Bilateral vestibular schwannoma with a cooccurring meningioma in a child: a case report and review of literature.

Introduction: Meningioma and vestibular schwannoma (VS) are the first and second most common benign central nervous system tumors. The coexistence of VS and meningioma presents a rare clinical scenario, particularly in pediatric patients. This report presents a case of bilateral VS with a cooccurring meningioma in a Nepali child and provides an overview of the literature on this condition. Case report: A 15-year-old male presented with bilateral sensorineural hearing loss, seizures, and neurological deficits and was ultimately diagnosed with concomitant bilateral acoustic neuroma and meningioma. The patient underwent radiosurgery for bilateral VS and nonoperative management of the meningioma. Long-term follow-up revealed symptomatic improvement, emphasizing the importance of a multidisciplinary approach in managing such complex cases. The management of these tumors requires tailored treatment strategies guided by tumor characteristics and associated risks. Discussion: Meningioma and VS are common tumors of the central nervous system. Their coexistence is possible in neurofibromatosis type 2 but is exceedingly rare in pediatric age group. The tumors, often coexisting, pose diagnostic challenges. Diagnosis relies on clinical and genetic features, with multidisciplinary management involving various specialists. Treatment aims to preserve function and quality of life, utilizing approaches such as bevacizumab and surgical intervention. The role of radiation therapy remains uncertain. Genetic testing and regular monitoring are vital for early detection and intervention. Conclusion: The cooccurrence of acoustic neuromas and meningiomas is poorly understood, with limited reported cases and unclear pathophysiological mechanisms. Further research into the genetic and molecular mechanisms underlying the coexistence of these tumors is needed to optimize patient outcomes in this rare clinical entity.

The modern landscape of radiotherapy in thyroid malignancies.

Thyroid carcinoma is the most common malignancy of the endocrine system and accounts for nearly 1.5% of all new cancer cases in India. The incidence of thyroid cancers is on the rise secondary to multiple factors including the widespread use of radiological imaging. Surgery remains the cornerstone of treatment, and radioactive iodine therapy plays a pivotal role in differentiated thyroid cancer. Radiation therapy appears to be an underutilized treatment modality. In this review, we have summarized the role of radiation in the treatment of thyroid cancer.

Presence of TRPV3 in macrophage lysosomes helps in skin wound healing against bacterial infection.

Transient Receptor Potential Vanilloid subtype 3 (TRPV3) is a non-selective cation channel that is known to be activated by physiological temperature and endogenous ligands. Involvement of TRPV3 in different skin functions has been reported. In this work, we demonstrate that activation of TRPV3 by FPP, an endogenous ligand enhances skin wound healing and bacterial clearance there. We report for the first time that TRPV3 is endogenously expressed in macrophages and activation of TRPV3 results in efficient bacterial clearance. At the subcellular level, TRPV3 is present in the lysosome and also in the nucleolus. We demonstrate that pharmacological modulation of TRPV3 protects lysosomal functions at hyperthermic shock conditions. The localization of TRPV3 at the nucleolus is specific, more in case of LPS-treatment and dynamic with respect to the cell signalling. We demonstrate that at certain conditions, the nucleolar localization of TRPV3 is correlated with the presence of TRPV3 at the lysosome and with the cellular stress in general. We propose that TRPV3 act as a lysosomal regulator and sensor for cellular stress. These findings may have broad implications in understanding the cellular stress and TRPV3-induced channelopathies and may have clinical relevance to skin infection treatment.

