Anticancer activity of koningic acid and semisynthetic derivatives.

A screening program aimed at discovering novel anticancer agents based on natural products led to the selection of koningic acid (KA), known as a potent inhibitor of glycolysis. A method was set up to produce this fungal sesquiterpene lactone in large quantities by fermentation, thus allowing (i) an extensive analysis of its anticancer potential in vitro and in vivo and (ii) the semi-synthesis of analogues to delineate structure-activity relationships. KA was characterized as a potent, but non-selective cytotoxic agent, active under both normoxic and hypoxic conditions and inactive in the A549 lung cancer xenograft model. According to our SAR, the acidic group could be replaced to keep bioactivity but an intact epoxide is essential.

Improving the Feasibility of Mitigating Phase Errors in 4DCT caused by a Random Reference Breathing Pattern in the Quasar Phantom and the Role of Slice Thickness.

PURPOSE: The study aimed to validate a method for minimizing phase errors by combining full-length lung 4DCT (f4DCT) scans with shorter tumor-restricted 4DCT (s4DCT) scans. It assessed the feasibility of integrating two scans one covering the entire phantom length and the other focused on the tumor area. The study also evaluated the impact of Maximum Intensity Projection (MIP) volume and imaging dose for different slice thicknesses (2.5mm and 1.25mm) in both full-length and short target-restricted 4DCT scans. METHODS: The study utilized the Quasar Programmable Respiratory Motion Phantom, simulating tumor motion with a variable lung insert. The setup included a tumor replica and a six-dot IR reflector marker on the breathing platform. The objective was to analyze volume differences in fMIP_2.5mm compared to sMIP_1.25mm within their respective 4D_MIP CT series. This involved varying breathing periods (2.5s, 3.0s, 4.0s, and 5.0s) and longitudinal tumor sizes (6mm, 8mm, and 10mm). The study also assessed exposure time and expected CTDIvol of s4D_2.5mm and s4D_1.25mm for different breathing periods (5.0s to 2.0s) in the sinusoidal wave motion of the six-dot marker on the breathing platform. RESULTS: Conducting two consecutive 4DCT scans is viable for patients with challenging breathing patterns or when the initial lung tumor scan is in close proximity to the tumor location, eliminating the need for an additional full-length 4DCT. The analysis involves assessing MIP volume, imaging dose (CTDIvol), and exposure time. Longitudinal tumor shifts for 6mm are [16.6-17.2] in fMIP_2.5mm and [16.8-17.5] in sMIP_1.25mm, for 8mm [17.2-18.3] in fMIP_2.5mm and [17.8-18.4] in sMIP_1.25mm, and for 10mm [19-19.9] in fMIP_2.5mm and [19.4-20] in sMIP_1.25mm (p≥ 0.005), respectively. CONCLUSION: The Quasar Programmable Respiratory Motion Phantom accurately replicated varied breathing patterns and tumor motions. Comprehensive analysis was facilitated through detailed manual segmentation of Internal Target Volumes and Internal Gross Target Volumes.

Analyzing RPM and RGSC Infrared Camera Sensitivity: A Comparative Study of Breathing Cycle Replication Verifications and Limitations.

OBJECTIVE: This study addresses challenges in delivering high radiation doses and managing organ motion in Stereotactic Body Radiation Therapy (SBRT) for thoracic and abdominal cancer. It evaluates Varian's Real Time Position Management (RPM) system's infrared camera sensitivity during crucial Four-Dimensional computed tomography (4D-CT) scans for planning and treatment. The analysis includes CT simulator, LINAC (Novalis Tx and TrueBeam STx). This research enhances SBRT precision by offering insights into RPM and RGSC system performance across machines, impacting treatment planning and delivery optimization. METHODS: The QUASAR™ Respiratory Motion Assembly phantom is aligned with precision using lasers. It is configured with either six-dot reflective or four-dot lens marker blocks featuring a retroreflective marker placed on the phantom's surface. Motion is induced by adjusting the amplitude, and the camera position is finely tuned to monitor the marker's movements. This investigation entails variations in seconds per breath (SPB) within the Quasar breath platform, specifically at intervals of 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, and 5.0 seconds while maintaining a 1cm amplitude camera setting. RESULT: For TrueBeam-STx: Ensure SPB values are kept above 1.8 seconds for accurate replication. For Novalis-Tx: Stay within an SPB range of up to 2.0 seconds for reliable reproducibility. For CT Simulator: Optimal replication up to an SPB of 2.2 seconds; avoid SPB values below 1.8 seconds for reliable detection. CONCLUSION: Data for TrueBeam-STx, Novalis-Tx, and the CT simulator shows discrepancies in replicating the breathing cycle as Seconds Per Breath (SPB) decreases. Effective Infrared (IR) sensitivity is observed until SPB thresholds: 1.8s (TrueBeam-STx), 2.2s (Novalis-Tx), and 2.2s (CT simulator). We should consider values equal to or greater than the mentioned breathing periods. Variations in replicating breathing cycles signal challenges in planning and delivering treatments, especially with lower SPB values. These insights guide clinicians to adapt treatments based on machine-specific capabilities for accurate and reproducible outcomes.

