Revolutionizing Wound Healing: Unleashing Nanostructured Lipid Carriers Embodied with Herbal Medicinal Plant.

Wound healing is crucial for maintaining skin integrity and preventing complications from external threats. Various plants, such as Achillea millefolium, Aloe vera, Curcuma longa, Calendula officinalis, Camellia sinensis, Azadirachta indica, and Plantago, have demonstrated wound healing capabilities and have been used in herbal medicine for wound care. NLCs are second-generation lipid nanoparticles, blending solid and liquid lipids to improve medication loading and limit leakage. NLCs have been used in various applications, including cosmeceuticals, chemotherapy, gene therapy, and brain targeting. Wound healing is divided into four stages: hemostasis, inflammatory response, proliferation, and remodeling. Factors such as age, gender, chronic disorders, and local agents like infections can affect recovery. These plants' antiinflammatory, antioxidant, and antibacterial activities have demonstrated potential in wound healing. Combining herbal medicinal plants and nanostructured lipid carriers (NLCs) can revolutionise wound treatment and improve overall healthcare outcomes.

HPTLC and GC-MS finger-printing of two potential multifunctional siddha tailams: Mathan and maha megarajanga tailam.

The Siddha system of medicine is an ancient medical lineage that is practiced primarily in the southern part of India. Siddha system of medicine has been in practice for thousands of years with documented evidence dating back to the 6th century BCE. According to siddha system of medicine's basic fundamental principle, the human body is made up of 96 thathuvam (primary components), which encompass physical, physiological, psychological, and intellectual aspects. Medicine (marunthu) is classified as a wide range of internal and external medicines. The major components of its medical formulations include plant parts, minerals and animal products. Various methods were carried out for the purification process to eliminate the toxins. Choornam, Guligai, Tailam, Parpam, Chendooram, Kattu, Pasai and Poochu are the most common medicines used in Siddha system of medicine for the treatment of various diseases. The pathophysiological classification of diseases is elaborated in detail in the classical Siddha literature. Siddha system of medicine plays an important role in protecting people from diseases such as COVID-19 by providing immune-protecting and immune-boosting medicines in today's world. Mathan tailam and maha megarajanga tailam are the two unique preparations used widely for various skin diseases including chronic wounds and burns. Scientific validation of both medicines will help in understanding their effectiveness against a typical wound condition. In the present study physio-chemical and phytochemical, HPTLC, and GC-MS analyses were carried out and discussed in detail on the multifunctional properties exhibited in the patient communities.

High-throughput approaches to uncover synergistic drug combinations in leukemia.

We report a comprehensive drug synergy study in acute myeloid leukemia (AML). In this work, we investigate a panel of cell lines spanning both MLL-rearranged and non-rearranged subtypes. The work comprises a resource for the community, with many synergistic drug combinations that could not have been predicted a priori, and open source code for automation and analyses. We base our definitions of drug synergy on the Chou-Talalay method, which is useful for visualizations of synergy experiments in isobolograms, and median-effects plots, among other representations. Our key findings include drug synergies affecting the chromatin state, specifically in the context of regulation of the modification state of histone H3 lysine-27. We report open source high throughput methodology such that multidimensional drug screening can be accomplished with equipment that is accessible to most laboratories. This study will enable preclinical investigation of new drug combinations in a lethal blood cancer, with data analysis and automation workflows freely available to the community.

Quantitative assessment of platelet rich fibrin for the repair of extraction socket in a rat model.

The present study evaluated the quantitative effects of platelet-rich fibrin (PRF) for the repair of extraction socket in Sprague Dawley (SD) rat model by assessing several key clinical parameters. Seventy two male SD rats were subjected to surgical extraction of the maxillary right incisor. Rats were randomly divided into four groups with eighteen rats in each group based on the treatment received: extraction socket without treatment of PRF was taken as control (group I). Extraction socket implanted with 0.1, 0.2, and 0.4 mL of PRF was taken as study groups (groups II, III, and IV). The obtained results demonstrated that, low dose of PRF efficiently enhanced the natural healing cascade. Whereas, high dose interfered with native tissue contribution and altered the natural healing process. The beneficial effects of quantity-based application of PRF may raise the possibility of a new approach as complementary therapy besides conventional treatment.