Sine oculis homeobox homolog 1 plays a critical role in pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a fatal disease with limited treatment options. The role of the developmental transcription factor Sine oculis homeobox homolog 1 (SIX1) in the pathophysiology of lung fibrosis is not known. IPF lung tissue samples and IPF-derived alveolar type II cells (AT2) showed a significant increase in SIX1 mRNA and protein levels, and the SIX1 transcriptional coactivators EYA1 and EYA2 were elevated. Six1 was also upregulated in bleomycin-treated (BLM-treated) mice and in a model of spontaneous lung fibrosis driven by deletion of Telomeric Repeat Binding Factor 1 (Trf1) in AT2 cells. Conditional deletion of Six1 in AT2 cells prevented or halted BLM-induced lung fibrosis, as measured by a significant reduction in histological burden of fibrosis, reduced fibrotic mediator expression, and improved lung function. These effects were associated with increased macrophage migration inhibitory factor (MIF) in lung epithelial cells in vivo following SIX1 overexpression in BLM-induced fibrosis. A MIF promoter-driven luciferase assay demonstrated direct binding of Six1 to the 5'-TCAGG-3' consensus sequence of the MIF promoter, identifying a likely mechanism of SIX1-driven MIF expression in the pathogenesis of lung fibrosis and providing a potentially novel pathway for targeting in IPF therapy.

Neurons undergo pathogenic metabolic reprogramming in models of familial ALS.

OBJECTIVES: Normal cellular function requires a rate of ATP production sufficient to meet demand. In most neurodegenerative diseases (including Amyotrophic Lateral Sclerosis [ALS]), mitochondrial dysfunction is postulated raising the possibility of impaired ATP production and a need for compensatory maneuvers to sustain the ATP production/demand balance. We investigated intermediary metabolism of neurons expressing familial ALS (fALS) genes and interrogated the functional consequences of glycolysis genes in fitness assays and neuronal survival. METHODS: We created a pure neuronal model system for isotopologue investigations of fuel utilization. In a yeast platform we studied the functional contributions of glycolysis genes in a growth fitness assay iafter expressing of a fALS gene. RESULTS: We find in our rodent models of fALS, a reduction in neuronal lactate production with maintained or enhanced activity of the neuronal citric acid cycle. This rewiring of metabolism is associated with normal ATP levels, bioenergetics, and redox status, thus supporting the notion that gross mitochondrial function is not compromised in neurons soon after expressing fALS genes. Genetic loss-of-function manipulation of individual steps in the glycolysis and the pentose phosphate pathway blunt the negative phenotypes seen in various fALS models. CONCLUSIONS: We propose that neurons adjust fuel utilization in the setting of neurodegenerative disease-associated alteration in mitochondrial function in a baleful manner and targeting this process can be healthful.

Aberrant Cellular Glycosylation May Increase the Ability of Influenza Viruses to Escape Host Immune Responses through Modification of the Viral Glycome.

Individuals with metabolic dysregulation of cellular glycosylation often experience severe influenza disease, with a poor immune response to the virus and low vaccine efficacy. Here, we investigate the consequences of aberrant cellular glycosylation for the glycome and the biology of influenza virus. We transiently induced aberrant N-linked glycosylation in cultured cells with an oligosaccharyltransferase inhibitor, NGI-1. Cells treated with NGI-1 produced morphologically unaltered viable influenza virus with sequence-neutral glycosylation changes (primarily reduced site occupancy) in the hemagglutinin and neuraminidase proteins. Hemagglutinin with reduced glycan occupancy required a higher concentration of surfactant protein D (an important innate immunity respiratory tract collectin) for inhibition compared to that with normal glycan occupancy. Immunization of mice with NGI-1-treated virus significantly reduced antihemagglutinin and antineuraminidase titers of total serum antibody and reduced hemagglutinin protective antibody responses. Our data suggest that aberrant cellular glycosylation may increase the risk of severe influenza as a result of the increased ability of glycome-modified influenza viruses to evade the immune response. IMPORTANCE People with disorders such as cancer, autoimmune disease, diabetes, or obesity often have metabolic dysregulation of cellular glycosylation and also have more severe influenza disease, a reduced immune response to the virus, and reduced vaccine efficacy. Since influenza viruses that infect such people do not show consistent genomic variations, it is generally assumed that the altered biology is mainly related to host factors. However, since host cells are responsible for glycosylation of influenza virus hemagglutinin and neuraminidase, and glycosylation is important for interactions of these proteins with the immune system, the viruses may have functional differences that are not reflected by their genomic sequence. Here, we show that imbalanced cellular glycosylation can modify the viral glycome without genomic changes, leading to reduced innate and adaptive host immune responses to infection. Our findings link metabolic dysregulation of host glycosylation to increased risk of severe influenza and reduced influenza virus vaccine efficacy.

