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The application of Ayurvedic Bhasma in cancer treatment has garnered increasing interest due to its potential as an alternative therapeutic approach. Bhasma, a herbo-mineral formulation that consists of bioactive nanoparticles used in traditional Indian medicine, has shown promising preclinical evidence for its anticancer properties. Ayurveda, an ancient medicine system practiced in the Indian subcontinent, has successfully used various formulations to prevent or treat arbuda, which can be correlated with cancer. These formulations include Swarna Bhasma, Heerak Bhasma, Abhrak Bhasma, Manikya Bhasma, Yashada Bhasma, and many more. Using Ayurvedic medicines, the side effects of chemotherapy can be minimized, thereby increasing the life span of patients. With the advent of nanotechnology, traditional drug design and delivery are being looked upon in a completely new perspective. The anticancer activity of certain Bhasma is attributed to the presence of metallic nanoparticle content, enhancing its bioavailability and targeted action on cancer cells. In preclinical studies, some Bhasmas have demonstrated potential in inhibiting cancer cell proliferation, inducing apoptosis, and suppressing tumor growth. However, at the same time, limitations in the use of Bhasma for cancer treatment, such as the lack of standardized synthesis processes and documented scientific validation, have also been acknowledged. The multifaceted analysis presented underscores the need for rigorous research, including clinical trials, to validate the safety, efficacy, and specific applications of Bhasma in different cancer types and stages. Although the health-beneficial effects of these Bhasmas have been known for a long time, their mechanism of action is not clearly understood yet at least for some Bhasmas that have shown potential in clinical trials. Therefore, further detailed studies are needed to understand the therapeutic mode of action for different Bhasma. However, despite these limitations, the integration of Ayurvedic Bhasma into cancer treatment regimens emerges as a compelling prospect, potentially yielding synergistic effects.

Introduction: The patterns of microRNA (miRNA) expression have opened up new avenues in the search for prognostic biomarkers and potential therapeutic targets for various tumours. In oral carcinogenesis research, analysing microRNAs expressed in Oral Squamous Cell Carcinoma (OSCC) unveils a complex network of interest. miR-21 is known to be overexpressed in numerous solid tumours and is linked to the progression of malignancies in hepatocellular carcinomas, breast cancer, and colon carcinomas. Aim: To determine the impact of surgical excision on serum miR-21 expression levels in OSCC cases and to establish correlations with clinicopathological parameters. Materials and Methods: The study was an exploratory prospective observational study conducted with proper institutional ethical approval at the Cancer Research Institute (CRI), Himalayan Institute of Medical Sciences (HIMS), Jolly Grant, Dehradun, Uttarakhand, India. Fifty-six histologically confirmed OSCC cases were enrolled along with 25 healthy subjects as controls from May 2021 to June 2023. The relative fold expression change was calculated using the Livak method (2-ΔΔct). Data analysis was performed using software such as Statistical Package for Social Sciences (SPSS) version 20.0 and MS Excel. Non parametric statistical tests such as Wilcoxon signed-rank test, Mann-Whitney test, and Kruskal-Wallis test were utilised. Results: Out of 56 sample included, 28 exhibited high expression of miR-21 (p-value

Abstract Background Cancer survivors experience a decrement in health-related quality of life (HRQoL) resulting from the disease as well as adverse effects of therapy. We evaluated the HRQoL of cancer patients, stratified by primary cancer site, stage, treatment response and associated adverse events, along with its determinants. Methods Data were collected from 12,148 patients, sampled from seven purposively chosen leading cancer hospitals in India, to elicit HRQoL using the EuroQol questionnaire comprising of 5-dimensions and 5-levels (EQ-5D-5L). Multiple linear regression was used to determine the association between HRQoL and various socio-demographic as well as clinical characteristics. Results Majority outpatients (78.4%) and inpatients (81.2%) had solid cancers. The disease was found to be more prevalent among outpatients (37.5%) and inpatients (40.5%) aged 45–60 years and females (49.3–58.3%). Most patients were found to be in stage III (40–40.6%) or stage IV (29.4–37.3%) at the time of recruitment. The mean EQ-5D-5 L utility score was significantly higher among outpatients [0.630 (95% CI: 0.623, 0.637)] as compared to inpatients [0.553 (95% CI: 0.539, 0.567)]. The HRQoL decreased with advancing cancer stage among both inpatients and outpatients, respectively [stage IV: (0.516 & 0.557); stage III (0.609 & 0.689); stage II (0.677 & 0.713); stage I (0.638 & 0.748), p value

Abstract Diabetes, characterized by high blood glucose level, is a progressive metabolic disease that leads to serious health complications. One of the major pathological consequences associated with diabetes is the accumulation of highly reactive carbonyl compounds called advanced glycation end products (AGEs). Most of the AGEs are dicarbonyls and have the potential to covalently modify proteins especially at the lysine residues in a non-enzymatic fashion (a process termed as glycation) resulting in the functional impairment and/or toxic gain in function. Therefore, non-toxic small molecules that can inhibit glycation are of interest for the therapeutic intervention of diabetes. In the present communication, we have investigated the effect of organosulfurs (S-allyl cysteine, SAC and N-acetyl cysteine, NAC) that are major principal components of Allium sativa against the glycation of different proteins. We discovered that both SAC and NAC are potent anti-glycating agents. We also found that both SAC and NAC reduce ROS level and inhibit apoptosis caused by protein glycation.

Abstract This workshop report summarizes the presentations and panel discussion related to the use of physiologically based pharmacokinetic (PBPK) modeling approaches for food effect assessment, collected from Session 2 of Day 2 of the workshop titled “Regulatory Utility of Mechanistic Modeling to Support Alternative Bioequivalence Approaches.” The US Food and Drug Administration in collaboration with the Center for Research on Complex Generics organized this workshop where this particular session titled “Oral PBPK for Evaluating the Impact of Food on BE” presented successful cases of PBPK modeling approaches for food effect assessment. Recently, PBPK modeling has started to gain popularity among academia, industries, and regulatory agencies for its potential utility during bioavailability (BA) and/or bioequivalence (BE) studies of new and generic drug products to assess the impact of food on BA/BE. Considering the promises of PBPK modeling in generic drug development, the aim of this workshop session was to facilitate knowledge sharing among academia, industries, and regulatory agencies to understand the knowledge gap and guide the path forward. This report collects and summarizes the information presented and discussed during this session to disseminate the information into a broader audience for further advancement in this area.

