Extra-Virgin Olive Oil in Alzheimer's Disease: A Comprehensive Review of Cellular, Animal, and Clinical Studies.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that is characterized by several pathological hallmarks, including the deposition of amyloid-ß (Aß) plaques, neurofibrillary tangles, blood-brain barrier (BBB) dysfunction, increased oxidative stress, and neuroinflammation. Current treatment options include monoclonal antibody drugs, acetylcholinesterase, and n-methyl-d-aspartate (NMDA) antagonists. Although those treatments provide some improvements in patients' quality of life, they fail to prevent or cure AD. Current research aims to identify novel targets and tools for AD prevention and modification. In this context, several studies showed the beneficial effect of the Mediterranean diet in the prevention and treatment of AD. One integral component of the Mediterranean diet is olive oil and extra-virgin olive oil (EVOO), which is high in phenolic compounds. EVOO and other olive-related phenolic compounds have been shown to reduce the risk of developing mild cognitive impairment (MCI) and AD. In this review, we discuss the mechanisms by which EVOO and phenolic compounds exert neuroprotective effects, including modulation of AD pathologies and promotion of cognitive health. Findings indicate that EVOO and its phenolic constituents influence key pathological processes of AD, such as Aß aggregation, tau phosphorylation, and neuroinflammation, while also enhancing BBB integrity and reducing oxidative stress. The human studies cited reveal a consistent trend where the consumption of olive oil is associated with cognitive benefits and a decreased risk of AD and related dementias. In conclusion, EVOO and its phenolic compounds hold promising potential for the prevention and treatment of AD, representing a significant shift towards more effective strategies against this complex neurodegenerative disorder.

Blood-Brain Barrier Breakdown in Alzheimer's Disease: Mechanisms and Targeted Strategies.

The blood-brain barrier (BBB) is a unique and selective feature of the central nervous system's vasculature. BBB dysfunction has been observed as an early sign of Alzheimer's Disease (AD) before the onset of dementia or neurodegeneration. The intricate relationship between the BBB and the pathogenesis of AD, especially in the context of neurovascular coupling and the overlap of pathophysiology in neurodegenerative and cerebrovascular diseases, underscores the urgency to understand the BBB's role more deeply. Preserving or restoring the BBB function emerges as a potentially promising strategy for mitigating the progression and severity of AD. Molecular and genetic changes, such as the isoform ε4 of apolipoprotein E (ApoEε4), a significant genetic risk factor and a promoter of the BBB dysfunction, have been shown to mediate the BBB disruption. Additionally, receptors and transporters like the low-density lipoprotein receptor-related protein 1 (LRP1), P-glycoprotein (P-gp), and the receptor for advanced glycation end products (RAGEs) have been implicated in AD's pathogenesis. In this comprehensive review, we endeavor to shed light on the intricate pathogenic and therapeutic connections between AD and the BBB. We also delve into the latest developments and pioneering strategies targeting the BBB for therapeutic interventions, addressing its potential as a barrier and a carrier. By providing an integrative perspective, we anticipate paving the way for future research and treatments focused on exploiting the BBB's role in AD pathogenesis and therapy.

Bacterial Genotype, Carrier Risk Factors, and an Antimicrobial Stewardship Approach Relevant to Methicillin-resistant Staphylococcus aureus Prevalence in a Population of Macaques Housed in a Research Facility.

Methicillin-resistant Staphylococcus aureus (MRSA) remains a significant problem for human and animal health and can negatively affect the health status of macaques and other nonhuman primates (NHP) in research colonies. However, few publications provide guidance on the prevalence, genotype, or risk factors for macaques with MRSA and even fewer on how to effectively respond to MRSA once identified in a population. After having a clinical case of MRSA in a rhesus macaque, we sought to determine the MRSA carrier prevalence, risk factors, and genotypes of MRSA in a population of research NHPs. Over a 6-wk period in 2015, we collected nasal swabs from 298 NHPs. MRSA was isolated from 28% (n = 83). We then reviewed each macaque's medical record for a variety of variables including animal housing room, sex, age, number of antibiotic courses, number of surgical interventions, and SIV status. Analysis of these data suggests that MRSA carriage is associated with the room location, age of the animal, SIV status, and the number of antibiotic courses. We used multilocus sequence typing and spa typing on a subset of MRSA and MSSA isolates to determine whether the MRSA present in NHPs was comparable with common human strains. Two MRSA sequence types were predominant: ST188 and a novel MRSA genotype, neither of which is a common human isolate in the United States. We subsequently implemented antimicrobial stewardship practices (significantly reducing antimicrobial use) and then resampled the colony in 2018 and found that MRSA carriage had fallen to 9% (26/285). These data suggest that, as in humans, macaques may have a high carrier status of MRSA despite low clinically apparent disease. Implementing strategic antimicrobial stewardship practices resulted in a marked reduction in MRSA carriage in the NHP colony, highlighting the importance of limiting antimicrobial use when possible.