Biologically synthesized iron nanoparticles (FeNPs) from Phoenix dactylifera have anti-bacterial activities.

Nanotechnology is a vast field of science with the most vibrant and conspicuous applications. The green synthesis approach is cost-effective, eco-friendly, and produces the most stable metal-based nanoparticles without the use of toxic chemicals. This study presents the green synthesis of iron nanoparticles (FeNPs). For biosynthesis of FeNPs, Phoenix dactylifera extract was used as a reducing agent and iron sulfate heptahydrate (FeSO4·7H2O) was used as a substrate. FeNPs were characterized by different techniques including UV-Visible spectroscopy, Fourier transform infrared spectroscopy (FTIR), and nano zeta-sizer analysis. The antimicrobial activity of FeNPs synthesized by using an aqueous extract of Phoenix dactylifera was evaluated against Escherichia coli, Bacillus subtilis, Micrococcus leutus, and Klebsiella pneumoniae. A notable color change from yellow to black confirmed the synthesis of FeNPs. The sharp peak at 450 nm UV-Visible spectroscopy confirmed the synthesis of FeNPs. FTIR showed the presence of O-H and C=C stretching due to the presence of phenol and alkene functional groups. The average size of FeNPs was 6092 d.nm. The results of antimicrobial activity showed that FeNPs exhibit different potential against different bacterial strains with a maximum 25 ± 0.360 zone of inhibition against Escherichia coli. Thus, green synthesized FeNPs could be used as potential antimicrobial agents.

In Vitro Anti-Inflammatory, Anticancer (MCF-7, 3T3, and HeLa Cell Lines), and Brine Shrimp Lethality Assay and FTIR Analysis of the Extract and Fractions of the Whole Plant of Heliotropium europaeum.

In this study, anti-inflammatory, anticancer, brine shrimp lethality, and FTIR studies were evaluated. The oxidative burst assay using the chemiluminescence technique, MTT assay, brine shrimp lethality assay, and FTIR analysis were the methods used for the evaluation of anti-inflammatory, anticancer, brine shrimp lethality, and FTIR studies, respectively. The whole-plant butanol fraction of Heliotropium europaeum (WBFHE) showed anti-inflammatory activity on ROS having IC5014.7 ± 2.5 while the extract and other fractions of the whole plant of Heliotropium europaeum exhibited no anti-inflammatory activity. None of the extract and fractions of the whole plant of Heliotropium europaeum exhibited anticancer (MCF-7, 3T3, and HeLa cell lines) activities. The whole-plant aqueous fraction of Heliotropium europaeum (WAFHE) and whole-plant butanol fraction of Heliotropium europaeum (WBFHE) showed lethality at high concentration while at low concentration, no toxicity was shown. The whole-plant methanolic extract of Heliotropium europaeum (WMEHE) and whole-plant n-hexane fraction of Heliotropium europaeum (WHFHE) exhibited no toxicity. FTIR interpretation showed the functional groups for the aromatic compounds, phenols, carboxylic acids, esters, alkanes, alkenes, alcohols, alkyl halides, sulfate esters, phosphines, silanes, nitriles, thiols, amines, phosphoric acids, and nitro compounds.

In Vitro Anticancer MCF-7, Anti-Inflammatory, and Brine Shrimp Lethality Assay (BSLA) and GC-MS Analysis of Whole Plant Butanol Fraction of Rheum ribes (WBFRR).