A Study on the Morphometry of a Medial Meniscus in the Knee Joint of Human Cadavers in the South Indian Population.

Introduction The knee joint is a complex system containing various hard and soft tissue components necessary for functioning in a coordinated manner. The menisci help to deepen the tibial plateau. Knowledge of the dimension of menisci in the knee joint is of paramount importance in arthroscopic surgery and the management of injuries due to sports or degeneration. The present study aims to describe the morphometric data of the medial meniscus and document the morphometric variation in the medial menisci. Methodology This study was conducted in the department of anatomy in two medical colleges under MGR University by measuring the dimensions of 100 medial menisci taken from 50 formalin-fixed embalmed cadavers. The width and thickness of the medial menisci were measured using digital vernier calipers. The outer and inner circumferences were measured using a measuring tape, non-elastic threads, and metallic pins. The area of the medial meniscus and the tibial plateau was measured by counting the small squares present in the circumference of the menisci drawn over the graph paper. The weight of the medial menisci was measured using the electronic weigh scale. Results The widest part of the medial meniscus was the posterior one-third, and the narrowest part was the anterior one-third. The thickest part was the middle one-third, followed by the anterior one-third. The average inner and outer circumferences of the menisci were 6.25 cm and 10.05 cm, respectively. The medial meniscus covers more than half of the area of the tibial plateau. Conclusion The present study provides a good understanding of the morphometric features of the medial menisci and will be of great help for managing knee joint pathologies and designing prostheses.

The role of feedback in improving the effectiveness of workplace based assessments: a systematic review.

BACKGROUND: With recent emphasis placed on workplace based assessment (WBA) as a method of formative performance assessment, there is limited evidence in the current literature regarding the role of feedback in improving the effectiveness of WBA. The aim of this systematic review was to elucidate the impact of feedback on the effectiveness of WBA in postgraduate medical training. METHODS: Searches were conducted using the following bibliographic databases to identify original published studies related to WBA and the role of feedback: Medline (1950-December 2010), Embase (1980-December 2010) and Journals@Ovid (English language only, 1996-December 2010). Studies which attempted to evaluate the role of feedback in WBA involving postgraduate doctors were included. RESULTS: 15 identified studies met the inclusion criteria and minimum quality threshold. They were heterogeneous in methodological design. 7 studies focused on multi source feedback, 3 studies were based on mini-clinical evaluation exercise, 2 looked at procedural based assessment, one study looked at workplace based assessments in general and 2 studies looked at a combination of 3 to 6 workplace based assessments. 7 studies originated from the United Kingdom. Others were from Canada, the United States and New Zealand. Study populations were doctors in various grades of training from a wide range of specialties including general practice, general medicine, general surgery, dermatology, paediatrics and anaesthetics. All studies were prospective in design, and non-comparative descriptive or observational studies using a variety of methods including questionnaires, one to one interviews and focus groups. CONCLUSIONS: The evidence base contains few high quality conclusive studies and more studies are required to provide further evidence for the effect of feedback from workplace based assessment on subsequent performance. There is, however, good evidence that if well implemented, feedback from workplace based assessments, particularly multisource feedback, leads to a perceived positive effect on practice.

Robot assisted laparoscopic adrenalectomy: Should this be the new standard?