Cellular and Molecular Phenotypes of pConsensus Peptide (pCons) Induced CD8+ and CD4+ Regulatory T Cells in Lupus.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with widespread inflammation, immune dysregulation, and is associated with the generation of destructive anti-DNA autoantibodies. We have shown previously the immune modulatory properties of pCons peptide in the induction of both CD4+ and CD8+ regulatory T cells which can in turn suppress development of the autoimmune disease in (NZB/NZW) F1 (BWF1) mice, an established model of lupus. In the present study, we add novel protein information and further demonstrate the molecular and cellular phenotypes of pCons-induced CD4+ and CD8+ Treg subsets. Flow cytometry analyses revealed that pCons induced CD8+ Treg cells with the following cell surface molecules: CD25highCD28high and low subsets (shown earlier), CD62Lhigh, CD122low, PD1low, CTLA4low, CCR7low and 41BBhigh. Quantitative real-time PCR (qRT-PCR) gene expression analyses revealed that pCons-induced CD8+ Treg cells downregulated the following several genes: Regulator of G protein signaling (RGS2), RGS16, RGS17, BAX, GPT2, PDE3b, GADD45ß and programmed cell death 1 (PD1). Further, we confirmed the down regulation of these genes by Western blot analyses at the protein level. To our translational significance, we showed herein that pCons significantly increased the percentage of CD8+FoxP3+ T cells and further increased the mean fluorescence intensity (MFI) of FoxP3 when healthy peripheral blood mononuclear cells (PBMCs) are treated with pCons (10 µg/ml, for 24-48 hours). In addition, we found that pCons reduced apoptosis in CD4+ and CD8+ T cells and B220+ B cells of BWF1 lupus mice. These data suggest that pCons stimulates cellular, immunological, and molecular changes in regulatory T cells which in turn protect against SLE autoimmunity.

Interferon Genes Are Influenced by 17ß-Estradiol in SLE.

Recent evidence suggests the existence of a nexus between inflammatory pathways and the female sex hormone 17ß-estradiol, resulting in increased interferon-stimulated genes (ISGs), autoantibodies, and dysregulation of immune cells in SLE. However, the molecular mechanisms and the effect of estradiol on candidate target genes and their pathways remains poorly understood. Our previous work suggests that female SLE patients have increased estradiol levels compared to healthy controls. In the present study, we explored the effects of 17ß-estradiol treatment on expression of IFN (interferons)-stimulated genes and pro-inflammatory cytokines/chemokines. We found significantly increased (5-10-fold) expression of IFN-regulated genes in healthy females. Furthermore, we found significantly increased plasma levels of IL-6, IL-12, IL-17, IL-18, stem cell factor (SCF), and IL-21/IL-23 in SLE patients compared to healthy controls, and those levels positively correlated with the plasma levels of 17ß-estradiol. In addition, levels of IL-21 positively correlated with the SLE disease activity index (SLEDAI) score of SLE patients. In vitro treatment of PBMCs from either SLE patients or healthy controls with 17ß-estradiol at physiological concentration (~50 pg/ml) also significantly increased secretion of many pro-inflammatory cytokines and chemokines (IL-6, IL-12, IL-17, IL-8, IFN-γ; MIP1α, and MIP1ß) in both groups. Further our data revealed that 17ß-estradiol significantly increased the percentage of CD3+CD69+ and CD3+IFNγ+ T cells; whereas, simultaneous addition of 17ß-estradiol and an ERα inhibitor prevented this effect. Collectively, our findings indicate that 17ß-estradiol participates in the induction of pro-inflammatory cytokines and chemokines and further influences interferon genes and pathways.

