Ayurvedic Amalaki Rasayana and Rasa-Sindoor suppress neurodegeneration in fly models of Huntington’s and Alzheimer’s diseases

We examined two Ayurvedic Rasayana formulations, claimed to facilitate ‘healthy ageing’, for their role in neuroprotection in fly models of polyQ (127Q and Huntington’s) and Alzheimer’s disorders. Our earlier findings showed that dietary supplement of Amalaki Rasayana, a preparation derived from Indian gooseberry fruits, and Rasa-Sindoor, an organo-metallic Bhasma prepared from mercury and sulphur, improves general well-being of fruit flies. Here we show that dietary supplement of either of these formulations during larval period substantially suppressed neurodegeneration in fly models of polyQ and Alzheimer’s disorders without any side-effects. Dietary Amalaki Rasayana or Rasa-Sindoor prevented accumulation of inclusion bodies and heat shock proteins, suppressed apoptosis, elevated the levels of heterogeneous nuclear ribonucleoproteins and cAMP response element binding protein and at the same time improved the ubiquitin–proteasomal system for better protein clearance in affected cells. Our studies suggest, the potential of these Ayurvedic formulations in providing a holistic relief from the increasingly common neurodegenerative disorders

Cross-Linked Polyphenol-Based Drug Nano-Self-Assemblies Engineered to Blockade Prostate Cancer Senescence

Cellular senescence is one of the prevailing issues in cancer therapeutics that promotes cancer relapse, chemoresistance, and recurrence. Patients undergoing persistent chemotherapy often develop drug-induced senescence. Docetaxel, an FDA-approved treatment for prostate cancer, is known to induce cellular senescence which often limits the overall survival of patients. Strategic therapies that counter the cellular and drug-induced senescence are an unmet clinical need. Towards this an effort was made to develop a novel therapeutic strategy that targets and removes senescent cells from the tumors, we developed a nanoformulation of tannic acid−docetaxel self-assemblies (DSAs). The construction of DSAs was confirmed through particle size measurements, spectroscopy, thermal, and biocompatibility studies. This formulation exhibited enhanced in vitro therapeutic activity in various biological functional assays with respect to native docetaxel treatments. Microarray and immunoblot analysis results demonstrated that DSAs exposure selectively deregulated senescence associated TGFβR1/FOXO1/p21 signaling. Decrease in β-galactosidase staining further suggested reversion of drug-induced senescence after DSAs exposure. Additionally, DSAs induced profound cell death by activation of apoptotic signaling through bypassing senescence. Furthermore, in vivo and ex vivo imaging analysis demonstrated the tumor targeting behavior of DSAs in mice bearing PC-3 xenograft tumors. The antisenescence and anticancer activity of DSAs was further shown in vivo by inhibiting TGFβR1 proteins and regressing tumor growth through apoptotic induction in the PC-3 xenograft mouse model. Overall, DSAs exhibited such advanced features due to a natural compound in the formulation as a matrix/binder for docetaxel. Overall, DSAs showed superior tumor targeting and improved cellular internalization, promoting docetaxel efficacy. These findings may have great implications in prostate cancer therapy

Reprogramming of pancreatic adenocarcinoma immunosurveillance by a microbial probiotic siderophore

There is increasing evidence suggesting the role of microbiome alterations in relation to pancreatic adenocarcinoma and tumor immune functionality. However, molecular mechanisms of the interplay between microbiome signatures and/or their metabolites in pancreatic tumor immunosurveillance are not well understood. We have identified that a probiotic strain (Lactobacillus casei) derived siderophore (ferrichrome) efficiently reprograms tumor-associated macrophages (TAMs) and increases CD8 + T cell infiltration into tumors that paralleled a marked reduction in tumor burden in a syngeneic mouse model of pancreatic cancer. Interestingly, this altered immune response improved anti-PD-L1 therapy that suggests promise of a novel combination (ferrichrome and immune checkpoint inhibitors) therapy for pancreatic cancer treatment. Mechanistically, ferrichrome induced TAMs polarization via activation of the TLR4 pathway that represses the expression of iron export protein ferroportin (FPN1) in macrophages. This study describes a novel probiotic based molecular mechanism that can effectively induce anti-tumor immunosurveillance and improve immune checkpoint inhibitors therapy response in pancreatic cancer

Genome-wide Analysis of STAT3-Mediated Transcription during Early Human Th17 Cell Differentiation

The development of therapeutic strategies to combat immune-associated diseases requires the molecular mechanisms of human Th17 cell differentiation to be fully identified and understood. To investigate transcriptional control of Th17 cell differentiation, we used primary human CD4+ T cells in small interfering RNA (siRNA)-mediated gene silencing and chromatin immunoprecipitation followed by massive parallel sequencing (ChIP-seq) to identify both the early direct and indirect targets of STAT3. The integrated dataset presented in this study confirms that STAT3 is critical for transcriptional regulation of early human Th17 cell differentiation. Additionally, we found that a number of SNPs from loci associated with immune-mediated disorders were located at sites where STAT3 binds to induce Th17 cell specification. Importantly, introduction of such SNPs alters STAT3 binding in DNA affinity precipitation assays. Overall, our study provides important insights for modulating Th17-mediated pathogenic immune responses in humans.</p

Comparative analysis of human and mouse transcriptomes of Th17 cell priming

Uncontrolled Th17 cell activity is associated with cancer and autoimmune and inflammatory diseases. To validate the potential relevance of mouse models of targeting the Th17 pathway in human diseases we used RNA sequencing to compare the expression of coding and non-coding transcripts during the priming of Th17 cell differentiation in both human and mouse. In addition to already known targets, several transcripts not previously linked to Th17 cell polarization were found in both species. Moreover, a considerable number of human-specific long non-coding RNAs were identified that responded to cytokines stimulating Th17 cell differentiation. We integrated our transcriptomics data with known disease-associated polymorphisms and show that conserved regulation pinpoints genes that are relevant to Th17 cell-mediated human diseases and that can be modelled in mouse. Substantial differences observed in non-coding transcriptomes between the two species as well as increased overlap between Th17 cell-specific gene expression and disease-associated polymorphisms underline the need of parallel analysis of human and mouse models. Comprehensive analysis of genes regulated during Th17 cell priming and their classification to conserved and non-conserved between human and mouse facilitates translational research, pointing out which candidate targets identified in human are worth studying by using in vivo mouse models

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

An excellent protocol for the synthesis of benzopyrans using basic resin under MWI

1561-1564A convenient, microwave promoted novel protocol for the synthesis of diverse kinds of substituted benzopyrans from the corresponding variety of substituted hydroxy acetophenones and keto compounds using Amberlite IRA 400 resin (basic resin) under solvent-free conditions, has been developed. This protocol is mild and more efficient than the other reported methods

Facile synthesis of various 4-carboxylic acid derivatives and their amide analogues of benzopyrans

605-610A series of 4-carboxyalkyl amide derivatives of benzopyrans 6a-d and 7a-d have been prepared in 40-64% overall yields. In the proposed synthetic strategy, the key intermediate 4-methyl substituted chroman 3 is obtained by condensing substituted phenol and mesityl oxide in presence of PPA. The required carboxylic acid function has been introduced at C-4 in benzopyran ring through a novel route