Gut microbiota in neurological diseases: Melatonin plays an important regulatory role.

Melatonin is a highly conserved molecule produced in the human pineal gland as a hormone. It is known for its essential biological effects, such as antioxidant activity, circadian rhythm regulator, and immunomodulatory effects. The gut is one of the primary known sources of melatonin. The gut microbiota helps produce melatonin from tryptophan, and melatonin has been shown to have a beneficial effect on gut barrier function and microbial population. Dysbiosis of the intestinal microbiota is associated with bacterial imbalance and decreased beneficial microbial metabolites, including melatonin. In this way, low melatonin levels may be related to several human diseases. Melatonin has shown both preventive and therapeutic effects against various conditions, including neurological diseases such as Alzheimer's disease, Parkinson's disease, and multiple sclerosis. This review was aimed to discuss the role of melatonin in the body, and to describe the possible relationship between gut microbiota and melatonin production, as well as the potential therapeutic effects of melatonin on neurological diseases.

Tuberculosis vaccine developments and efficient delivery systems: A comprehensive appraisal.

Despite the widespread use of the Bacillus Calmette-Guérin (BCG) vaccine, Mycobacterium tuberculosis (MTB) continues to be a global burden. Vaccination has been proposed to prevent and treat tuberculosis (TB) infection, and several of them are in different phases of clinical trials. Though vaccine production is in progress but requires more attention. There are several TB vaccines in the trial phase, most of which are based on a combination of proteins/adjuvants or recombinant viral vectors used for selected MTB antigens. In this review, we attempted to discuss different types of TB vaccines based on the vaccine composition, the immune responses generated, and their clinical trial phases. Furthermore, we have briefly overviewed the effective delivery systems used for the TB vaccine and their effectiveness in different vaccines.

Preparation, Physicochemical Characterization, Antimicrobial Effects, Biocompatibility and Cytotoxicity of Co-Loaded Meropenem and Vancomycin in Mesoporous Silica Nanoparticles.

Mesoporous silica nanoparticles (MSNPs) have been reported as an effective system to co-deliver a variety of different agents to enhance efficiency and improve biocompatibility. This study was aimed at the preparation, physicochemical characterization, antimicrobial effects, biocompatibility, and cytotoxicity of vancomycin and meropenem co-loaded in the mesoporous silica nanoparticles (Van/Mrp-MSNPs). The prepared nanoparticles were explored for their physicochemical features, antibacterial and antibiofilm effects, biocompatibility, and cytotoxicity. The minimum inhibitory concentrations (MICs) of the Van/Mrp-MSNPs (0.12-1 µg/mL) against Staphylococcus aureus isolates were observed to be lower than those of the same concentrations of vancomycin and meropenem. The minimum biofilm inhibitory concentration (MBIC) range of the Van/Mrp-MSNPs was 8-64 µg/mL, which was lower than the meropenem and vancomycin MBICs. The bacterial adherence was not significantly decreased upon exposure to levels lower than the MICs of the MSNPs and Van/Mrp-MSNPs. The viability of NIH/3T3 cells treated with serial concentrations of the MSNPs and Van/Mrp-MSNPs were 73-88% and 74-90%, respectively. The Van/Mrp-MSNPs displayed considerable inhibitory effects against MRSA, favorable biocompatibility, and low cytotoxicity. The Van/Mrp-MSNPs could be a potential system for the treatment of infections.

Collateral sensitivity: An evolutionary trade-off between antibiotic resistance mechanisms, attractive for dealing with drug-resistance crisis.

