BACTERIAL EXTRACELLULAR VESICLES IN THE REGULATION OF INFLAMMATORY RESPONSE AND HOST-MICROBE INTERACTIONS.

ABSTRACT: Extracellular vesicles (EVs) are a new revelation in cross-kingdom communication, with increasing evidence showing the diverse roles of bacterial EVs (BEVs) in mammalian cells and host-microbe interactions. Bacterial EVs include outer membrane vesicles released by gram-negative bacteria and membrane vesicles generated from gram-positive bacteria. Recently, BEVs have drawn attention for their potential as biomarkers and therapeutic tools because they are nano-sized and can deliver bacterial cargo into host cells. Importantly, exposure to BEVs significantly affects various physiological and pathological responses in mammalian cells. Herein, we provide a comprehensive overview of the various effects of BEVs on host cells (i.e., immune cells, endothelial cells, and epithelial cells) and inflammatory/infectious diseases. First, the biogenesis and purification methods of BEVs are summarized. Next, the mechanisms and pathways identified by BEVs that stimulate either proinflammatory or anti-inflammatory responses are highlighted. In addition, we discuss the mechanisms by which BEVs regulate host-microbe interactions and their effects on the immune system. Finally, this review focuses on the contribution of BEVs to the pathogenesis of sepsis/septic shock and their therapeutic potential for the treatment of sepsis.

Cannabinoformins: Designing Biguanide-Embedded, Orally Available, Peripherally Selective Cannabinoid-1 Receptor Antagonists for Metabolic Syndrome Disorders.

We have designed orally bioavailable, non-brain-penetrant antagonists of the cannabinoid-1 receptor (CB1R) with a built-in biguanide sensor to mimic 5'-adenosine monophosphate kinase (AMPK) activation for treating obesity-associated co-morbidities. A series of 3,4-diarylpyrazolines bearing rational pharmacophoric pendants designed to limit brain penetration were synthesized and evaluated in CB1R ligand binding assays and recombinant AMPK assays. The compounds displayed high CB1R binding affinity and potent CB1R antagonist activities and acted as AMPK activators. Select compounds showed good oral exposure, with compounds 36, 38-S, and 39-S showing <5% brain penetrance, attesting to peripheral restriction. In vivo studies of 38-S revealed decreased food intake and body weight reduction in diet-induced obese mice as well as oral in vivo efficacy of 38-S in ameliorating glucose tolerance and insulin resistance. The designed "cannabinoformin" four-arm CB1R antagonists could serve as potential leads for treatment of metabolic syndrome disorders with negligible neuropsychiatric side effects.

Short-term administration of tibolone plus GnRH analog before laparoscopic myomectomy.

STUDY OBJECTIVE: To evaluate whether tibolone modifies the effectiveness of gonadotropin-releasing hormone (GnRH) analog administered before laparoscopic myomectomy. DESIGN: Prospective, randomized, open, placebo-controlled clinical trial (Canadian Task Force classification I). SETTING: University-affiliated hospital. PATIENTS: Sixty-six women with symptomatic leiomyomas. INTERVENTIONS: Patients received 2 months of treatment with GnRH analog and iron plus tibolone (group A) or placebo (group B); group C received only iron. Laparoscopic myomectomy was performed after medical treatment. MEASUREMENTS AND MAIN RESULTS: Uterine volume, number and volume of leiomyomas, echogenicity and volume of the largest leiomyomas, hematologic values, and myoma-related symptoms were evaluated at baseline, 1 week before, and 1 week after surgery. We observed significant (p <0.05) reductions in uterine and leiomyomata volume, myoma-related symptoms, and improvement in hematologic values before surgery in groups A and B, without significant difference between groups compared with baseline values and group C. Operating time and blood loss were significantly (p <0.05) lower in groups A and B, without significant difference compared with group C. After surgery, significant numbers of women in group C had worsening of hematologic values (p <0.05). CONCLUSION: Adding tibolone to the GnRH analog regimen before laparoscopic myomectomy does not modify the effectiveness of GnRH analog administered alone.