INTRODUCTION: Minimal invasive surgeries (MIS) for large size adrenal tumors are still debatable. The objective is to evaluate the contemporary peri- and post-operative outcomes of patients undergoing (open = OA, laparoscopic = LA, and robotic = RA) adrenalectomies in three institutions. MATERIALS AND METHODS: Retrospectively gathered peri- and post-operative data of 235 patients, underwent adrenalectomy at three Institutions over a 7-year period (2013-2020) were analyzed. All patients underwent thorough radiological and endocrine workup. RESULTS: Two hundred and thirty five patients who underwent adrenalectomy (OA (n = 29), LA (n = 146), and RA (n = 60)) were assessed. OA (n = 29) versus Minimally invasive surgery (n = 206) showed significant differences (median, p value) in larger tumour size, cm (9.4 vs 5, (p = 0.0001)), longer operative time, mins (240 vs 100, (p = 0.0001)), longer hospital stay, days (8 vs 3,(p = .0001)), Higher readmission rates (14% vs 1.9%), higher blood loss, ml (400 vs 100, (p = 0.0001)) requiring blood transfusion (14% vs 4.3%) (p = 0.03), higher intraoperative complication (21% vs 6%) (p = 0.0004), and post op complications (17% vs 5.3%) (p = 0.01). Amongst the MIS (RA vs LA), RA appeared be have better outcomes in terms of shorter operative time, less blood loss and less intra operative complications with a p value <0.05. These results were consistent for the assessment of patients who had ⩾6 cm tumor size. The postoperative complication rates were lowest with RA (3.3%) compared to OA (17%) and LA (6.1%). CONCLUSIONS: Contemporary practice of adrenalectomy shows that robotic adrenalectomy is safe and effective irrespective of the tumor size.

Influence of Webinar-Based Learning on Practice of Percutaneous Nephrolithotomy: Outcomes of a Global Survey.

Background: With webinars looking to be the mainstay post-pandemic, it is important to demonstrate whether webinars are, indeed, effective educational tools for professional training and skill acquisition. We aim at demonstrating, via a global survey, the efficacy of webinars on percutaneous nephrolithotomy (PCNL) and how this knowledge transforms clinical practice. Methods: A structured online survey covering the following sections: (1) Demographics, (2) PCNL techniques, and (3) PCNL equipment was circulated. The target study population were practicing urologists and residents. Categorical data were presented with counts and percentages, and they were compared by using Chi-square test. Continuous data were analyzed with non-parametric methods. Respondents were dichotomized according to attendance of webinar type, attendees of dedicated PCNL webinars (Group A), or attendees of endourological webinars that discussed some aspects of PCNL (Group B). Results: A total of 303 respondents from 38 countries participated. Overall, 91.7% (n = 278) were in Group A and 8.3% (n = 25) were in Group B; 77.9% were younger than 50 years, whereas 51.8% had more than 10 years of urology experience. In group A, urologists of all ages, in academic institutions and private practitioners, significantly benefited in gaining knowledge about the merits of newer devices and the role of suction-assisted devices in modern PCNL. The majority of group A also reflected that by attending a dedicated PCNL-based webinar they benefited in learning newer positions for PCNL access, especially supine, and how to effectively use laser as energy devices for lithotripsy. In Group B, the only area of benefit was in lasing techniques and the use of newer lasers such as the thulium fibre laser. Conclusion: Our survey positively validates the two proposed hypothesis, that is, webinars as a medium of education do benefit practicing urologists in knowledge and the clinical practice domains. Age, experience, or place of practice is no barrier to adopting newer mediums of education such as webinars.

3beta-taraxerol of Mangifera indica, a PI3K dependent dual activator of glucose transport and glycogen synthesis in 3T3-L1 adipocytes.

BACKGROUND: The present study focuses on identifying and developing an anti-diabetic molecule from plant sources that would effectively combat insulin resistance through proper channeling of glucose metabolism involving glucose transport and storage. METHODS: Insulin-stimulated glucose uptake formed the basis for isolation of a bioactive molecule through column chromatography followed by its characterization using NMR and mass spectroscopic analysis. Mechanism of glucose transport and storage was evaluated based on the expression profiling of signaling molecules involved in the process. RESULTS: The study reports (i) the isolation of a bioactive compound 3beta-taraxerol from the ethyl acetate extract (EAE) of the leaves of Mangifera indica (ii) the bioactive compound exhibited insulin-stimulated glucose uptake through translocation and activation of the glucose transporter (GLUT4) in an IRTK and PI3K dependent fashion. (iii) the fate of glucose following insulin-stimulated glucose uptake was ascertained through glycogen synthesis assay that involved the activation of PKB and suppression of GSK3beta. GENERAL SIGNIFICANCE: This study demonstrates the dual activity of 3beta-taraxerol and the ethyl acetate extract of Mangifera indica as a glucose transport activator and stimulator of glycogen synthesis. 3beta-taraxerol can be validated as a potent candidate for managing the hyperglycemic state.

