Gut microbiota alterations promote traumatic stress susceptibility associated with p-cresol-induced dopaminergic dysfunctions.

Mounting evidence suggests a link between gut microbiota abnormalities and post-traumatic stress disorder (PTSD). However, whether and how the gut microbiota influences PTSD susceptibility is poorly understood. Here using the arousal-based individual screening model, we provide evidence for pre-trauma and post-trauma gut microbiota alterations in susceptible mice exhibiting persistent PTSD-related phenotypes. A more in-depth analysis revealed an increased abundance of bacteria affecting brain processes including myelination, and brain systems like the dopaminergic neurotransmission. Because dopaminergic dysfunctions play a key role in the pathophysiological mechanisms subserving PTSD, we assessed whether these alterations in gut microbiota composition could be associated with abnormal levels of metabolites inducing dopaminergic dysfunctions. We found high levels of the l-tyrosine-derived metabolite p-cresol exclusively in the prefrontal cortex of susceptible mice. We further uncovered abnormal levels of dopamine and DOPAC, together with a detrimental increase of dopamine D3 receptor expression, exclusively in the prefrontal cortex of susceptible mice. Conversely, we observed either resilience mechanisms aimed at counteracting these p-cresol-induced dopaminergic dysfunctions or myelination-related resilience mechanisms only in the prefrontal cortex of resilient mice. These findings reveal that gut microbiota abnormalities foster trauma susceptibility and thus it may represent a promising target for therapeutic interventions.

Natural Substances in the Fight of SARS-CoV-2: A Critical Evaluation Resulting from the Cross-Fertilization of Molecular Modeling Data with the Pharmacological Aspects.

The recent pandemic due to SARS-CoV-2, the last isolated human betacoronavirus, has revolutionized modern knowledge of the pathogenesis of viral pneumonia. The lack of specific antiviral drugs and the need to develop adequate research for new antiviral drugs capable of treating this new form of the disease undertook three different research paths quickly. The first one is aimed to test antiviral molecules already present in therapeutic use, with a mechanism of action directed towards viral proteins functional to replication or adsorption; the second one, it is the repositioning of molecules with known pharmacological activity for which various chemistry studies have been prepared in an attempt to find new and specific viral targets; the third, it is the search for molecules of natural origin for which to demonstrate a specific anti-coronavirus activity. Many databases of natural and synthetic substances have been used for the identification of potent inhibitors of various viral targets. The field of computer-aided drug design seems to be promising and useful for the identification of SARS-CoV-2 inhibitors; hence, different structure- and ligand- based computational approaches have been used for their identification. This review analyzes in-depth and critically the most recent publications in the field of applied computational chemistry to find out molecules of natural origin with potent antiviral activity. Furthermore, a critical and functional selection of some molecules with the best hypothetical anti-SARS-CoV-2 activity is made for further studies by biological tests.

Bacteriocins, A Natural Weapon Against Bacterial Contamination for Greater Safety and Preservation of Food: A Review.

Nowadays, consumers have become increasingly attentive to human health and the use of more natural products. Consequently, the demand for natural preservatives in the food industry is more frequent. This has led to intense research to discover new antimicrobial compounds of natural origin that could effectively fight foodborne pathogens. This research aims to safeguard the health of consumers and, above all, to avoid potentially harmful chemical compounds. Lactobacillus is a bacterial genus belonging to the Lactic Acid Bacteria and many strains are defined GRAS, generally recognized as safe. These strains are able to produce substances with antibacterial activity against food spoilage bacteria and contaminating pathogens: the bacteriocins. The aim of this review was to focus on this genus and its capability to produce antibacterial peptides. The review collected all the information from the last few years about bacteriocins produced by Lactobacillus strains, isolated from clinical or food samples, with remarkable antimicrobial activities useful for being exploited in the food field. In addition, the advantages and disadvantages of their use and the possible ways of improvement for industrial applications were described.

Investigation on the Antibacterial Activity of Electronic Cigarette Liquids (ECLs): A Proof of Concept Study.

BACKGROUND: The key ingredients of e-cigarettes liquid are commonly propane-1,2-diol (also called propylene glycol) and propane-1,2,3-triol (vegetal glycerol) and their antimicrobial effects are already established. The nicotine and flavors which are often present in e-liquids can interfere with the growth of some microorganisms. OBJECTIVE: The effect of combining these elements in e-liquids is unknown. The aim of the study was to investigate the possible effects of these liquids on bacterial growth in the presence or absence of nicotine and flavors. METHODS: Susceptibilities of pathogenic strains (Klebsiella pneumoniae, Staphylococcus aureus, Pseudomonas aeruginosa, Acinetobacter baumannii, Escherichia coli, Enterococcus faecalis and Sarcina lutea) were studied by means of a multidisciplinary approach. Cell viability and antioxidant assays were also evaluated. RESULTS: All e-liquids investigated showed antibacterial activity against at least one pathogenic strain. Higher activity was correlated to the presence of flavors and nicotine. DISCUSSION: In most cases, the value of minimal bactericidal concentration is equal to the value of minimal inhibitory concentration showing that these substances have a bactericidal effect. This effect was observed in concentrations up to 6.25% v/v. Antioxidant activity was also correlated to the presence of flavors. Over time, the viability assay in human epithelial lung A549 cells showed a dose-dependent inhibition of cell growth. CONCLUSION: Our results have shown that flavors considerably enhance the antibacterial activity of propane-1,2-diol and propane-1,2,3-triol. This study provides important evidence that should be taken into consideration in further investigative approaches, to clarify the different sensitivity of the various bacterial species to e-liquids, including the respiratory microbiota, to highlight the possible role of flavors and nicotine.

Probiotic Properties of Lactobacillus fermentum Strains Isolated from Human Oral Samples and Description of their Antibacterial Activity.