Background: The discovery and development of antimicrobial drugs were one of the most significant advances in medicine, but the evolution of microbial resistance limited the efficiency of these drugs. Aim: This paper reviews the collateral sensitivity in bacteria and its potential and limitation as a new target for treating infections. Results and Discussion: Knowledge mechanisms of resistance to antimicrobial agents are useful to trace a practical approach to treat and control of resistant pathogens. The effect of a resistance mechanism to certain antibiotics on the susceptibility or resistance to other drugs is a key point that may be helpful for applying a strategy to control resistance challenges. In an evolutionary trade-off known as collateral sensitivity, the resistance mechanism to a certain drug may be mediated by the hypersensitivity to other drugs. Collateral sensitivity has been described for different drugs in various bacteria, but the molecular mechanisms affecting susceptibility are not well demonstrated. Collateral sensitivity could be studied to detect its potential in the battle against resistance crisis as well as in the treatment of pathogens adapting to antibiotics. Collateral sensitivity-based antimicrobial therapy may have the potential to limit the emergence of antibiotic resistance.

Immunologic biomarkers for bacterial meningitis.

Meningitis is defined as the inflammation of the meninges that is most often caused by various bacterial and viral pathogens, and is associated with high rates of mortality and morbidity. Early detection of bacterial meningitis is essential to appropriate antibiotic therapy. Alterations in immunologic biomarkers levels have been considered the diagnostic approach in medical laboratories for the identifying of infections. The early increasing immunologic mediators such as cytokines and acute phase proteins (APPs) during bacterial meningitis have made they significant indicators for laboratory diagnosis. Immunology biomarkers showed wide variable sensitivity and specificity values that influenced by different reference values, selected a certain cutoff point, methods of detection, patient characterization and inclusion criteria, as well as etiology of meningitis and time of CSF or blood specimens' collection. This study provides an overview of different immunologic biomarkers as diagnostic markers for the identification of bacterial meningitis and their efficiencies in the differentiating of bacterial from viral meningitis.

Antibacterial and biofilm-inhibitory effects of vancomycin-loaded mesoporous silica nanoparticles on methicillin-resistant staphylococcus aureus and gram-negative bacteria.

The present study aimed to prepare and characterize vancomycin-loaded mesoporous silica nanoparticles (Van-MSNs) to detect inhibitory effects on the planktonic and biofilm forms of methicillin-resistant Staphylococcus aureus (MRSA) isolates, and study the biocompatibility and toxicity of Van-MSNs in vitro as well as antibacterial activity of Van-MSNs against Gram-negative bacteria. The inhibitory effects of Van-MSNs were investigated on MRSA using the determination of minimum inhibitory (MIC) and minimum biofilm-inhibitory concentrations (MBIC) as well as the effect on bacterial attachment. Biocompatibility was studied by examining the effect of Van-MSNs on the lysis and sedimentation rate of red blood cells (RBC). The interaction of Van-MSNs with human blood plasma was detected by the SDS-PAGE approach. The cytotoxic effect of the Van-MSNs on human bone marrow mesenchymal stem cells (hBM-MSCs) was evaluated by the MTT assay. The antibacterial effects of vancomycin and Van-MSNs on Gram-negative bacteria were also investigated using MIC determination using the broth microdilution method. Furthermore, bacteria outer membrane (OM) permeabilization was determined. Van-MSNs showed inhibitory effects on planktonic and biofilm forms of bacteria on all isolates at levels lower than MICs and MBICs of free vancomycin, but the antibiofilm effect of Van-MSNs was not significant. However, Van-MSNs did not affect bacterial attachment to surfaces. Van-loaded MSNs did not show a considerable effect on the lysis and sedimentation of RBC. A low interaction of Van-MSNs was detected with albumin (66.5 kDa). The hBM-MSCs viability in exposure to different levels of Van-MSNs was 91-100%. MICs of ≥ 128 µg/mL were observed for vancomycin against all Gram-negative bacteria. In contrast, Van-MSNs exhibited modest antibacterial activity inhibiting the tested Gram-negative bacterial strains, at concentrations of ≤ 16 µg/mL. Van-MSNs increased the OM permeability of bacteria that can increase the antimicrobial effect of vancomycin. According to our findings, Van-loaded MSNs have low cytotoxicity, desirable biocompatibility, and antibacterial effects and can be an option for the battle against planktonic MRSA.