Spatiotemporal aspects of real-time PM(2.5): low- and middle-income neighborhoods in Bangalore, India.

We measured outdoor fine particulate matter (PM(2.5)) concentrations in a low- and a nearby middle-income neighborhood in Bangalore, India. Each neighborhood included sampling locations near and not near a major road. One-minute average concentrations were recorded for 168 days during September 2008 to May 2009 using a gravimetric-corrected nephelometer. We also measured wind speed and direction, and PM(2.5) concentration as a function of distance from road. Average concentrations are 21-46% higher in the low- than in the middle-income neighborhood, and exhibit differing spatiotemporal patterns. For example, in the middle-income neighborhood, median concentrations are higher near-road than not near-road (56 versus 50 µg m(-3)); in the low-income neighborhood, the reverse holds (68 µg m(-3) near-road, 74 µg m(-3) not near-road), likely because of within-neighborhood residential emissions (e.g., cooking; trash combustion). A moving-average subtraction method used to infer local- versus urban-scale emissions confirms that local emissions are greater in the low-income neighborhood than in the middle-income neighborhood; however, relative contributions from local sources vary by time-of-day. Real-time relative humidity correction factors are important for accurately interpreting real-time nephelometer data.

Intensity modulated radiotherapy in anal canal squamous cell carcinoma: Implementation and outcomes.

OBJECTIVE: Concurrent chemoradiotherapy (CCRT) is the standard curative treatment option for nonmetastatic anal squamous cell carcinoma (SCC). Intensity modulated radiotherapy (IMRT) can reduce doses delivered to bowel and skin and reduce toxicities associated with conventional fields. Here, we present our institutional data on dosimetry, toxicity, and clinical outcomes with IMRT for anal cancer. MATERIALS AND METHODS: We analyzed 23 patients of anal SCC treated with curative-intent CCRT/radiation therapy alone, utilizing IMRT, between August 2011 and December 2016. The standard prescription dose was 54 Gy/27Fr/5.5 weeks, delivered in two phases, and concurrent chemotherapy with 5-fluorouracil and mitomycin-C. Acute and late toxicities and dosimetric data were compiled and analyzed. RESULTS: The median age was 65 years. Fourteen (60.7%) patients had Stage IIIC disease. Eighteen patients received concurrent chemotherapy. No patient had any treatment breaks. Grade 3 acute perianal dermatitis was recorded in 11 (47.8%) patients. Proctitis, diarrhea, and cystitis were limited to Grade 1 in 73.9%, 47.8%, and 8.6% patients, respectively. The only late Grade 2+ toxicities were gastrointestinal toxicities in 4 (17.4%) patients. Twenty (87%) patients had complete response at 6 months. The 3-year local control, nodal control, and distant metastases-free survival were 85.9%, 86.6%, 84.7%, respectively, with 3-year disease-free survival and overall survival of 63.4% and 81%, respectively. CONCLUSION: In this report on IMRT in anal cancer from India, treatment was well tolerated with lower acute toxicity than reported in other prospective studies. Long-term results are at par with other published studies.

7-Hydroxy Frullanolide, a sesquiterpene lactone, increases intracellular calcium amounts, lowers CD4+ T cell and macrophage responses, and ameliorates DSS-induced colitis.