Comparison of Oleocanthal-Low EVOO and Oleocanthal against Amyloid-ß and Related Pathology in a Mouse Model of Alzheimer's Disease.

Alzheimer's disease (AD) is characterized by several pathological hallmarks, including the deposition of amyloid-ß (Aß) plaques, neurofibrillary tangles, blood-brain barrier (BBB) dysfunction, and neuroinflammation. Growing evidence support the neuroprotective effects of extra-virgin olive oil (EVOO) and oleocanthal (OC). In this work, we aimed to evaluate and compare the beneficial effects of equivalent doses of OC-low EVOO (0.5 mg total phenolic content/kg) and OC (0.5 mg OC/kg) on Aß and related pathology and to assess their effect on neuroinflammation in a 5xFAD mouse model with advanced pathology. Homozygous 5xFAD mice were fed with refined olive oil (ROO), OC-low EVOO, or OC for 3 months starting at the age of 3 months. Our findings demonstrated that a low dose of 0.5 mg/kg EVOO-phenols and OC reduced brain Aß levels and neuroinflammation by suppressing the nuclear factor-κB (NF-κB) pathway and reducing the activation of NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasomes. On the other hand, only OC suppressed the receptor for advanced glycation endproducts/high-mobility group box 1 (RAGE/HMGB1) pathway. In conclusion, our results indicated that while OC-low EVOO demonstrated a beneficial effect against Aß-related pathology in 5xFAD mice, EVOO rich with OC could provide a higher anti-inflammatory effect by targeting multiple mechanisms. Collectively, diet supplementation with EVOO or OC could prevent, halt progression, and treat AD.

Gastrointestinal Stromal Tumor Recurrence Presenting as a Small Bowel Obstruction: A Case Report.

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the alimentary tract in adults. The most common site is the stomach, followed by the small intestine. The clinical presentation varies from an incidental finding in asymptomatic patients to a large palpable mass causing complications such as bowel obstruction or viscus perforation. The best imaging modality is a CT scan of the abdomen. Treatment is determined by the size and location of the GISTs. Surgical intervention is considered for resectable tumors, while tyrosine kinase inhibitor therapy is considered for irresectable, metastatic, or recurrent GISTs. In this case report, we present a 30-year-old female who is a known case of gastric GIST and liver metastases. She presented to the emergency department with intestinal obstruction secondary to a recurrent GIST abdominal mass and underwent emergency laparotomy for mass resection. Following surgery, the patient developed aspiration pneumonia, which was treated with proper antibiotics. She was discharged in stable clinical condition with a recommendation to start alternative tyrosine kinase therapy. GISTs are difficult to diagnose preoperatively, as most patients are asymptomatic, and they may present with complications, as in our case, a small bowel obstruction. A proper imaging modality will guide the physician toward the diagnosis, but the final diagnosis will be achieved by biopsy. The diagnosis may be challenging, as small bowel obstruction has many causes, although GISTs should be kept in mind as one of the deferential diagnoses.

Identification and characterization of the pathogenic potential of phenol-soluble modulin toxins in the mouse commensal Staphylococcus xylosus.