Effects of Peptide-Induced Immune Tolerance on Murine Lupus.

The regulation of autoimmunity and the molecular mechanisms by which different immune cells, including T cells, polymorphonuclear leukocytes (PMN-granulocytes), and B cells suppress autoimmune diseases is complex. We have shown previously that BWF1 lupus mice are protected from autoimmunity after i.v. injection or oral administration of tolerogenic doses of pCons, an artificial synthetic peptide based on sequences containing MHC class I and MHC class II determinants in the VH region of a J558-encoded BWF1 anti-DNA Ab. Several T cell subsets can transfer this tolerance. In this study, we determined the potential roles of granulocytes, B cells and regulatory T cells altered by pCons treatment in the BWF1 (NZB/NZW) mouse model of lupus. Immunophenotyping studies indicated that pCons treatment of BWF1 mice significantly increased CD4+FoxP3+ T cells, reduced the percent of B cells expressing CD19+CD5+ but increased the percent of CD19+CD1d+ regulatory B cells and increased the ability of the whole B cell population to suppress IgG anti-DNA production in vitro. pCons treatment significantly decreased the expression of CTLA-4 (cytotoxic T-lymphocyte-associated protein-4) in CD8+ T cells. In addition, peptide administration modified granulocytes so they became suppressive. We co-cultured sorted naïve B cells from mice making anti-DNA Ab (supported by addition of sorted naive CD4+ and CD8+ T cells from young auto-antibody-negative BWF1 mice) with sorted B cells or granulocytes from tolerized mice. Both tolerized granulocytes and tolerized B cells significantly suppressed the production of anti-DNA in vitro. In granulocytes from tolerized mice compared to saline-treated littermate controls, real-time PCR analysis indicated that expression of interferon-induced TNFAIP2 increased more than 2-fold while Ptdss2 and GATA1 mRNA were up-regulated more than 10-fold. In contrast, expression of these genes was significantly down-regulated in tolerized B cells. Further, another IFN-induced protein, Bcl2, was reduced in tolerized B cells as determined by Western blot analyses. In contrast, expression of FoxP3 was significantly increased in tolerized B cells. Together, these data suggest that B cells and granulocytes are altered toward suppressive functions by in vivo tolerization of BWF1 mice with pCons and it is possible these cell types participate in the clinical benefits seen in vivo.

Self-Assembly of Nicotinic Acid-Conjugated Selenopeptides into Mesotubes.

The study of controlling the morphology for designing advanced supramolecular architectures by tuning the molecular motif at the elemental level has been rarely carried out. Here, we report the synthesis of a nicotinic acid-conjugated selenopeptide, which induced the formation of an unbranched mesoscale elongated tubular morphology. We rationally designed two additional peptides to find out the decisive role played by the nitrogen atom (in nicotinic acid) and selenium (in the peptide backbone) toward the formation of the mesotube. We found that the peptide, devoid of nitrogen, forms a fibrillar structure, whereas the peptide without selenium self-assembled into a cylindrical filled rodlike morphology. Here, we report an entirely different class of peptide inspired from the selenopeptide chemistry that forms a tubular structure and unambiguously establish that both nicotinic acid and selenium are essential toward the formation of such mesotubes.

Inhibition of transient receptor potential vanilloid 1 (TRPV1) channel regulates chikungunya virus infection in macrophages.