Sesquiterpene lactones are a class of anti-inflammatory molecules obtained from plants belonging to the Asteraceae family. In this study, the effects of 7-hydroxy frullanolide (7HF), a sesquiterpene lactone, in inhibiting CD4+ T cell and peritoneal macrophage responses were investigated. 7HF, in a dose dependent manner, lowers CD69 upregulation, IL2 production and CD4+ T cell cycling upon activation with the combination of anti-CD3 and anti-CD28. Further mechanistic studies demonstrated that 7HF, at early time points, increases intracellular Ca2+ amounts, over and above the levels induced upon activation. The functional relevance of 7HF-induced Ca2+ increase was confirmed using sub-optimal amounts of BAPTA, an intracellular Ca2+ chelator, which lowers lactate and rescues CD4+ T cell cycling. In addition, 7HF lowers T cell cycling with the combination of PMA and Ionomycin. However, 7HF increases CD4+ T cell cycling with sub-optimal activating signals: only PMA or anti-CD3. Furthermore, LPS-induced nitrite and IL6 production by peritoneal macrophages is inhibited by 7HF in a Ca2+-dependent manner. Studies with Ca2+ channel inhibitors, Ruthenium Red and 2-Aminoethoxydiphenyl borate, lowers the inhibitory effects of 7HF on CD4+ T cell and macrophage responses. In silico studies demonstrated that 7HF binds to Ca2+ channels, TRPV1, IP3R and SERCA, which is mechanistically important. Finally, intraperitoneal administration of 7HF lowers serum inflammatory cytokines, IFNγ and IL6, and reduces the effects of DSS-induced colitis with respect to colon length and colon damage. Overall, this study sheds mechanistic light on the anti-inflammatory potential of 7HF, a natural plant compound, in lowering immune responses.

Prioritizing Delivery of Cancer Treatment During a COVID-19 Lockdown: The Experience of a Clinical Oncology Service in India.

PURPOSE: A COVID-19 lockdown in India posed significant challenges to the continuation of radiotherapy (RT) and systemic therapy services. Although several COVID-19 service guidelines have been promulgated, implementation data are yet unavailable. We performed a comprehensive audit of the implementation of services in a clinical oncology department. METHODS: A departmental protocol of priority-based treatment guidance was developed, and a departmental staff rotation policy was implemented. Data were collected for the period of lockdown on outpatient visits, starting, and delivery of RT and systemic therapy. Adherence to protocol was audited, and factors affecting change from pre-COVID standards analyzed by multivariate logistic regression. RESULTS: Outpatient consults dropped by 58%. Planned RT starts were implemented in 90%, 100%, 92%, 90%, and 75% of priority level 1-5 patients. Although 17% had a deferred start, the median time to start of adjuvant RT and overall treatment times were maintained. Concurrent chemotherapy was administered in 89% of those eligible. Systemic therapy was administered to 84.5% of planned patients. However, 33% and 57% of curative and palliative patients had modifications in cycle duration or deferrals. The patient's inability to come was the most common reason for RT or ST deviation. Factors independently associated with a change from pre-COVID practice was priority-level allocation for RT and age and palliative intent for systemic therapy. CONCLUSION: Despite significant access limitations, a planned priority-based system of delivery of treatment could be implemented.

Molecular basis of the anti-inflammatory property exhibited by cyclo-pentano phenanthrenol isolated from Lippia nodiflora.

The objective of this study was to assess the anti-inflammatory potential of the active molecule isolated from Lippia nodiflora and to understand its molecular dynamics in Vitro inflammation models. Human Peripheral Blood Mononuclear Cells were used as models to study mitogen induced lymphocyte proliferation, cytokine mRNA expression (TNF-α, IL-1ß and IL-6) and intracellular protein levels of pro-inflammatory mediators (MAPK and NF-κB). The NO release levels, on treatment with the extract and molecule, were correlated with the underlying iNOS mRNA expression in the murine macrophage cell line RAW 264.7. RT-PCR for COX-2, MMP2 and MMP9 were also performed in the cell line. The rat basophilic leukemia cell line RBL-2H3 was used as an in Vitro model for PLA2 activity. Then, 20 µg/ml of Lippia nodiflora crude methanol extract and 10 µg/ml of the purified CPP were used for subsequent studies based on the IC50 values obtained in the proliferation assay. Results demonstrate that the isolated Cyclo-pentano phenanthrenol inhibits TNF-α, IL-1ß and IL-6 expression, NO release via iNOS suppression, prostaglandin biosynthesis via PLA2 and COX-2 inhibition and the activation of intracellular targets, MAPK and NF-κB. We conclude, cyclo-pentano phenanthrenol exerts its anti-inflammatory effect via inhibition of MAPK phosphorylation and NF-κB translocation.

Robot Assisted Laparoscopic Adrenalectomy: Does Size Matter?