In contrast to the virulent human skin commensal Staphylococcus aureus, which secretes a plethora of toxins, other staphylococci have much reduced virulence. In these species, commonly the only toxins are those of the phenol-soluble modulin (PSM) family. PSMs are species-specific and have only been characterized in a limited number of species. S. xylosus is a usually innocuous commensal on the skin of mice and other mammals. Prompted by reports on the involvement of PSMs in atopic dermatitis (AD) and the isolation of S. xylosus from mice with AD-like symptoms, we here identified and characterized PSMs of S. xylosus with a focus on a potential involvement in AD phenotypes. We found that most clinical S. xylosus strains produce two PSMs, one of the shorter α- and one of the longer ß-type, which were responsible for almost the entire lytic and pro-inflammatory capacities of S. xylosus. Importantly, PSMα of S. xylosus caused lysis and degranulation of mast cells at degrees higher than that of S. aureus δ-toxin, the main PSM previously associated with AD. However, S. xylosus did not produce significant AD symptoms in wild-type mice as opposed to S. aureus, indicating that promotion of AD by S. xylosus likely requires a predisposed host. Our study indicates that non-specific cytolytic potency rather than specific interaction underlies PSM-mediated mast cell degranulation and suggest that the previously reported exceptional potency of δ-toxin of S. aureus is due to its high-level production. Furthermore, they suggest that species that produce cytolytic PSMs, such as S. xylosus, all have the capacity to promote AD, but a high combined level of PSM cytolytic potency is required to cause AD in a non-predisposed host.

Glial Cell-Mediated Neuroinflammation in Alzheimer's Disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder; it is the most common cause of dementia and has no treatment. It is characterized by two pathological hallmarks, the extracellular deposits of amyloid beta (Aß) and the intraneuronal deposits of Neurofibrillary tangles (NFTs). Yet, those two hallmarks do not explain the full pathology seen with AD, suggesting the involvement of other mechanisms. Neuroinflammation could offer another explanation for the progression of the disease. This review provides an overview of recent advances on the role of the immune cells' microglia and astrocytes in neuroinflammation. In AD, microglia and astrocytes become reactive by several mechanisms leading to the release of proinflammatory cytokines that cause further neuronal damage. We then provide updates on neuroinflammation diagnostic markers and investigational therapeutics currently in clinical trials to target neuroinflammation.

Estrogen-Related Receptors Gene Expression and Copy Number Alteration Association With the Clinicopathologic Characteristics of Breast Cancer.

Purpose: It has been suggested that dysregulation of transcription factors expression or activity plays significant roles in breast cancer (BC) severity and poor prognosis. Therefore, our study aims to thoroughly evaluate the estrogen-related receptor isoforms (ESRRs) expression and copy number alteration (CNA) status and their association with clinicopathologic characteristics in BC. Methods: A METABRIC dataset consist of 2509 BC patients' samples was obtained from the cBioPortal public domain. The gene expression, putative CNA, and relevant tumor information of ESRRs were retrieved. ESRRs messenger RNA (mRNA) expression in BC cell lines was obtained from the Cancer Cell Line Encyclopedia (CCLE). Association and correlation analysis of ESRRs expression with BC clinicopathologic characteristics and molecular subtype were performed. Kaplan-Meier survival analysis was conducted to evaluate the prognostic value of ESRRs expression on patient survival. Results: ESRRα expression correlated negatively with patients' age and overall survival, whereas positively correlated with tumor size, the number of positive lymph nodes, and Nottingham prognostic index (NPI). Conversely, ESRRγ expression was positively correlated with patients' age and negatively correlated with NPI. ESRRα and ESRRγ expression were significantly associated with tumor grade, expression of hormone receptors, human epidermal growth factor receptor 2 (HER2), and molecular subtype, whereas ESRRß was only associated with tumor stage. A significant and distinct association of each of ESRRs CNA with various clinicopathologic and prognostic factors was also observed. Kaplan-Meier survival analysis demonstrated no significant difference for survival curves among BC patients with high or low expression of ESRRα, ß, or γ. On stratification, high ESRRα expression significantly reduced survival among premenopausal patients, patients with grade I/II, and early-stage disease. In BC cell lines, only ESRRα expression was significantly higher in HER2-positive cells. No significant association was observed between ESRRß expression and any of the clinicopathologic characteristics examined. Conclusions: In this clinical dataset, ESRRα and ESRRγ mRNA expression and CNA show a significant correlation and association with distinct clinicopathologic and prognostic parameters known to influence treatment outcomes; however, ESRRß failed to show a robust role in BC pathogenesis. ESRRα and ESRRγ can be employed as therapeutic targets in BC-targeted therapy. However, the role of ESRRß in BC pathogenesis remains unclear.

Targeting Angiogenesis in Breast Cancer: Current Evidence and Future Perspectives of Novel Anti-Angiogenic Approaches.

