Hepatotprotective Natural Products

Medicinal herbs are significant source of pharmaceutical drugs. Latest trends have shown increasing demand of phytodrugs and some medicinal herbs have proven hepatotprotective potential. Silymarin, a flavonol lignan mixture) extracted from the Silybum marianum (milk thistle) is a popular remedy for hepatic diseases. Today every herbal company is marketing formulations for liver disorders but the actual scene is that only selected medicinal herbs have been tested for hepatotprotective activity. Some herbal formulations claiming to be hepatoprotective may actually contain chemical constituents having hepatotoxic potential. Andrographolide (Andrographis paniculata), Glycyrrhizin (Glychyrrhiza glabra), Picrrorihzin (Picrorrhiza kurroa) and Hypo-phyllanthin (Phyllanthus niruri) are potential candidates with hepatoprotective activity. The article reviews latest trends in testing of isolated constituents with hepatoprotective activity

Hepatotprotective Natural Products

Medicinal herbs are significant source of pharmaceutical drugs. Latest trends have shown increasing demand of phytodrugs and some medicinal herbs have proven hepatotprotective potential. Silymarin, a flavonol lignan mixture) extracted from the Silybum marianum (milk thistle) is a popular remedy for hepatic diseases. Today every herbal company is marketing formulations for liver disorders but the actual scene is that only selected medicinal herbs have been tested for hepatotprotective activity. Some herbal formulations claiming to be hepatoprotective may actually contain chemical constituents having hepatotoxic potential. Andrographolide (Andrographis paniculata), Glycyrrhizin (Glychyrrhiza glabra), Picrrorihzin (Picrorrhiza kurroa) and Hypo-phyllanthin (Phyllanthus niruri) are potential candidates with hepatoprotective activity. The article reviews latest trends in testing of isolated constituents with hepatoprotective activity

In vivo and In vitro Interactions between Pseudomonas aeruginosa and Staphylococcus spp.

The significance of polymicrobial infections is increasingly being recognized especially in a biofilm context wherein multiple bacterial species—including both potential pathogens and members of the commensal flora—communicate, cooperate, and compete with each other. Two important bacterial pathogens that have developed a complex network of evasion, counter-inhibition, and subjugation in their battle for space and nutrients are Pseudomonas aeruginosa and Staphylococcus aureus. Their strain- and environment-specific interactions, for instance in the cystic fibrosis lung or in wound infections, show severe competition that is generally linked to worse patient outcomes. For instance, the extracellular factors secreted by P. aeruginosa have been shown to subjugate S. aureus to persist as small colony variants (SCVs). On the other hand, data also exist where S. aureus inhibits biofilm formation by P. aeruginosa but also protects the pathogen by inhibiting its phagocytosis. Interestingly, such interspecies interactions differ between the planktonic and biofilm phenotype, with the extracellular matrix components of the latter likely being a key, and largely underexplored, influence. This review attempts to understand the complex relationship between P. aeruginosa and Staphylococcus spp., focusing on S. aureus, that not only is interesting from the bacterial evolution point of view, but also has important consequences for our understanding of the disease pathogenesis for better patient management

Consolidating and Exploring Antibiotic Resistance Gene Data Resources

The unrestricted use of antibiotics has resulted in rapid acquisition of antibiotic resistance (AR) and spread of multidrug-resistant (MDR) bacterial pathogens. With the advent of next-generation sequencing technologies and their application in understanding MDR pathogen dynamics, it has become imperative to unify AR gene data resources for easy accessibility for researchers. However, due to the absence of a centralized platform for AR gene resources, availability, consistency, and accuracy of information vary considerably across different databases. In this article, we explore existing AR gene data resources in order to make them more visible to the clinical microbiology community, to identify their limitations, and to propose potential solutions

Average Metallicity and Star Formation Rate of Lya Emitters Probed by a Triple Narrow-Band Survey

We present the average metallicity and star-formation rate of Lya emitters (LAEs) measured from our large-area survey with three narrow-band (NB) filters covering the Lya, [OII]3727, and Ha+[NII] lines of LAEs at z=2.2. We select 919 z=2.2 LAEs from Subaru/Suprime-Cam NB data in conjunction with Magellan/IMACS spectroscopy. Of these LAEs, 561 and 105 are observed with KPNO/NEWFIRM near-infrared NB filters whose central wavelengths are matched to redshifted [OII] and Ha nebular lines, respectively. By stacking the near-infrared images of the LAEs, we successfully obtain average nebular-line fluxes of LAEs, the majority of which are too faint to be identified individually by narrow-band imaging or deep spectroscopy. The stacked object has an Ha luminosity of 1.7x10^{42} erg s^{-1} corresponding to a star formation rate (SFR) of 14 M_{sun} yr^{-1}. We place, for the first time, a firm lower limit to the average metallicity of LAEs of Z>~0.09 Z_{sun} (2sigma) based on the [OII]/(Ha+[NII]) index together with photo-ionization models and empirical relations. This lower limit of metallicity rules out the hypothesis that LAEs, so far observed at z~2, are extremely metal poor (Z<2x10^{-2} Z_{sun}) young galaxies at the 4sigma level. This limit is higher than a simple extrapolation of the observed mass-metallicity relation of z~2 UV-selected galaxies toward lower masses (5x10^{8} M_{sun}), but roughly consistent with a recently proposed fundamental mass-metallicity relation when the LAEs' relatively low SFR is taken into account. The Ha and Lya luminosities of our NB-selected LAEs indicate that the escape fraction of Lya photons is ~12-30 %, much higher than the values derived for other galaxy populations at z~2.Comment: 21 pages, 15 figures, 8 tables. Accepted for publication in Ap