In this study, GC-MS analysis has shown that whole plant butanol fraction of rheum ribes (WBFRR) comprises of 21 compounds which exhibited anticancer (MCF-7) activity having IC50 value of 36.01± 0.26. MTT assay (MCF-7), Oxidative Burst assay using chemiluminescence technique, and B-Hatching techniques were the methods used for anticancer MCF-7, anti-inflammatory, and Brine Shrimp Lethality Assay (BSLA). GC-MS was used for structural elucidation. Whole plant methanol extract of rheum ribes (WMERR), whole plant n-hexane fraction of rheum ribes (WHFRR), and whole plant aqueous fraction of rheum ribes (WAFRR) were inactive against anticancer (MCF-7) cell line. Whole plant methanol extract of rheum ribes (WMERR), whole plant aqueous fraction of rheum ribes (WAFRR) and whole plant butanol fraction of rheum ribes (WBFRR) showed anti-inflammatory activity on ROS having IC50 value of 23.2±1.9, 24.2±2.7 and 12.0±0.6. Whole plant butanol fraction of rheum ribes (WBFRR) showed Brine Shrimp Lethality with LD50 693.302 while whole plant methanol extract of rheum ribes (WMERR) and whole plant aqueous fraction of rheum ribes (WAFRR) showed high lethality at highest concentration. This study revealed that whole plant butanol fraction of rheum ribes (WBFRR) exhibited significant anticancer (MCF-7) activity. In the near future, the constituent of whole plant butanol fraction of rheum ribes (WBFRR) can be the alternative drug against MCF-7 cell line with least toxicity and side effects.

Discovery of highly potent, selective, covalent inhibitors of JAK3.

A useful and novel set of tool molecules have been identified which bind irreversibly to the JAK3 active site cysteine residue. The design was based on crystal structure information and a comparative study of several electrophilic warheads.

Discovery of potent and efficacious pyrrolopyridazines as dual JAK1/3 inhibitors.

A series of potent dual JAK1/3 inhibitors have been developed from a moderately selective JAK3 inhibitor. Substitution at the C6 position of the pyrrolopyridazine core with aryl groups provided exceptional biochemical potency against JAK1 and JAK3 while maintaining good selectivity against JAK2 and Tyk2. Translation to in vivo efficacy was observed in a murine model of chronic inflammation. X-ray co-crystal structure determination confirmed the presumed inhibitor binding orientation in JAK3. Efforts to reduce hERG channel inhibition will be described.

Current state of pediatric sarcoma biology and opportunities for future discovery: A report from the sarcoma translational research workshop.

Sarcomas are a rare subgroup of pediatric cancers comprised of a variety of bone and soft-tissue tumors. While significant advances have been made in improving outcomes of patients with localized pediatric sarcomas since the addition of systemic chemotherapy to local control many decades ago, outcomes for patients with metastatic and relapsed sarcoma remain poor with few novel therapeutics identified to date. With the advent of new technologies to study cancer genomes, transcriptomes and epigenomes, our understanding of sarcoma biology has improved tremendously in a relatively short period of time. However, much remains to be accomplished in this arena especially with regard to translating all of this new knowledge to the bedside. To this end, a meeting was convened in Philadelphia, PA, on April 18, 2015 sponsored by the QuadW foundation, Children's Oncology Group and CureSearch for Children's Cancer that brought together sarcoma clinicians and scientists from North America to review the current state of pediatric sarcoma biology and ongoing/planned genomics based clinical trials in an effort to identify and bridge knowledge gaps that continue to exist at present. At the conclusion of the workshop, three key objectives that would significantly further our understanding of sarcoma were identified and a proposal was put forward to develop an all-encompassing pediatric sarcoma biology protocol that would address these specific needs. This review summarizes the proceedings of the workshop.

Concentration-dependent antagonistic persuasion of SDS and naphthalene derivatives on the fibrillation of stem bromelain.