Angiogenesis is a vital process for the growth and dissemination of solid cancers. Numerous molecular pathways are known to drive angiogenic switch in cancer cells promoting the growth of new blood vessels and increased incidence of distant metastasis. Several angiogenesis inhibitors are clinically available for the treatment of different types of advanced solid cancers. These inhibitors mostly belong to monoclonal antibodies or small-molecule tyrosine kinase inhibitors targeting the classical vascular endothelial growth factor (VEGF) and its receptors. Nevertheless, breast cancer is one example of solid tumors that had constantly failed to respond to angiogenesis inhibitors in terms of improved survival outcomes of patients. Accordingly, it is of paramount importance to assess the molecular mechanisms driving angiogenic signaling in breast cancer to explore suitable drug targets that can be further investigated in preclinical and clinical settings. This review summarizes the current evidence for the effect of clinically available anti-angiogenic drugs in breast cancer treatment. Further, major mechanisms associated with intrinsic or acquired resistance to anti-VEGF therapy are discussed. The review also describes evidence from preclinical and clinical studies on targeting novel non-VEGF angiogenic pathways in breast cancer and several approaches to the normalization of tumor vasculature by targeting pericytes, utilization of microRNAs and extracellular tumor-associate vesicles, using immunotherapeutic drugs, and nanotechnology.

Commensal Staphylococcus epidermidis contributes to skin barrier homeostasis by generating protective ceramides.

Previously either regarded as insignificant or feared as potential sources of infection, the bacteria living on our skin are increasingly recognized for their role in benefitting human health. Skin commensals modulate mucosal immune defenses and directly interfere with pathogens; however, their contribution to the skin's physical integrity is less understood. Here, we show that the abundant skin commensal Staphylococcus epidermidis contributes to skin barrier integrity. S. epidermidis secretes a sphingomyelinase that acquires essential nutrients for the bacteria and assists the host in producing ceramides, the main constituent of the epithelial barrier that averts skin dehydration and aging. In mouse models, S. epidermidis significantly increases skin ceramide levels and prevents water loss of damaged skin in a fashion entirely dependent on its sphingomyelinase. Our findings reveal a symbiotic mechanism that demonstrates an important role of the skin microbiota in the maintenance of the skin's protective barrier.

Rapid pathogen-specific recruitment of immune effector cells in the skin by secreted toxins.

Swift recruitment of phagocytic leucocytes is critical in preventing infection when bacteria breach through the protective layers of the skin. According to canonical models, this occurs via an indirect process that is initiated by contact of bacteria with resident skin cells and which is independent of the pathogenic potential of the invader. Here we describe a more rapid mechanism of leucocyte recruitment to the site of intrusion of the important skin pathogen Staphylococcus aureus that is based on direct recognition of specific bacterial toxins, the phenol-soluble modulins (PSMs), by circulating leucocytes. We used a combination of intravital imaging, ear infection and skin abscess models, and in vitro gene expression studies to demonstrate that this early recruitment was dependent on the transcription factor EGR1 and contributed to the prevention of infection. Our findings refine the classical notion of the non-specific and resident cell-dependent character of the innate immune response to bacterial infection by demonstrating a pathogen-specific high-alert mechanism involving direct recruitment of immune effector cells by secreted bacterial products.

Overcoming resistance to targeted therapy using MET inhibitors in solid cancers: evidence from preclinical and clinical studies.

Targeted therapy is a hallmark of cancer treatment that has changed the landscape of cancer management and enabled a personalized treatment approach. Nevertheless, the development of cancer resistance is a major challenge that is currently threatening the effective utilization of targeted therapies. The hepatocyte growth factor receptor, MET, is a receptor tyrosine kinase known for its oncogenic activity and tumorigenic potential. MET is a well-known driver of cancer resistance. A growing body of evidence revealed a major role of MET in mediating acquired resistance to several classes of targeted therapies. Deregulations of MET commonly associated with the development of cancer resistance include gene amplification, overexpression, autocrine activation, and crosstalk with other signaling pathways. Small-molecule tyrosine kinase inhibitors of MET are currently approved for the treatment of different solid cancers. This review summarizes the current evidence regarding MET-mediated cancer resistance toward targeted therapies. The molecular mechanisms associated with resistance are described along with findings from preclinical and clinical studies on using MET inhibitors to restore the anticancer activity of targeted therapies for the treatment of solid tumors.

