GERANIOL, A COMPONENT OF PLANT ESSENTIAL OILS–A REVIEW OF ITS PHARMACOLOGICAL ACTIVITIES

Essential oils are a mixture of volatile and natural substances, identified and characterized by the strong odor, produced by aromatic plants as secondary metabolites. Their metabolites have a wide range of applications and have been commercially important to the pharmaceutical, food and cosmetic industries. One of the plants essential oil Geraniol, a monoterpene alcohol has the verity of pharmacological activities are reported in preclinical studies. Generally, monoterpenes are non nutritive dietary components found in the essential oils of citrus fruits and other plants. Geraniol has antibacterial, antiseptic, anti-inflammatory, in vivo and in vitro anticancer against in leukemia, hepatoma, melanoma and pancreatic cancer cell lines, and activity on lipid metabolisms and Mevelonate metabolisms. In this review, article highlights the important pharmacological activities of plant essential oil geraniol.Â

Effect of silymarin on N-nitrosodiethylamine induced hepatocarcinogenesis in rats

Aim: To study the effect of silymarin on the levels of tumor markers and MDA (malondialdehyde) – DNA adduct formation during N-nitrosodiethylamine induced hepatocellular carcinoma in male Wistar albino rats. Methods: The levels of AFP, CEA and activities of liver marker enzymes in serum, MDA-DNA immunohistochemistry were done according to standard procedures in the control and experimental groups of rats. Results: Hepatocellular carcinoma was evidenced from significant (p < 0.05) increases of alpha-fetoprotein, carcinoembryonic antigen, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, acid phosphatase, lactate dehydrogenase, gamma-glutamyltransferase and 5?-nucleotidase in serum and increased MDA-DNA adducts were also observed in the tissue sections of hepatocellular carcinoma. Silymarin treatment significantly attenuated the alteration of these markers and decreased the levels of MDA-DNA adduct formation. Conclusion: Silymarin could be developed as a promising chemotherapeutic adjuvant for the treatment of liver cancer.Цель: изучить влияние силимарина на уровень экспрессии опухолевых и биохимических маркеров и формирование аддуктов малонового диальдегида с ДНК (MDA-DNA) при развитии гепатокариномы у крыс линии истар. Методы: стандартными биохимическими методами определяли активность ферментов в сыворотке крови и проводили иммуногистохимическое определение MDA-DNA в ткани печени крыс. Результаты: показано, что при развитии злокачественной гепатокарциномы в сыворотке крови животных значительно увеличивается количество альфа-фетопротеина, раковоэмбрионального антигена, активность аспартат- и аланинаминотрансферазы, щелочной и кислой фосфатазы, лактатдегидрогеназы, гаммаглутамилтрансферазы и 5-нуклеотидазы. При проведении иммуногистохимического исследования отмечали повышенное образование аддуктов MDA-DNA в ткани печени крыс со злокачественной гепатокариномой. При введении силимарина значительно снижался уровень указанных ферментов в сыворотке крови и формирование аддуктов MDA-DNA в ткани печени. Заключение: применение силимарина может быть эффективно для предупреждения развития злокачественной гепатокарциномы, индуцированной N-нитрозодиэтиламином у крыс, и этот препарат может быть многообещающим химиотерапевтическим адъювантом для лечения рака печени

Treatment Outcomes in Patients With Metastatic Renal Cell Carcinoma With Sarcomatoid and/or Rhabdoid Dedifferentiation After Progression on Immune Checkpoint Therapy