Abstract Breast cancer (BC)‐related mortality primarily results from metastatic colonization of disseminated cells. Actin polymerization plays an important role in driving post‐extravasation metastatic outgrowth of tumor cells. This study examines the role of myocardin‐related transcription factor (MRTF)/serum‐response (SRF), a transcription system well known for regulation of cytoskeletal genes, in metastatic colonization of BC cells. We demonstrated that co‐depletion of MRTF isoforms (MRTF‐A and MRTF‐B) dramatically impairs single‐cell outgrowth ability of BC cells as well as retards growth progression of pre‐established BC cell colonies in three‐dimensional (3D) cultures. Conversely, overexpression of MRTF‐A promotes initiation and progression of tumor‐cell outgrowth in vitro, primary tumor formation, and metastatic outgrowth of seeded BC cells in vivo, and these changes can be dramatically blocked by molecular disruption of MRTF‐A's interaction with SRF. Correlated with the outgrowth phenotypes, we further demonstrate MRTF's ability to augment the intrinsic cellular ability to polymerize actin and formation of F‐actin‐based protrusive structures requiring SRF's interaction. Pharmacological proof‐of‐concept studies show that small molecules capable of interfering with MRTF/SRF signaling robustly suppresses single‐cell outgrowth and progression of pre‐established outgrowth of BC cells in vitro as well as experimental metastatic burden of BC cells in vivo. Based on these data, we conclude that MRTF activity potentiates metastatic colonization of BC cells and therefore, targeting MRTF may be a promising strategy to diminish metastatic burden in BC.

Opportunistic behavior of commensal bacteria during severe infection, especially of the intestine is always considered as a predisposing threat for the severely ill patient admitted to hospitals. A descriptive-analytical case-control study was carried out to detect the prevalence and risk factor analysis of fecal carriage of Carbapenem-resistant Enterobacteriaceae. Patients having fecal carriage of Carbapenem-resistant Enterobacteriaceae were considered as cases and patients who were without Carbapenem-resistant Enterobacteriaceae were taken as the control in a proportion of 1:4. Carbapenem-resistant Enterobacteriaceae (CRE) was confirmed by both conventional as well as molecular methods. Methods such as Combined Disk Test, mCIMtest, and RAPIDEC CarbaNP Test were used for phenotypic identification of CRE, Whereas Real-Time (RT)-PCR was used for the detection of bla-gene encoded for CRE (blaNDM1, blaVIM, blaKPC, blaIMP, and blaOXA48). All patients belonging to medicine wards were included in the study. we screened 436 patients during the study and found 160 patients suitable for our study, out of which 32 (20%) were cases and 128 (80%) were controls. We found a total number of 25 genes out of 16 isolates, where NDM 1 was identified in maximum numbers followed by KPC &VIM. Standard statistical analyses such as chi-squire and odd ratios were conducted to determine the risk factor of different variables. Stepwise multiple logistic regressions were carried out, where we found, that transfer from other wards to medicine ward, use of nebulizer and intravenous catheter, and use of multiple antibiotics were still statistically significant. Implementation of Multi-modal colonization prevention and control is the need for the present situation throughout the world.

Abstract In this work, we report, the synthesis of Boron and Sulfur co-doped graphene quantum dots (BS-GQDs) and its applicability as a label-free fluorescence sensing probe for the highly sensitive and selective detection of dopamine (DA). Upon addition of DA, the fluorescence intensity of BS-GQDs were effectively quenched over a wide concentration range of DA (0–340 μM) with an ultra-low detection limit of 3.6 μM. The quenching mechanism involved photoinduced electron transfer process from BS-GQDs to dopamine-quinone, produced by the oxidization of DA under alkaline conditions. The proposed sensing mechanism was probed using a detailed study of UV–Vis absorbance, steady state and time resolved fluorescence spectroscopy. The high selectivity of the fluorescent sensor towards DA is established. Our study opens up the possibility of designing a low-cost biosensor which will be suitable for detecting DA in real samples.

Background: Adenocarcinoma is a more common type of Non-small cell lung cancer (NSCLC). Lung cancer showed a statistically significant increment in the Kamrup Urban district of Assam, Tripura, Sikkim, and Manipur of India. The goal of our pilot study is to identify non-invasive microbial biomarkers to detect lung adenocarcinoma (LAC). Material and Methods: DNA extraction from saliva samples of five LAC patients and five healthy controls was performed by Qiagen DNeasy blood and tissue kit using Lysozyme (3mg/ml) treatment. 16S rRNA genes of distinct regions (V3-V4) were amplified from saliva DNA by PCR. Paired-end sequencing targeting the V3-V4 region of the 16S rRNA gene has been performed on the Illumina MiSeq platform. Raw sequences were analyzed using the QIIME(Quantitative Insights Into Microbial Ecology) software package. Results: Our preliminary results showed that Rothia mucilaginosa, Veillonella dispar, Prevotella melaninogenica, Prevotella pallens, Prevotella copri, Haemophilus parainfluenzae, Neisseria bacilliformis and Aggregatibacter segnis were significantly elevated in saliva of LAC which may serve as potential non-invasive biomarkers for LAC detection. Functional prediction analysis showed that bacterial genes involved in glycosyltransferase, peptidases, amino sugar, and nucleotide sugar metabolism, starch and sucrose metabolism were significantly enriched in LAC. Conclusion: These salivary bacteria may contribute to the development of LAC by increasing expression of glycosyltransferase and peptidases. However to understand their role in pathobiology, studies are required to perform in large cohort.

Background: Cissampelos pareira L. (Menispermaceae) has been used in Indian traditional medicine for a variety of human ailments including diabetes mellitus. Although its anti-hyperglycemic activity has been validated by previous studies, a detailed mechanism of action and the responsible components are still unknown. Purpose: The present study aimed to evaluate the antidiabetic effect of aqueous-ethanolic extract of C. pareira roots in streptozotocin-nicotinamide (STZ-NAM)-induced diabetic rats via targeting SGLT2 inhibition. Methods: In vitro α-amylase and α-glucosidase inhibitory assays were conducted using Epoch Microplate Spectrophotometer. A-498 cells viability assay and SGLT2 protein expression study were conducted using MTT assay and western blot respectively. STZ-NAM-induced diabetic rats were used as a model to evaluate the antidiabetic effect of the extract. Selected bioactive compounds reported earlier from the plant were studied for their in silico SGLT2 inhibitory activity. Results: The extract showed α-amylase and α-glucosidase inhibitory effects with IC50 values of 18.0 ± 1.01 and 4.87±0.54 mg/mL, respectively. A-498 cells viability assay showed its CC50 value of 0.8 mg/mL. The extract showed a notable effect on SGLT2 protein expression. The in vivo study revealed that the extract significantly (p

Inflammation is a multifaceted set of cellular communications generated against foreign infection, toxic influence or autoimmune injury. The present study investigates the anti-inflammatory effect of wheatgrass extract against the harmful impact of lipopolysaccharide (LPS) in macrophage cells, i.e., RAW 264.7 cells. Our results indicate that 5- and 7- days old wheatgrass extracts inhibit the LPS-stimulated production of nitric oxide. Moreover, wheatgrass extract significantly downregulates the mRNA expression of LPS-stimulated various pro-inflammatory markers, tumor necrosis factor-α, interleukin-6, interleukin-1β, AP-1 and also iNOS-2 and COX-2. Our flow cytometry analyses confirmed that wheatgrass extract prevents the generation of reactive oxygen species in LPS-stimulated RAW 264.7 cells, thus arresting oxidative stress in cells. The immunoblot analyses also confirmed a significant reduction in the expression of inflammatory proteins, namely, iNOS-2 and COX-2, in wheatgrass extract-treated cells, compared to LPS-stimulated condition. The NF-κB transactivation assay further confirmed the inhibitory effect of wheatgrass extracts on the LPS-stimulated expression of NF-κB. Molecular docking based studies showed the plausible binding of two significant wheatgrass constituents, i.e., apigenin and myo-inositol with COX-2 protein, with binding energies of −10.59 kcal/mol and −7.88 kcal/mol, respectively. Based on the above results, wheatgrass may be considered as a potential therapeutic candidate for preventing inflammation.