Interaction between Staphylococcus Agr virulence and neutrophils regulates pathogen expansion in the skin.

Staphylococcus aureus commonly infects the skin, but the host-pathogen interactions controlling bacterial growth remain unclear. S. aureus virulence is regulated by the Agr quorum-sensing system that controls factors including phenol-soluble modulins (PSMs), a group of cytotoxic peptides. We found a differential requirement for Agr and PSMα for pathogen growth in the skin. In neutrophil-deficient mice, S. aureus growth on the epidermis was unaffected, but the pathogen penetrated the dermis through mechanisms that require PSMα. In the dermis, pathogen expansion required Agr in wild-type mice, but not in neutrophil-deficient mice. Agr limited oxidative and non-oxidative killing in neutrophils by inhibiting pathogen late endosome localization and promoting phagosome escape. Unlike Agr, the SaeR/S virulence program was dispensable for growth in the epidermis and promoted dermal pathogen expansion independently of neutrophils. Thus, S. aureus growth and invasion are differentially regulated with Agr limiting intracellular killing within neutrophils to promote pathogen expansion in the dermis and subcutaneous tissue.

Combined crizotinib and endocrine drugs inhibit proliferation, migration, and colony formation of breast cancer cells via downregulation of MET and estrogen receptor.

Hormone-dependent breast cancer is the most abundant molecular subtype of the disease. Despite the availability of endocrine treatments, the use of these drugs is limited by their serious adverse reactions and development of acquired resistance often mediated by growth factor receptors. The hepatocyte growth factor receptor, MET, is a receptor tyrosine kinase known for its oncogenic activity and mediating resistance to targeted therapies. Crizotinib is a small-molecule tyrosine kinase inhibitor of MET. In this study, the anticancer effects of combined crizotinib and endocrine drugs were investigated in breast cancer cells in vitro along with the molecular mechanisms associated with these effects. Results showed that crizotinib inhibited growth of MCF7 and T-47D breast cancer cells in a dose-dependent manner with IC50 values of 2.88 µM and 0.93 µM, respectively. Combined treatment of crizotinib and 4-hydroxytamoxifen resulted in synergistic growth inhibition of MCF7 and T-47D cells with combination index values of 0.39 and 0.8, respectively. The combined treatment significantly suppressed migration and colony formation of MCF7 and T-47D cells. Immunofluorescence showed a significant reduction of the expression of the nuclear protein Ki-67 with the combination of crizotinib and 4-hydroxytamoxifen in both cell lines. Western blotting indicated that the combination treatment reduced the levels of active and total MET, estrogen receptor α (ERα), total and active levels of AKT, ERK, c-SRC, NFĸB p65, GSK-3ß, and the anti-apoptotic BCL-2 protein. Findings from this study suggest a potential role of MET inhibitors in breast cancer treatment as monotherapy or combination with endocrine drugs.

ING4 Expression Landscape and Association With Clinicopathologic Characteristics in Breast Cancer.

BACKGROUND: Breast cancer (BC) development and progression is complex and still not fully understood. The expression or dysregulation of a variety of transcription factors has been suggested as contributing to disease severity and a poor prognosis. Therefore, the present study was designed to systematically outline ING4 expression and characteristics in clinical samples and cell lines of BC. MATERIALS AND METHODS: A METABRIC (Molecular Taxonomy of Breast Cancer International Consortium) dataset was obtained from a cBioPortal public domain. ING4 gene expression, putative copy number alterations, and pertinent tumor information were retrieved. ING4 gene expression was identified for 1904 BC patients. ING4 mRNA expression data in BC cell lines were obtained from the Cancer Cell Line Encyclopedia. Analyses were conducted for associations between ING4 expression and age at diagnosis, tumor clinicopathologic characteristics, and molecular subtypes. The prognostic value of ING4 in BC patients was evaluated using Kaplan-Meier survival analysis. RESULTS: The ING4 mRNA expression log intensity mean was 6.95, and 1005 (52.8%) of patients were determined to have high ING4 mRNA expression (mRNA log intensity > 6.95). Although ING4 gene expression correlated significantly and negatively with the Nottingham Prognostic Index and the number of positive lymph nodes (P < .05) and positively with overall survival time (P < .001). However, these correlations were weak in magnitude (r ∼ 0.1). The expression of ING4 was significantly associated with tumor grade, hormone receptor expression, human epidermal growth factor receptor 2, and molecular subtype. ING4 copy number alteration was also significantly associated with several clinicopathologic and prognostic factors. Kaplan-Meier survival analysis demonstrated greater overall survival for BC patients with high ING4 expression (P = .0046). Stratification of the data by menopausal status and tumor characteristics revealed a significant effect of ING4 expression on survival among premenopausal patients and women with a nonluminal subtype. Furthermore, the expression of ING4 in BC cell lines was significantly greater in luminal A and basal-like cells compared with human epidermal growth factor receptor 2-positive cells, which was also observed in the clinical samples. CONCLUSIONS: The present study showed that ING4 gene expression is modulated in BC. High ING4 gene expression was associated with favorable prognostic parameters and positive clinical outcomes in our series of BC patients. ING4 could be used as a potential therapeutic target in BC-targeted therapy.