BACKGROUND: Metastatic RCC with sarcomatoid and/or rhabdoid (S/R) dedifferentiation is an aggressive disease associated with improved response to immune checkpoint therapy (ICT). The outcomes of patients treated with VEGFR-targeted therapies (TT) following ICT progression have not been investigated. PATIENTS AND METHODS: Retrospective review of 57 patients with sarcomatoid (S), rhabdoid (R), or sarcomatoid plus rhabdoid (S + R) dedifferentiation who received any TT after progression on ICT at an academic cancer center. Clinical endpoints of interest included time on TT, overall survival (OS) from initiation of TT, and objective response rate (ORR) by RECIST version 1.1. Multivariable models adjusted for epithelial histology, IMDC risk, prior VEGFR TT, and inclusion of cabozantinib in the post-ICT TT regimen. RESULTS: 29/57 patients had S dedifferentiation and 19 had R dedifferentiation. The most frequently used TT was cabozantinib (43.9%) followed by selective VEGFR TT (22.8%). The median time on TT was 6.4 months for all, 6.1 months for those with S dedifferentiation, 15.6 months for R dedifferentiation, and 6.1 months for S + R dedifferentiation. Median OS from initiation of TT was 24.9 months for the entire cohort, and the ORR was 20.0%. Patients with R dedifferentiation had significantly longer time on TT than those with S dedifferentiation (HR 0.44, 95% CI, 0.21-0.94). IMDC risk was associated with OS. CONCLUSIONS: A subset of patients with S/R dedifferentiation derive clinical benefit from TT after they have progressive disease on ICT. Patients with R dedifferentiation appeared to derive more benefit from TT than those with S dedifferentiation

Germ Warfare in a Microbial Mat Community: CRISPRs Provide Insights into the Co-Evolution of Host and Viral Genomes

CRISPR arrays and associated cas genes are widespread in bacteria and archaea and confer acquired resistance to viruses. To examine viral immunity in the context of naturally evolving microbial populations we analyzed genomic data from two thermophilic Synechococcus isolates (Syn OS-A and Syn OS-B′) as well as a prokaryotic metagenome and viral metagenome derived from microbial mats in hotsprings at Yellowstone National Park. Two distinct CRISPR types, distinguished by the repeat sequence, are found in both the Syn OS-A and Syn OS-B′ genomes. The genome of Syn OS-A contains a third CRISPR type with a distinct repeat sequence, which is not found in Syn OS-B′, but appears to be shared with other microorganisms that inhabit the mat. The CRISPR repeats identified in the microbial metagenome are highly conserved, while the spacer sequences (hereafter referred to as “viritopes” to emphasize their critical role in viral immunity) were mostly unique and had no high identity matches when searched against GenBank. Searching the viritopes against the viral metagenome, however, yielded several matches with high similarity some of which were within a gene identified as a likely viral lysozyme/lysin protein. Analysis of viral metagenome sequences corresponding to this lysozyme/lysin protein revealed several mutations all of which translate into silent or conservative mutations which are unlikely to affect protein function, but may help the virus evade the host CRISPR resistance mechanism. These results demonstrate the varied challenges presented by a natural virus population, and support the notion that the CRISPR/viritope system must be able to adapt quickly to provide host immunity. The ability of metagenomics to track population-level variation in viritope sequences allows for a culture-independent method for evaluating the fast co-evolution of host and viral genomes and its consequence on the structuring of complex microbial communities

Changes in Parasite Virulence Induced by the Disruption of a Single Member of the 235 kDa Rhoptry Protein Multigene Family of Plasmodium yoelii

Invasion of the erythrocyte by the merozoites of the malaria parasite is a complex process involving a range of receptor-ligand interactions. Two protein families termed Erythrocyte Binding Like (EBL) proteins and Reticulocyte Binding Protein Homologues (RH) play an important role in host cell recognition by the merozoite. In the rodent malaria parasite, Plasmodium yoelii, the 235 kDa rhoptry proteins (Py235) are coded for by a multigene family and are members of the RH. In P. yoelii Py235 as well as a single member of EBL have been shown to be key mediators of virulence enabling the parasite to invade a wider range of host erythrocytes. One member of Py235, PY01365 is most abundantly transcribed in parasite populations and the protein specifically binds to erythrocytes and is recognized by the protective monoclonal antibody 25.77, suggesting a key role of this particular member in virulence. Recent studies have indicated that overall levels of Py235 expression are essential for parasite virulence. Here we show that disruption of PY01365 in the virulent YM line directly impacts parasite virulence. Furthermore the disruption of PY01365 leads to a reduction in the number of schizonts that express members of Py235 that react specifically with the mcAb 25.77. Erythrocyte binding assays show reduced binding of Py235 to red blood cells in the PY01365 knockout parasite as compared to YM. While our results identify PY01365 as a mediator of parasite virulence, they also confirm that other members of Py235 are able to substitute for PY01365