Terminalia arjuna in Chronic Stable Angina: Systematic Review and Meta-Analysis

Background. Terminalia arjuna is a popular Indian medicinal plant with its bark been used for over centuries as cardiotonic. The bark has been found to contain several bioactive compounds including saponins and flavonoids. A number of experimental and clinical studies have been conducted to explore therapeutic potential of Terminalia arjuna in cardiovascular ailments specially in patients of coronary heart disease. A number of narrative reviews have been done but no systematic review has been conducted to date. Objective. To systematically review and conduct a meta-analysis on the available literature evaluating the efficacy of Terminalia arjuna in patients of chronic stable angina. Study selection. We included randomised, pseudo-randomized and beforeafter comparative studies which compared Terminalia arjuna/commercial preparation of Terminalia arjuna with current standard/ conventional treatment regimens in patients with chronic stable angina. Findings. Studies were found to be of poor methodological design. We found no significant difference in the Terminalia arjuna group as compared to control arm in the outcomes for which we were able to pool data and undertake meta-analysis. Conclusions. Currently, the evidence is insufficient to draw any definite conclusions in favour of or against Terminalia arjuna in patients of chronic stable angina. Further, well-controlled multicentric clinical trials need to be conducted in large number of patients to explore the therapeutic potential of Terminalia arjuna if any

Dissecting the role of the gut microbiome and fecal microbiota transplantation in radio- and immunotherapy treatment of colorectal cancer

Colorectal cancer (CRC) is one of the most commonly diagnosed cancers and poses a major burden on the human health worldwide. At the moment, treatment of CRC consists of surgery in combination with (neo)adjuvant chemotherapy and/or radiotherapy. More recently, immune checkpoint blockers (ICBs) have also been approved for CRC treatment. In addition, recent studies have shown that radiotherapy and ICBs act synergistically, with radiotherapy stimulating the immune system that is activated by ICBs. However, both treatments are also associated with severe toxicity and efficacy issues, which can lead to temporary or permanent discontinuation of these treatment programs. There's growing evidence pointing to the gut microbiome playing a role in these issues. Some microorganisms seem to contribute to radiotherapy-associated toxicity and hinder ICB efficacy, while others seem to reduce radiotherapy-associated toxicity or enhance ICB efficacy. Consequently, fecal microbiota transplantation (FMT) has been applied to reduce radio- and immunotherapy-related toxicity and enhance their efficacies. Here, we have reviewed the currently available preclinical and clinical data in CRC treatment, with a focus on how the gut microbiome influences radio- and immunotherapy toxicity and efficacy and if these treatments could benefit from FMT

Characterization of two new CTX-M-25-group extended-spectrum β-lactamase variants identified in Escherichia coli isolates from Israel.

OBJECTIVES: We characterized two new CTX-M-type extended-spectrum β-lactamase (ESBL) variants in Escherichia coli isolates from stool samples of two elderly patients admitted at the Tel Aviv Sourasky Medical Center, Israel. Both patients underwent treatment with cephalosporins prior to isolation of the E. coli strains. METHODS: ESBLs were detected by the double-disk synergy test and PCR-sequencing of β-lactamase genes. The bla(CTX-M) genes were cloned into the pCR-BluntII-TOPO vector in E. coli TOP10. The role of amino-acid substitutions V77A and D240G was analyzed by site-directed mutagenesis of the bla(CTX-M-94) and bla(CTX-M-100) genes and comparative characterization of the resulting E. coli recombinants. MICs of β-lactams were determined by Etest. Plasmid profiling, mating experiments, replicon typing and sequencing of bla(CTX-M) flanking regions were performed to identify the genetic background of the new CTX-M variants. RESULTS: The novel CTX-M β-lactamases, CTX-M-94 and -100, belonged to the CTX-M-25-group. Both variants differed from CTX-M-25 by the substitution V77A, and from CTX-M-39 by D240G. CTX-M-94 differed from all CTX-M-25-group enzymes by the substitution F119L. Glycine-240 was associated with reduced susceptibility to ceftazidime and leucine-119 with increased resistance to ceftriaxone. bla(CTX-M-94) and bla(CTX-M-100) were located within ISEcp1 transposition units inserted into ∼93 kb non-conjugative IncFI and ∼130 kb conjugative IncA/C plasmids, respectively. The plasmids carried also different class 1 integrons. CONCLUSIONS: This is the first report on CTX-M-94 and -100 ESBLs, novel members of the CTX-M-25-group