Crizotinib induced antitumor activity and synergized with chemotherapy and hormonal drugs in breast cancer cells via downregulating MET and estrogen receptor levels.

MET is a receptor tyrosine kinase known to drive neoplastic transformation and aggressive tumor phenotypes. Crizotinib is an oral multi-targeted tyrosine kinase inhibitor of MET, ALK, RON, and ROS1 kinases. In this study, the anticancer effects of crizotinib on breast cancer cells were investigated in vitro along with the molecular mechanisms associated with these effects. Besides, the antiproliferative effects of crizotinib in combination with chemotherapy, hormonal drugs, and targeted agents were examined. Results showed that crizotinib produced dose-dependent antiproliferative effects in BT-474 and SK-BR-3 breast cancer cells with IC50 values of 1.7 µM and 5.2 µM, respectively. Crizotinib inhibited colony formation of BT-474 cells at low micromolar concentrations (1-5 µM). Immunofluorescence and Western blotting indicated that crizotinib reduced total levels of MET and estrogen receptor (ERα) in BT-474 cells. Also, crizotinib reduced the levels of phosphorylated (active) MET and HER2 in BT-474 cells. The combined treatment of crizotinib with doxorubicin and paclitaxel resulted in synergistic growth inhibition of BT-474 cells with combination index values of 0.46 and 0.35, respectively. Synergy was also observed with the combination of crizotinib with the hormonal drugs 4-hydroxytamoxifen and fulvestrant in BT-474 cells. Alternatively, the combination of crizotinib with lapatinib produced antagonistic antiproliferative effects in both BT-474 and SK-BR-3 cells. Collectively, these findings demonstrate the anticancer effects of crizotinib in breast cancer cells and reveal ERα as a potential therapeutic target of the drug apart from its classical kinase inhibitory activity. Crizotinib could be an appealing option in combination with chemotherapy or hormonal drugs for the management of breast cancer.

Discovery of a nanomolar inhibitor of the human glyoxalase-I enzyme using structure-based poly-pharmacophore modelling and molecular docking.

The glyoxalase-I (GLO-I) enzyme, which is the initial enzyme of the glyoxalase system that is responsible for the detoxification of cytotoxic α-ketoaldehydes, such as methylglyoxal, has been approved as a valid target in cancer therapy. Overexpression of GLO-I has been observed in several types of carcinomas, including breast, colorectal, prostate, and bladder cancer. In this work we aimed to identify potential GLO-I inhibitors via employing different structure-based drug design techniques including structure-based poly-pharmacophore modelling, virtual screening, and molecular docking. Poly-pharmacophore modelling was applied in this study in order to thoroughly explore the binding site of the target enzyme, thereby, revealing hits that could bind in a nonconventional way which can pave the way for designing more potent and selective ligands with novel chemotypes. The modelling phase has resulted in the selection of 31 compounds that were biologically evaluated against human GLO-I enzyme. Among the tested set, seven compounds showed excellent inhibitory activities with IC50 values ranging from 0.34 to 30.57 µM. The most active compound (ST018515) showed an IC50 of 0.34 ± 0.03 µM, which, compared to reported GLO-I inhibitors, can be considered a potent inhibitor, making it a good candidate for further optimization towards designing more potent GLO-I inhibitors.

Role of Phenol-Soluble Modulins in Staphylococcus epidermidis Biofilm Formation and Infection of Indwelling Medical Devices.