Chikungunya virus (CHIKV), a virus that induces pathogenic inflammatory host immune responses, is re-emerging worldwide, and there are currently no established antiviral control measures. Transient receptor potential vanilloid 1 (TRPV1), a non-selective Ca2+-permeable ion channel, has been found to regulate various host inflammatory responses including several viral infections. Immune responses to CHIKV infection in host macrophages have been reported recently. However, the possible involvement of TRPV1 during CHIKV infection in host macrophages has not been studied. Here, we investigated the possible role of TRPV1 in CHIKV infection of the macrophage cell line RAW 264.7. It was found that CHIKV infection upregulates TRPV1 expression in macrophages. To confirm this observation, the TRPV1-specific modulators 5'-iodoresiniferatoxin (5'-IRTX, a TRPV1 antagonist) and resiniferatoxin (RTX, a TRPV1 agonist) were used. Our results indicated that TRPV1 inhibition leads to a reduction in CHIKV infection, whereas TRPV1 activation significantly enhances CHIKV infection. Using a plaque assay and a time-of-addition assay, it was observed that functional modulation of TRPV1 affects the early stages of the viral lifecycle in RAW 264.7 cells. Moreover, CHIKV infection was found to induce of pNF-κB (p65) expression and nuclear localization. However, both activation and inhibition of TRPV1 were found to enhance the expression and nuclear localization of pNF-κB (p65) and production of pro-inflammatory TNF and IL-6 during CHIKV infection. In addition, it was demonstrated by Ca2+ imaging that TRPV1 regulates Ca2+ influx during CHIKV infection. Hence, the current findings highlight a potentially important regulatory role of TRPV1 during CHIKV infection in macrophages. This study might also have broad implications in the context of other viral infections as well.

Immune Checkpoint Blockade Enhances Immune Activity of Therapeutic Lung Cancer Vaccine.

BACKGROUND: Immune checkpoint blockade that downregulates T cell evasion for effective immunity has provided a renewed interest in therapeutic cancer vaccines. METHODS: Utilizing murine lung cancer models, we determined: tumor burden, TIL cytolysis, immunohistochemistry, flow cytometry, RNA Sequencing, CD4 T cells, CD8 T cells, CXCL9 chemokine, and CXCL10 chemokine neutralization to evaluate the efficacy of Programmed cell death protein 1 (PD-1) blockade combined with chemokine (C-C motif) ligand 21-dendritic cell tumor antigen (CCL21-DC tumor Ag) vaccine. RESULTS: Anti-PD1 combined with CCL21-DC tumor Ag vaccine eradicated 75% of 12-day established tumors (150 mm3) that was enhanced to 90% by administering CCL21-DC tumor Ag vaccine prior to combined therapy. The effect of combined therapy was blocked by CD4, CD8, CXCL9, and CXCL10 neutralizing antibodies. CONCLUSION: PD-1 blockade therapy plus CCL21-DC tumor Ag vaccine could be beneficial to lung cancer patients.

Lymphatic Proliferation Ameliorates Pulmonary Fibrosis after Lung Injury.

Despite many reports about pulmonary blood vessels in lung fibrosis, the contribution of lymphatics to fibrosis is unknown. We examined the mechanism and consequences of lymphatic remodeling in mice with lung fibrosis after bleomycin injury or telomere dysfunction. Widespread lymphangiogenesis was observed after bleomycin treatment and in fibrotic lungs of prospero homeobox 1-enhanced green fluorescent protein (Prox1-EGFP) transgenic mice with telomere dysfunction. In loss-of-function studies, blocking antibodies revealed that lymphangiogenesis 14 days after bleomycin treatment was dependent on vascular endothelial growth factor (Vegf) receptor 3 signaling, but not on Vegf receptor 2. Vegfc gene and protein expression increased specifically. Extensive extravasated plasma, platelets, and macrophages at sites of lymphatic growth were potential sources of Vegfc. Lymphangiogenesis peaked at 14 to 28 days after bleomycin challenge, was accompanied by doubling of chemokine (C-C motif) ligand 21 in lung lymphatics and tertiary lymphoid organ formation, and then decreased as lung injury resolved by 56 days. In gain-of-function studies, expansion of the lung lymphatic network by transgenic overexpression of Vegfc in club cell secretory protein (CCSP)/VEGF-C mice reduced macrophage accumulation and fibrosis and accelerated recovery after bleomycin treatment. These findings suggest that lymphatics have an overall protective effect in lung injury and fibrosis and fit with a mechanism whereby lung lymphatic network expansion reduces lymph stasis and increases clearance of fluid and cells, including profibrotic macrophages.