The metabolic, protective, and immune functions of Akkermansia muciniphila.

Numerous studies have almost proven the beneficial effects of gut microbiota in various aspects of human health, and even the gut microbiota is known as a new and forgotten organ. Akkermansia muciniphila, as a member of the gut microbiota, is considered a bacterium with probiotic properties; consequently, it has a remarkable position in microbiome research. This bacterium accounts for about 1-4 % of the total fecal microbiota population and is also considered a health marker. The accumulated evidence has shown a significant association between A. muciniphila and several disorders and diseases, such as obesity, fatty liver disease, diabetes, and even behavioral disorders. On the other hand, the beneficial effects of A. muciniphila in different studies have shown, such as protective role against pathogenic agents, antitumor properties, tight junctions' improvement, reduction of inflammation, gut permeability, and boosting adaptive immune responses. In this review, based on the available evidence and the latest research, we comprehensively evaluated the impact of A. muciniphila on host health from three points of view: metabolic, protective, and immune functions, as well as the possible mechanisms of each process.

Preparation of rutin-loaded mesoporous silica nanoparticles and evaluation of its physicochemical, anticancer, and antibacterial properties.

BACKGROUND: The studies have shown that rutin has great potential as an anticancer and antimicrobial plant base agent; nevertheless, poor bioavailability and low aqueous solubility of rutin limit its application. One of the beneficial routes to increase the solubility and bioavailability of rutin is the development of nanoparticulate material. This study aimed to assess the anticancer and antibacterial effects of rutin-loaded mesoporous silica nanoparticles (RUT-MSNs). METHODS: RUT-MSNs were prepared and physicochemically characterized. The cytotoxicity of RUT-MSNs on the HN5 cells as head and neck cancer cells was evaluated. The expression level of apoptosis-related genes such as Bcl-2 and Bax genes were evaluated. In addition, ROS production of RUT-MSNs treated cells was assessed. In addition, minimum inhibitory concentration (MIC), biofilm, and attachment inhibitory effects of RUT-MSNs compared with free rutin were assessed against different bacterial strains. RESULTS: Transmission electron microscopy (TEM) showed mesoporous rod-shaped nanoparticles with an average particle size of less than 100 nm. RUT-MSNs displayed the cytotoxic effect with IC50 of 20.23 µM in 48 h of incubation time (p < 0.05). The elevation in the ratio of Bax/Bcl-2 was displayed within the IC50 concentration of RUT-MSNs in 48 h (p < 0.05). The antibacterial action of rutin was improved by loading rutin in MSNs to the nano-sized range in the MIC test. CONCLUSION: The anticancer and antibacterial effects of RUT-MSNs were considerably more than rutin. RUT-MSNs inhibited the growth of HN5 cells by inducing apoptosis and producing ROS. These results suggest that RUT-MSNs may be useful in the treatment of cancers and infections.

Curcumin-Loaded Silica Nanoparticles: Applications in Infectious Disease and Food Industry.

Curcumin has multiple properties that are used to cure different diseases such as cancer, infections, inflammatory, arthritic disease, etc. Despite having many effects, the inherent physicochemical properties-such as poor water solubility, chemical instability, low bioavailability, photodegradation, fast metabolism, and short half-life-of curcumin's derivatives have limited its medical importance. Recently, unprecedented advances in biomedical nanotechnology have led to the development of nanomaterial-based drug delivery systems in the treatment of diseases and diagnostic goals that simultaneously enhance therapeutic outcomes and avoid side effects. Mesoporous silica nanoparticles (MSNs) are promising drug delivery systems for more effective and safer treatment of several diseases, such as infections, cancers, and osteoporosis. Achieving a high drug loading in MSNs is critical to the success of this type of treatment. Their notable inherent properties-such as adjustable size and porosity, high pore volume, large surface area, functionality of versatile surfaces, as well as biocompatibility-have prompted extraordinary research on MSNs as multi-purpose delivery platforms. In this review, we focused on curcumin-loaded silica nanoparticles and their effects on the diagnosis and treatment of infections as well as their use in food packaging.