Phenol-soluble modulins (PSMs) are amphipathic, alpha-helical peptides that are secreted by staphylococci in high amounts in a quorum-sensing-controlled fashion. Studies performed predominantly in Staphylococcus aureus showed that PSMs structure biofilms, which results in reduced biofilm mass, while it has also been reported that S. aureus PSMs stabilize biofilms due to amyloid formation. We here analyzed the roles of PSMs in in vitro and in vivo biofilms of Staphylococcus epidermidis, the leading cause of indwelling device-associated biofilm infection. We produced isogenic deletion mutants for every S. epidermidis psm locus and a sequential deletion mutant in which production of all PSMs was abolished. In vitro analysis substantiated the role of all PSMs in biofilm structuring. PSM-dependent biofilm expansion was not observed, in accordance with our finding that no S. epidermidis PSM produced amyloids. In a mouse model of indwelling device-associated infection, the total psm deletion mutant had a significant defect in dissemination. Notably, the total psm mutant produced a significantly more substantial biofilm on the implanted catheter than the wild-type strain. Our study, which for the first time directly quantified the impact of PSMs on biofilm expansion on an implanted device, shows that the in vivo biofilm infection phenotype in S. epidermidis is in accordance with the PSM biofilm structuring and detachment model, which has important implications for the potential therapeutic application of quorum-sensing blockers.

Adipose mesenchymal stem cells-derived exosomes attenuate retina degeneration of streptozotocin-induced diabetes in rabbits.

This study aimed to evaluate the effect of mesenchymal stem cells (MSCs)-derived exosomes in retina regeneration of experimentally induced diabetes mellitus (DM) in a rabbit model. Exosomes are extracellular vesicles that contain many microRNAs (micRNAs), mRNAs, and proteins from their cells of origin. DM was induced by intravenous (IV) injection of streptozotocin in rabbits. MSCs were isolated from adipose tissue of rabbits. Exosomes were extracted from MSCs by ultracentrifugation. Exosomes were injected by different routes (IV, subconjunctival (SC), and intraocular (IO)). Evaluation of the treatment was carried out by histopathological examination of retinal tissues and assessment of micRNA-222 expression level in retinal tissue by real-time polymerase chain reaction. Histologically, by 12 weeks following SC exosomal treatment, the cellular components of the retina were organized in well-defined layers, while IO exosomal injection showed well-defined retinal layers which were obviously similar to layers of the normal retina. However, the retina appeared after IV exosomal injection as irregular ganglionic layer with increased thickness. MicRNA-222 expression level was significantly reduced in diabetic controls when compared to each of healthy controls and other diabetic groups with IV, SC, and IO routes of injected exosomes (0.06 ± 0.02 vs. 0.51 ± 0.07, 0.28 ± 0.08, 0.48 ± 0.06, and 0.42 ± 0.11, respectively). We detected a significant negative correlation between serum glucose and retinal tissue micRNA-222 expression level (r = -0.749, p = 0.001). We can associate the increased expression of micRNA-222 with regenerative changes of retina following administration of MSCs-derived exosomes. The study demonstrates the potency of rabbit adipose tissue-derived MSCs exosomes in retinal repair. So, exosomes are considered as novel therapeutic vectors in MSCs-based therapy through its role in shuttling of many factors including micRNA-222.

Pathogen elimination by probiotic Bacillus via signalling interference.

Probiotic nutrition is frequently claimed to improve human health. In particular, live probiotic bacteria obtained with food are thought to reduce intestinal colonization by pathogens, and thus to reduce susceptibility to infection. However, the mechanisms that underlie these effects remain poorly understood. Here we report that the consumption of probiotic Bacillus bacteria comprehensively abolished colonization by the dangerous pathogen Staphylococcus aureus in a rural Thai population. We show that a widespread class of Bacillus lipopeptides, the fengycins, eliminates S. aureus by inhibiting S. aureus quorum sensing-a process through which bacteria respond to their population density by altering gene regulation. Our study presents a detailed molecular mechanism that underlines the importance of probiotic nutrition in reducing infectious disease. We also provide evidence that supports the biological significance of probiotic bacterial interference in humans, and show that such interference can be achieved by blocking a pathogen's signalling system. Furthermore, our findings suggest a probiotic-based method for S. aureus decolonization and new ways to fight S. aureus infections.