Tuning the pharmacokinetics and efficacy of irinotecan (IRI) loaded gelatin nanoparticles through folate conjugation.

Gelatin based nanocarriers have major limitation of shorter circulation half-life (t1/2). Present study addressed this issue by conjugating gelatin with folate followed by nanoprecipitation in presence of polysorbate 80 to form folate attached gelatin nanoparticles (GNP-F). The folic acid was conjugated with gelatin through the formation of amide linkage with a maximum conjugation yield of ~69%. Cryo-SEM analysis indicated that unconjugated gelatin nanoparticles (GNP) and GNP-F were spherical of nearly identical size of ~200 nm. The irinotecan (IRI)-loading efficiency estimated for IRI-GNP and IRI-GNP-F was 6.6 ± 0.42% and 11.2 ± 0.73% respectively and both formulations showed faster release of IRI at acidic pH (~5) than at physiological pH (~7). Further IRI-GNP-F demonstrated significantly higher cytotoxicity in folate receptor (FR)-positive HeLa cells than the unconjugated IRI-GNP nanoparticles confirming active targeting. Subsequently the antitumor activity of above formulations in FR-positive fibrosarcoma (syngeneic) tumor-bearing mice followed the order of IRI-GNP-F > IRI-GNP > free IRI. The pharmacokinetic evaluation of IRI-GNP and IRI-GNP-F revealed that encapsulation of IRI within GNP without folate improved its plasma maximum concentration (Cmax). However, folate conjugation of GNP remarkably improved the t1/2 of IRI. Taken together, folate as a targeting ligand modulates the pharmacokinetic property of IRI loaded GNP to favor active verses passive targeting.

Single particle inductively coupled plasma mass spectrometry with and without flow injection for the characterization of nickel nanoparticles.

This work compares the performance of transmission electron microscopy (TEM), scanning electron microscopy (SEM), X-ray diffraction (XRD), single particle inductively coupled plasma mass spectrometry (spICPMS) and flow injection (FI) coupled to spICPMS for the characterization of synthetic ferromagnetic Ni nanoparticles (NPs) prepared with and without polyvinylpyrrolidone (PVP) stabilizer. Whereas single NPs measurement by XRD yielded nominal diameters of 13.7 and 16.6 nm with and without PVP respectively, a diameter of 100-130 nm was obtained by TEM and SEM with or without PVP, indicating extensive agglomeration during preparation for microscopy. In contrast, without PVP stabilization, mean and mode sizes of respectively 35 ± 18 and 21 nm by spICPMS and 33 ± 15 and 20 nm by FI-spICPMS were obtained for suspensions of Ni NPs using external calibration with Ni standard solutions. With PVP stabilization, the mean and mode sizes respectively decreased to 27 ± 12 and 18 nm by spICPMS and 25 ± 10 and 16 nm by FI-spICPMS. Mass balance taking into account the amount of dissolved Ni was verified in all cases. No degradation in performance resulted from using FI-spICPMS instead of spICPMS, even though measurement of NPs mass by FI-spICPMS is done without knowledge of the transport efficiency and the sample uptake rate. This is the first time that spICPMS and FI-spICPMS are demonstrated to be suitable for the characterization of ferromagnetic NPs.

Defining the landscape of ATP-competitive inhibitor resistance residues in protein kinases.

Kinases are involved in disease development and modulation of their activity can be therapeutically beneficial. Drug-resistant mutant kinases are valuable tools in drug discovery efforts, but the prediction of mutants across the kinome is challenging. Here, we generate deep mutational scanning data to identify mutant mammalian kinases that drive resistance to clinically relevant inhibitors. We aggregate these data with subsaturation mutagenesis data and use it to develop, test and validate a framework to prospectively identify residues that mediate kinase activity and drug resistance across the kinome. We validate predicted resistance mutations in CDK4, CDK6, ERK2, EGFR and HER2. Capitalizing on a highly predictable residue, we generate resistance mutations in TBK1, CSNK2A1 and BRAF. Unexpectedly, we uncover a potentially generalizable activation site that mediates drug resistance and confirm its impact in BRAF, EGFR, HER2 and MEK1. We anticipate that the identification of these residues will enable the broad interrogation of the kinome and its inhibitors.