Carbapenem resistance in Bacteroides fragilis: A review of molecular mechanisms.

Carbapenems are an applicable subclass of ß-lactam drugs in the antibiotic therapy of anaerobic infections, especially for poly-microbial cases, due to their broad antimicrobial spectrum on aerobic and anaerobic bacteria. Bacteroides fragilis is the most commonly recovered anaerobic bacteria in the clinical laboratories from mono- and poly-microbial infections. B. fragilis is relatively non-susceptible to different antibiotics, including ß-lactams, tetracyclines, fluoroquinolones, and macrolides. Carbapenems are among the most effective drugs against B. fragilis strains with high-level resistance to different antibiotics. Increased antibiotic resistance of B. fragilis strains has been reported following the overuse of an antimicrobial agent. Earlier contact with carbapenems is linked with increased resistance to them that limits the options for treatment of B. fragilis caused infections, especially in cases caused by multidrug-resistant strains. Several molecular mechanisms of resistance to carbapenems have been described for different carbapenem-resistant bacteria. Understanding the mechanisms of resistance to antimicrobial agents is necessary for selecting alternative antimicrobial agents and the application of control strategies. In the present study, we reviewed the mechanisms contributing to resistance to carbapenems in B. fragilis strains.

Antimicrobial and antibiofilm activities of meropenem loaded-mesoporous silica nanoparticles against carbapenem-resistant Pseudomonas aeruginosa.

The aims of the present study were the determination of antimicrobial and antibiofilm effects of meropenem-loaded mesoporous silica nanoparticles (MSNs) on carbapenem resistant Pseudomonas aeruginosa (P. aeruginosa) and cytotoxicity properties in vitro. The meropenem-loaded MSNs had shown antibacterial and biofilm inhibitory activities on all isolates at different levels lower than MICs and BICs of meropenem. The viability of HC-04 cells treated with serial concentrations as MICs and BICs of meropenem-loaded MSNs was 92-100%. According to the obtained results, meropenem-loaded MSNs display the significant antibacterial and antibiofilm effects against carbapenem resistant and biofilm forming P. aeruginosa and low cell toxicity in vitro. Then, the prepared system can be an appropriate option for the delivery of carbapenem for further evaluation in vivo assays.

Tightly controlled response to oxidative stress; an important factor in the tolerance of Bacteroides fragilis.

The exposure of Bacteroides fragilis to highly oxygenated tissues induces an oxidative stress due to a shift from the reduced condition of the gastrointestinal tract to an aerobic environment of host tissues. The potent and effective responses to reactive oxygen species (ROS) make the B. fragilis tolerant to atmospheric oxygen for several days. The response to oxidative stress in B. fragilis is a complicated event that is induced and regulated by different agents. In this review, we will focus on the B. fragilis response to oxidative stress and present an overview of the regulators of responses to oxidative stress in this bacterium.

Biocompatibility, cytotoxicity and antibacterial effects of meropenem-loaded mesoporous silica nanoparticles against carbapenem-resistant Enterobacteriaceae.

BACKGROUND: The ever-increasing resistance to antimicrobial agents among bacteria associated with nosocomial infections indicate the necessity of new antimicrobial therapy. The nanoparticles are considered as new drug delivery systems to increase the efficiency and decrease the unfavourable effects of the antimicrobial agents. METHODS: Herein we report the preparation and characterization of mesoporous silica nanoparticles (MSNs) loaded with meropenem against carbapenem-resistant Enterobacteriaceae. The antimicrobial effect of meropenem-loaded MSNs was determined against Enterobacteriaceae using the minimum inhibitory (MIC) method. The biocompatibility of meropenem-loaded MSNs was studied by the impact on the haemolysis and sedimentation rates of human red blood cells (HRBCs). Cytotoxicity of the meropenem-loaded MSNs was studied by the MTT test (hBM-MSC cell viability). RESULTS: The meropenem-loaded MSNs have shown antibacterial activity on all isolates at different MIC values lower than MICs of meropenem. Free MSNs did not show any significant antibacterial effect. Meropenem-loaded MSNs have no significant effect on haemolysis and ESR of HRBCs. The viability of hBM-MSC cells treated with serial concentrations of meropenem-loaded MSNs was 92-100%. CONCLUSION: Due to the desirable biocompatibility, low cytotoxicity and the improved antibacterial effect, MSNs can be considered as a promising drug delivery system for meropenem as a potential antimicrobial agent.