The processing of sequential and temporal data is essential to computer vision and speech recognition, two of the most common applications of artificial intelligence (AI). Reservoir computing (RC) is a branch of AI that offers a highly efficient framework for processing temporal inputs at a low training cost compared to conventional Recurrent Neural Networks (RNNs). However, despite extensive effort, two-terminal memristor-based reservoirs have, until now, been implemented to process sequential data by reading their conductance states only once, at the end of the entire sequence. This method reduces the dimensionality, related to the number of signals from the reservoir and thereby lowers the overall performance of reservoir systems. Higher dimensionality facilitates the separation of originally inseparable inputs by reading out from a larger set of spatiotemporal features of inputs. Moreover, memristor-based reservoirs either use multiple pulse rates, fast or slow read (immediately or with a delay introduced after the end of the sequence), or excitatory pulses to enhance the dimensionality of reservoir states. This adds to the complexity of the reservoir system and reduces power efficiency. In this paper, we demonstrate the first reservoir computing system based on a dynamic three terminal solid electrolyte ZnO/Ta2O5 Thin-film Transistor fabricated at less than 100°C. The inherent nonlinearity and dynamic memory of the device lead to a rich separation property of reservoir states that results in, to our knowledge, the highest accuracy of 94.44%, using electronic charge-based system, for the classification of hand-written digits. This improvement is attributed to an increase in the dimensionality of the reservoir by reading the reservoir states after each pulse rather than at the end of the sequence. The third terminal enables a read operation in the off state, that is when no pulse is applied at the gate terminal, via a small read pulse at the drain. This fundamentally allows multiple read operations without increasing energy consumption, which is not possible in the conventional two-terminal memristor counterpart. Further, we have also shown that devices do not saturate even after multiple write pulses which demonstrates the device’s ability to process longer sequences.

Cancer management presents multifarious problems. Triple negative breast cancer (TNBC) is associated with inaccurate prognosis and limited chemotherapeutic options. Betulinic acid (BA) prevents angiogenesis and causes apoptosis of TNBC cells. NIH recommends BA for rapid access in cancer chemotherapy because of its cell-specific toxicity. BA however faces major challenges in therapeutic practices due to its limited solubility and cellular entree. We report lactoferrin (Lf) attached BA nanoparticles (Lf-BAnp) for rapid delivery in triple negative breast (MDA-MB-231) and laryngeal (HEp-2) cancer cell types. Lf association was confirmed by SDS-PAGE and FT-IR analysis. Average hydrodynamic size of Lf-BAnp was 147.7 ± 6.20 nm with ζ potential of −28.51 ± 3.52 mV. BA entrapment efficiency was 75.38 ± 2.70% and the release mechanism followed non-fickian pattern. Impact of Lf-BAnp on cell cycle and cytotoxicity of triple negative breast cancer and its metastatic site laryngeal cancer cell lines were analyzed. Lf-BAnp demonstrated strong anti-proliferative and cytotoxic effects, along with increased sub-G1 population and reduced number of cells in G1 and G2/M phases of the cell cycle, confirming reduced cell proliferation and significant cell death. Speedy intracellular entry of Lf-BAnp occurred within 30 min. Lf-BAnp design was explored for the first time as safer chemotherapeutic arsenals against complex TNBC conditions.

Boerhavia diffusa is a perennial herb belonging to the Nyctaginaceae family. This plant has been widely used in Indian traditional medicinal system to cure several human ailments. However, traditional use of this plant in the treatment and management of wounds has not been validated by any comprehensive scientific study. The present study was aimed to explore the in vitro and in vivo wound healing potential of methanol extract (ME) and chloroform extract (CE) from B. diffusa leaf and subsequent identification of the bioactive metabolites, which might be responsible for enhancement of wound healing property of the extracts.The study included in vitro cell viability and wound scratch assays as well as in vivo excision wound assays in rat models. Both ME and CE were analysed for their antioxidant properties and phenolics content. The gas chromatography-mass spectrometry analyses were performed for identification of bioactive metabolites present in the ME and CE. ME of B. diffusa leaf significantly enhanced viability and migration of human keratinocyte cells (HaCaT) as compared to the untreated and CE-treated groups. The topical application of ME of B. diffusa leaf in excision wound model significantly decreased the wound area by the 14th day (91%) as compared to control (22%) (p

Background: Chimaphila umbellata (CU) is a small perennial plant whose roots and leaves are used in the preparation of homeopathic medicines. In this study, the anti-proliferative and apoptotic effects of CU extract, obtained from its homeopathic mother tincture, were evaluated in human breast cancer cell lines. Methods: MTT assay was used to evaluate the dose- and time-dependent cytotoxicity of the extract in MCF-7 and HEK293 cells. The anti-proliferative effect of the extract was evaluated using the clonogenic and wound healing assays. The anti-angiogenic activity of the drug was evaluated using the chick chorioallantoic membrane assay. The mode of cell death was analyzed using Annexin V and PI staining assays through flow cytometry. In addition, the expression patterns of associated genes were evaluated using immunoblot analysis. Results: CU extracts exerted anti-proliferative effect in breast cancer cell line, i.e., MCF-7 cells, by inhibiting their growth and migration. The extract also demonstrated significant anti-angiogenic ability, limiting the de-novo blood vessel growth and development in chick embryos. The extract was found to increase caspase-independent necroptosis by involving RIP1/RIP3 kinases and MLKL proteins. This finding was further confirmed by using NEC-1 (an inhibitor of necroptosis), which significantly abolished the CU extract-induced necroptotic effect. Conclusions: The CU extract exhibits great potential in preventing breast cancer and thus warrants further investigations in vivo.

Triclosan (TCS) is widely used in cosmetics and healthcare industry as a broad-spectrum antibacterial agent. The lipophilic property and persistent nature of TCS has led to severe health issues. In the present study, we have evaluated the neuroinflammatory effect of TCS on mouse Neuro-2a cells. Initial investigation confirmed a dose-dependent loss in viability and morphology of cells in presence of TCS. The transcription and translation studies confirmed a downregulation in the expression of autophagy markers in Neuro-2a cells. The confocal microscopy study revealed that the abrogated autophagy in TCS-treated cells occurred due to loss in the autophagy flux and prevention in the lipidation of autophagosome bilayer. The fluorescence microscopy also confirmed a loss in the formation of autophagolysosomes in neuronal cells with increasing TCS concentrations. TCS treatment resulted in loss of mitochondrial integrity in cells as evidenced by a decrease in mitochondrial membrane potential in JC-1 staining. Further, the transcriptional and translational studies confirmed the activation of TNF-α signaling pathway in TCS-treated cells thus enhancing the expression of RIPK1, RIPK3 and MLKL proteins and their phosphorylated forms. TCS was also found to increase the tau protein pathogenesis in Neuro-2a cells, which alludes to the development of tau-associated neurodegeneration. Altogether, this study confirms the neuroinflammatory actions of TCS in Neuro-2a cells involving a TNF-α-induced MLKL-mediated signaling.

The emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis calls for an immediate search for novel treatment strategies. Recently, BlaC, the principal beta-lactamase of Mycobacterium tuberculosis, was recognized as a potential therapeutic target. BlaC belongs to Ambler class A, which is generally susceptible to the beta-lactamase inhibitors currently used in clinics: tazobactam, sulbactam, and clavulanate. Alterations at Ser130 in conserved SDN loop confer resistance to mechanism-based inhibitors (MBIs) commonly observed in various clinical isolates. The absence of clinical evidence of S130G conversion in M. tuberculosis draws our attention to build laboratory mutants of S130G and S130A of BlaC. The study involving steady state, inhibition kinetics, and fluorescence microscopy shows the emergence of resistance against MBIs to the mutants expressing S130G and S130A. To understand the molecular reasoning behind the unavailability of such mutation in real life, we have used circular dichroism (CD) spectroscopy, differential scanning calorimetry (DSC), molecular dynamics (MD) simulation, and stability-based enzyme activity to compare the stability and dynamic behaviors of native and S130G/A mutant form of BlaC. A significant decrease in melting temperature (BlaC TM 60°C, S130A TM 50°C, and S130G TM 45°C), kinetic instability at higher temperature, and comparative dynamic instability correlate the fact that resistance to beta-lactam/beta-lactamase inhibitor combinations will likely not arise from the structural alteration of BlaC, therefore establishing confidence that this therapeutic modality can be potentially applied as a part of a successful treatment regimen against M. tuberculosis.

India holds a significant rank in production and consumption of the age old protein rich crop Lentil with only one cultivated species and a large number of phenotypically similar cultivars. The need for a reliable and cost effective method of genetic characterization to unravel differences within the Lentil cultivars was felt. The present paper adopted EMA based chromosome preparation followed by staining with two contrasting fluorochromes dyes CMA and DAPI that bind directly to GC and AT rich heterochromatic segments on chromosomes. Analysis of fluorochrome banding pattern furnished a comparative account of genetic diversity within the cultivars that could not be achieved by traditional karyotyping. The marker pair of nucleolar chromosomes (4th and 3rd, majorly) occupied a pivotal position to intensify differences between cultivars in terms of banding patterns around secondary constrictions, suggestive of yet unknown variation in heterochromatin composition. Our study has strengthened genetic background and relationships of Lentil cultivars. We observed certain types of unusual fluorochrome bands that put forward the exclusivity of Indian germplasm and have questioned the mainstream heterochromatin elements of plant chromosomes captured by CMA-DAPI stains. The comprehensive fluorescent karyotypes of 30 L. culinaris cultivars prepared for the first time, serve as an archetype for the benefit of future breeding programmes in any Indian crop.

The human brain is a well-connected, intricate network of neurons and supporting glial cells. Neurodegenerative diseases arise as a consequence of extensive loss of neuronal cells leading to disruption of their natural structure and function. On the contrary, rapid proliferation and growth of glial as well as neuronal cells account for the occurrence of malignancy in brain. In both cases, the molecular microenvironment holds pivotal importance in the progression of the disease. MicroRNAs (miRNA) are one of the major components of the molecular microenvironment. miRNAs are small, noncoding RNAs that control gene expression post-transcriptionally. As compared to other tissues, the brain expresses a substantially high number of miRNAs. In the early stage of neurodegeneration, miRNA expression upregulates, while in oncogenesis, miRNA expression is gradually lost. Neurodegeneration and brain cancer is presumed to be under the influence of identical pathways of cell proliferation, differentiation and cell death which are tightly regulated by miRNAs. It has been confirmed experimentally that miRNA expression can be regulated by nutraceuticals - macronutrients, micronutrients or natural products derived from food; thereby making dietary supplements immensely significant for targeting miRNAs having altered expression patterns during neurodegeneration or oncogenesis. In this review, we will discuss in detail, about the common miRNAs involved in brain cancers and neurodegenerative diseases along with the comprehensive list of miRNAs involved separately in both pathological conditions. We will also discuss the role of nutraceuticals in the regulation of those miRNAs which are involved in both of these pathological conditions.

In this study, we screened some flavonoids for their anti-obesity and antidiabetic activities. We report that all tested flavonoids were effective in inhibiting the differentiation of pre-adipocytes to mature adipocytes. Additionally, all tested flavonoids were found to be effective in significantly up-regulating GLUT4 expression and glucose uptake, out of which, kaempferol and quercetin showed the best activities. Myricetin and rutin treatment exhibited increased expression of p-Akt whereas, kaempferol and quercetin showed a significant increase in the expression of AMPK phosphorylation (Thr172), indicative of the role of AMPK in inducing glucose uptake. In vivo (HFD-STZ induced diabetic mice), all flavonoids showed a marked reduction in serum triglyceride, cholesterol, LDL and non-esterified fatty acid (NEFA) levels in treated mice. Moreover, blood glucose level, glucose tolerance and insulin sensitivity were significantly improved in response to flavonoids treatment. The present study thus suggested that among above-selected flavonoids kaempferol had most potent antidiabetic and anti-obesity activities.

Abstract Background Lignocellulose biomass such as agricultural residues is increasingly important for biofuel production. Using agricultural residues like rice straw for biofuel production has dual purposes of utilizing the huge waste generated. The abundant availability and high polysaccharide contents are the main reason for biofuel production. However, the use is limited due to the reluctant nature of lignin in the biomass. Therefore, sodium hydroxide was used for solubilizing lignin and preserving the polysaccharides. Results About 71.29% of lignin (maximum amount of lignin) was removed after 7% sodium hydroxide (NaOH) pretreatment followed by 3% pretreatment (about 67.13%). Also, maximum cellulose (about 71.33%) was preserved after 7% NaOH pretreatment. Results of reducing sugars obtained by spectrophotometric analysis (3,5-dinitrosalycilic acid method) of pretreated rice straw show about 88.27% conversion (753 mg/g) after the 13th day of hydrolysis by bacteria isolated from a termite. FE-SEM, XRD, FTIR, and TGA analyses show a significant amount of lignin was removed which helps in releasing cellulose tangled in lignin. Conclusion Rice straw pretreatment at 7% NaOH and hydrolysis by Bacillus sp. BMP01 achieved the release of a high yield of fermentable sugars that increased the yield of bioethanol. This study demonstrates the potential of alkali pretreatment coupled with microbial hydrolysis for efficient bioethanol production from agricultural residues like rice straw.

