ARSHOGHNA (ANTI-HEMORRHOIDAL) HERBAL DRUGS OF RAJNIGHANTU: A LITERARY REVIEW

Ayurveda plays vital role in curing Arsha (Hemorrhoids) without surgical intervention there are so many herbal drug having Arshoghna property. Many treatment modalities have been explained in Brihatrayi (Charak, Sushruta, Vagbhata) and Laghutrayi (Sharangdhara, Bhavaprakash and Madhav Nidan). In Rajnighantu pandit Narahari mentions numerous drugs acting on hemorrhoids. The present study is designed to screen the drugs with Arshoghna, Visheshat, Gudajapaham, Raktarshara, Gudaraktahruta, Gudankurnash, Gudartinash, Vatarshahara properties. Out of 789 herbal drugs 38 were described in for the treatment of hemorrhoids throughout the text of Rajnighantu. In Arshas management the systemic medicines act by improving appetite, regularize bowl habits, astringent action on blood vessels and maintaining Agni and Srotas in equilibrium. Among all the Arshoghna drugs are described in Rajnighantu, maximum drug are Tikta or Katu or Kasaya rasa Pradhana and most of the drug is Usna in Virya. It can also be said that the drugs having Katu, Tikta, Kashaya rasa, Guru, Tikshna and Ksharaguna, Ushnavirya and Katuvipaka play major role in the treatment of Arsha

PREVALENCE OF VARIOUS BETA LACTAMASES AMONG GRAM NEGATIVE BACILLI IN URINARY ISOLATES FROM PATIENTS IN A TERTIARY CARE HOSPITAL OF NORTHERN INDIA

Objective: Urinary tract infections are considered among the most common infections, occurring either in the community or health-care setting. We are left with very few options for the treatment due to rapid development of antibiotic resistance among the organisms. To find out the prevalence of various types of β-lactamases among urinary isolates.Methods: Seven antibiotic discs (HiMedia) were placed in combinations and approximation in a particular sequence on a 90 mm diameter MuellerHintonagar plate.Results: Out of a total 165 urinary isolates, 66 (40%) isolates were positive for extended spectrum β-lactamase (ESBL) production, AmpC β-lactamases(AmpC) activity was present in 31 (18.78%) isolates, co-production of both ESBL and AmpC was seen in 16 (9.69%) isolates, 3 (1.81%) isolatesproduced metallo β-lactamase (MBL), 2 (1.21%) isolates produced both MBL, and ESBL and 1 (0.60%) isolates were positive for inducible third generation cephalosporin resistance.Conclusion: With the presence of such high prevalence of various β-lactamases in clinical isolates of gram-negative bacilli and also other types ofantibiotic resistance, antibiotic policy should be made, and strict adherence should be followed.Keywords: Extended spectrum β-lactamase, AmpC β-lactamase, Metallo β-lactamase

P53 tumor suppressor gene mutations in hepatocellular carcinoma patients in India

Background: Specific mutations of the p53 tumor suppressor gene in hepatocellular carcinoma (HCC) have been reported from several parts of the world, but to the authors' knowledge to date the status of this gene has not been studied in HCC patients in India, where HCC is one of the major cancers and the frequency of chronic hepatitis B virus (HBV) as well as hepatitis C virus (HCV) infection and exposure to dietary aflatoxin B1 is very high. The most frequent mutation of the p53 gene in HCC is an AGGArg to AGTSer missense mutation at codon 249 of exon 7. Methods: Liver biopsy specimens from 21 HCC patients and 10 healthy controls were obtained through surgery or by needle biopsy technique. Phenol-chloroform-extracted DNA specimens were employed for the detection of HBV infection and p53 gene mutations. Nucleotide mutations of exons 4-9 of the p53 gene were analyzed by polymerase chain reaction (PCR), single strand confirmation polymorphism, and direct sequencing. Third-generation sandwich enzyme-linked immunosorbent assay (ELISA) was used for the serologic detection of HBV and HCV infection. Results: Analysis of exons 4-9 of the p53 gene revealed only 3 mutations (3 of 21 specimens, 14.28%; 95% confidence interval, -0.7-29.3), 2 mutations at codon 249 showing G→T transversions, and 1 mutation (4.7%) at codon 250 with a C→T transition. The base substitutions at the third base of codon 249 resulted in a missense mutation leading to a change in amino acid from arginine to serine whereas at codon 250 it caused a change from proline to serine. Dot blot hybridization and PCR for HBV DNA from HCCs revealed 58.8% (10 of 17 specimens) and 90.47% (19 of 21 specimens), positivity, respectively. ELISA for hepatitis B virus surface antigen in serum showed a positivity of 71.42% (15 of 21 specimens), but there was only 40% positivity (8 of 20 specimens) for hepatitis B virus envelope antigen whereas 6 of 17 patients (35.29%) showed the presence of antibodies against hepatitis B virus envelope protein. No patient was found to be positive for the HCV antibody. Conclusions: The very low frequency of p53 mutations and the extremely high frequency of HBV infection (> 90%) in HCC indicate that the mutations in the p53 gene frequently found in HCC reported from different endemic areas of the world may not play a direct role in the development of HCC in India. HBV infection and, possibly, exposure to the dietary aflatoxin B1 appear to play major roles in the molecular pathogenesis of HCC in India