The central role of the SOS DNA repair system in antibiotics resistance: A new target for a new infectious treatment strategy.

Bacteria have a considerable ability and potential to acquire resistance against antimicrobial agents by acting diverse mechanisms such as target modification or overexpression, multidrug transporter systems, and acquisition of drug hydrolyzing enzymes. Studying the mechanisms of bacterial cell physiology is mandatory for the development of novel strategies to control the antimicrobial resistance phenomenon, as well as for the control of infections in clinics. The SOS response is a cellular DNA repair mechanism that has an essential role in the bacterial biologic process involved in resistance to antibiotics. The activation of the SOS network increases the resistance and tolerance of bacteria to stress and, as a consequence, to antimicrobial agents. Therefore, SOS can be an applicable target for the discovery of new antimicrobial drugs. In the present review, we focus on the central role of SOS response in bacterial resistance mechanisms and its potential as a new target for control of resistant pathogens.

To resist and persist: Important factors in the pathogenesis of Bacteroides fragilis.

Bacteroides fragilis is a most frequent anaerobic pathogen isolated from human infections, particularly found in the abdominal cavity. Different factors contribute to the pathogenesis and persistence of B. fragilis at infection sites. The knowledge of the virulence factors can provide applicable information for finding alternative options for the antibiotic therapy and treatment of B. fragilis caused infections. Herein, a comprehensive review of the important B. fragilis virulence factors was prepared. In addition to B. fragilis toxin (BFT) and its potential role in the diarrhea and cancer development, some other important virulence factors and characteristics of B. fragilis are described including capsular polysaccharides, iron acquisition, resistance to antimicrobial agents, and survival during the prolonged oxidative stress, quorum sensing, and secretion systems.

Characterization of carbapenem-resistant but cephalosporin-susceptible Pseudomonas aeruginosa.

In this study, mechanisms of carbapenem resistance in carbapenem-resistant but cephalosporin-susceptible (Car-R/Ceph-S) Pseudomonas aeruginosa were investigated. A total of 243 P. aeruginosa isolates were studied. The disk diffusion and agar dilution methods were used for determination of antibiotic susceptibility patterns. AmpC and efflux pump overproductions were detected by phenotypic methods. The presence of carbapenemase-encoding genes was detected by polymerase chain reaction (PCR). The expression of OprD, MexAB-OprM, and MexXY-OprM efflux pumps was assessed by real-time PCR. According to disk diffusion method, altogether 116 P. aeruginosa isolates (47.7%) were carbapenem-resistant and among them, 23 isolates (19.8%) were cephalosporin-susceptible. Carbapenemase producer was not detected. Overexpression of AmpC was detected in one (4.3%) isolate that was ceftazidime-susceptible but cefepime-resistant. Overexpression of MexAB-OprM and MexXY-OprM efflux pumps was detected in 12 (60.9%) and 16 (68.8%) of isolates, respectively. A total of 16 (68.8%) isolates showed decreased expression of OprD. The Car-R/Ceph-S P. aeruginosa did not develop by carbapenemase production. The resistance to carbapenem was mediated in our clinical isolates by decreased expression of OprD and overexpression of MexAB-OprM and MexXY-OprM efflux systems or the combination of these mechanisms.

Hyperbaric oxygen therapy: Antimicrobial mechanisms and clinical application for infections.