The dynamic transcriptome during maturation of biofilms formed by methicillin-resistant Staphylococcus aureus

BackgroundMethicillin-resistant Staphylococcus aureus (MRSA), a leading cause of chronic infections, forms prolific biofilms which afford an escape route from antibiotic treatment and host immunity. However, MRSA clones are genetically diverse, and mechanisms underlying biofilm formation remain under-studied. Such studies form the basis for developing targeted therapeutics. Here, we studied the temporal changes in the biofilm transcriptome of three pandemic MRSA clones: USA300, HEMRSA-15, and ST239.MethodsBiofilm formation was assessed using a static model with one representative strain per clone. Total RNA was extracted from biofilm and planktonic cultures after 24, 48, and 72 h of growth, followed by rRNA depletion and sequencing (Illumina Inc., San Diego, CA, United States, NextSeq500, v2, 1 × 75 bp). Differentially expressed gene (DEG) analysis between phenotypes and among early (24 h), intermediate (48 h), and late (72 h) stages of biofilms was performed together with in silico co-expression network construction and compared between clones. To understand the influence of SCCmec and ACME on biofilm formation, isogenic mutants containing deletions of the entire elements or of single genes therein were constructed in USA300.ResultsGenes involved in primarily core genome-encoded KEGG pathways (transporters and others) were upregulated in 24-h biofilm culture compared to 24-h planktonic culture. However, the number of affected pathways in the ST239 24 h biofilm (n = 11) was remarkably lower than that in USA300/EMRSA-15 biofilms (USA300: n = 27, HEMRSA-15: n = 58). The clfA gene, which encodes clumping factor A, was the single common DEG identified across the three clones in 24-h biofilm culture (2.2- to 2.66-fold). In intermediate (48 h) and late (72 h) stages of biofilms, decreased expression of central metabolic and fermentative pathways (glycolysis/gluconeogenesis, fatty acid biosynthesis), indicating a shift to anaerobic conditions, was already evident in USA300 and HEMRSA-15 in 48-h biofilm cultures; ST239 showed a similar profile at 72 h. Last, SCCmec+ACME deletion and opp3D disruption negatively affected USA300 biofilm formation.ConclusionOur data show striking differences in gene expression during biofilm formation by three of the most important pandemic MRSA clones, USA300, HEMRSA-15, and ST239. The clfA gene was the only significantly upregulated gene across all three strains in 24-h biofilm cultures and exemplifies an important target to disrupt early biofilms. Furthermore, our data indicate a critical role for arginine catabolism pathways in early biofilm formation

Clinical Impact of Monoclonal Antibodies in the Treatment of High-Risk Patients with SARS-CoV-2 Breakthrough Infections:The ORCHESTRA Prospective Cohort Study

The clinical impact of anti-spike monoclonal antibodies (mAb) in Coronavirus Disease 2019 (COVID-19) breakthrough infections is unclear. We present the results of an observational prospective cohort study assessing and comparing COVID-19 progression in high-risk outpatients receiving mAb according to primary or breakthrough infection. Clinical, serological and virological predictors associated with 28-day COVID-19-related hospitalization were identified using multivariate logistic regression and summarized with odds ratio (aOR) and 95% confidence interval (CI). A total of 847 COVID-19 outpatients were included: 414 with primary and 433 with breakthrough infection. Hospitalization was observed in 42/414 (10.1%) patients with primary and 8/433 (1.8%) patients with breakthrough infection (p &lt; 0.001). aOR for hospitalization was significantly lower for breakthrough infection (aOR 0.12, 95%CI: 0.05–0.27, p &lt; 0.001) and higher for immunocompromised status (aOR:2.35, 95%CI:1.08–5.08, p = 0.003), advanced age (aOR:1.06, 95%CI: 1.03–1.08, p &lt; 0.001), and male gender (aOR:1.97, 95%CI: 1.04–3.73, p = 0.037). Among the breakthrough infection group, the median SARS-CoV-2 anti-spike IgGs was lower (p &lt; 0.001) in immunocompromised and elderly patients &gt;75 years compared with that in the immunocompetent patients. Our findings suggest that, among mAb patients, those with breakthrough infection have significantly lower hospitalization risk compared with patients with primary infection. Prognostic algorithms combining clinical and immune-virological characteristics are needed to ensure appropriate and up-to-date clinical protocols targeting high-risk categories.</p