Sodium dodecyl sulfate, a biological membrane mimetic, can be used to study the conversion of globular proteins into amyloid fibrils in vitro. Using multiple approaches, the effect of SDS was examined on stem bromelain (SB), a widely recognized therapeutic protein. SB is known to exist as a partially folded intermediate at pH 2.0, situation also encountered in the gastrointestinal tract (its site of absorption). In the presence of sub-micellar SDS concentration (500-1000 µM), this intermediate was found to exhibit great propensity to form large-sized ß-sheeted aggregates with fibrillar morphology, the hall marks of amyloid structure. We also observed inhibition of fibrillation by two naphthalene-based compounds, ANS and bis-ANS. While bis-ANS significantly inhibited fibril formation at 50 µM, ANS did so at relatively higher concentration (400 µM). Alcohols, but not salts, were found to weaken the inhibitory action of these compounds suggesting the possible involvement of hydrophobic interactions in their binding to protein. Besides, isothermal titration calorimetry and molecular docking studies suggested that inhibition of fibrillation by these naphthalene derivatives is mediated not just through hydrophobic forces, but also by disruption of π-π interactions between the aromatic residues together with the inter-polypeptide chain repulsion among negatively charged ANS/bis-ANS bound SB.

Effect of provision of daily zinc and iron with several micronutrients on growth and morbidity among young children in Pakistan: a cluster-randomised trial.

BACKGROUND: Powders containing iron and other micronutrients are recommended as a strategy to prevent nutritional anaemia and other micronutrient deficiencies in children. We assessed the effects of provision of two micronutrient powder formulations, with or without zinc, to children in Pakistan. METHODS: We did a cluster randomised trial in urban and rural sites in Sindh, Pakistan. A baseline survey identified 256 clusters, which were randomly assigned (within urban and rural strata, by computer-generated random numbers) to one of three groups: non-supplemented control (group A), micronutrient powder without zinc (group B), or micronutrient powder with 10 mg zinc (group C). Children in the clusters aged 6 months were eligible for inclusion in the study. Powders were to be given daily between 6 and 18 months of age; follow-up was to age 2 years. Micronutrient powder sachets for groups B and C were identical except for colour; investigators and field and supervisory staff were masked to composition of the micronutrient powders until trial completion. Parents knew whether their child was receiving supplementation, but did not know whether the powder contained zinc. Primary outcomes were growth, episodes of diarrhoea, acute lower respiratory tract infection, fever, and incidence of admission to hospital. This trial is registered with ClinicalTrials.gov, number NCT00705445. RESULTS: The trial was done between Nov 1, 2008, and Dec 31, 2011. 947 children were enrolled in group A clusters, 910 in group B clusters, and 889 in group C clusters. Micronutrient powder administration was associated with lower risk of iron-deficiency anaemia at 18 months compared with the control group (odds ratio [OR] for micronutrient powder without zinc=0·20, 95% CI 0·11-0·36; OR for micronutrient powder with zinc=0·25, 95% CI 0·14-0·44). Compared with the control group, children in the group receiving micronutrient powder without zinc gained an extra 0·31 cm (95% CI 0·03-0·59) between 6 and 18 months of age and children receiving micronutrient powder with zinc an extra 0·56 cm (0·29-0·84). We recorded strong evidence of an increased proportion of days with diarrhoea (p=0·001) and increased incidence of bloody diarrhoea (p=0·003) between 6 and 18 months in the two micronutrient powder groups, and reported chest indrawing (p=0·03). Incidence of febrile episodes or admission to hospital for diarrhoea, respiratory problems, or febrile episodes did not differ between the three groups. INTERPRETATION: Use of micronutrient powders reduces iron-deficiency anaemia in young children. However, the excess burden of diarrhoea and respiratory morbidities associated with micronutrient powder use and the very small effect on growth recorded suggest that a careful assessment of risks and benefits must be done in populations with malnourished children and high diarrhoea burdens. FUNDING: Bill & Melinda Gates Foundation.

Systematic proteome analysis identifies transcription factor YY1 as a direct target of miR-34a.