Custard Apple (Annona squamosa L.) Leaves: Nutritional Composition, Phytochemical Profile, and Health-Promoting Biological Activities

Annona squamosa L. (custard apple) belongs to the family Annonaceae and is an important tropical fruit cultivated in the West Indies, South and Central America, Ecuador, Peru, Brazil, India, Mexico, the Bahamas, Bermuda, and Egypt. Leaves of custard apple plants have been studied for their health benefits, which are attributed to a considerable diversity of phytochemicals. These compounds include phenol-based compounds, e.g., proanthocyanidins, comprising 18 different phenolic compounds, mainly alkaloids and flavonoids. Extracts from Annona squamosa leaves (ASLs) have been studied for their biological activities, including anticancer, antidiabetic, antioxidant, antimicrobial, antiobesity, lipid-lowering, and hepatoprotective functions. In the current article, we discussed the nutritional and phytochemical diversity of ASLs. Additionally, ASL extracts were discussed with respect to their biological activities, which were established by in vivo and in vitro experiments. A survey of the literature based on the phytochemical profile and health-promoting effects of ASLs showed that they can be used as potential ingredients for the development of pharmaceutical drugs and functional foods. Although there are sufficient findings available from in vitro and in vivo investigations, clinical trials are still needed to determine the exact effects of ASL extracts on human health

Randomized Clinical Trial of High-Dose Rifampicin With or Without Levofloxacin Versus Standard of Care for Pediatric Tuberculous Meningitis: The TBM-KIDS Trial

Background. Pediatric tuberculous meningitis (TBM) commonly causes death or disability. In adults, high-dose rifampicin may reduce mortality. The role of fluoroquinolones remains unclear. There have been no antimicrobial treatment trials for pediatric TBM. Methods. TBM-KIDS was a phase 2 open-label randomized trial among children with TBM in India and Malawi. Participants received isoniazid and pyrazinamide plus: (i) high-dose rifampicin (30 mg/kg) and ethambutol (R30HZE, arm 1); (ii) high-dose rifampicin and levofloxacin (R30HZL, arm 2); or (iii) standard-dose rifampicin and ethambutol (R15HZE, arm 3) for 8 weeks, followed by 10 months of standard treatment. Functional and neurocognitive outcomes were measured longitudinally using Modified Rankin Scale (MRS) and Mullen Scales of Early Learning (MSEL). Results. Of 2487 children prescreened, 79 were screened and 37 enrolled. Median age was 72 months; 49%, 43%, and 8% had stage I, II, and III disease, respectively. Grade 3 or higher adverse events occurred in 58%, 55%, and 36% of children in arms 1, 2, and 3, with 1 death (arm 1) and 6 early treatment discontinuations (4 in arm 1, 1 each in arms 2 and 3). By week 8, all children recovered to MRS score of 0 or 1. Average MSEL scores were significantly better in arm 1 than arm 3 in fine motor, receptive language, and expressive language domains (P < .01). Conclusions. In a pediatric TBM trial, functional outcomes were excellent overall. The trend toward higher frequency of adverse events but better neurocognitive outcomes in children receiving high-dose rifampicin requires confirmation in a larger trial. Clinical Trials Registration. NCT02958709