Abstract Background The depletion of fossil fuel and its huge environmental problem are currently a concern for a scientific community in the area of energy engineering. This opened research opportunities for searching alternate renewable energy sources especially biofuel production from lignocellulose biomass resources. The main objective of this paper is to review the delignification and hydrolysis capabilities of microorganisms (bacteria and fungi). Results Currently, different types of lignocellulose biomass pretreatment technologies are available. All of the technologies are either in lab scale or in pilot scale. Among the pretreatment technologies, biological pretreatments attract many attentions because of their eco-friendly advantages, performed at a mild temperature and do not produce inhibitory compounds during the pretreatment process. Industrial-scale biofuel production using biological delignification and hydrolysis process is still at lab scale, and intensive research works are required. The cost of biofuel production from lignocellulose biomass is currently expensive. Conclusion Searching for the best microbial strains having efficient lignin-degrading and polysaccharide-hydrolyzing capabilities is vital to realize industrial-scale biofuel production from lignocellulose biomass. Process optimization along with genetic engineering of microorganisms is seen as a potential for biofuel production from lignocellulose biomass.

Green synthesis of gold-zinc oxide (Au-ZnO) nanocomposite was successfully attempted under organic solvent–free conditions at room temperature. Prolonged stirring of the reaction mixture introduced crystallinity in the ZnO phase of Au-ZnO nanocomposites. Luminescence properties were observed in these crystalline Au-ZnO nanocomposites due to in situ embedding of gold nanoparticles (AuNP) of 5–6 nm diameter on the surface. This efficient strategy involved the reduction of Au(III) by Zn(0) powder in aqueous medium, where sodium citrate (NaCt) was the stabilizing agent. Reaction time and variation of reagent concentrations were investigated to control the Au:Zn ratio within the nanocomposites. The reaction with the least amount of NaCt for a long duration resulted in Au-ZnO/Zn(OH)2 nanocomposite. X-ray photoelectron spectroscopy (XPS) confirmed the formation of Zn(OH)2 and ZnO in the same nanocomposite. These nanocomposites were reconnoitered as bioimaging materials in human cells and applied for visible light–induced photodegradation of rhodamine-B dye.

Tumor-derived cachectic factors such as proinflammatory cytokines and neuromodulators not only affect skeletal muscle but also affect other organs, including the heart, in the form of cardiac muscle atrophy, fibrosis, and eventual cardiac dysfunction, resulting in poor quality of life and reduced survival. This article reviews the holistic approaches of existing diagnostic, pathophysiological, and multimodal therapeutic interventions targeting the molecular mechanisms that are responsible for cancer-induced cardiac cachexia. The major drivers of cardiac muscle wasting in cancer patients are autophagy activation by the cytokine-NFkB, TGF β-SMAD3, and angiotensin II-SOCE-STIM-Ca2+ pathways. A lack of diagnostic markers and standard treatment protocols hinder the early diagnosis of cardiac dysfunction and the initiation of preventive measures. However, some novel therapeutic strategies, including the use of Withaferin A, have shown promising results in experimental models, but Withaferin A’s effectiveness in human remains to be verified. The combined efforts of cardiologists and oncologists would help to identify cost effective and feasible solutions to restore cardiac function and to increase the survival potential of cancer patients.

This paper aims to introduce the notions of a generalized weakly symmetric Kenmotsu manifolds and a generalized weakly Ricci-symmetric Kenmotsu manifolds. The existence of a generalized weakly symmetric Kenmotsu manifold is ensured by a non-trivial example.

Kinases function as regulators of many cellular processes such as cell migration. These enzymes typically phosphorylate target motif sequences. Mass spec or phospho-specific antibody detection can be used to determine whether a kinase can phosphorylate proteins of interest, however, mass spec can be expensive and phospho-antibodies for the protein of interest may not exist. In this protocol, we will describe an in vitro kinase assay to provide a preliminary readout on whether a protein of interest may be phosphorylated by PKA. Our protein of interest is purified after expression in bacteria and treated with recombinant PKA from bovine heart. Protein is then extracted and a western blot is performed using a phospho-specific antibody for PKA’s target motif. This will allow us to quickly determine if it is possible for PKA to phosphorylate our protein of interest.

Cell migration is a fundamental cellular process that plays a crucial role in many physioglogical and pathological processes such as wound healing or cancer metastasis. Many assays have been developed to examine cell migration, such as the wound healing or scratch assay, Boyden Chamber or transwell assay, and the method we will describe here, single cell migration assay. In this assay, cells are plated sparsely on a collagen coated plate and live cell imaging is performed over a period of 2 h at 1 frame per minute. After imaging is completed, cells are tracked manually using ImageJ by tracking movement of the centroid of the cell. These data points are then exported and overall distance travelled from frame to frame is determined and divided by total time imaged to determine speed of the cell. This method provides a quick way to examine effect of cellular manipulation on cell migration before proceeding to perform more complex assays.

BackgroundThe outbreak of the novel coronavirus disease COVID-19, caused by the SARS-CoV-2 virus has spread rapidly around the globe during the past 3 months. As the virus infected cases and mortality rate of this disease is increasing exponentially, scientists and researchers all over the world are relentlessly working to understand this new virus along with possible treatment regimens by discovering active therapeutic agents and vaccines. So, there is an urgent requirement of new and effective medications that can treat the disease caused by SARS-CoV-2.Methods and findingsWe perform the study of drugs that are already available in the market and being used for other diseases to accelerate clinical recovery, in other words repurposing of existing drugs. The vast complexity in drug design and protocols regarding clinical trials often prohibit developing various new drug combinations for this epidemic disease in a limited time. Recently, remarkable improvements in computational power coupled with advancements in Machine Learning (ML) technology have been utilized to revolutionize the drug development process. Consequently, a detailed study using ML for the repurposing of therapeutic agents is urgently required. Here, we report the ML model based on the Naive Bayes algorithm, which has an accuracy of around 73% to predict the drugs that could be used for the treatment of COVID-19. Our study predicts around ten FDA approved commercial drugs that can be used for repurposing. Among all, we found that 3 of the drugs fulfils the criterions well among which the antiretroviral drug Amprenavir (DrugBank ID-DB00701) would probably be the most effective drug based on the selected criterions.ConclusionsOur study can help clinical scientists in being more selective in identifying and testing the therapeutic agents for COVID-19 treatment. The ML based approach for drug discovery as reported here can be a futuristic smart drug designing strategy for community applications.