MicroRNA 34a (miR-34a) is a potential tumor suppressor gene and has been identified as a miRNA component of the p53 network. To better understand the biological pathways involved in miR-34a action, a parallel global protein and mRNA expression profiling on miR-34a treated neuroblastoma cells (IMR32) was performed using isotope-coded affinity tags (ICAT) and Affymetrix U133plus2 microarray, respectively. Global profiling showed that miR-34a causes much smaller mRNA expression changes compared to changes at the protein level. A total of 1495 proteins represented by two or more peptides were identified from the quantitative ICAT analysis, of which 143 and 192 proteins are significantly up- or down-regulated by miR-34a, respectively. Pathway analysis of these differentially expressed proteins showed the enrichment of apoptosis and cell death processes in up-regulated proteins but DNA replication and cell cycle processes in the down-regulated proteins. Ribosomal proteins are the most significant set down-regulated by miR-34a. Additionally, biological network analysis to identify direct interactions among the differentially expressed proteins demonstrated that the expression of the ubiquitous transcription factor YY1, as well as its downstream proteins, is significantly reduced by miR-34a. We further demonstrated that miR-34a directly targets YY1 through a miR-34a-binding site within the 3' UTR of YY1 using a luciferase reporter system. YY1 is a negative regulator of p53, and it plays an essential role in cancer biology. Therefore, YY1 is another important direct target of miR-34a which closely regulates TP53 activities.

Molecular characterization of the pediatric preclinical testing panel.

PURPOSE: Identifying novel therapeutic agents for the treatment of childhood cancers requires preclinical models that recapitulate the molecular characteristics of their respective clinical histotypes. EXPERIMENTAL DESIGN AND RESULTS: Here, we have applied Affymetrix HG-U133Plus2 profiling to an expanded panel of models in the Pediatric Preclinical Testing Program. Profiling led to exclusion of two tumor lines that were of mouse origin and five osteosarcoma lines that did not cluster with human or xenograft osteosarcoma samples. We compared expression profiles of the remaining 87 models with profiles from 112 clinical samples representing the same histologies and show that model tumors cluster with the appropriate clinical histotype, once "immunosurveillance" genes (contributed by infiltrating immune cells in clinical samples) are eliminated from the analysis. Analysis of copy number alterations using the Affymetrix 100K single nucleotide polymorphism GeneChip showed that the models have similar copy number alterations to their clinical counterparts. Several consistent copy number changes not reported previously were found (e.g., gain at 22q11.21 that was observed in 5 of 7 glioblastoma samples, loss at 16q22.3 that was observed in 5 of 9 Ewing's sarcoma and 4 of 12 rhabdomyosarcoma models, and amplification of 21q22.3 that was observed in 5 of 7 osteosarcoma models). We then asked whether changes in copy number were reflected by coordinate changes in gene expression. We identified 493 copy number-altered genes that are nonrandom and appear to identify histotype-specific programs of genetic alterations. CONCLUSIONS: These data indicate that the preclinical models accurately recapitulate expression profiles and genetic alterations common to childhood cancer, supporting their value in drug development.

BBC3 mediates fenretinide-induced cell death in neuroblastoma.

Fenretinide (4-HPR) is a synthetic retinoid whose apoptosis-inducing effects have been demonstrated in many tumor types. The precise mechanism of its apoptotic action is not fully understood. To further study the mechanism by which 4-HPR exerts its biological effects in neuroblastoma (NB) and to identify the genes that contribute to the induction of apoptosis, we determined the sensitivity of eight NB cell lines to 4-HPR. Additionally, cDNA microarray analysis was performed on a 4-HPR-sensitive cell line to investigate the temporal changes in gene expression, primarily focusing on the induction of proapoptotic genes. BBC3, a transcriptionally regulated proapoptotic member of the BCL2 family, was the most highly induced proapoptotic gene. Western analysis confirmed the induction of BBC3 protein by 4-HPR. Furthermore, the induction of BBC3 was associated with the sensitivity to this agent in the cell lines tested. Finally we demonstrated that BBC3 alone is sufficient to induce cell death in the 4-HPR-sensitive and resistant NB cell lines, and that siRNA against BBC3 significantly decreases apoptosis induced by 4-HPR. Our results indicate that BBC3 mediates cell death in NB cells in response to 4-HPR.