Efficacy and safety of bempedoic acid for the treatment of hypercholesterolemia: A systematic review and meta-analysis

Background Bempedoic acid is a first-in-class lipid-lowering drug recommended by guidelines for the treatment of hypercholesterolemia. Our objective was to estimate its average effect on plasma lipids in humans and its safety profile. Methods and findings We carried out a systematic review and meta-analysis of phase II and III randomized controlled trials on bempedoic acid (PROSPERO: CRD42019129687). PubMed (Medline), Scopus, Google Scholar, and Web of Science databases were searched, with no language restriction, from inception to 5 August 2019. We included 10 RCTs (n = 3,788) comprising 26 arms (active arm [n = 2,460]; control arm [n = 1,328]). Effect sizes for changes in lipids and high-sensitivity C-reactive protein (hsCRP) serum concentration were expressed as mean differences (MDs) and 95% confidence intervals (CIs). For safety analyses, odds ratios (ORs) and 95% CIs were calculated using the Mantel–Haenszel method. Bempedoic acid significantly reduced total cholesterol (MD −14.94%; 95% CI −17.31%, −12.57%; p &lt; 0.001), non-high-density lipoprotein cholesterol (MD −18.17%; 95% CI −21.14%, −15.19%; p &lt; 0.001), low-density lipoprotein cholesterol (MD −22.94%; 95% CI −26.63%, −19.25%; p &lt; 0.001), low-density lipoprotein particle number (MD −20.67%; 95% CI −23.84%, −17.48%; p &lt; 0.001), apolipoprotein B (MD −15.18%; 95% CI −17.41%, −12.95%; p &lt; 0.001), high-density lipoprotein cholesterol (MD −5.83%; 95% CI −6.14%, −5.52%; p &lt; 0.001), high-density lipoprotein particle number (MD −3.21%; 95% CI −6.40%, −0.02%; p = 0.049), and hsCRP (MD −27.03%; 95% CI −31.42%, −22.64%; p &lt; 0.001). Bempedoic acid did not significantly modify triglyceride level (MD −1.51%; 95% CI −3.75%, 0.74%; p = 0.189), verylow-density lipoprotein particle number (MD 3.79%; 95% CI −9.81%, 17.39%; p = 0.585), and apolipoprotein A-1 (MD −1.83%; 95% CI −5.23%, 1.56%; p = 0.290). Treatment with bempedoic acid was positively associated with an increased risk of discontinuation of treatment (OR 1.37; 95% CI 1.06, 1.76; p = 0.015), elevated serum uric acid (OR 3.55; 95% CI 1.03, 12.27; p = 0.045), elevated liver enzymes (OR 4.28; 95% CI 1.34, 13.71; p = 0.014), and elevated creatine kinase (OR 3.79; 95% CI 1.06, 13.51; p = 0.04), though it was strongly associated with a decreased risk of new onset or worsening diabetes (OR 0.59; 95% CI 0.39, 0.90; p = 0.01). The main limitation of this meta-analysis is related to the relatively small number of individuals involved in the studies, which were often short or middle term in length. Conclusions Our results show that bempedoic acid has favorable effects on lipid profile and hsCRP levels and an acceptable safety profile. Further well-designed studies are needed to explore its longer-term safety