Infertility creates an immense impact on the psychosocial wellbeing of affected couples, leading to poor quality of life. Infertility is now considered to be a global health issue affecting approximately 15% of couples worldwide. It may arise from factors related to the male (30%), including varicocele, undescended testes, testicular cancer, and azoospermia; the female (30%), including premature ovarian failure and uterine disorders; or both partners (30%). With the recent advancement in assisted reproduction technology (ART), many affected couples (80%) could find a solution. However, a substantial number of couples cannot conceive even after ART. Stem cells are now increasingly being investigated as promising alternative therapeutics in translational research of regenerative medicine. Tremendous headway has been made to understand the biology and function of stem cells. Considering the minimum ethical concern and easily available abundant resources, extensive research is being conducted on induced pluripotent stem cells (iPSCs) and mesenchymal stem cells (MSC) for their potential application in reproductive medicine, especially in cases of infertility resulting from azoospermia and premature ovarian insufficiency. However, most of these investigations have been carried out in animal models. Evolutionary divergence observed in pluripotency among animals and humans requires caution when extrapolating the data obtained from murine models to safely apply them to clinical applications in humans. Hence, more clinical trials based on larger populations need to be carried out to investigate the relevance of stem cell therapy, including its safety and efficacy, in translational infertility medicine.

Information retrieval systems are generally used to find documents that are most appropriate according to some query that comes dynamically from users. In this paper a novel Fuzzy Document based Information Retrieval Model (FDIRM) is proposed for the purpose of Stock Market Index forecasting. The novelty of proposed approach is a modified tf-idf scoring scheme to predict the future trend of the stock market index. The contribution of this paper has two dimensions, 1) In the proposed system the simple time series is converted to an enriched fuzzy linguistic time series with a unique approach of incorporating market sentiment related information along with the price and 2) A unique approach is followed while modeling the information retrieval (IR) system which converts a simple IR system into a forecasting system. From the performance comparison of FDIRM with standard benchmark models it can be affirmed that the proposed model has a potential of becoming a good forecasting model. The stock market data provided by Standard & Poor’s CRISIL NSE Index 50 (CNX NIFTY-50 index) of National Stock Exchange of India (NSE) is used to experiment and validate the proposed model. The authentic data for validation and experimentation is obtained from http://www.nseindia.com which is the official website of NSE. A java program is under construction to implement the model in real-time with graphical users’ interface.

Background: Antihypertensive drug therapies have been reported to be associated with new onset of type 2 diabetes mellitus in some hypertensive patients after prolonged use. Angiotensin converting enzyme (ACE) gene has been found to affect essential hypertension, response of antihypertensive therapies, and glycemic disturbances. Therefore, ACE gene I/D polymorphism may be associated with risk of new onset of type 2 diabetes via metabolic disturbances, glycemic dysregulation, and insulin resistance. Aim: To assess the correlation between ACE gene I/D polymorphism and glycemic disturbance under influence of diuretic and other antihypertensive drug therapies. Materials and methods: We recruited 270 normotensive patients as control (150 men and 120 women), 270 hypertensive patients (95 men and 175 women), and 240 hypertensive with new onset of diabetes patients (80 men and 160 women). All samples were genotyped for ACE gene polymorphic alleles and relationship between different genotypes and anthropometric and clinical parameters along with drug therapies was established and analyzed. Results: Baseline clinical (systolic blood pressure, diastolic blood pressure, and fasting blood glucose level) and anthropometric parameters (height, weight, waist circumference, hip circumference, waist-hip ratio, and body mass index) of study populations were found highly statistically significant ( P

In this paper, a new technique to attain a tunable parametric amplifier for application in the communication wavelength, based on near-zero ultraflat dispersion with PCF, has been explored. The chromatic dispersion profile and the corresponding zero dispersion wavelength (ZDW) of the optimized PCF can be well tuned to provide a wide gain spectrum in the communication wavelength just by changing the temperature of the fiber. A detailed investigation reveals that the fiber retains its near-zero ultraflat nature when the temperature is increased by 2.50 °C from room temperature. While changing the temperature, the ZDWs can be well tuned, giving rise to a gain region of hundreds of nanometers around the pumping wavelength by changing the temperature of the fiber externally.

Cryptococcosis is an emerging and recalcitrant systemic infection occurring in immunocompromised patients. This invasive fungal infection is difficult to treat due to the ability of Cryptococcus neoformans and Cryptococcus laurentii to form biofilms resistant to standard antifungal treatment. The toxicity concern of these drugs has stimulated the search for natural therapeutic alternatives. Essential oil and their active components (EO-ACs) have shown to possess the variety of biological and pharmacological properties. In the present investigation the effect of six (EO-ACs) sourced from Oregano oil (Carvacrol), Cinnamon oil (Cinnamaldehyde), Lemongrass oil (Citral), Clove oil (Eugenol), Peppermint oil (Menthol) and Thyme oil (thymol) against three infectious forms; planktonic cells, biofilm formation and preformed biofilm of C. neoformans and C. laurentii were evaluated as compared to standard drugs. Data showed that antibiofilm activity of the tested EO-ACs were in the order: thymol>carvacrol>citral>eugenol=cinnamaldehyde>menthol respectively. The three most potent EO-ACs, thymol, carvacrol, and citral showed excellent antibiofilm activity at a much lower concentration against C. laurentii in comparison to C. neoformans indicating the resistant nature of the latter. Effect of the potent EO-ACs on the biofilm morphology was visualized using scanning electron microscopy (SEM) and confocal laser scanning microscopy (CLSM), which revealed the absence of extracellular polymeric matrix (EPM), reduction in cellular density and alteration in the surface morphology of biofilm cells. Further, to realize the efficacy of the EO-ACs in terms of human safety, cytotoxicity assays and co-culture model were evaluated. Thymol and carvacrol as compared to citral were the most efficient in terms of human safety in keratinocyte- Cryptococcus sp. co-culture infection model suggesting that these two can be further exploited as cost-effective and non-toxic anti-cryptococcal drugs.

OBJECTIVE:Dynamic regulation of actin cytoskeleton is at the heart of all actin-based cellular events. In this study, we sought to identify novel post-translational modifications of Profilin-1 (Pfn1), an important regulator of actin polymerization in cells. METHODOLOGY:We performed in vitro protein kinase assay followed by mass-spectrometry to identify Protein Kinase A (PKA) phosphorylation sites of Pfn1. By two-dimensional gel electrophoresis (2D-GE) analysis, we further examined the changes in the isoelectric profile of ectopically expressed Pfn1 in HEK-293 cells in response to forskolin (FSK), an activator of cAMP/PKA pathway. Finally, we combined molecular dynamics simulations (MDS), GST pull-down assay and F-actin analyses of mammalian cells expressing site-specific phosphomimetic variants of Pfn1 to predict the potential consequences of phosphorylation of Pfn1. RESULTS AND SIGNIFICANCE:We identified several PKA phosphorylation sites of Pfn1 including Threonine 89 (T89), a novel site. Consistent with PKA's ability to phosphorylate Pfn1 in vitro, FSK stimulation increased the pool of the most negatively charged form of Pfn1 in HEK-293 cells which can be attenuated by PKA inhibitor H89. MDS predicted that T89 phosphorylation destabilizes an intramolecular interaction of Pfn1, potentially increasing its affinity for actin. The T89D phosphomimetic mutation of Pfn1 elicits several changes that are hallmarks of proteins folded into alternative three-dimensional conformations including detergent insolubility, protein aggregation and accelerated proteolysis, suggesting that T89 is a structurally important residue of Pfn1. Expression of T89D-Pfn1 induces actin:T89D-Pfn1 co-clusters and dramatically reduces overall actin polymerization in cells, indicating an actin-sequestering action of T89D-Pfn1. Finally, rendering T89 non-phosphorylatable causes a positive charge shift in the isoelectric profile of Pfn1 in a 2D gel electrophoresis analysis of cell extracts, a finding that is consistent with phosphorylation of a certain pool of intracellular Pfn1 on the T89 residue. In summary, we propose that T89 phosphorylation could have major functional consequences on Pfn1. This study paves the way for further investigation of the potential role of Pfn1 phosphorylation in PKA-mediated regulation of actin-dependent biological processes.