Hyperbaric oxygen therapy (HBOT) is a treatment procedure that involves breathing 100% O2 for a certain time and under a certain pressure. HBOT is commonly administrated as a primary or alternative therapy for different diseases such as infections. In this paper, we reviewed the general aspect of HBOT procedures, the mechanisms of antimicrobial effects and the application in the treatment of infections. Parts of the antimicrobial effects of HBOT are believed to result of reactive from the formation of reactive oxygen species (ROS). It is also said that HBOT enhances the antimicrobial effects of the immune system and has an additive or synergistic effect with certain antimicrobial agents. HBOT has been described as a useful procedure for different infections, particularly in deep and chronic infections such as necrotizing fasciitis, osteomyelitis, chronic soft tissue infections, and infective endocarditis. The anti-inflammation property of HBOT has demonstrated that it may play a significant role in decreasing tissue damage and infection expansion. Patients treated by HBOT need carful pre-examination and monitoring. If safety standards are strictly tracked, HBOT can be considered a suitable procedure with an apt rate of complication.

The rates of quinolone, trimethoprim/sulfamethoxazole and aminoglycoside resistance among Enterobacteriaceae isolated from urinary tract infections in Azerbaijan, Iran.

Aim: Antibiotic susceptibility patterns help to select appropriate empirical treatments of urinary tract infections (UTIs). This study aimed to investigate antibiotic resistance among Enterobacteriaceae isolated from UTIs in Azerbaijan, Iran. Methods: This study was carried out during 2016 in hospitals located in Tabriz, Urmia, and Khoy. Midstream urine specimens were cultured and identified by the standard methods. Susceptibility testing was carried out using the disk diffusion agar method for cefotaxime, ceftazidime, ceftriaxone, cefoxitin, imipenem, meropenem, ertapenem, cefepime, ampicillin, cefazolin, cefuroxime, aztreonam, nitrofurantoin, and fosfomycin and the agar dilution method for MIC determination of aminoglycosides, quinolones, sulfamethoxazole, and trimethoprim. Results: A total of 219 non-duplicated Enterobacteriaceae were isolated from UTIs. According to the agar dilution assay, the following resistance rates were determined: trimethoprim/sulfamethoxazole (co-trimoxazole) 69.8%, nalidixic acid 68.9%, ciprofloxacin 66.2%, levofloxacin 58.5%, tobramycin 47.9%, kanamycin 39.3%, gentamicin 27.8%, and amikacin 5.5%. High levels of resistance were observed to trimethoprim (78.5%), sulfamethoxazole (88.1%), ampicillin (86.3%), and cephazoline (79.4%). Conclusion: The most effective agents against Enterobacteriaceae were fosfomycin, carbapenems, and amikacin. Quinolones, trimethoprim and sulfamethoxazole are not appropriate for empirical therapy due to high levels of resistance. Amikacin is more effective among aminoglycosides and may be more effective, in complicated cases, when used in combination with fosfomycin and carbapenems.

Mechanisms of Bacteroides fragilis resistance to metronidazole.

Metronidazole-resistant Bacteroides fragilis (B. fragilis) have been reported worldwide. Several mechanisms contribute to B. fragilis resistance to metronidazole. In some cases, the mechanisms of metronidazole resistance are unknown. Understanding the mechanisms of resistance is important for therapy, the design of new alternative drugs, and control of resistant strains. In this study, a comprehensive review of the B. fragilis resistance mechanisms to metronidazole was prepared. The rate of metronidazole-resistant B. fragilis has been reported as ranging from 0.5% to 7.8% in many surveys. According to CLSI, isolates with MICs ≥32 µg/mL are considered to be metronidazole-resistant. In the majority of cases, metronidazole resistance in B. fragilis is coupled with the existence of nim genes. Metronidazole resistance could be induced in nim-negative strains by exposure to sub-MIC levels of metronidazole. There are multi-drug efflux pumps in B. fragilis which can pump out a variety of substrates such as metronidazole. The recA overexpression and deficiency of feoAB are other reported metronidazole resistance mechanisms in this bacterium.