Passive and Active Drug Targeting: Role of Nanocarriers in Rational Design of Anticancer Formulations.

BACKGROUND: Cancer is the major public health problem in developing countries. The treatment of cancer requires a multimodal approach and chemotherapy is one of them. Chemotherapeutic drug is administered to cancer patients in the form of a formulation which is prepared by mixing an active ingredient (drug) with the excipient. The role of excipient in a formulation is to regulate the release, bio-distribution, and selectivity of drug within the body. METHODS: In this context, selectivity of an anticancer formulation is achieved through two mechanisms like passive and active targeting. The passive targeting of a formulation is generally through enhanced permeation retention (EPR) effect which is dictated by physical properties of the carrier such as shape and size. On the contrary, active targeting means surface functionalization of excipient with target-specific ligands and/or receptors to increase its selectivity. RESULTS: Over the past several decades, remarkable progress has been made in the development and application of an engineered excipient or carrier to treat cancer more effectively. Especially nanoparticulate systems composed of metal/liposomes/polymeric material/proteins have received significant attention in the rational design of anticancer drug formulations; for example, therapeutic agents have been integrated with nanoparticles of optimal sizes, shapes and surface properties to improve their solubility, circulation half-life, and bio-distribution. In this review article, recent literature is included to discuss the role of physicochemical properties of excipients in achieving tumour targeting through passive and active approaches. CONCLUSION: The selection of an excipient/carrier and targeting ligand plays a very important role in rational design and development of anticancer drug formulations.

Designer Peptide and Protein Dendrimers: A Cross-Sectional Analysis.

Dendrimers have attracted immense interest in science and technology due to their unique chemical structure that offers a myriad of opportunities for researchers. Dendritic design allows us to present peptides in a branched three-dimensional fashion that eventually leads to a globular shape, thus mimicking globular proteins. Peptide dendrimers, unlike other classes of dendrimers, have immense applications in biomedical research due to their biological origin. The diversity of potential building blocks and innumerable possibilities for design, along with the fact that the area is relatively underexplored, make peptide dendrimers sought-after candidates for various applications. This review summarizes the stepwise evolution of peptidic dendrimers along with their multifaceted applications in various fields. Further, the introduction of biomacromolecules such as proteins to a dendritic scaffold, resulting in complex macromolecules with discrete molecular weights, is an altogether new addition to the area of organic chemistry. The synthesis of highly complex and fully folded biomacromolecules on a dendritic scaffold requires expertise in synthetic organic chemistry and biology. Presently, there are only a handful of examples of protein dendrimers; we believe that these limited examples will fuel further research in this area.

Myrmenaphthol A, Isolated from a Hawaiian Sponge of the Genus Myrmekioderma.

Four compounds (1-4) were isolated from a Hawaiian sponge of the genus Myrmekioderma. Myrmenaphthol A (1) incorporates two unusual elements into an oxidized steroidal core: a naphthyl AB-ring system and a hydroxy group at C-2. A comparison of the experimental and predicted electronic circular dichroism (ECD) spectra of 1 assigned an S configuration to the lone stereocenter (ΔESI = 0.75; similarity factor 0.8137). Known compounds, cinanthrenol A (2), 3,4-dihydroxypregna-5,17-diene-10,2-carbolactone (3), and 3,4-dihydroxypregna-5,20-diene-10,2-carbolactone (4), were also isolated. Despite literature reports of competitive inhibition at nanomolar levels for 2, neither 2 nor the structurally related 1 showed any activity against estrogen receptors at the concentrations tested.