OBJECTIVE:  Open adrenalectomy (OA) is considered to be the standard care for large adrenal tumors. Minimally invasive surgery (MIS) using laparoscopic technique is considered for many patients in the modern era. Robot assisted laparoscopic adrenalectomy (RALA) can be an extremely useful tool which will negate the disadvantage of laparoscopic method. The aim of the present study is to determine whether adrenal tumor size and laterality have an impact on patients undergoing RALA with respect to perioperative and postoperative outcomes.  Methods: During the study period, 38 patients who underwent RALA in a tertiary care center were considered for retrospectively analysis. The study populations were subdivided into distinctive groups based on the tumor size (<5 cm and ≥5 cm, <8 cm and ≥8 cm), and side (right and left side). For all the subgroups, perioperative and postoperative outcomes were analyzed. Perioperative and postoperative outcomes were assessed between patient groups, group a) <5 cm and ≥5 cm tumor, group b) <8 cm and ≥8 cm, and group c) laterality (right vs left). RESULTS:  None of the patients showed any differences. In the current study, the conversion rate, readmission, and mortality were not observed. No major complications were noted. CONCLUSION:  RALA appears to be an extremely viable alternative to MIS using laparoscopic technique. The operative time, console time, blood loss, complication rates, and stay were extremely minimal irrespective of the size or laterality of the adrenal tumor.

Outer membrane proteins of wild-type and intimin-deficient enteropathogenic Escherichia coli induce Hep-2 cell death through intrinsic and extrinsic pathways of apoptosis.

Enteropathogenic Escherichia coli cause protracted diarrhoea and malnutrition in infants by cytoskeletal depolymerisation and effacement of enterocyte microvilli. In this study, outer membrane proteins of wild-type enteropathogenic E. coli and an intimin-deficient mutant are shown to induce apoptosis by up-regulation of tumour necrosis factor alpha and activation of c-jun N-terminal kinase. Fluorescence-activated cell sorter analysis revealed apoptosis of cells treated with outer membrane proteins of wild-type and intimin-deficient strains. Proteinase K treatment of outer membrane proteins reduced apoptosis significantly, as did neutralising tumour necrosis factor alpha with specific antibodies. Elevated tumour necrosis factor receptor 1-associated death domain and caspase-3 expression were also observed on treatment with both types of outer membrane proteins. Furthermore, apoptosis was associated with suppression of Bcl-2 protein expression, up-regulation of Bax mRNA levels and increased cytochrome c release from mitochondria. Elevated phospho-c-jun N-terminal kinase, c-jun mRNA and activator protein-1 expression were observed, and phosphorylation of activator protein-1 was also observed by DNA-binding assays. Inhibition of c-jun N-terminal kinase, but not inhibition of p38 mitogen-activated protein kinase, resulted in reduction of tumour necrosis factor alpha mRNA levels and caspase-3 protein levels, and a reduction in apoptosis as observed by fluorescence-activated cell sorter analysis. From the host point of view, this study suggests a possible interplay between the death receptor and mitochondrial pathways when cell-free bacterial outer membrane preparations are used to trigger apoptosis.

Anti-inflammatory and anticancer activity of ergoflavin isolated from an endophytic fungus.

Biodiversity is a major resource for identification of new molecules with specific therapeutic activities. To identify such an active resource, high throughput screening (HTS) of the extracts prepared from such diversity are examined on specific functional assays. Based on such HTS studies and bioactivity-based fractionation, we have isolated ergoflavin, a pigment from an endophytic fungus, growing on the leaves of an Indian medicinal plant Mimosops elengi (bakul). We report here the isolation, structure elucidation, and biological properties of this compound, which showed good anti-inflammatory and anticancer activities.

Discovery of diacylphloroglucinols as a new class of GPR40 (FFAR1) agonists.

In this letter, we report discovery of diacylphloroglucinol compounds as a new class of GPR40 (FFAR1) agonists. Several diacylphloroglucinols with varying length of acyl functionality and substitution on aromatic hydroxyls were synthesized and evaluated for GPR40 agonism using functional calcium-flux assay. Out of 17 compounds evaluated, 14, 17, 19 and 25 exhibited good GPR40 agonistic activity with EC(50) values ranging from 0.07 to 8 microM (pEC(50) 7.12-5.09), respectively, with maximal agonistic response of 84-102%.