BACKGROUND: Gram positive bacteria produce peptides, defined bacteriocins which exhibit good antibacterial activity. OBJECTIVE: We evaluated the ability of L. fermentum to produce bacteriocins having therefore, good probiotic features and finally, be safe towards microglial cells. METHOD: Eight wild strains, identified using molecular techniques, were investigated for the evaluation of resistance to bile salts, low pH, H2O2 production, biofilm formation, antibacterial activity and safety on microglia cells (BV2). RESULTS: The determination of the susceptibility/resistance profile showed that the strains are sensitive to the antibiotics tested. All strains showed a good tolerability to extremely low pH as well as resisting in presence of bile salts. In addition, the strains showed excellent activity against pathogens and one of them (LAC 42) showed activity also against Pseudomonas aeruginosa and Klebsiella pneumoniae. Finally, LAC 42 and its active compound did not change microglia cell viability following 24h exposure. Our data on this antibacterial molecule suggest that it is a compound with low molecular weight and with highly hydrophilic component. CONCLUSION: These results describe the characteristics of Lactobacillus strains and provide evidences for their possible use as new potential probiotic. In addition, other studies are now warranted to exploit the antibacterial activity of the supernatant LAC 42 and for its complete chemical characterization.

Anti-Adhesion Activity of A2-type Proanthocyanidins (a Cranberry Major Component) on Uropathogenic E. coli and P. mirabilis Strains.

Urinary tract infections (UTIs) are relatively common in women and may be classified as uncomplicated or complicated, depending upon the urinary tract anatomy and physiology. Acute uncomplicated cystitis (AUC) occurs when urinary pathogens from the bowel or vagina colonize the periurethral mucosa and reach the bladder. The vast majority of episodes in healthy women involving the same bacterial strain that caused the initial infection are thought to be reinfections. About 90% of AUC are caused by uropathogenic Escherichia coli (UPEC), but Proteus mirabilis also plays an important role. Several studies support the importance of cranberry (Vaccinium macrocarpon) proanthocyanidins in preventing adhesion of P-fimbriated UPEC to uroepithelial cells. In this study, we evaluated the in vitro anti-adhesion activity of A2-linked proanthocyanidins from cranberry on a UPEC and Proteus mirabilis strains and their possible influence on urease activity of the latter. A significant reduction of UPEC adhesion (up to 75%) on the HT1376 cell line was observed vs. control. For the strains of P. mirabilis there was also a reduction of adhesion (up to 75%) compared to controls, as well as a reduction in motility and urease activity. These results suggest that A2-type cranberry proanthocyanidins could aid in maintaining urinary tract health.

Amphiphilic ion pairs of tobramycin with lipoamino acids.

A series of amphiphilic ion pairs of the aminoglycoside antibiotic tobramycin (TOB) with lipoamino acids (LAA) bearing an alkyl side chain of 10-14 carbon atoms are described. TOB-LAA ion pairs were obtained by reduced pressure evaporation of an aqueous-ethanol co-solution of TOB and LAAs. A different degree of substitution of TOB amine groups was obtained by using increasing the drug to LAA molar fractions (1:1 to 1:5). FTIR analysis corroborated their structure, powder X-ray diffractometry (PXRD) and differential scanning calorimetry (DSC) were used to identify the formation of new chemical species. The prepared compounds were submitted to an in vitro microbiological assay against different bacterial strains, both susceptible and resistant to aminoglycosides. The presence of only one LAA moiety did not improve the in vitro antibacterial activity of TOB free base. Analogously, equimolar physical mixtures (PhM) of TOB with LAA failed to exert a remarkable cell growth inhibitory activity. Noteworthy, when three or all the five amine groups of TOB were salified with LAA residues, very active compounds were produced, showing MIC values lower than the detectable limit of 0.03 µg/ml.

Combining molecular modeling with experimental methodologies: mechanism of membrane permeation and accumulation of ofloxacin.

The interaction between ofloxacin, as a model drug of the fluoroquinolone class, and biomembranes was examined as the possible initial step in a transmembrane diffusion process. Dipalmitoylphosphatidylcholine was used for the preparation of biomembrane models. The influence of environmental conditions and protonation on molecular physicochemical behavior, and hence on the membrane interaction, was investigated by differential scanning calorimetry (DSC). This technique has been shown to be very effective in the interpretation of interactions of drug microspeciations with biomembranes. These findings suggest that the interaction occurred owing to ionic and hydrophobic forces showing how the passage through the membrane is mainly favored in the pH interval 6-7.4. It was demonstrated that a pH gradient through model membranes may be responsible for a poorly homogeneous distribution of ofloxacin (or other related fluoroquinolones), which justifies the in vivo accumulation properties of this drug. DSC experiments, which are in agreement with computational data, also showed that the complexing capability of ofloxacin with regard to Mg(++) or Ca(++) may govern the drug entrance into bacterial cells before the DNA Girase inhibition and could ensure the formation of hydrophobic and more fluid phospholipid domains on the surface of the model membrane. These regions are more permeable with regard to various solutes, as well as ofloxacin, allowing a so-called 'self-promoted entrance pathway'. The combination of experimental methodologies with computational data allowed a further rationalization of the results and opened new perspectives into the mechanism of action of ofloxacin, namely its interaction with lipid bilayers and drug-divalent cation complex formation, which might be extended to the entire fluoroquinolone class. Ofloxacin accumulation within Escherichia coli ATCC 25922 was measured as a function of time. Also in this example, the environmental conditions influenced ofloxacin penetration and accumulation. The in vitro experiments, reported here, show that a suitable balance of hydrophilic and hydrophobic fluoroquinolone properties needs to occur for there to be increased drug permeation.