The availability of robust superhydrophobic materials with the ability to withstand harsh environments are in high demand for many applications. In this study, we have presented a simple method to fabricate superhydrophobic materials from TiO2 nanotube arrays (TNTAs) and investigated the resilience of the materials when they are subjected to harsh conditions such as intense cavitation upon ultrasonication, corrosion in saline water, water-jet impact, and abrasion. The TNTAs were prepared by anodization of Ti foil in buffered aqueous electrolyte containing fluoride ions. The hydrophilic TNTAs were functionalized with octadecylphosphonic acid (ODPA) or 1H, 1H′, 2H, 2H′-perfluorodecyl phosphonic acid (PFDPA) to form a self-assembled monolayer on the TNTA surface to produce superhydrophobic ODPA@TNTA or PFDPA@TNTA surfaces. The superhydrophobic ODPA@TNTA and PFDPA@TNTA have contact angles of 156.0° ± 1.5° and 168° ± 1.5°, and contact angle hysteresis of 3.0° and 0.8°, respectively. The superhydrophobic ODPA@TNTA and PFDPA@TNTA were subjected to ultrasonication, corrosion in saline water, and water-jet impact and abrasion, and the resilience of the systems was characterized by electrochemical impedance spectroscopy (EIS), contact angle (CA) measurements, diffuse reflectance Fourier transform infrared spectroscopy (DRIFTS), and field-emission scanning electron microscopy (FESEM). The results presented here show that superhydrophobic ODPA@TNTA and PFDPA@TNTA are robust and resilient under the harsh conditions studied in this work, and indicate the potential of these materials to be deployed in practical applications.

A method is proposed for the rapid measurement of translational diffusion coefficient by employing the unique multiphase flow of perfectly miscible incompressible fluids in microchannels. The molecule of interest is injected, as a bolus or continuously, into the middle phase of a three phase flow system. Subsequently, the phase or stream is depleted of molecule by diffusion into the adjacent streams through the common interface. By monitoring the elution profile of the molecule, one may obtain estimates of the diffusion coefficient under fixed experimental conditions. Transport of molecule in the microchannel is described by a transient convection-diffusion-dispersion model. Analytical and numerical solutions are provided to illustrate the change of elution profile with stream velocity and other design parameters. The diffusion coefficient is estimated from a graphical plot. It is shown that diffusion coefficient may be measured without prior knowledge of dispersion. Experimental data is presented for the proteins, fibrinogen and insulin. A number of advantages over the T-sensor and Taylor-Aris methods are highlighted.

Trans-3,5-dimethoxy-4'-hydroxystilbene (PTER), a natural dimethylated analog of resveratrol, preferentially induces certain cancer cells to undergo apoptosis and could thus have a role in cancer chemoprevention. Peroxisome proliferator-activated receptor γ (PPARγ), a member of the nuclear receptor superfamily, is a ligand-dependent transcription factor whose activation results in growth arrest and/or apoptosis in a variety of cancer cells. Here we investigated the potential of PTER-isothiocyanate (ITC) conjugate, a novel class of hybrid compound (PTER-ITC) synthesized by appending an ITC moiety to the PTER backbone, to induce apoptotic cell death in hormone-dependent (MCF-7) and -independent (MDA-MB-231) breast cancer cell lines and to elucidate PPARγ involvement in PTER-ITC action. Our results showed that when pre-treated with PPARγ antagonists or PPARγ siRNA, both breast cancer cell lines suppressed PTER-ITC-induced apoptosis, as determined by annexin V/propidium iodide staining and cleaved caspase-9 expression. Furthermore, PTER-ITC significantly increased PPARγ mRNA and protein levels in a dose-dependent manner and modulated expression of PPARγ-related genes in both breast cancer cell lines. This increase in PPARγ activity was prevented by a PPARγ-specific inhibitor, in support of our hypothesis that PTER-ITC can act as a PPARγ activator. PTER-ITC-mediated upregulation of PPARγ was counteracted by co-incubation with p38 MAPK or JNK inhibitors, suggesting involvement of these pathways in PTER-ITC action. Molecular docking analysis further suggested that PTER-ITC interacted with 5 polar and 8 non-polar residues within the PPARγ ligand-binding pocket, which are reported to be critical for its activity. Collectively, our observations suggest potential applications for PTER-ITC in breast cancer prevention and treatment through modulation of the PPARγ activation pathway.

Silybin, is one imminent therapeutic for drug induced hepatotoxicity, human prostate adenocarcinoma and other degenerative organ diseases. Recent evidences suggest that silybin influences gluconeogenesis pathways favorably and is beneficial in the treatment of type 1 and type 2 diabetes. The compound however is constrained due to solubility (0.4 mg/mL) and bioavailabilty limitations. Appropriate nanoparticle design for silybin in biocompatible polymers was thus proposed as a probable solution for therapeutic inadequacy. New surface engineered biopolymeric nanoparticles with high silybin encapsulation efficiency of 92.11% and zeta potential of +21 mV were designed. Both the pure compound and the nanoparticles were evaluated in vivo for the first time in experimental diabetic conditions. Animal health recovered substantially and the blood glucose levels came down to near normal values after 28 days treatment schedule with the engineered nanoparticles. Restoration from hyperglycemic damage condition was traced to serum insulin regeneration. Serum insulin recovered from the streptozotocin induced pancreatic damage levels of 0.17 ± 0.01 µg/lit to 0.57 ± 0.11 µg/lit after nanoparticle treatment. Significant reduction in glycated hemoglobin level, and restoration of liver glycogen content were some of the other interesting observations. Engineered silybin nanoparticle assisted recovery in diabetic conditions was reasoned due to improved silybin dissolution, passive transport in nanoscale, and restoration of antioxidant status.