Synthesis and evaluation of pyrazolo[3,4-b]pyridines and its structural analogues as TNF-alpha and IL-6 inhibitors.

In the present article, we have synthesized three different series of pyrazolo[3,4-b]pyridines and their structural analogues using novel synthetic strategy involving one-pot condensation of 5,6-dihydro-4H-pyran-3-carbaldehyde/2-formyl-3,4,6-tri-O-methyl-D-glucal/chromone-3-carbaldehyde with heteroaromatic amines. All synthesized compounds were evaluated for their anti-inflammatory activity against TNF-alpha and IL-6. Out of 28 compounds screened, 40, 51, 52 and 56 exhibited promising activity against IL-6 with 60-65% inhibition at 10 microM concentration. Amongst these, 51, 52 and 56 showed potent IL-6 inhibitory activity with IC(50)'s of 0.2, 0.3 and 0.16 microM, respectively. Compound 56 was not cytotoxic in CCK-8 cells up to the concentration of >100 microM.

Quinomycin A targets Notch signaling pathway in pancreatic cancer stem cells.

Cancer stem cells (CSCs) appear to explain many aspects of the neoplastic evolution of tumors and likely account for enhanced therapeutic resistance following treatment. Dysregulated Notch signaling, which affects CSCs plays an important role in pancreatic cancer progression. We have determined the ability of Quinomycin to inhibit CSCs and the Notch signaling pathway. Quinomycin treatment resulted in significant inhibition of proliferation and colony formation in pancreatic cancer cell lines, but not in normal pancreatic epithelial cells. Moreover, Quinomycin affected pancreatosphere formation. The compound also decreased the expression of CSC marker proteins DCLK1, CD44, CD24 and EPCAM. In addition, flow cytometry studies demonstrated that Quinomycin reduced the number of DCLK1+ cells. Furthermore, levels of Notch 1-4 receptors, their ligands Jagged1, Jagged2, DLL1, DLL3, DLL4 and the downstream target protein Hes-1 were reduced. The γ-secretase complex proteins, Presenilin 1, Nicastrin, Pen2, and APH-1, required for Notch activation also exhibited decreased expression. Ectopic expression of the Notch Intracellular Domain (NICD) partially rescued the cells from Quinomycin mediated growth suppression. To determine the effect of Quinomycin on tumor growth in vivo, nude mice carrying tumor xenografts were administered Quinomycin intraperitoneally every day for 21 days. Treatment with the compound significantly inhibited tumor xenograft growth, coupled with significant reduction in the expression of CSC markers and Notch signaling proteins. Together, these data suggest that Quinomycin is a potent inhibitor of pancreatic cancer that targets the stem cells by inhibiting Notch signaling proteins.

Upregulation of Glut-4 and PPAR gamma by an isoflavone from Pterocarpus marsupium on L6 myotubes: a possible mechanism of action.

The purpose of the present study is to analyse the influence of Pterocarpus marsupium methanolic extract and isolated Pterocarpus marsupium isoflavone on a battery of cellular targets Glut-4, PPAR gamma and PI3 kinase. Pterocarpus marsupium is an anti-diabetic plant indigenous to South India. Sequential extraction performed with different solvents were analysed for glucose uptake activity at each step. Fraction-9 showing maximum glucose activity on glucose uptake was purified by column chromatography and the structure was elucidated as 7-O-alpha-L-rhamnopyranosyl oxy-4'-methoxy-5-hydroxy isoflavone using NMR and mass spectroscopy. The significant glucose uptake showed by Pterocarpus marsupium crude and pure was comparable with insulin and rosiglitazone. Elevation of Glut-4 and PPARgamma gene expression in parallel with glucose uptake supported the in vitro glucose uptake activity of Pterocarpus marsupium methanolic extract and Pterocarpus marsupium isoflavone. The inhibitory effect of cycloheximide on Pterocarpus marsupium methanolic extract and Pterocarpus marsupium isoflavone-mediated glucose uptake suggested that new protein synthesis is required for elevated Glut-4 protein expression. PI3 kinase plays an important role in glucose transport and activated by Pterocarpus marsupium methanolic extract but not the isolated pure isoflavone. Therefore, we postulate that the isoflavone from Pterocarpus marsupium may activate glucose transport by a PI3 kinase independent pathway, which require further analysis.