INFLUENCE OF PEG-4000 ON THE MICELLIZATION BEHAVIOR OF SDBS AND CPC AT DIFFERENT TEMPERATURES

Objective: The main objective of this research work was to gain a qualitative understanding of polymer-surfactant interactions by comparing the micellar properties of anionic (SDBS) and cationic (CPC) surfactants in aqueous mixtures of PEG-4000.Methods: Conductivity method was employed to investigate the micellization behavior of two oppositely charged ionic surfactants in polymer solutions at a temperature range between 298.15 K to 308.15K. Thermodynamic parameters of micellization were also derived (∆G °m, ∆H °m and ∆S °m) to support the findings.Results: CMC of both the surfactants was directly proportional to the concentration of PEG-4000. Negative values of ∆G °m suggested that the micellization was a spontaneous process, but these values were inversely proportional to PEG concentration suggesting the origin of London dispersion interactions on increasing polymer concentration in the system.Conclusion: Comparative study of polymer–surfactant interactions enabled us to evaluate the relative contribution of electrostatic and hydrophobic interactions between surfactant and polymer molecules. Studies showed that the micellization is more favored by CPC-PEG system as compared to SDBS-PEG system.Keywords: Micellization, Polymer, Surfactan

The membrane tethered matrix metalloproteinase MT1-MMP at the forefront of melanoma cell invasion and metastasis

The Extracellular Matrix (ECM) plays an important role in normal physiological development and functioning of cells, tissues and organs [1]. Under normal physiological conditions degradation of the ECM is a finely regulated process, and altered homeostasis of ECM degradation (excessive or insufficient) is associated with many diseases [2-5] such as cancer, fibrosis, arthritis, nephritis, encephalomyelitis and chronic ulcers. The remodeling of the ECM is carried out by a family of enzymes known as matrix metalloproteinases (MMP). MMPs constitute a large group of multidomain, zinc dependent endopeptidases capable of hydrolyzing all protein components of the ECM [6]. Additional functions of MMPs have also been identified. MMPs, and in particular MT1-MMP, the prototypic membrane-tethered matrix metalloproteinase, are no longer only ECM remodeling enzymes but rather regulators of several cellular functions including growth, migration, invasion and gene expression. Here we will focus on the role of the membrane bound MT1-MMP in melanoma growth, invasion and metastasis. MT1-MMP has in fact emerged as a multifaceted protease capable of influencing melanoma metastasis by canonical means, i.e. ECM degradation, but also via regulation of genes involved in several pro-tumorigenic functions including tumor cell growth and motility

Abstract B27: MT1-MMP targeting in melanoma brain metastasis

Abstract Background: Melanoma brain metastases contribute to morbidity and mortality of melanoma, and the treatment is limited due to its accessibility for drugs and also for surgical approaches. Radiotherapy is a widely used approach for disseminated metastatic foci in the brain. However, there is a gap in therapeutics since there are few to no alternatives to melanoma brain metastasis after the radiotherapy dose has been maximized. MT1-MMP is a metalloproteinase that has shown a direct correlation with metastasis and whose inhibition slows down the occurrence of metastasis and tumor growth. By microarray analysis, it has been found that inhibition of MT1-MMP downregulates the expression of DNA-damage response genes. Objective/Hypothesis: We hypothesize that the inhibition of MT1-MMP in combination with radiotherapy will enhance the tumor cell killing efficacy by means of preventing cells from responding to the DNA damage that is caused by radiation. Further, we hypothesize that the Integrin beta 1 pathway downstream of MT1-MMP is the mediator in the downregulation of DNA-damage response genes. Methods: We utilized melanoma cell lines, A375, WM-266-4-Luciferase, and K457, in which we introduced shMT1-MMP lentivirus with control shGFP. Cell culture assays compared the response of shMT1-MMP cells and shGFP cells in the presence of radiotherapy and the assays included comet assay, foci of gammaH2AX staining, clonogenic assay, and evaluation of radiotherapy response by Western blot. Furthermore, a nude mouse model was utilized in which WM-266-4-luciferase shMT1-MMP and control shGFP cells were inoculated by stereotactic injection. In vivo imaging system (IVIS) was utilized to follow up the tumors. Results: Ongoing experiments aim to look at the response of shMT1-MMP cells to radiotherapy compared to shGFP cells by DNA damage evaluation assays (Comet assay, gammaH2AX foci, DNA-damage response proteins by Western blot), downstream signaling of Integrin beta 1 pathway, and the survival of nude mice in shMT1-MMP inoculated tumors and their response to radiotherapy. Impact: This project has the potential to advance the current treatment of melanoma brain metastasis and also has the potential of advancing the understanding of the DNA-damage response in melanoma. Citation Format: Julia Escandon, Varsha Thakur, Barbara Bedogni. MT1-MMP targeting in melanoma brain metastasis [abstract]. In: Proceedings of the AACR Special Conference on Melanoma: From Biology to Target; 2019 Jan 15-18; Houston, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(19 Suppl):Abstract nr B27