gut microbiota affect development of inflammation and GBS and suggest that probiotics following C. jejuni infection may ameliorate inflammation and autoimmune disease.