Chemotherapy and anti-hormonal therapies are the most common treatments for non-organ-confined prostate cancer (PCa). However, the effectiveness of these therapies is limited, thus necessitating the development of alternative approaches. The present study focused on analyzing the role of pterostilbene (PTER)-isothiocyanate (ITC) conjugate--a novel class of hybrid compound synthesized by appending an ITC moiety on PTER backbone--in regulating the functions of androgen receptor (AR), thereby causing apoptosis of PCa cells. The conjugate molecule caused 50% growth inhibition (IC50) at 40 ± 1.12 and 45 ± 1.50 μM in AR positive (LNCaP) and negative (PC-3) cells, respectively. The reduced proliferation of PC-3 as well as LNCaP cells by conjugate correlated with accumulation of cells in G2/M phase and induction of caspase dependent apoptosis. Both PI3K/Akt and MAPK/ERK pathways played an important and differential role in conjugate-induced apoptosis of these PCa cells. While the inhibitor of Akt (A6730) or Akt-specific small interference RNA (siRNA) greatly sensitized PC-3 cells to conjugate-induced apoptosis, on the contrary, apoptosis was accelerated by inhibition of ERK (by PD98059 or ERK siRNA) in case of LNCaP cells, both ultimately culminating in the expression of cleaved caspase-3 protein. Moreover, anti-androgenic activity of the conjugate was mediated by decreased expression of AR and its co-activators (SRC-1, GRIP-1), thus interfering in their interactions with AR. All these data suggests that conjugate-induced inhibition of cell proliferation and induction of apoptosis are partly mediated by the down regulation of AR, Akt, and ERK signaling. These observations provide a rationale for devising novel therapeutic approaches for treating PCa by using conjugate alone or in combination with other therapeutics.

Profilin-1 (Pfn-1) is a ubiquitously expressed actin-binding protein that is essential for normal cell proliferation and migration. In breast cancer and several other adenocarcinomas, Pfn-1 expression is downregulated when compared to normal tissues. Previous studies from our laboratory have shown that genetically modulating Pfn-1 expression significantly impacts proliferation, migration, and invasion of breast cancer cells in vitro, and mammary tumor growth, dissemination, and metastatic colonization in vivo. Therefore, small molecules that can modulate Pfn-1 expression could have therapeutic potential in the treatment of metastatic breast cancer. The overall goal of this study was to perform a multiplexed phenotypic screen to identify compounds that inhibit cell motility through upregulation of Pfn-1. Screening of a test cassette of 1280 compounds with known biological activities on an Oris™ Pro 384 cell migration platform identified several agents that increased Pfn-1 expression greater than two-fold over vehicle controls and exerted anti-migratory effects in the absence of overt cytotoxicity in MDA-MB-231 human breast cancer cells. Concentration-response confirmation and orthogonal follow-up assays identified two bona fide inducers of Pfn-1, purvalanol and tyrphostin A9, that confirmed in single-cell motility assays and Western blot analyses. SiRNA-mediated knockdown of Pfn-1 abrogated the inhibitory effect of tyrphostin A9 on cell migration, suggesting Pfn-1 is mechanistically linked to tyrphostin A9's anti-migratory activity. The data illustrate the utility of the high-content cell motility assay to discover novel targeted anti-migratory agents by integrating functional phenotypic analyses with target-specific readouts in a single assay platform.

Visceral leishmaniasis (VL) is a chronic protozoan infection in humans associated with significant global morbidity and mortality. There is an urgent need to develop drugs and strategy that will improve therapeutic response for effective clinical treatment of drug resistant VL. To address this need, andrographolide (AG) nanoparticles were designed with P-gp efflux inhibitor vitamin E TPGS (D-α-tocopheryl polyethyleneglycol 1000 succinate) for sensitivity against drug resistant Leishmania strains. AG loaded PLGA (50∶50) nanoparticles (AGnps) stabilized by vitamin E TPGS were prepared for delivery into macrophage cells infested with sensitive and drug resistant amastigotes of Leishmania parasites. Physico-chemical characterization of AGnps by photon correlation spectroscopy exhibited an average particle size of 179.6 nm, polydispersity index of 0.245 and zeta potential of -37.6 mV. Atomic force microscopy and transmission electron microscopy visualization revealed spherical nanoparticles with smooth surfaces. AGnps displayed sustained AG release up to 288 hours as well as minimal particle aggregation and drug loss even after three months study period. Antileishmanial activity as revealed from selectivity index in wild-type strain was found to be significant for AGnp with TPGS in about one-tenth of the dosage of the free AG and one-third of the dosage of the AGnp without TPGS. Similar observations were also found in case of in vitro generated drug resistant and field isolated resistant strains of Leishmania. Cytotoxicity of AGnp with and without TPGS was significantly less than standard antileishmanial chemotherapeutics like amphotericin B, paromomycin or sodium stibogluconate. Macrophage uptake of AGnps was almost complete within one hour as evident from fluorescent microscopy studies. Thus, based on these observations, it can be concluded that the low-selectivity of AG in in vitro generated drug resistant and field isolated resistant strains was improved in case of AG nanomedicines designed with vitamin E TPGS.

Background: Sophora belongs to the family of Fabaceae and the species in this genus are currently used as a folklore medicine for preventing a variety of ailments including cancer. Our aim was to identify and validate an anticancer compound from Sophora interrupta using multi-spectroscopic, anticancer screening, and molecular docking approach. Methods: The cytotoxicity of the various solvent extracts, petroleum ether, n-butanol, and ethyl acetate (EtOAc) of the S. interrupta root powder was evaluated in a breast cancer cell lines (MCF-7). The extract that had anticancer activity was subjected to column chromatography based on the polarity of the solvents. The anticancer activity of the elution fractions was validated using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. The isolated metabolite fraction with anticancer activity was run through a C18 column isocratic and gradient high-performance liquid chromatography (HPLC). The structure of the isolated compound was characterized using 1 H nuclear magnetic resonance (NMR), 13 C-NMR, Fourier transform infrared spectroscopy, and liquid chromatography-mass spectrometer methods. Results: The crude EtAOc extract effectively inhibited the proliferation of MCF-7 cells. The column eluted chloroform and EtOAc (4:6) fraction of the EtOAc extract showed significant anticancer activity in the MCF-7 cells compared with normal mesenchymal stem cells. This fraction showed three major peaks in the HPLC chromatogram and the first major peak with a retention time (RT) of 7.153 was purified using preparative-HPLC. The structure of the compound is a piceatannol, which is a metabolic product of resveratrol. Piceatannol formed direct two hydrogen bond interactions between Cys912 (2H), and Glu878 of vascular endothelial growth factor receptor 1 (VEGFR1) with a glide-score (G-score) of −10.193, and two hydrogen bond interactions between Cys919, and Asp1046 of VEGFR2, with a G-score of −8.359. The structure is similar to that of the crystallized protein for VEGFR1 and R2. Conclusions: Piceatannol is a secondary metabolite of S. interrupta that has anticancer activity. Moreover, piceatannol has been isolated for the first time from S. interrupta.

Ethoxyresorufin-o-deethylation (EROD) can be used as a sensitive measure of hepatic detoxification function. In this study, we employed a fluorescence assay based on EROD to study the effect of varying Peclet number (or flow) on hepatic function in a microchannel flat-plate bioartificial liver (BAL) reactor containing a coculture of hepatocytes and fibroblasts. Static culture and reactor flow experiments established that: 1) a pseudo-steady-state detoxification rate could be attained at each Peclet number, 2) the steady-state detoxification rate increased nonlinearly with Peclet number (ranging from 167 to 2500), 3) the uptake rate of substrate was a linear function of cell surface substrate concentration (